Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:9]=2[CH:8]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15][C:9]=2[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(NS(C)(=O)=O)cc2CC1
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (0.56 ml) was added dropwise to a solution of 7-amino-3-tertiary-butoxycarbonyl-1,2,4,5-tetrahydro-3H-3-benzazepine (1.9 g) in pyridine (40 ml) cooled to 0°. Stirring was continued at room temperature for 18 hours. The solvent was removed by evaporation to give an oil which was taken up in methylene chloride, washed three times with aqueous sodium bicarbonate and three times with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 5%). The product-containing fractions were combined and evaporated in vacuo to give a semi-solid which was triturated with ether to give the title compound, yield 1.2 g, m.p. 153°-154°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Yield: 90.2 %

Procedure:
Using 4-bromobenzoic acid (0.50 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (0.48 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (0.84 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C:6]2([NH:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]2)[CH2:40][CH2:39]1)=[O:37])[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2].Cl.C(Cl)Cl.CO>CO.C(O)(C)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C:6]2([NH:35][C:36]([N:38]1[CH2:39][CH2:40][CH:41]([N:44]2[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]2)[CH2:42][CH2:43]1)=[O:37])[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2]
Reactant: CCOc1ncccc1C1(NC(=O)N2CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CO
Product: CCOc1ncccc1C1(NC(=O)N2CCC(N3CCNCC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Temperature: 25 °C

Procedure:
55.3 mg (0.07 mmol) of tert-butyl 4-[1-({[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3,-dihydro-1H-indol-3-yl]amino}carbonyl)piperidin-4-yl]piperazine-1-carboxylate were initially charged in 4 ml of methanol, and 1.0 ml of 5-6 M hydrochloric acid in isopropanol was added. The mixture was stirred at room temperature. The progress of the reaction was monitored by TLC (silica gel, CH2Cl2/MeOH 9:1). After complete conversion, the alcoholic solvent residues were removed, and the residue was taken up in dichloromethane and, using 1 N aqueous sodium hydroxide solution, adjusted by extraction to pH 9. The organic phase was separated from the aqueous phase, and the aqueous phase was reextracted with dichloromethane (2×). The combined organic phase was dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was crystallized from diethyl ether. Alternatively, the residue can also be purified either by conventional column chromatography on a normal phase (NP-SiO2 cartridge, Chromabond) using dichloromethane/methanol as mobile phases or by preparative HPLC (RP, mobile phases acetonitrile/water, 0.01% TFA). After crystallization, 15.9 mg (0.023 mmol, 33%) of N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-O-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carbox amide were isolated.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29]C)=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=3[F:39])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl.C(O)(C)C>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=3[F:39])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3cc(F)cc(F)c3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2cc(F)cc(F)c2F)ccc2cc(O)ccc12
Temperature: 0 °C
Yield: 94.8 %

Procedure:
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-methoxy-2-(2,3,5-trifluorophenyl)-naphthalen-1-yl]-methanone (2.85 g, 5.34 mmol) in 50 mL methylene chloride and cool to 0° C. Add boron tribromide (3.0 mL, 31.7 mmol) and allow to come to room temperature. Pour into a two phase system of saturated sodium bicarbonate and 3/1 chloroform/isopropanol. Wash the organic layer with brine and dry over 3 Å molecular sieves. Concentrate to give 2.63 g (95%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(N(CC)CC)C.[C:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)#[N:39]>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:44](=[O:45])[C:43]4[CH:47]=[CH:48][C:40]([C:38]#[N:39])=[CH:41][CH:42]=4)[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cn(C3CCN(C(=O)c4ccc(C#N)cc4)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), triethylamine (404 mg, 4 mmol) and p-cyanobenzoyl chloride (496.5 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=15:1) to yield the target product as white solid powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:25][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1-c1ccc(O)cc1
Reactant: CCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 85.2 %

