Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:21])=[N:14][C:15]([O:19][CH3:20])=[N:16][C:17]=3[CH3:18])[N:7]([CH2:22][CH2:23][CH2:24]Cl)[C:6]=2[C:5]([C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]([O:28][CH3:29])=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[C:17]([CH3:18])=[N:16][C:15]([O:19][CH3:20])=[N:14][C:13]=3[CH3:21])[CH2:24][CH2:23][CH2:22][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)nc(OC)nc3C)n(CCCCl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
A mixture of methyl 4-chloro-1-(3-chloropropyl)-2-[(2-methoxy-4,6-dimethylpyrimidin-5-yl)amino]1H-benzimidazole-7-carboxylate (560 mg, 1.28 mmol) and potassium carbonate (1.92 mmol) in N,N-dimethylformamide (5.6 mL) was stirred at 80° C. for 1 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (504 mg, 1.25 mmol, 98%).
Reaction SMILES: C1(S([NH2:10])(=O)=O)C=CC=CC=1.CC(C)=O.[CH3:15][O:16][CH:17]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH:19]([N:24]=[C:25]=[O:26])[CH2:18]1>[OH-].[Na+].O>[CH3:15][O:16][CH:17]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH:19]([NH:24][C:25](=[O:26])[NH2:10])[CH2:18]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COC1CC(N=C=O)CCC1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC1CC(NC(N)=O)CCC1C
Reaction time: 2 h

Procedure:
5 g of 4-(β-<3-methoxy-methoxy-thiophen-2-carbonamido>-ethyl)-benzenesulfonamide (melting point 160° - 162°C) were dissolved in 7 ml of 2N sodium hydroxide solution and 50 ml of acetone and 2.4 g of 3-methoxy-4-methylcyclohexyl-isocyanate (boiling at 90°C under a pressure of 10 mm of mercury) were added dropwise at 0° - 5° C. Then stirring was continued for 2 hours, then the whole was diluted with water, and any undissolved matter was filtered off, and the filtrate was acidified with dilute hydrochloric acid. The N-[4-(β-<3-methoxy-methoxy-thiophen-2-carbonamido> -ethyl)-benzenesulfonyl]-N'-(3-methoxy-4-methyl-cyclohexyl)-urea precipitating in crystalline form melted at 125° - 127° C after recrystallization from methanol.
Reaction SMILES: [C:1]([N:5]1[CH2:38][CH2:37][CH2:36][CH2:35][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([C@@H:20]5[O:24][C:23]([CH3:26])([CH3:25])[O:22][C@H:21]5[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:16]([O:32][CH3:33])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:39])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:45]1[S:46][CH:47]=[CH:48][CH:49]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.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:1]([N:5]1[CH2:38][CH2:37][CH2:36][CH2:35][C:8]2[C:9]([C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C@@H:20]5[O:24][C:23]([CH3:26])([CH3:25])[O:22][C@H:21]5[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:16]([O:32][CH3:33])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:39])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c3c(c(Br)c1-2)CCCCN(C(C)(C)C)C3=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c3c(c(-c4cccs4)c1-2)CCCCN(C(C)(C)C)C3=O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 750 mg of 21e, 550 mg of 2-(tributylstannyl)-thiophene and 28 mg of tetrakis(triphenylphosphine)palladium(0) in 14 ml of degassed toluene was heated under N2 atmosphere for 16 hr at 110° C. The reaction mixture was cooled, 15 ml of sat. aq. KF was added, and stirring prolonged for 2 hr. The reaction was filtered through Celite, and the product was extracted with ethyl acetate. The organic layer was washed, dried and concentrated and the product purified by chromatography over silicagel (using a gradient of heptane-ethylacetate as eluent). This provided 630 mg of 21f; LC-MS-ESI: [M+1] 607.26. NMR (CDCl3) δ 7.35, 7.08, and 6.93 (3×m, 3, thienyl-H), 6.67 and 7.30 (2×s, 2, Ar—H) 5.35 (d 1, CHO), 3.95 (d, 1, CHO), 3.75 (s, 3, OCH3), 0.20 (m, 2, ethyl ester), 1.28 (t, 3, ethyl ester), 4.60, and 3.80 (2×bm, 2, CH2), 3.55 and 4.15 (2×br.m, 2, CH2), 2.92 and 3.13 (2×b.m, 2, CH2) 1.6-2.0 (bm, 4, 2×CH2), 1.32 and 1.50 (2×s, 6, dimethylketal), 1.57 (s, 9, tertC4H9).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[C:5]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][N:26]([CH3:54])[C:27](=[O:53])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)=[O:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>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.O>[F:24][C:21]1[N:20]=[CH:19][C:18]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([NH:37][C:35](=[O:36])[NH:34][C:31]4[CH:30]=[CH:29][C:28]([C:27]([N:26]([CH3:54])[CH3:25])=[O:53])=[CH:33][CH:32]=4)=[CH:43][CH:42]=2)[N:11]=[C:10]3[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:23][CH:22]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Fc1ccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4cccc(-c5ccc(F)nc5)c4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-8-(6-fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazoline (70 mg, 0.000203 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido]-benzamide (100 mg, 0.0002436 mol), cesium carbonate (133 mg, 0.000406 mol), DMF (3.5 mL) and water (0.9 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (7 mg, 0.0000101 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 2% MeOH in chloroform) to yield the title compound as a light yellow solid [8 mg, 7%]. 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.95 (s, 1H), 8.60 (s, 1H), 8.43 (m, 1H), 8.28 (d, J=8.8 Hz, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.58 (m, 3H), 7.49 (m, 2H), 7.39 (m, 3H), 3.84 (s, 8H), 2.95 (s, 6H); LC-MS (ESI): Calculated mass: 591.2; Observed mass: 591.9 [M+H]+ (RT: 1.53 min).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH3:13][O:14][NH2:15]>C(O)C>[CH3:13][O:14][N:15]=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CC(C)=O)=NOC
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A mixture of 2.5 g of ethyl 2,4-dioxovalerate, 1.45 g of O-methylhydroxylamine hydrochloride and 10 ml of ethanol was heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, and partitioned between water and ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.34 g of ethyl 2-methoxyimino-4-oxopentanoate of the formula:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[O:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][C@@H:13]([SH:18])[C@H:12]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].IC.[C:34](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:31])[O:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][C@@H:13]([S:18][CH3:34])[C@H:12]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:10]=2[CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1(CC)c2cc(OC(=O)OC(C)(C)C)ccc2C[C@@H](S)[C@@H]1NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCC1(CC)c2cc(OC(=O)OC(C)(C)C)ccc2C[C@@H](SC)[C@@H]1NC(=O)OC(C)(C)C

