Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CN1C(=O)CCC1>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH:10]=2)[O:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CN1CCCC1=O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.2 g, 41 mmol) in NMP (60 mL) was added K2 CO3 (12 g, 82 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.8 mL, 43 mmol) in sequence. The reaction mixture was stirred at r.t. under N2 for 16 h. Then, the reaction mixture was diluted and filtered, and then the filtrate was diluted with EtOAc (300 mL). The resulting solution was washed with sat. NaHCO3 (aq) (3×200 mL), H2O (4×200 mL), brine (1×200 mL), dried over Na2SO4, filtered, concentrated and dried in vacuo to yield intermediate Int-15a (11.4 g, 86%) as a clear yellowish oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccncc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
To a suspension of 3.05 g of 60% sodium hydride (76.0 mmol) in toluene (50 mL) in a 250 mL RB flask was added 12.2 g of diethyl malonate (76.0 mmol) dropwise. The reaction mixture was stirred for 30 min under nitrogen, and a solution of 10.8 g of 4-chloro-3-nitropyridine (prepared according to the procedure of Houston et al. J. Med. Chem. 1985, 28, 467) in toluene (50 mL) was added dropwise and the resulting mixture refluxed for 4 hours. The reaction mixture was concentrate, and the residue was partitioned between 100 mL each of dilute hydrochloric acid and diethyl ether. The aqueous phase was extracted twice with 100 mL of ether, and the combined ether phases were dried over magnesium sulfate and concentrated to give a dark oil. This was chromatographed on silica gel eluting with a hexane-30% hexane/EtOAc gradient to give 3.5 g of the title compound as a colorless oil which crystallized on standing. 1H NMR (DMSO-d6): δ1.15 (t, J=7.1 Hz, 6H), 4.16 (q, J=7.1 Hz, 4H), 5.55 (s, 1H), 7.59 (d, J=5.1 Hz, 1H), 8.89 (d, J=5.1 Hz, 1H), 9.24 (s, 1H); C12H14N2O6: APES−MS m/z 281 (M−H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])[C:8]([O:20][CH3:21])=[C:7]2[C:3]=1[C:4]1[CH:32]=[C:31]([CH3:33])[CH:30]=[N:29][C:5]=1[N:6]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[CH2:34]([S:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)(=[O:38])=[O:37])[CH3:35].O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([O:15][C:13]([N:11]([CH3:12])[C:9]1[C:8]([O:20][CH3:21])=[C:7]2[C:3]([C:4]3[CH:32]=[C:31]([CH3:33])[CH:30]=[N:29][C:5]=3[N:6]2[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[C:2]([C:41]2[CH:42]=[CH:43][CH:44]=[C:39]([S:36]([CH2:34][CH3:35])(=[O:37])=[O:38])[CH:40]=2)[CH:10]=1)=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(N(C)C(=O)OC(C)(C)C)cc(Br)c2c3cc(C)cnc3n(C(=O)OC(C)(C)C)c12
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2cc(N(C)C(=O)OC(C)(C)C)c(OC)c3c2c2cc(C)cnc2n3C(=O)OC(C)(C)C)c1
Temperature: 140 °C

Procedure:
A 5 mL microwave vial was charged with Compound 250 (520 mg, 1.0 mmol), 3-(ethylsulfonyl)phenylboronic acid (321 mg, 1.5 mmol) and Pd(PPh3)4 (116 mg, 0.10 mmol). To the mixture was added dioxane (2 mL) and a saturated aqueous solution of K2CO3 (1 mL). The reaction mixture was heated at 140° C. for 20 min. in microwave. The reaction was diluted with EtOAc and washed with water and brine. The organic extracts were dried (Na2SO4) and concentrated and the crude Compound 251 was taken forward for Boc deprotection.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:31][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[O:22])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CN(C)CCN
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)NCCN(C)C)cc3)no2)cc1C
Yield: 20.4 %

