Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16]C)[C:5](N)=[N:6][CH:7]=1.N(OC(C)(C)C)=O>C(O)(=O)C.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]3[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=3[O:16][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)cnc1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc2oc3ncc(Cl)cc3c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
Solution of 5-chloro-3-(5-chloro-2-methoxyphenyl)pyridin-2-amine (5.2 g, 19.3 mmol) in 50 mL of glacial acetic acid and 20 mL of THF was cooled down to −10° C. and tert-butyl nitrite (4.6 mL) was added dropwise. The reaction mixture was stirred overnight at 0° C., warmed to room temperature, diluted with 100 mL of water. Solid material was filtered and dried, providing 2.9 g of pure 3,6-dichlorobenzofuro[2,3-b]pyridine.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([NH:17][CH:18]5[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:20][CH2:19]5)[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=3)(=[O:32])=[O:33])[CH:3]=2)[C:48]([CH3:61])=[N:47]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 67.4 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-((3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)piperidine-1-carboxylate (intermediate 66E) (200 mg, 0.297 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (141 mg, 0.446 mmol) using Pd(PPh3)2Cl2 (11 mg, 0.014 mmol) and sodium carbonate (79 mg, 0.744 mmol) in Toluene/ethanol/water (5/2/1 ml) to afford 150 mg (67.5% yield) of the titled compound after column purification using 1% methanol in DCM as eluent. MS: m/z=749.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)[CH:5]=[N:6][CH:7]=1.[F:15][C:16]([F:20])([F:19])[CH2:17][NH2:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: CC(C)(Nc1cncc(Br)c1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.4 %

Procedure:
To a mixture of 2-[(5-bromopyridin-3-yl)amino]-2-methylpropanoic acid I-4b (2.0 g, 7.72 mmol), 2,2,2-trifluoroethylamine (1.214 mL, 15.44 mmol), HOBT (1.773 g, 11.58 mmol) and DIPEA (2.70 mL, 15.44 mmol) in DMF (20 mL) was added EDC (2.220 g, 11.58 mmol). The mixture was allowed to stir at RT for 18 hr. The reaction was quenched into water (100 mL) and ethyl acetate (100 mL) and aq. KHSO4 added to adjust the pH to 6.5. Organic layer removed, washed with aqueous NaHCO3 (50 mL) and then brine (50 mL). The aqueous extracts were washed with ethyl acetate (50 mL). Organics combined, dried over sodium sulfate, filtered thru a pad of silica and concentrated to give a solid 2.9 gms. Solid slurried in ether, sonicated and filtered to give 2.4 g, (91%) title compound, I-4, as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([CH2:54][NH2:55])=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21]([NH:55][CH2:54][C:51]3[CH:52]=[N:53][C:48]([CH3:47])=[CH:49][CH:50]=3)=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCCC3=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(N3CCCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(2-oxopiperidin-1-yl)biphenyl-3-carboxylic acid (45 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56 mg, 0.29 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.14 mmol), and CH2Cl2 (3 mL) were added (6-methylpyridin-3-yl)methanamine (27 mg, 0.22 mmol) and N,N-diisopropylethylamine (51 μL, 0.29 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water [10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45](=O)[O:46]C1C=CC([N+]([O-])=O)=CC=1)([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45]([NH:4][CH2:3][C:2]([CH3:1])([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH3:5])=[O:46])([CH3:30])[CH3:29]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CC(C)(CN)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCC(C)(C)c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 95 using 2-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CB29) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown glassy foam (0.084 g, 46%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[Cl-].[OH:16][NH3+:17].N1C=CC=CC=1>C(O)C>[F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N:17][OH:16]
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 49.4 %