Procedure:
A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.50 g, 4.22 mmol), 1-bromoundecane (1.31 ml, 6.33 mmol) and potassium carbonate (874 mg, 6.33 mmol) in DMF (15 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate anhydride and solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.78 g (yield: 85.2%)
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:17]=1[N:18]1[CH2:25][CH:24]2[CH:20]([CH2:21][N:22]([CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23]2)[CH2:19]1)=[O:11])C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>CO>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:17]=1[N:18]1[CH2:25][CH:24]2[CH:20]([CH2:21][N:22]([CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23]2)[CH2:19]1)=[O:11]
Reactant: CC(C)COC(C)ONC(=O)c1cccnc1N1CC2CN(Cc3ccc4ccccc4c3)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(NO)c1cccnc1N1CC2CN(Cc3ccc4ccccc4c3)CC2C1
Reaction time: 6 h
Yield: 5.8 %

Procedure:
To N-(1-isobutoxyethoxy) 6-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)pyridine-5-carboxamide (0.199 g, 0.4 mmol) was added TFA:DCM:MeOH (8 ml, 1:2:2). The solution was stirred for 6 h and then concentrated under vacuum. The residue was suspended in MeOH and poured into EtOH (250 ml). The mixture was washed with 1:1 saturated sodium bicarbonate/1M NaOH (100 ml), and water (50 ml). The organic fraction was dried (Na2SO4), concentrated and purified by reverse phase HPLC to yield the title compound (9 mg, 5%). m/z 389.25 [M+H]+; 1H NMR (300 MHz, CD3OD) δ: 2.64 (2H, d, J=5.3 Hz), 2.90-3.07 (4H, m), 3.37-3.58 (4H, m), 3.89 (2H, s), 6.46 (1H, d, J=8.9 Hz), 7.33-7.44 (3H, m), 7.70-7.80 (5H, m), 8.37 (1H, d, J=2.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH3:20])[CH:18]=3)[C:13]([C:21](O)=[O:22])=[CH:12]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:24][CH2:25][CH2:26][NH2:27]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH3:20])[CH:18]=3)[C:13]([C:21]([NH:27][CH2:26][CH2:25][F:24])=[O:22])=[CH:12]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1Cn1cc(C(=O)O)c2ncc(C)cc21
Reactant: NCCF
Product: COc1ncc(F)cc1Cn1cc(C(=O)NCCF)c2ncc(C)cc21
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
See FIG. 19(c). 1-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (60 mg, 0.19 mmol) and 2-fluoroethanamine (21.60 mg, 0.34 mmol), TEA (0.080 mL, 0.57 mmol) was added. After 3 min1-Propanephosphonic acid cyclic anhydride (151 mg, 0.48 mmol) was added. The resulting reaction mixture was stirred at rt for 50 min. LCMS analysis showed formation of required product. Reaction was diluted with DCM and water.DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was done on Waters RP system to get product 1-((5-fluoro-2-methoxypyridin-3-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (25.00 mg, 36.5%). ES+MS m/z: 361.33. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.44 (s, 3 H ) 3.65 (d, J=5.27 Hz, 1 H ) 3.75 (d, J=5.27 Hz, 1 H ) 3.90 (s, 3 H ) 4.49 (t, J=4.99 Hz, 1H ) 4.64 (t, J=4.99 Hz, 1 H ) 5.42 (s, 2 H ) 7.36 (dd, J=8.29, 3.01 Hz, 1 H ) 7.93 (s, 1H ) 8.12 (d, J=3.01 Hz, 1 H ) 8.23 (s, 1H ) 8.38 (s, 5 H ) 8.88 (t, J=5.65 Hz, 1 H ).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:9](=[O:27])[N:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:3][CH:2]=1.[C:34](N[C@H](C(O)=O)C)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[O:68]1C[CH2:71][CH2:70][CH2:69]1>ClCCl>[C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:9](=[O:27])[N:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]2[CH2:19][CH2:18][N:17]([C:69](=[O:68])[CH:70]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH3:71])[CH2:16][CH2:15]2)=[CH:3][CH:2]=1
Reactant: O=c1c(Oc2ccc(-c3ccccc3)cc2)c(N2CCNCC2)cnn1-c1ccc(Cl)cc1
Reactant: C1CCOC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C(=O)OC(C)(C)C)C(=O)N1CCN(c2cnn(-c3ccc(Cl)cc3)c(=O)c2Oc2ccc(-c3ccccc3)cc2)CC1
Temperature: 0 °C

