Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12](/[C:15](/[CH2:28][CH3:29])=[C:16](/[F:27])\[CH:17]=[CH:18]\[C:19](\[CH3:26])=[CH:20]\[C:21]([O:23]CC)=[O:22])[C:11]([O:30][CH2:31][CH3:32])=[CH:10][C:9]=2[C:8]([CH3:34])([CH3:33])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.C(O)C>[C:1]([C:5]1[C:14]2[CH:13]=[C:12](/[C:15](/[CH2:28][CH3:29])=[C:16](/[F:27])\[CH:17]=[CH:18]\[C:19](\[CH3:26])=[CH:20]\[C:21]([OH:23])=[O:22])[C:11]([O:30][CH2:31][CH3:32])=[CH:10][C:9]=2[C:8]([CH3:33])([CH3:34])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CC=C2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C\C(=O)O)C(C(C)(C)C)=CCC2(C)C

Procedure:
As described in General Procedure J-1, ethyl (2E,4E,6E)-7-(8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-6-fluoro-3-methyl-nona-2,4,6-trienoate (Compound A-74, 520 mg, 1.111 mmol) in THF (5 mL) and ethanol (5 mL) was hydrolyzed with 1.5 N NaOH (5 mL) to produce the title compound as a yellow solid after purification by recrystallization from acetonitrile.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.Cl[C:42]1[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([NH:49][CH3:50])[N:43]=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:42]4[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([NH:49][CH3:50])[N:43]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Reactant: CNc1nc(C)cc(Cl)n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: CNc1nc(C)cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 4-chloro-N,6-dimethyl-2-pyrimidinamine. MS (ESI) mass calcd. for O21H23FN8O, 422.5; m/z found, 423.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5](/[N:8]=C/N(C)C)=[N:6][CH:7]=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N)=N>N1C=CC=CC=1>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:44]([NH:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])=[CH:7][N:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(-c2csc3c(N)cnc(/N=C/N(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: N=CN
Solvent: c1ccncc1
Product: COc1cc(-c2csc3c(NC(=O)Nc4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.1 %

Procedure:
To a solution of N-[4-(7-amino-4-{[(1E)-(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (0.020 g, 0.040 mmol) in pyridine (1.1 mL) at 0° C. was added phenyl isocyanate (0.0043 mL, 0.040 mmol). The mixture was allowed to warm to ambient temperature, and was stirred at ambient temperature for 12 h. The reaction mixture was concentrated, and the residue was purified by flash column chromatography on silica gel, which had been deactivated with triethylamine (10% by volume of silica gel used), using methanol/dichloromethane as the mobile phase, to afford an intermediate that was then subjected to General Procedure M for formamidine hydrolysis to yield the title compound (0.007 g, 32%) as an off-white foam: 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 9.07 (s, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 8.06 (d, 1H), 7.73 (m, 2H), 7.60 (d, 1H), 7.49 (d, 2H), 7.36 (s, 1H), 7.30 (m, 4H), 7.14 (m, 2H), 7.00 (t, 1H), 6.10 (br, 2H), 4.04 (s, 3H), 3.93 (s, 3H); MS: (MH)+ 563.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.N1C=CC=CC=1.O.[NH2:23][NH2:24]>O>[Br:1][C:2]1[C:3]([NH:23][NH2:24])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: NN
Reactant: Clc1ccc(-c2ccnc(Cl)c2Br)cc1
Solvent: O
Solvent: c1ccncc1
Product: NNc1nccc(-c2ccc(Cl)cc2)c1Br
Temperature: 120 °C

Procedure:
A mixture of 3-bromo-2-chloro-4-(4-chlorophenyl)pyridine (10 g, 33 mmol), pyridine (50 mL) and hydrazine monohydrate (4.8 g, 96 mmol) was heated to 120° C. for 16 h. After cooling to room temperature, water (300 mL) was added, which caused solid desired product to precipitate. This was filtered, washed with water (2×50 mL), and dried to obtain the title compound as a pale yellow solid (6 g), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[Li+].CC([N-]C(C)C)C.[C:25](=[O:27])=[O:26]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:25]([OH:27])=[O:26])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: O=C=O
Reactant: COC(=O)C1CCc2cccc(OC)c2C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)O)CCc2cccc(OC)c2C1
Reaction time: 1.5 h