Procedure:
To a solution of carbonic acid 7-tert-butoxycarbonylamino-8,8-diethyl-trans-6-mercapto-5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester (28.2 mg, 0.062 mmol) in acetone (2 mL) was added the iodomethane (20 μL, 0.31 mmol) and the potassium carbonate (26 mg, 0.18 mmol), and stirred at reflux for 4 h. The mixture was quenched with H2O, diluted with Et2O (50 mL), washed with H2O, brine, dried over MgSO4. The residu was purified by a flash chromatography (10% AcOEt/Hex) (21.2 mg , 73%). 1H NMR (CDCl3): 7.08 (1H, d, J=8.5 Hz, H5), 7.00-6.95 (2H, m, H6 and H8), 4.56 (1H, d, J=11 Hz, NH), 4.09 (1H, t, J=11.0 Hz, CHNH), 3.25-3.00 (3H, m), 2.15 (3H , broad, SCH3), 1.76 (4H, m, CH2), 1.57 (9H, s, t-butyl), 1.50 (9H, s, t-butyl), 0.73 (6H, m, CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].CN.[CH2:16]([N:18](CC)CC)C>ClCCl.O>[CH3:16][NH:18][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN
Solvent: O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (30 g, 0.14 mol) in dichloromethane (500 mL) was slowly added a solution of methylamine in water (30%, 15.3 g) and triethylamine (38 mL, 0.27 mol) respectively. The mixture was stirred at room temperature for 1 hour and then evaporated. The residue was subjected to silica gel chromatography to afford the product N-methyl-2-nitrobenzenesulfonamide (26 g, yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25](O)=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[OH:29][C@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([N:32]4[CH2:33][CH2:34][CH2:35][C@H:30]([OH:29])[CH2:31]4)=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Reactant: O[C@H]1CCCNC1
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)N3CCC[C@H](O)C3)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and (S)-3-hydroxypiperidine were coupled to give 110bp. LCMS (ESI) m/z: 485.0
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=4[CH3:15])[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1cccc(C)c1N1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1N1CCN(C[C@H](O)COc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2,6-dimethylphenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 50% overall yield. FDMS m/e=379 (M+ of free base). α[D]589 =-11.89 (c=0.47, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH2:13]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22](Cl)[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=2)[N:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Product: COC(=O)c1ccc(Nc2nc(C)cc(Cc3ccccc3)n2)cc1F

