Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][CH3:21])[N:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=3)([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][CH3:21])[N:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: COc1cc(C2C(=O)Nc3cc(Cl)ccc32)nc(OC)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)nc(OC)n1
Temperature: 80 °C

Procedure:
A mixture of rac-6-chloro-3-(2,6-dimethoxy-pyrimidin-4-yl)-1,3-dihydro-indol-2-one (0.23 g, 0.75 mmol) (from Example 29a supra), 3-chlorobenzyl bromide (0.19 g, 0.9 mmol) (Aldrich), potassium iodide (0.15 g, 0.9 mmol) and potassium carbonate (0.23 g, 1.66 mmol) in acetone (20 mL) was heated at 80° C. for 30 minutes. After cooling, mixture was diluted with ethyl acetate and washed with water and brine. Aqueous layers were back washed with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-hexanes, 1:6, V/V) to give rac-6-chloro-3-(3-chloro-benzyl)-3-(2,6-dimethoxy-pyrimidin-4-yl)-1,3-dihydro-indol-2-one as an orange solid. (Yield 0.21 g, 65%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([N:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[C:9]3[CH:15]=[CH:14][N:13](S(C4C=CC=CC=4)(=O)=O)[C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.CO.[Li+].[OH-]>O>[C:1]1([C:7]2[C:8]([N:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]3)=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Temperature: 50 °C
Yield: 49.9 %

Procedure:
tert-Butyl 4-(5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (1.10 g, 2.12 mmol) was placed in 1:1 THF:MeOH (20 mL). LiOH (3.54 mL, 10.6 mmol) was then added, and the reaction was heated to 50° C. for 1 hour. The reaction was cooled to room temperature, poured into water, and extracted with DCM (3×50 mL). The combined organic fractions were dried, filtered, concentrated, and then purified by column chromatography (500:5 DCM:MeOH) to give tert-butyl 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.40 g, 49.8% yield).
Reaction SMILES: Cl.ClC1C=CC=C[C:4]=1[N:9]1C=NN=[C:10]1C1SC2C3C=CC(N)=CC=3OCCC=2C=1.CCN(C(C)C)C(C)C.ClCC(Cl)=O.Cl[CH2:44][C:45]([NH:47][C:48]1[CH:49]=[CH:50][C:51]2[C:57]3[S:58][C:59]([C:61]4[N:65]([C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=5[Cl:72])[CH:64]=[N:63][N:62]=4)=[CH:60][C:56]=3[CH2:55][CH2:54][O:53][C:52]=2[CH:73]=1)=[O:46].Cl.N(C)C.CCN(CC)CC>C(Cl)Cl>[Cl:72][C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=1[N:65]1[CH:64]=[N:63][N:62]=[C:61]1[C:59]1[S:58][C:57]2[C:51]3[CH:50]=[CH:49][C:48]([NH:47][C:45](=[O:46])[CH2:44][N:9]([CH3:10])[CH3:4])=[CH:73][C:52]=3[O:53][CH2:54][CH2:55][C:56]=2[CH:60]=1
Reactant: Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Reactant: O=C(CCl)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Agent: CNC
Agent: Cl
Agent: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 19.7 %