Procedure:
The title compound (9 mg) is prepared in analogy to Example 189 step b) starting from 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (37 mg, 100 μmol) and N1,N1-dimethyl-ethane-1,2-diamine (10 mg, 110 μmol); LC-MS: tR=0.42 min; [M+1]+=442.23. 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.32 (s, 6H), 2.58 (t, J=6.0 Hz, 2H), 2.64 (q, J=7.0 Hz, 4H), 3.55-3.62 (m, 2H), 3.73 (s, 2H), 6.95 (t br, J=4.8 Hz, 1H), 7.68 (s, 1H), 7.92-7.96 (m, 2H), 8.21-8.25 (m, 2H).
Reaction SMILES: CC1NC=NC=1C(OCC)=O.C1([Mg]Br)C=CC=CC=1.[CH2:20]([O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[N:25]=[CH:26][NH:27][C:28]=1[CH3:29])[CH3:21].[CH3:42][N:43]([CH3:48])[S:44](Cl)(=[O:46])=[O:45]>>[CH3:42][N:43]([CH3:48])[S:44]([N:27]1[C:28]([CH3:29])=[C:24]([C:23]([O:22][CH2:20][CH3:21])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:25]=[CH:26]1)(=[O:46])=[O:45]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOC(c1ccccc1)(c1ccccc1)c1nc[nH]c1C
Agent: Br[Mg]c1ccccc1
Agent: CCOC(=O)c1nc[nH]c1C
Product: CCOC(c1ccccc1)(c1ccccc1)c1ncn(S(=O)(=O)N(C)C)c1C

Procedure:
Ethyl 5-methylimidazole-4-carboxylate was converted by a Grignard reaction, using phenylmagnesium bromide, to 4-[ethoxy(diphenyl)methyl]-5-methylimidazole, m.p. 205°. This was then treated with dimethylsulphamoyl chloride in a similar manner to that described in Example 1, to give 1-dimethylsulphamoyl-4-[ethoxy(diphenyl)methyl)-5-methylimidazole, m.p. 150°.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([OH:12])=O)[CH3:2].Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[CH2:25][CH2:24]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:36])[C:31]([CH3:34])([CH3:35])[CH2:32][OH:33])[CH2:27][CH2:28]1)=[O:12])[CH3:2]
Reactant: CC(C)(CO)C(=O)NC1CCC(N)CC1
Reactant: CCSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](NC(=O)C(C)(C)CO)CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-(3-Ethylsulfanyl-phenoxy)-5-fluoro-nicotinic acid (150 mg, 0.51 mmol) was added to a solution of N-(4-amino-cyclohexyl)-3-hydroxy-2,2-dimethyl-propionamide hydrochloride (80:20 cis:trans, 135 mg, 0.54 mmol) and triethylamine (0.21 ml, 1.5 mmol) in dimethylformamide (3 ml) under nitrogen at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (108 mg, 0.56 mmol) followed by 1-hydroxybenzotriazole (76 mg, 0.56 mmol) were then added and the reaction was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate (20 ml) and water (20 ml) and the organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel eluting with a solvent gradient of dichloromethane:methanol (95:5) and the product was purified by preparative HPLC to give two products.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH2:26]([O:28][CH:29]([O:32][CH2:33][CH3:34])[C:30]#[CH:31])[CH3:27]>C(N(CC)CC)C.O1CCCC1.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:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:31]#[C:30][CH:29]([O:32][CH2:33][CH3:34])[O:28][CH2:26][CH3:27])=[CH:20][CH:19]=1)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C=C(c1ccccc1I)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C#CC(OCC)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(c1ccc(C#CC(OCC)OCC)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A mixture of 2-(2,4-difluorophenyl)-3-(iodophenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol (4.0 g, 8.8 mmol-see Preparation 20), 3,3-diethyloxyprop-1-yne (1.52 ml, 10.6 mmol), copper(l)iodide (0.02 g) and bis(triphenylphosphine)palladium dichloride (0.12 g) In triethylamine (40 ml) and tetrahydrofuran (13 ml) was stirred at room temperature for 18 hours. The solvents were removed under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was flash chromatographed on silica by elution with ethyl acetate. Fractions containing the desired product were combined and evaporated under reduced pressure to yield 2-(2,4-difluorophenyl)-3-(4-[3,3-diethoxyprop-1-yn-1-yl]phenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol as a yellow gum (2,4 g, 60%). Trituration with cyclohexane gave an off-white solid which was characterised by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH2:14]O)=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:28]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH2:14][N:28]3[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]3)=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: OCc1ncc(-c2ccc(Cl)c(Cl)c2)s1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(Cc2ncc(-c3ccc(Cl)c(Cl)c3)s2)c1
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of the compound (260 mg, 1.00 mmol) obtained in Example 22a and triethylamine (0.21 mL, 1.50 mmol) in tetrahydrofuran (4 ml) was added methanesulfonyl chloride (0.093 mL, 1.20 mmol), and the mixture was stirred for 30 min. The reaction mixture was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL), ethyl 1H-pyrazole-4-carboxylate (140 mg, 1.00 mmol) and potassium carbonate (207 mg, 1.50 mmol) were added, and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (85 mg, 22%) as colorless crystals.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.[ClH:24].C(OCC)C>O1CCOCC1>[ClH:24].[N:12]1([C:10](=[O:11])[C@@H:9]([NH2:8])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCOCC1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@H](C(=O)N1CCOCC1)c1ccccc1
Yield: 90 %