Procedure:
The title compound was prepared from methyl 4-amino-2-fluoro-benzoate (480 mg, 2.84 mmol) and 4-benzyl-2-chloro-6-methyl-pyrimidine (620 mg, 2.84 mmol) in the same manner as described for example 1e). Obtained as white solid (840 mg, 84%). Mp 148-151° C.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[H][H].[OH-].[Na+]>C(O)(=O)C.O>[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: [H][H]
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCN2
Reaction time: 3 h
Yield: 75 %

Procedure:
28.74 g (457 mmol) of sodium cyanoborohydride are added in small portions at below 20° C. to a solution of 20.0 g (152 mmol) of 5-methylindole in 300 ml of glacial acetic acid. The addition, which is slightly exothermic, is made over 3 hours and is accompanied by slight evolution of hydrogen. The mixture is stirred for 12 hours at below 20° C., and then 300 ml of water are added and the pH of the reaction medium is adjusted to between 10 and 12 by addition of 500 ml of 30% sodium hydroxide solution. The mixture is extracted twice with dichloromethane and the organic phase is washed with 100 ml of water. It is evaporated and the residue is purified by flash chromatography on a silica column, the eluent used being a mixture of increasing polarity of methanol in methylene chloride. 15.3 g (yield=75%) are obtained of a colourless oil which develops a brown colour on storage (under a nitrogen atmosphere with the exclusion of light).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[C:16]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:30]=2)[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1csc(COc2ccc(-c3cccc(-c4ccccc4)c3)cc2)n1

Procedure:
A solution of 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of intermediate 2; 71 mg, 0.2 mmol) in dioxane (3.5 mL) was added to a reaction tube containing biphenyl-3-boronic acid (available from Lancaster Synthesis Ltd., Morecambe, UK; 119 mg, 0.6 mmol). A solution of potassium carbonate (74 mg, 0.5 mmol) in water (0.4 mL) was added and the mixture was degassed. A solution of bis(tricyclohexylphosphine)-palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) in dioxane (0.5 mL) was added and the tube was heated in a microwave oven at 170 degrees for 25 min. Concentrated hydrochloric acid (0.1 mL) was added and the mixture was passed through a silica gel column (1 g of silica), and washed with dimethylacetamide (2×1 mL). The filtrate was evaporated to dryness and the resulting gum was triturated twice with 50% aqueous methanol to give 2-([1,1′;3′,1″]terphenyl-4-yloxymethyl) -thiazole-4-carboxylic acid. Mass spectrum MH+=388
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13](=[O:20])[C:12]=2[C:11]([CH3:21])=[N:10]1.C1CCCCC1>C(O)C>[OH:20][CH:13]1[CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][C:17]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=3)[N:10]=[C:11]([CH3:21])[C:12]1=2
Reactant: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCO
Product: Cc1nn(-c2ccccn2)c2c1C(O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
0.09 g (2.36 mol) of sodium borohydride were added portionwise to the solution of 1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole (0.3 g, 1.18 mmol), prepared as described in example 3, in ethanol (15 ml) maintained under inert atmosphere and under magnetic stirring at room temperature. After about 20 hours, additional sodium borohydride (0.09 g) was added and the reaction mixture was heated at about 50° C. for about 8 hours. The solvent was evaporated and the residue was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to give a foam which was treated with cyclohexane and filtered to yield the title compound as a colourless solid (0.2 g, 66%): m.p. 125-126° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39](Br)[N:38]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:39]4[CH:40]=[CH:41][CH:42]=[C:37]([S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:36])=[O:35])[N:38]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)c1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(S(=O)(=O)c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzenesulfonyl-6-bromo-pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH2:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1([CH2:30][CH2:31][CH:32]=O)[CH:29]=[CH:28][N:27]=[CH:26]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:24][CH2:32][CH2:31][CH2:30][N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)([CH3:22])[CH3:23])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCn1ccnc1
Reactant: CC(C)(N)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Product: CC(C)(NCCCn1ccnc1)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
In a similar manner to Example 24, 1-(4'-benzyloxybiphenyl-4-yl)-1-methylethylamine (A15) (1.4 g) and 3-(imidazol-1-yl)propionaldehyde (0.72 g) were reacted to give N-[1-(4'-benzyloxybiphenyl-4-yl)-1-methylethyl)-3-(imidazol-1-yl)propylamine, m.p. 93-95° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=1)([O-])=O>C(O)C.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=1
Reactant: NS(=O)(=O)c1ccc(C2CCN(c3cc([N+](=O)[O-])ccn3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccnc(N2CCC(c3ccc(S(N)(=O)=O)cc3)CC2)c1
Reaction time: 3 h