Procedure:
To a solution of 2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b] thieno[2,3-d]oxepin-8-amine HCl salt (0.5 g, 1.16 mmol) in dried DCM (30 mL) was added DIPEA (0.61 mL, 3.48 mmol). The solution was stirred at 0° C. for 20 min and 2-chloro-acetyl chloride (0.2 g, 1.74 mmol) was added dropwise. The mixture was allowed to reach room temperature and stirred for a further 2 hours. The reaction solution was poured into ice water and extracted with EtOAc. The organics were combined, dried over Na2SO4 and evaporated in vacuum to afford the crude product (0.45 g, yield: 82%). 2-chloro-N-(2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)acetamide (0.2 g, 0.424 mmol) was mixed with HCl salt of NH(CH3)2 (0.172 g, 2.12 mmol) and NEt3 (0.3 mL, 2.12 mmol) in 15 mL of DCM. The solution was stirred at room temperature for 4 hours and quenched with ice water. Extraction with EtOAc and evaporation of the organics gave the crude product. It was purified by preparative TLC to afford 237 (40 mg, isolated yield: 20%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].N1C=CC=CC=1.[C:21](Cl)(Cl)=[O:22].C1(C)C=CC=CC=1>ClCCl>[N:6]([C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:3][CH3:2])=[O:14])=[C:21]=[O:22]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)N=C=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A well-stirred cold mixture (0° C.) of phenylalanine methyl ester hydrochloride (200 mg), anhydrous dichloromethane (3 ml), and anhydrous pyridine (295 μl, 4 eq.) was stirred for 15 min. A 2M phosgene solution in toluene (455 μl, 0.98 eq.) was added over 30 sec. followed by stirring for 2 h at 0° C. The reaction mixture was poured into dichloromethane washed with cold IN hydrochloric acid then ice water. Each aqueous layer was back extracted once with dichloromethane. The combined organic layer was washed once with brine, dried over anhydrous magnesium sulfate and concentrated. Distillation under vacuum afforded methyl (S)-2-isocyanato-3-phenylpropanoate (125 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH3:16])=[C:14]([C:17]([NH:19][C:20]3[CH:21]=[N:22][C:23]([CH:26]4[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[O:18])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH3:16])=[C:14]([C:17]([NH:19][C:20]3[CH:21]=[N:22][C:23]([C@H:26]4[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]4)=[CH:24][CH:25]=3)=[O:18])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)Nc2ccc(C3CCC(=O)CC3)nc2)cnn1-c1ccc(C(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)Nc2ccc([C@H]3CC[C@H](O)CC3)nc2)cnn1-c1ccc(C(C)(C)C)cc1
Temperature: 0 °C

Procedure:
A solution of 1-(4-tert-butylphenyl)-5-methyl-N-[6-(4-oxocyclohexyl)pyridin-3-yl]-1H-pyrazole-4-carboxamide (136 mg) in ethanol (5 ml) was cooled in ice water, sodium borohydride (48 mg) was added and stirred at the same temperature for an hour. After the reaction, water was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with a silica gel column chromatography (n-hexane/ethyl acetate), washed with ethanol, the resulting solid was filtered and dried at 60° C. in vacuo to give the titled compound (29 mg) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C@@H:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=2[F:16])[C@@H:5]([CH3:17])[N:4]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:3]1=[O:23].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33]([OH:35])=[O:34]>C(OC(C)C)(=O)C.C1COCC1.ClC1C(O)=C(C=C(Cl)C=1)C=O>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33]([O-:35])=[O:34].[CH3:17][C@H:5]1[N:4]([CH2:18][C:19]([F:20])([F:22])[F:21])[C:3](=[O:23])[C@@H:2]([NH3+:1])[CH2:7][C@H:6]1[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[F:16]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)CC(N)C(=O)N1CC(F)(F)F
Agent: O=Cc1cc(Cl)cc(Cl)c1O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Product: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)C[C@H]([NH3+])C(=O)N1CC(F)(F)F
Product: O=C([O-])c1cc2ccccc2[nH]1
Temperature: 57.5 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a mixture of crude material containing 24 (2.00 g, 5.88 mmol) and 3,5-dichloro-2-hydroxybenzaldehyde (0.011 g, 0.059 mmol) in isopropyl acetate (15.0 ml) at 55-60° C. under nitrogen was slowly added a solution of 1H-indole-2-carboxylic acid (0.96 g, 5.88 mmol) in THF (10.0 ml) over 2 hours. Upon completion of acid addition, a thick salt suspension was agitated at 55-60° C. for another 18 h and then was allowed to cool to ambient temperature. The salt was filtered and washed with isopropyl acetate. After drying at 60° C. in a vacuum oven with nitrogen purge for 8 h, 26 (2.33 g, 79.0%) was isolated as crystals. 1H NMR (500 MHz, DMSO): δ 11.40 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.45 (br, 3H), 7.47 (ddd, J=14.8, 10.1, 8.3 Hz, 1H), 7.41-7.40 (m, 1H), 7.16-7.14 (m, 2H), 6.98-6.97 (m, 1H), 6.87 (s, 1H), 4.69 (dq, J=15.3, 9.6 Hz, 1H), 3.84-3.81 (m, 4H), 2.76-2.71 (m, 1H), 2.34 (dd, J=12.7, 6.3 Hz, 1H), 1.13 (d, J=6.5 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 164.8, 156.8 (ddd, J=244, 7.0, 2.5 Hz), 149.1 (ddd, J=249, 14.4, 8.5 Hz), 147.2 (ddd, J=246, 13.9, 3.2 Hz), 137.0, 133.5, 127.8, 125.4 (q, J=282 Hz), 123.3, 121.8, 119.7, 117.8 (dd, J=19.8, 13.8 Hz), 117.2 (dd, J=19.2, 10.6 Hz), 112.7, 112.3 (ddd, J=26.1, 6.7, 3.3 Hz), 105.1, 57.1, 51.3, 44.8 (q, J=32.7 Hz), 35.2, 26.9, 14.5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[N:15]=[C:14]([NH:16][C:17]([NH:19][C:20]3[N:21]=[C:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[S:23][CH:24]=3)=[O:18])[CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+]>C(Cl)Cl>[CH3:35][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[N:15]=[C:14]([NH:16][C:17]([NH:19][C:20]3[N:21]=[C:22]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[S:23][CH:24]=3)=[O:18])[CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(Nc1cccc(OCCC2CCNCC2)n1)Nc1csc(-c2ccncc2)n1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(CCOc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of N-[2-(4-pyridinyl)-4-thiazolyl]-N′-2-[6-(4-piperidinylethoxy)pyridinyl]urea (0.17 g, 0.40 mmol, Example 167), paraformaldehyde (0.17 g), and NaBH(OAc)3 (0.21 g, 1.0 mmol) in 40 mL of CH2Cl2 was stirred at RT under N2 for 12 h. After 12 h, the solvent was removed in vacuo, and the residue was diluted with 20 mL of H2O, then extracted with CHCl3/IpOH (3:1, 3×20 mL). The combined organic portions were washed with brine, and dried over MgSO4, and the solvents were removed in vacuo to yield a residue. Purification over silica gel (gradient, 5% to 7.5% MeOH/CH2Cl2 with 0.5% of TEA) provided the title compound as an off-white solid. MS m/z: 439 (M+H). Calc'd for C22H26N6O2S: 438.18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26](=O)[CH3:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[NH3:29].[H][H]>[Ni].CO>[NH2:29][CH:26]([CH3:27])[CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:20][CH2:21]1
Reactant: [H][H]
Reactant: N
Reactant: CC(=O)CN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [Ni]
Solvent: CO
Product: CC(N)CN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 34 %