Procedure:
10 g (49.0 mmol) of 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanone are dissolved in 100 ml of ethanol. To the solution are added 4.1 g (58.8 mmol) of hydroxylammonium chloride and 11.9 ml (147 mmol) of pyridine. The reaction mixture is refluxed for 4 hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into 50 ml of water, and extracted with 100 ml and 50 ml of ethyl acetate. The organic phase is washed with potassium hydrogen sulfate aqueous solution, water, and brine, dried over MgSO4, and concentrated. The residue is purified by chromatography with methylene chloride, yielding 5.3 g of 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanone oxime as a white solid with a melting point of 62-80° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 3.84 (s, 3H), 6.93(E)/6.99(Z) (d, 2H), 7.45(E)/7.55(Z) (d, 2H), 8.78 (br s, 1H). The signals are tentatively assigned to the E- and Z-conformations. The spectrum indicates the compound is a mixture of E- and Z-isomers. The ratio of the mixture is estimated to be E:Z=1:1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:5][C:6]([C:14]1[CH:13]=[C:12]2[C:17]([N:18]3[C@H:10]([CH2:11]2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:20][C@H:19]3[CH3:21])=[N:16][C:15]=1[CH2:22][O:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)=[O:7]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(COCC4CC4)nc3N21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc2c(nc1COCC1CC1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 100 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
A mixture of 1.5 g (3.31 mmol) (4R,9aR)-7-bromo-6-cyclopropylmethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, 0.11 g (0.50 mmol) palladium(II) acetate, 0.68 g (1.66 mmol) 1,3-bis(diphenylphosphino)propane and 1.4 mL (1.0 g, 10.0 mmol) triethylamine in 15 mL MeOH was stirred for 48 h at 100° C. under a carbon monoxide atmosphere (50 bar). The reaction mixture was cooled to room temperature, filtered and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulphate, filtered and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:3) as eluant to give the compound as a yellow oil (87%).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][C:34](=[O:44])[N:35](C1C=CC(N)=CC=1)[CH3:36].ClC1N=C(NC2CC2)C2C=CNC=2N=1>>[CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:35]([CH3:36])[C:34](=[O:44])[O:33][CH3:32])=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N(C)c1ccc(N)cc1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Agent: Clc1nc(NC2CC2)c2cc[nH]c2n1
Product: COC(=O)N(C)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, Methyl-4-aminophenyl(methyl)carbamate and 2-chloro-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave methyl 4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl(methyl)carbamate (MS calcd for C18H20N6O2 352.2. found [MH] 353.0; UV 227.5, 292.6 nm).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][C:6]([F:17])=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[CH3:29][O:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25][N:13]1[CH:14]=[C:9]([C:8]2[C:3]([Cl:2])=[N:4][CH:5]=[C:6]([F:17])[CH:7]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2cc(F)cnc2Cl)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2cc(F)cnc2Cl)c(=O)[nH]c1=O)OC
Yield: 48.5 %

Procedure:
5-(2-Chloro-5-fluoro-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep71, 249 mg, 0.9 mmol), K2CO3 (124 mg, 0.9 mmol) and 3-bromo-1,1dimethoxy-propane (205 mg, 1.1 mmol) were suspended in DMF (3 ml). After stirring the reaction at room temperature for 18 hours, water was added. The aqueous layer washed with diethylether and then the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 150 mg of the final compound that was used without further purification in the next step (48% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: C1CCOC1
Product: OCc1ccc(Br)cc1Cl

Procedure:
To a stirring solution of 4-bromo-2-chlorobenzoic acid (11.1 g, 47 mmol) in THF (100 mL) at 0° C. under nitrogen was added borane-methyl sulfide complex (9.4 ml, 94 mmol) via syringe over 10 min. Gas evolution quite evident. Ice bath removed, and once gas evolution subsided reaction gently heated to reflux for 1 h. Reaction slowly quenched with MeOH (50 mL) and 2M HCl (20 mL). Aqueous extracted with 9:1 CHCl3/IPA (150 mL). Organic dried with sat NH4Cl, MgSO4, then concentrated to a colorless oil under reduced pressure. Product crystallized after 1 week sitting neat.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[N:40][CH:39]=[C:38]([CH3:42])[N:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[N:40][CH:39]=[C:38]([CH3:42])[N:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (290 mg, 1.0 mmol) and 3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K16) (312 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (460 mg, 87%).
Reaction SMILES: C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1CCOCC1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([OH:35])=O)[CH2:28][CH2:27]1.Cl.[CH2:37]([O:44][C:45](=[O:49])[C@H:46]([CH3:48])[NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.C(Cl)Cl>[O:26]1[CH2:27][CH2:28][N:29]([CH2:32][C:33]([NH:47][C@@H:46]([CH3:48])[C:45]([O:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:49])=[O:35])[CH2:30][CH2:31]1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(O)CN1CCOCC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49908.6 %

Procedure:
To DMTMM (76.1 g, 0.276 mol) and N-methylmorpholine (NMM; 32.9 mL, 0.300 mol) was added to a 0° C. solution of 2-morpholinoacetic acid (20.0 g, 0.138 mmol) and L-alanine benzyl ester hydrochloride (35.7 g, 0.166 mol) in DMF (100 mL) and DCM (200 mL). The reaction mixture was stirred for 4 h at ambient temperature then concentrated. EtOAc (500 mL) and water (500 mL) was added to the residue. The resulting two layers were separated and the aqueous phase was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (3×500 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=100:3) to afford (S)-benzyl 2-(2-morpholinoacetamido)propanoate (21.1 g, 50% yield).
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[CH:14]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2].[BH4-].[Na+].C(NC1C=CC2C3C(=CC=CC=3)CC=2C=1)(OC(C)(C)C)=O.CC(OC)(C)C>CO.O.CCOC(C)=O.CC(O)=O>[OH:2][CH2:1][CH:3]1[C:15]2[CH:14]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(C=O)c1ccccc1-2
Agent: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(CO)c1ccccc1-2
Reaction time: 4 h