Procedure:
A mixture of the product from part (i) (100 mg) and 5% palladium/carbon (25 mg) in ethanol (25 ml) and acetic acid (25 ml) was hydrogenated at 3.5 bars at room temperature for 3 hours. The catalyst was filtered off, the filtrate was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/ethanol (19:1) gave some impurity and further elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:1) gave the pure product. The combined product-containing fractions were evaporated to give the title compound as a monohydrate, m.p. 290°-295° (with decomp).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH2:37][CH2:38][CH3:39])[N:11]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]4[NH:36][N:35]=[N:34][N:33]=4)=[CH:22][CH:21]=3)[C:12]=2/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])[C:4]([CH3:7])=[CH:5][CH:6]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH2:37][CH2:38][CH3:39])[N:11]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]4[NH:33][N:34]=[N:35][N:36]=4)=[CH:22][CH:21]=3)[C:12]=2/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CCCc1nc(-n2c(C)ccc2C)c(/C=C/C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1nc(-n2c(C)ccc2C)c(/C=C/C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 85.4 %

Procedure:
A solution of methyl (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl]-1H-imidazol-5-yl]-2-propenoate (Example 52, 1.55 g, 3 mmol), and potassium trimethylsilanolate (0.96 g, 7.5 mmol) in dry THF (80 mL) was stirred at room temperature for 3 hours under an atmosphere of dry nitrogen. The resulting precipitate was collected by filtration, air dried, and then dissolved in water (50 mL). The free acid was precipitated out by the addition of 1N HCl and collected by filtration giving (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl]-1H-imidazol-5-yl]-2-propenoic acid (1.3 g, 83%) as a partial hydrate, mp 144°-150° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:24]=[CH:25][C:18]=23)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:8][C:4]1[N:3]=[C:2]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:27])=[O:28])[CH:24]=[CH:25][C:18]=23)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Reactant: Fc1cccc(Br)n1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(F)n4)ccnc32)cc1

Procedure:
In a 20 mL microwave tube, 2-Bromo-6-fluoropyridine (L) (682 mg, 3.3 mmol, 1.2 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (B)(1.1 g, 2.8 mmol, 1 equiv.) and Pd(PPh3)4 (323 mg, 0.28 mmol), 0.1 equiv.) were suspended in a mixture of DME (10 mL) and aqueous Na2CO3 2M (3 mL). The container was sealed and the reaction mixture was exposed to microwave irradiation for 30 min at 160° C. The resulting mixture was diluted in ethyl acetate, washed with water and dried over anhydrous Na2SO4. The crude material was purified by flash chromatography on silica gel, eluting with hexanes/ethyl acetate mixtures (90:10 to 60:40). The title compound J was isolated as a pale yellow solid (2.1 g, 50%).