Procedure:
A mixture of 4 parts of 1-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-propanone, oxime and 120 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 1.3 parts (34%) of N-[1-(2-aminopropyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, mp. 178.3° C. (intermediate 132).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccn1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 2-aminopyridine (1.00 g, 10.6 mmol) and pyridine (1.01 ml, 12.7 mmol) in tetrahydrofuran (35 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.76 ml, 12.7 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.77 g (61.6%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.[OH-].[K+].Cl>CO.C(O)CCCCCCC>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCCCCO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 22.4 %

Procedure:
To a mixture of 307 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 833 mg (5.57 mmol) of 2-cyclopropyl-6-methylphenol were added 1-octanol (3.36 mL) and 324 mg (5.50 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 113 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 23%) and 1.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.3%) were obtained.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]([F:27])([F:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1>CO>[NH2:11][C@@H:12]([CH2:17][C:18]([F:26])([F:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a three-neck flask, methyl (S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoate (1.0 g, 2.65 mmol) was dissolved in 25 ml of methanol. After repeated evacuation and sparging with argon, 350 mg of Pd/C (10%) were added. After degassing and sparging with argon again, the argon atmosphere was replaced by hydrogen (balloon with H2 gas). The mixture was stirred at RT for 3 h. Owing to incomplete conversion, a further 350 mg of catalyst were added and the mixture was hydrogenated at RT for a further 5 h. On completion of conversion, the reaction mixture was filtered. The mixture was washed with 20 ml of methanol and the filtrate was concentrated by evaporation under reduced pressure. A waxy residue was obtained which, as well as the desired product, also contained smaller amounts of the monodefluorinated and didefluorinated product. This residue was used without further purification for the further reaction.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](O)[CH:41]=1)([CH3:38])[CH3:37])[CH3:33]>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:3]3[CH:2]=[C:1]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:6]=[CH:5][CH:4]=3)[O:8][C:9]=2[CH3:25])[CH:41]=1)([CH3:38])[CH3:37])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(O)c1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)c1