Procedure:
9-Formyl-2-(Boc-amino)fluorene was suspended in 100 ml methanol and 2.0 g NaBH4 [52.9 mmol, 1.1 equiv with respect to the starting 2-(Boc-amino)fluorene] was added portion wise. The suspension that rapidly cleared up was magnetically stirred until the starting product disappeared for 4 h at room temperature [TLC, Rf=0.57, PE:MTBE (1:2)]. The reaction mixture was diluted with 300 ml H2O and acidified with 15 ml glacial HOAc to pH 5.0, and the precipitate was directly dissolved in 150 ml EtOAc. The organic phase was washed with 3×50 ml sat. NaHCO3 and 1×50 ml brine and dried over anhydrous Na2SO4. The solvent was rotary evaporated to give a solid, which could be used without further purification. The product was analyzed by NMR (13.1 g, 88% yield).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([CH2:20][C:21]#[N:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C>C1COCC1>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([CH2:20][CH2:21][NH2:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NCCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 30.2 %

Procedure:
(7-Benzenesulfonyl-chroman-4-yl)-acetonitrile (397 mg, 1.26 mmol) was dissolved in 5 mL THF, and 190 ul (1.9 mmol) of BH3.DMF was added. The reaction mixture was heated to reflux for one hour and then cooled to room temperature, quenched by addition of methanol, and diluted with water. The aqueous mixture was extrated with EtOAc. The organic phase was dried over MgSO4, and solvent was removed under reduced pressure. The residue was chromatographed through silica gel (MeOH:CH2Cl2:NH4OH 8%:90%:2%), and solvent was removed under reduced pressure to yield 120 mg (0.38 mmol, 30%) of 2-(7-benzenesulfonyl-chroman-4-yl)-ethylamine. This product was dissolved in 2N HCl/EtOH and recrystallized by addition of Et2O to afford 95 mg of the corresponding hydrochloride salt. Mp: 244.6-245.8° C.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl-].[NH4+].C[N:34](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23]([C:26]([NH2:34])=[O:28])=[CH:22][C:20]=5[N:21]=4)=[CH:29][CH:30]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Temperature: 25 °C
Yield: 3.7 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (72.1 mg, 0.18 mmol), ammonium chloride (19.1 mg, 0.36 mmol) in DMF 4.0 mL was added HBTU (136.53 mg, 0.36 mmol) and DIPEA (0.063 ml, 0.36 mmol). After stirring at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=15:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid amide as a yellow solid (2.7 mg, 4% yield).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[CH2:20]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[CH2:20][Br:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cc(I)ccc1OCc1ccccc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: BrCc1cc(I)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
3.3 ml (35 mmol) of phosphorus tribromide are added dropwise to a solution of 35 g (103 mmol) of (2-benzyloxy-5-iodophenyl)methanol (Example 3A) in 350 ml of toluene at 40° C. The temperature of the reaction mixture is raised to 100° C. over the course of 15 min and the reaction mixture is stirred at this temperature for a further 10 min. After cooling, the two phases are separated. The organic phase is washed twice with distilled water and once with a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The yield amounts to 41 g (99% of theory).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)(=[O:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.[ClH:33].C(O)C.C(=O)([O-])[O-].[NH4+:41].[NH4+]>ClCCl.CO>[ClH:33].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)(=[O:12])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[NH:41])[NH2:32])=[CH:29][CH:30]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(S(=O)(=O)N3Cc4ccccc4C3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(S(=O)(=O)N3Cc4ccccc4C3)ccc21
Yield: 33 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]-5-(isoindolin-2-yl-sulfonyl)benzimidazole and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 33% of theory, C24H24N6O2S (460.6); Rf value: 0.32 (silica gel; dichloromethane/methanol=4:1); EKA mass spectrum: (M+H)+=461.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:13]Br.O>C(O)(=O)C>[Br:13][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9][NH:10][CH:11]=1
Reactant: Clc1ccc(-c2cc[nH]n2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(-c2n[nH]cc2Br)cc1
Yield: 100 %

Procedure:
1.5 g (0.0084 mol) of 3-(4-chlorophenyl)-1H-pyrazole, prepared in the above example (19), are dissolved, at room temperature and with stirring, in 25 ml of acetic acid. 1.6 g (0.01 mol) of bromine are then run in dropwise while maintaining the temperature below 30° C. Stirring is maintained for 30 hours 30 min and then the reaction mixture is poured into water. The precipitate is filtered and washed with water and heptane. 2.1 g (0.0084 mol) (yield: 100%; melting point: 143° C.) of 4-bromo-3-(4-chlorophenyl)-1H-pyrazole are obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.Br[C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=1.C[Si]([C:36]#[C:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[C:41]#[N:42])(C)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:31][C:29]1[CH:30]=[C:25]([C:36]#[C:37][C:38]2[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=2)[C:41]#[N:42])[CH:26]=[N:27][CH:28]=1
Reactant: C[Si](C)(C)C#Cc1cccc(C#N)c1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C#Cc2cncc(Br)c2)c1
Yield: 37.8 %

Procedure:
Prepare essentially as described in PREPARATION 17 using a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (4.2 mL, 4.2 mmol), 3,5-dibromopyridine (1.00 g, 4.2 mmol), 3-trimethylsilanylethynylbenzonitrile (0.84 g, 4.2 mmol), (prepared as described in PREPARATION 5), bis(triphenylphosphine)palladium (II) dichloride (0.06 g, 0.08 mmol) and copper (I) iodide (0.03 g, 0.17 mmol) to give the title compound (0.45 g, 39%).