Procedure:
1.327 g of N-(tert-butoxycarbonyl)-(1S)-2-morpholin-4-yl-2-oxo-1-phenylethylamine was dissolved in 15 mL of dioxane and treated with 3.5 mL of HCl 4 M in dioxane overnight. The solvent was removed and the solid was triturated with diethylether yielding 920 mg of the product (yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[O:29][N:28]=[C:27]([C:30]([O:32]CC)=O)[N:26]=2)([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[NH3:35]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[O:29][N:28]=[C:27]([C:30]([NH2:35])=[O:32])[N:26]=2)([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(NS(C)(=O)=O)cccc32)n1
Solvent: CO
Product: CCC(c1ccc(Cl)cc1)(c1nc(C(N)=O)no1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The product from Step E above (0.015 g, 0.030 mmol) was dissolved in a 7 N solution of ammonia in methanol (2.6 mL). After stirring at RT for 45 min, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=475.0[M+H]+. 1H NMR (500 MHz, CD3OD): δ (ppm) 8.34 (s, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.16-7.14 (m, 2H); 6.48-6.45 (m, 1H), 3.20-3.12 (m, 1H), 3.14-3.05 (m, 1H), 3.04 (s, 3H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[CH:10]3)[C:6]=2[CH:23]=1.[C:24]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([N:28]1[CH2:33][CH2:32][CH:31]([S:34][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)[N:8]=[C:7]4[C:6]=3[CH:23]=2)[CH2:30][CH2:29]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: CC(C)(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C)CC3)ccc1OCC2
Temperature: 120 °C

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (100 mg, 0.27 mmol), 1-tert-butylpiperidine-4-thiol (120 mg, 0.69 mmol), Pd2(dba)3 (24 mg, 10 mol %), XantPhos (31 mg, 20 mol %) and DIPEA (186 μL, 1.07 mmol) in dioxane (3 mL) was purged with argon and heated at 120° C. for 40 min using microwave irradiation. The reaction mixture was diluted with DCM and purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM then C18, gradient 20-50% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The residue was triturated with Et2O affording 139 as a white solid (16 mg, 51%). LCMS: RT 3.11 min [M+H]+ 467.4. 1H NMR (DMSO, 400 MHz): δ 8.54 (1H, d, J=2.35 Hz), 7.94 (1H, d, J=0.67 Hz), 7.77 (1H, s), 7.36 (1H, dd, J=8.49, 2.37 Hz), 7.02 (1H, d, J=8.48 Hz), 5.92-5.91 (1H, m), 4.55-4.49 (4H, m), 3.06-3.04 (3H, m), 2.30 (2H, t, J=11.23 Hz), 2.08-1.96 (2H, m), 1.65-1.64 (2H, m), 1.58 (6H, d, J=6.65 Hz), 1.08 (9H, s)
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C(OC(=O)C)(=O)C.[H][H]>C(O)(=O)C.[Pd]>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: [H][H]
Reactant: OC1CCOc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a stirred solution of 4-hydroxychroman (10.14 g, 67.5 mmol) in acetic acid (150 mL) under Ar was added acetic anhydride (12.7 mL, 135 mmol) and the mixture was heated at reflux for 3 h, then allowed to cool to ambient temperature. Palladium on carbon (10 wt %; 1.8 g, 2.5 mol %) was added and the mixture was shaken in a Parr hydrogenator under a 42 psi atmosphere of hydrogen overnight. The reaction mixture was filtered, the solvent was removed in vacuo and the residue was taken-up in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution, brine, dried (magnesium sulfate) and concentrated in vacuo to afford the product (7.73 g, 85%) as a pale yellow liquid: IR νmax (film)/cm−1 2937, 2863, 1737, 1609, 1582, 1490, 1456, 1304, 1267, 1228, 1189, 1116, 1065, 1008 and 754; NMR (400 MHz, CDCl3) δH 2.00 (2H, m), 2.78 (2H, t, J 6.5 Hz), 4.17 (2H, t, J 7 Hz), 6.81 (2H, m) and 7.05 (2H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21]OC1C=C(S([O-])(=O)=O)C=CC=1C>CN(C)C=O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: COCCOCCOCCOc1cc(S(=O)(=O)[O-])ccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCN1C(=O)NC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
5,5-Dimethylhydantoin (1.32 g, 10.3 mmol) was dissolved in N,N-dimethylformamide (100 ml). To the stirring room temperature solution was added sodium hydride (60%, 412 mg, 10.2 mmol). After an additional one hour of stirring at room temperature, [2-[2-(2-methoxyethoxy)ethoxy]ethoxy]p-toluenesulfonate (3.28 g, 10.3 mmol) was slowly added to the basic solution over a 20 minute period. The reaction mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was concentrated under high vacuum. The solid material was dissolved in dichloromethane and the solution was filtered to remove any solid material. The organic layer was concentrated in vacuo, and crude material was purified by preparative-high pressure liquid chromatography to give 900 mg (31%) of the title compound. 1H NMR (D2O, 400 MHz) δ 3.56-3.51 (m, 12H), 3.37 (s, 3H), 1.42 (s, 6H); LRMS (ESI/APCI) m/z 275 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=[CH:31]3)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[CH:34]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=[CH:31]4)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2c1
Temperature: 80 °C
Yield: 24.5 %