Procedure:
160 mg (0.348 mmol) of the compound from Example 12, dissolved in 1 ml of dichloromethane, are added dropwise to a solution of 92 mg (0.487 mmol) of Boc-L-alanine, 93.4 mg (0.487 mmol) of EDC, 65.8 mg (0.487 mmol) of HOBt and 0.1 ml (0.717 mmol) of triethylamine in 2 ml of tetrahydrofuran and 10 ml of dichloromethane while stirring under argon at 0° C. The mixture is stirred at room temperature overnight. The reaction solution is diluted with 100 ml of dichloromethane, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue is stirred with ether and filtered off with suction.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[N:17]=[C:16](O)[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=2)=[CH:10][CH:11]=1)=[O:4].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:34]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[N:17]=[C:16]([Cl:34])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=2)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: O=C(CCl)Nc1ccc(-c2nc(Cl)cc(C(F)(F)F)n2)nc1

Procedure:
To a solution of compound of example 53 (0.100 g, 0.301 mmol) in acetonitrile (5 mL), was added benzyl triethyl ammonium chloride (0.274 g, 1.204 mmol), dimethylaniline (0.143 g, 1.183 mmol) and POCl3 (2.3 g, 15.05 mmol). The reaction mixture was refluxed for 3 hours. Acetonitrile was removed under vacuum, reaction mass neutralized by sodium bicarbonate solution and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5 % methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [C:1]([P:6](Cl)[C:7]([CH2:10][CH3:11])([CH3:9])[CH3:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH:13]1(Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:6]([C:7]([CH2:10][CH3:11])([CH3:9])[CH3:8])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)P(Cl)C(C)(C)CC
Reactant: ClC1CCCCC1
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(C)(C)P(C1CCCCC1)C(C)(C)CC
Reaction time: 6 h
Yield: 96.7 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 10.4 g (0.05 mol) of di-tert-amylphosphinous chloride, 0.10 g (0.001 mol (corresponding to 2% by mol)) of copper(I) chloride and 30 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 8.3 g (0.060 mol) of cyclohexyl chloride and 2.0 g (0.08 mol) of metallic magnesium in 50 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at a temperature of 35° C. to 40° C. for 6 hours. After the temperature of the reaction solution was returned to room temperature, 20 ml of toluene and 20 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain 12.4 g (purity: 94.9%) of the aimed di-tert-amylcyclohexylphosphine as an oily substance. The yield was 90.2%.
Reaction SMILES: FC(F)(F)C(O)=O.CC(OC([N:15]1[CH2:20][CH2:19][C:18]2[O:21][C:22]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:17]=2[CH2:16]1)=O)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:25]([CH2:24][C:22]1[O:21][C:18]2[CH2:19][CH2:20][NH:15][CH2:16][C:17]=2[N:23]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc(COc3ccccc3)nc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(OCc2nc3c(o2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Trifluoroacetic acid (1.0 mL, 13.0 mmol) was added to a solution of 6,7-dihydro-2-(phenoxymethyl)-oxazolo[4,5-c]pyridine-5(4H)-carboxylic acid 1,1-dimethylethyl ester (0.11 g, 0.35 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 30 minutes and basified with a saturated solution of Na2CO3. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[4,5-c]pyridine (80 mg, 100% yield, 30% pure) that was used in the next step without further purification. C13H14N2O2 LCMS: Rt 0.65, m/z 231 [M+H]+ (using method, LC-MS Method 7).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][Sn](C)(C)C>CCOC(C)=O>[CH3:14][C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: C[Sn](C)(C)C
Reactant: O=[N+]([O-])c1cc(Br)c2scnc2c1
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc2ncsc12
Yield: 67 %