Procedure:
A THF (1.0 mL) solution of 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester (660 mg, 3.0 mmol) was added to freshly made LDA (made by addition of 2.0 mL of 2.3 M BuLi to 1.5 mL THF solution of 0.7 mL iPr2NH) at −78° C. and the mixture was allowed to stir for 1.5 hour. A CO2 balloon was then applied. The reaction mixture was quenched with aqueous NH4Cl and the resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to provide the crude-8-methoxy-3,4-dihydro-1H-naphthalene-2,2-dicarboxylic acid methyl ester (470 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:23]([CH3:26])([CH3:25])[CH3:24].[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=[CH:29][CH:28]=1.O>C(O)CCC.C1(C)C=CC=CC=1>[CH2:32]([O:10][C:9](=[O:11])[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:4]=1)[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)c1cc(C(C(=O)O)c2ccc(O)c(C(C)(C)C)c2)ccc1O
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)C(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1

Procedure:
35.6 g of bis(4-hydroxy-3-tert.-butyl-phenyl)ethanoic acid (0.1 mol) were dissolved in a mixture of 222 g of n-butanol and 240 g of toluene. As an esterification catalyst, 1 g of p-toluene-sulfonic acid was added. Azeotropic distillation was continued until 1.8 mol of water had separated at the separator. The butanol-toluene phase was washed with 10% sodium bicarbonate solution and then with water. The solvent mixture was distilled off and the residue was dissolved and precipitated in 300 ml of heptane. After distillation of the solvent, 38 g (92 %, calculated on the acid used) of bis(4'-hydroxy-3'-tert-butyl-phenyl)ethanoic acid n-butyl ester were obtained, m.p. 124° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22]CC2C=CC=CC=2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([OH:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(OCc4ccccc4)nc3N21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 3.90 g (9.86 mmol) (4R,9aR)-6-benzyloxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 21, intermediate) in 30 ml methanol:ethyl acetate (1:1 v/v) 0.20 g 10% palladium on charcoal was added and the reaction was hydrogenated at atmospheric pressure for 2 h. After filtration over dicalite speed plus the filtrate was evaporated and the residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant to afford the desired compound as a colorless foam (82.0%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].P(Cl)(Cl)(Cl)=O.CN(C=O)C.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2)=[O:24]>ClCCCl>[CH3:21][O:22][C:23]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[C:30]2[CH:8]=[O:9])=[O:24]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2cc[nH]c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1cccc2c(C=O)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a stirred mixture of phosphorus oxychloride-dimethylformamide in anhydrous 1,2-dichloroethane (prepared by the slow addition of phosphorus oxychloride (0.43 ml, 4.6 mmol) to anhydrous DMF (0.35 ml, 4.6 mmol) in anhydrous 1,2-dichloroethane (6 ml) cooled below 5° C.) a solution of 7-methoxycarbonylindole (0.69 g, 4 mmol) in anhydrous 1,2-dichloroethane (6 ml) was dropwise below 5° C. The mixture was stirred at room temperature for 2 h and then was heated at 50° C. for 30 minutes. After cooling, the precipitate was filtered off and washed with 1,2-dichloroethane. This precipitate was suspended in aq Na2CO3 10% (30 ml) and stirred at room temperature for 20 minutes; dichloromethane was added and stirring was continued 10 minutes more. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to yield 0.75 g (93%) of the entitled product. Mp: 153–4° C.
Reaction SMILES: O1CCCC1.Cl.C(OC([N:14]1[CH2:19][CH2:18][C:17](=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][Si](C(C)(C)C)(C)C)[CH:39]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:37])[N:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[CH3:29])[CH:22]=2)[CH2:16][CH2:15]1)=O)(C)(C)C>O>[F:36][C:32]1[CH:31]=[C:30]([N:28]([CH3:29])[C:27](=[O:37])[C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=3)=[C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]3)[CH:22]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CN(C(=O)c1cccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)c1)c1cccc(F)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cccc(C(=C2CCNCC2)c2cccc(O)c2)c1)c1cccc(F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
Tetrahydrofuran (70 mL) and 3 N HCl (50 mL) were added to the above crude 4-([3-(tert-butyldimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methylcarbamoyl]phenyl}-methylene)piperidine-1-carboxylic acid tert-butyl ester (2.75 g). The resulting mixture was stirred at 60° C. for 4 h. The reaction mixture was cooled to room temperature, followed by the addition of water (100 mL). The resulting solution was extracted with diethyl ether (100 mL×2). The remaining water layer was neutralized to pH≅9. by 10% NaOH. The water layer became cloudy at this stage. The cloudy water mixture was extracted by n-butanol (100 mL×3). The combined n-butanol layers were washed by water (75 mL×2) and brine (75 mL×1), dried by Na2SO4 and concentrated to give crude product (2.27 g; crude), which was purified to give N-(3-fluorophenyl)-3-[(3-hydroxyphenyl)-piperidin-4-ylidene-methyl]-N-methyl-benzamide (579 mg). 1H NMR (600 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.23 (m, 3H), 7.09 (d, 1H, J=10.0 Hz), 7.03 (dd, 1H, J=8.0, 8.0 Hz), 6.96 (ddd, 1H, J=8.5, 8.5, 2.5 Hz), 6.92 (m, 2H), 6.85 (s, 1H), 6.56 (dd, 1H, J=8.0, 2.0 Hz), 6.34 (s, 1H), 6.31 (d, 1H, J=7.5 Hz), 3.35 (s, 3H), 2.65 (m, 2H), 2.55 (m, 2H), 2.13 (bs, 1H), 2.07 (m, 2H), 1.72 (m, 2H); Found: C, 72.87; H, 6.51; N, 5.86. Calc. C, 72.77; H, 6.62; N, 5.98.
Reaction SMILES: C([CH:8]1[C:12]2([CH2:17][CH2:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][CH2:13]2)[CH2:11][CH2:10][NH:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[N:21]1[CH:20]=[CH:19][C:18]([CH:15]2[CH2:16][CH2:17][C:12]3([CH2:8][NH:9][CH2:10][CH2:11]3)[CH2:13][CH2:14]2)=[CH:23][CH:22]=1
Reactant: C1=C(c2ccncc2)CCC2(C1)CCNC2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1cc(C2CCC3(CCNC3)CC2)ccn1
Reaction time: 4 h
Yield: 80 %