Procedure:
A solution of [3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.085 g, 0.27 mmol), methyl 6-(4-hydroxyphenyl)-2-naphthalenecarboxylate (0.075 g, 0.27 mmol), triphenyl phosphine (0.071 g, 0.27 mmol) and diisopropyl azodicarboxylate (0.049 mL, 0.27 mmol) in toluene (2.7 mL) was placed in microwave reaction tube and heated to 80° C. for 1000 seconds. The solution was concentrated and the residue dissolved in a solution of ethyl acetate and methanol, filtered and concentrated. The filtrate was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.038 g, 24.5%). 1H NMR (DMSO-d6): δ 8.62 (s, 1H), 8.25 (s, 1H), 8.18 (d, J=9 Hz, 1H), 8.06 (d, J=9 Hz, 1H), 7.97 (dd, J=1, 9 Hz, 1H), 7.92 (dd, J=2, 9 Hz, 1H), 7.81 (d, J=9 Hz, 2H), 7.42 (d, J=8 Hz, 2H), 7.25 (t, J=8 Hz, 1H), 7.14 (d, J=9 Hz, 2H), 4.99 (s, 2H), 3.90 (s, 3H), 3.35 (septet, J=7 Hz, overlapping H2O 1H), 3.24-3.20 (m, 2H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 574 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]1([CH:55]=[CH:56][S:57](Cl)(=[O:59])=[O:58])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:57](/[CH:56]=[CH:55]/[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)(=[O:59])=[O:58])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)/C=C/c3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 66 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added 2-phenyl-ethenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 66% yield.
Reaction SMILES: CS(O[CH:6]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([N+:32]([O-:34])=[O:33])[CH:26]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=O)=O.[F:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([N+:32]([O-:34])=[O:33])[CH:26]=3)[N:40]2[C:39]2[CH:41]=[CH:42][C:36]([F:35])=[CH:37][CH:38]=2)=[CH:11][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(F)cc1
Solvent: O
Product: O=[N+]([O-])c1cc(C2CCC(c3ccc(Cl)c([N+](=O)[O-])c3)N2c2ccc(F)cc2)ccc1Cl
Temperature: 45 °C
Yield: 23.8 %

Procedure:
The product from Example 28C (2.9 g, 5.2 mmol) and 4-fluoroaniline (5.0 mL, 52.0 mmol) were combined, neat, and heated at 45° C. for 20 h then cooled and poured into water and extracted into dichloromethane. The organics were concentrated the residue was purified by chromatography on silica gel with a 120 g column, eluting with 0-5% ethyl acetate/hexanes to give 0.59 g (24%) of a thick oil.