Procedure:
A mixture of the toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (66.9 mmol) and 2-(3-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (Columbia University WO 9731530) (12.5 g, 55.71 mmol) and CS2CO3 (22.7 g, 69.6 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between ethyl acetate (160 mL) and H2O (180 mL), and the aqueous phase extracted with ethyl acetate (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to provide 2-{3-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester. Rf=0.50 in 20% ethyl acetate/hexanes; 1H NMR (400 MHz, CDCl3) δ8.18 (s, 1H), 7.95 (d, 1H), 7.65-7.59 (m, 3H), 7.44-7.39 (m, 3H), 7.36 (t, 1H), 7.08 (t, 1H), 6.55 (d, 1H), 6.41 (s, 1H), 6.37 (d, 1H), 4.20-4.14 (m, 4H), 2.97 (t, 2H), 2.38 (s, 3H), 1.57 (s, 6H), 1.20 (t, 3H); MS (EI) 508.2 (M+Na)+, 486.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][N:21](C=O)[CH3:22]>O>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:20][NH:21][CH3:22])=[CH:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CNCc1cn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-[N-(Benzyioxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole NaH (60% dispersion in mineral oil, 0.15 g, 3.8 mmole) was added portionwise, allowing for gas evolution, to a solution of 3-(N-(benzyloxycarbonyt)-N-methylaminomethyl]methylaminomethyl]-1H-indole (0.7 g, 2.5 mmole) in DMF (25 mL) at 0° C. When the NaH addition was complete, benzyl bromide (1.2 nL, 10.0 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound. (0.9 g, 93%) as an off white solid: MS (ES) mVe 385 (M+H)+.
Reaction SMILES: C(P(CCCCCCCC)CCCCCCCC)CCCCCCC.[C:26]([Br:30])(Br)(Br)Br.[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42](CO)=[CH:41][C:40]=1[CH2:47][O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C(OCC)C>[Br:30][CH2:26][C:42]1[CH:43]=[CH:44][C:39]([O:38][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[C:40]([CH2:47][O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:50])[CH3:51])[CH:41]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C

Procedure:
In a manner similar to Example 3(b), by reacting 4.2 ml (9.4 mmol) of trioctylphosphine, 3.1 g (9.4 mmol) of carbon tetrabromide with 1.7 g (4.3 mmol) of [4-(tert-butyldimethylsilanyloxy)-3-(tert-butyldimethylsilanyloxymethyl)phenyl]methanol in 30 ml of ethyl ether, after purification on a silica column (AcOEt 10-Heptane 90), a yellow oil (m=1.7 g; Y=86%) is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([B:19]4[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]4)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31].C1(C)C=CC=CC=1.C(NC(C)C)(C)C.[Cl:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:52]=1[C:53](Cl)=[O:54]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:52]=1[C:53]([N:12]1[C:13]2=[N:14][CH:15]=[C:16]([B:19]3[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:24])([CH3:25])[O:23]3)[CH:17]=[C:18]2[C:10]([C:8]([C:7]2[C:2]([F:1])=[C:3]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:31])=[O:32])[CH:4]=[CH:5][C:6]=2[F:28])=[O:9])=[CH:11]1)=[O:54]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (30, 2.1 g, 4.16 mmol), 21 mL of toluene, diisopropylamine (1.5 mL, 8.31 mmol), 4-dimethylaminopyridine (101 mg, 0.83 mmol) and 2,6-dichloro-benzoyl chloride (10, 0.7 mL, 4.78 mmol) are combined in a reaction flask under nitrogen. The reaction is stirred at room temperature for 17 hours, then diluted with 100 mL of ethyl acetate and extracted. The organic layer is washed sequentially with 40 mL of saturated aqueous sodium bicarbonate, 40 mL of water, and 40 mL of brine, then dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum and the resulting material is triturated with diethyl ether to provide the desired compound.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>CO>[CH:27]1([NH:30][CH2:2][C:3]2([OH:1])[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:29][CH2:28]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: NC1CC1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CNC4CC4)CC3)c(F)c2)C(=O)O1
Yield: 73 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with cyclopropylamine (2.06 mmol) in methanol (10 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 73% yield.