Procedure:
A solution of benzyl-8-(pyridin-4-yl)-2-azaspiro[4.5]dec-7-ene (300 mg, 0.987 mmol, 1.0 eq.) in MeOH (10 ml) was degassed with argon for 15 min followed by addition of Pd(OH)2 (150 mg). The reaction mixture was stirred under H2 balloon pressure for 4 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield the desired compound as an off-white solid which was used in the next step without further purification. Yield: 80% (170 mg, 0.787 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][O:27]1>>[CH3:23][N:24]([CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][O:27]1)[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNC[C@H]1CCCO1
Product: CN(C[C@H]1CCCO1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)—N-methyl-1(tetrahydrofuran-2-yl)methanamine (1.2 equiv) to give 174 (18.4 mg, M+1 411.1)
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[F:15][C:16]1[CH:42]=[CH:41][C:19]([O:20][C:21]2[C:35]([CH:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)=[CH:34][C:24]3[NH:25][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:27][C:23]=3[CH:22]=2)=[CH:18][CH:17]=1>C(O)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][C:21]2[C:35]([CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:34][C:24]3[NH:25][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:27][C:23]=3[CH:22]=2)=[CH:41][CH:42]=1
Reactant: Clc1ncccn1
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2c2ncccn2)cc1

Procedure:
0.013 ml of triethylamine and 6.3 mg of 2-chloro-pyrimidine were added in order to an ethanol (2 ml) solution of 17.1 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was heated under reflux for 3 hours. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid], and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[F:31][C:32]([F:40])([F:39])[CH:33]1[CH2:37][NH:36][C:35](=[O:38])[CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=CC=1C=NO>C(#N)C.[Cu-]=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:36]3[CH2:37][CH:33]([C:32]([F:40])([F:39])[F:31])[CH2:34][C:35]3=[O:38])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: O=C1CC(C(F)(F)F)CN1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N3CC(C(F)(F)F)CC3=O)c21
Temperature: 200 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 2.5 ml of absolute acetonitrile, and 738 mg (4.82 mmol) of 4-(trifluoromethyl)pyrrolidin-2-one, 157 mg (0.48 mmol) of caesium carbonate, 7 mg (0.05 mmol) of copper(I) oxide and 26 mg (0.19 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was heated in the microwave for 1 h at 200° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 26 mg (19% of theor.) of the target compound was obtained.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:13]([O:15]CC)=[O:14])[CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:18][CH:19]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20]1>CO>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:13]([OH:15])=[O:14])[CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:18][CH:19]1[CH2:23][CH2:22][S:21](=[O:24])(=[O:25])[CH2:20]1
Reactant: CCOC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12