Procedure:
A solution of 7-bromo-5-nitrobenzothiazole (0.15 g, 0.58 mmol), tetramethyltin (0.20 mL, 0.1.5 mmol) and catalytic amount of Cl2Pd(PPh3) 2 in a sealed tube was stirred for 12 h at 90° C. The reaction mixture was diluted with EtOAc and washed with brine several times. Organic solution was dried over Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (EtOAc, neat) to provide 65 mg (0.32 mmol, 67%) of the desired product.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:49][C:50]1[N:55]=[CH:54][C:53]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)=[CH:52][CH:51]=1>CN(C=O)C>[OH:49][C:50]1[N:55]=[CH:54][C:53]([C:56]2[CH:57]=[C:58]([NH:62][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)=[CH:52][CH:51]=1
Reactant: Nc1cccc(-c2ccc(O)nc2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc(O)nc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 18.6 %

Procedure:
DIEA (0.008 mL, 0.048 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.009 g, 0.043 mmol) and HATU (0.018 g, 0.048 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-hydroxy-pyridin-3-yl)-phenylamine (0.008 g, 0.043 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.003 g of product in 15% yield: LCMS (ESI) m/z 375 (MH+).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:24]Br.O>ClCCl>[Br:24][C:19]1[CH:18]=[C:17]([C:14]2[N:15]=[CH:16][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][N:13]=2)[CH:22]=[CH:21][C:20]=1[OH:23]
Reactant: BrBr
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCc1cnc(-c2ccc(O)c(Br)c2)nc1
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A solution of 5 g of 4-(5-decyl-2-pyrimidinyl)phenol in 50 ml of dichloromethane was treated at 0° C. while gassing with argon with a solution of 2.6 g of bromine in 50 ml of dichloromethane. The reaction mixture was stirred for a further 2 hours and then treated with water. The organic phase was separated and the aqueous phase was back-extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed with water, sodium hydrogen carbonate solution and again with water, dried over magnesium sulfate, filtered and subsequently concentrated. The residue was purified by chromatography on silica gel with toluene/ethyl acetate (vol. 4:1). Recrystallization from hexane gave 4.8 g of 2-bromo-4-(5-decyl-2-pyrimidinyl)phenol.
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:24])[CH:10]=2)[N:5]2[CH:25]=[CH:26][CH:27]=[C:4]12)[CH3:2].[Br:28]N1C(=O)CCC1=O>C(Cl)Cl>[Br:28][C:25]1[N:5]2[C:6]3[C:11]([N:12]([S:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=4)(=[O:15])=[O:14])[CH:3]([CH2:1][CH3:2])[C:4]2=[CH:27][CH:26]=1)=[CH:10][C:9]([F:24])=[CH:8][CH:7]=3
Reactant: CCC1c2cccn2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCC1c2ccc(Br)n2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)c(C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a 50 ml round bottom flask with addition funnel was added 30 ml of methylene chloride and 0.38 g (1 mmol) of the product from Example 19. The flask was cooled to −78° C. and a solution of 0.18 g (1 mmol) of N-bromosuccinimide in 10 ml of methylene chloride was slowly added via addition funnel. After addition was complete, the reaction was allowed to stir at this temperature for 1 hr, then cooling removed. When the reaction had warmed to room temperature it was extracted with 20 ml of saturated sodium bicarbonate solution and separated. The aqueous layer was extracted twice with 10 ml of methylene chloride and the combined organic layers were dried (MgSO4) and concentrated. The crude solid was subjected to column chromatography eluting with 40% ethyl acetate:hexane to yield 0.32 g (69%) of solid which was crystallized from ethyl acetate:hexane to produce colorless crystals, mp 119° C. (dec).