Procedure:
An aqueous solution of lithium hydroxide (0.64 g, 26.49 mmol) was added to a solution of ethyl 5-bromo-3-[(1,1-dioxidotetrahydro-3-thienyl)methyl]-1H-indole-7-carboxylate (3.52 g, 8.83 mmol) in methanol (100 mL) at room temperature. The mixture was heated at reflux for 1 h and then concentrated. The residue was washed with water, acidified with 1N HCl (pH ˜3), and filtered, giving the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23]4[CH:28]=[C:27]([F:29])[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][C:24]=4[F:34])[C:17]3=[O:35])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[F:34][C:24]1[CH:25]=[C:26]([S:30]([CH3:33])(=[O:31])=[O:32])[C:27]([F:29])=[CH:28][C:23]=1[NH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][N:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][N:8]=3)[CH2:11][CH2:12]2)[C:17]1=[O:35]
Reactant: CC(=O)c1ccc(N2CCC(N3CCC[C@H](Nc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(N2CCC(N3CCC[C@H](Nc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
(S)-1′-(5-acetylpyridin-2-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.310 g, 0.612 mmol) was dissolved in methanol (5 mL). NaBH4 (0.0232 g, 0.612 mmol) was added slowly and stirred at ambient temperature for 1 hour. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes) to afford (3S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1′-(5-(1-hydroxyethyl)pyridin-2-yl)-1,4′-bipiperidin-2-one (0.265 g, 0.469 mmol, 76.6% yield). Mass spectrum (apci) m/z=509.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][C:28](O)=[O:29]>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]4[O:22][CH:26]=[CH:25][CH:24]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)Cc1ccco1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)Cc2ccco2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}6-methyl -1,1′-biphenyl-3-yl)-2-(fur-2-yl)acetamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and fur-2-ylacetic acid using method D. NMR; δH [2H6]—DMSO 10.17,(1H, s), 8.61,(1H, t), 7.91,(2H, d), 7.55,(1H, m), 7.50-7.48,(2H, m), 7.40,(2H, d), 7.23,(1H, d), 6.38,(1H, m), 6.25,(1H, d), 3.70,(2H, s), 3.16,(2H, t), 2.16,(3H, s), 1.04,(2H, m), 0.42,(2H, m). LCMS: retention time 3.26 min, MH+389.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[C:6]([NH:26][C@H:27]([C:29]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33](=[O:41])[C:32]3=[CH:42][CH:43]=[CH:44][N:31]3[N:30]=2)[CH3:28])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[C:6]([NH:26][C@H:27]([C:29]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33](=[O:41])[C:32]3=[CH:42][CH:43]=[CH:44][N:31]3[N:30]=2)[CH3:28])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(-c3c(N)ncnc3N[C@@H](C)c3nn4cccc4c(=O)n3-c3ccccc3)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](Nc1ncnc(N)c1-c1cccc(NS(=O)(=O)c2ccc(O)cc2)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 38 %

Procedure:
(S)—N-(3-(4-Amino-6-((1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)phenyl)-4-methoxybenzenesulfonamide (126 mg, 0.21 mmol) was treated with boron tribromide (1M in dichloromethane, 0.62 ml, 0.62 mmol) with dichloromethane (1.5 ml) as a solvent according to the method described in Example 23. The residue was purified by reverse phase chromatography using SP1® Purification System to give 47 mg (38% yield) as a solid. Purity 99%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N:21]1([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][N:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[N:28][CH:29]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCOCC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-morpholin-4-yl-nicotinamide was prepared starting from intermediate D and 6-morpholin-4-yl-nicotinic acid. MS calcd. for C26H23ClN4O3 [(M+H)+] 474.9, obsd. 474.9.