Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:20]([CH3:22])[CH3:21])[C:9]2[C:14]3[N:15]([CH3:19])[C:16](=O)[NH:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:16]1[N:15]([CH3:19])[C:14]2[C:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:20]([CH3:22])[CH3:21])=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: CC(C)N(c1ccc(Cl)cc1)c1cccc2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)N(c1ccc(Cl)cc1)c1cccc2nc(Cl)n(C)c12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A mixture of 7-[(4-chlorophenyl)(isopropyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (42 mg, 0.13 mmol) and phosphorous oxychloride (1.5 ml) was stirred at 80° C. for 1.5 h. The mixture was concentrated in vacuo and quenched with saturated aqueous sodium bicarbonate (10 ml) and extracted with ethyl acetate (20 ml). The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was flash chromatographed eluting with a 17% ethyl acetate/hexanes to give 31.9 mg (72%) of the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH2:15][CH3:16])[CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+]([C:20]1C=C([C@@H](CC)CC(O)=O)C=CC=1)([O-])=O.S(=O)(=O)(O)O>CO>[CH3:20][O:13][C:12](=[O:14])[CH2:11][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:15][CH3:16]
Reactant: CC[C@@H](CC(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: CCC(CC(=O)O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC(CC(=O)OC)c1cccc([N+](=O)[O-])c1

Procedure:
To a solution of (±)-3-(3-nitrophenyl)pentanoic acid (XXIV, 30.21 g, 135 mmol, in methanol (250 mL) is added concentrated sulfuric acid (0.6 mL). The resulting mixture is heated to reflux for 3 hours. Upon cooling, the mixture is partitioned between ethyl acetate and sodium bicarbonate (5% aqueous). The aqueous layer is separated and back-extracted with two additional portions of ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound, TLC (silica gel GF) for acetic acid/ethyl acetate/hexane (2/20/80) Rf=0.54, for ethyl acetate/hexane (20/80) Rf=0.54; NMR (CDCl3, TMS) 0.80, 1.56-1.83, 2.55-2.75, 3.05-3.2, 3.57, 7.4-7.55 and 8.03-8.12 δ.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](=O)[CH3:27]>C1COCC1>[CH2:3]([O:5][C:6](=[O:16])[CH:7]=[C:26]([CH3:27])[CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17])[CH3:4]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccccc1CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Cc1ccccc1OC
Temperature: 25 °C

Procedure:
In a 3-neck round bottom flask, fitted with an internal thermometer and addition funnel, a mixture of sodium hydride (60% in mineral oil, 4.14 g) in THF (200 mL), under argon, was cooled to 10° C. (Diethoxyphosphoryl)acetic acid ethyl ester (21 mL) was added dropwise (heat and gas evolution), keeping the internal temperature below room temperature. After addition, the reaction mixture was stirred at room temperature for minutes, and then cooled to 0° C. A solution of 2-methoxyphenyl acetone (5 g) in THF (25 mL) was added dropwise over 5 minutes. The reaction was allowed to warm to room temperature overnight. With active cooling, the reaction was quenched with H2O (200 mL), then AcOH (to pH ˜6) and extracted with EtOAc. The combined organics were washed with NaHCO3, water, and brine, dried over Na2SO4, and concentrated. The crude residue was purified by flash column chromatography to give the desired compound (5.73 g). 1H-NMR: 400 MHz, (CDCl3) δ: 7.24 (app dt, 1H), 7.10 (dd, 1H), 6.92 (d, 1H), 6.88 (d, 1H), 5.58 (s, 1H), 4.13 (q, 2H), 3.82 (s, 3H), 3.46 (s, 2H), 1.26 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:47])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:46]=[CH:45][C:34]([CH2:35][CH2:36][NH:37]C(=O)OC(C)(C)C)=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:37][CH2:36][CH2:35][C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:47])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:46][CH:45]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCN)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
A solution of tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenethylcarbamate (77.3 mg, 0.113 mmol) in dichloromethane (3 ml) was treated with trifluoroacetic acid (2.23 g, 19.6 mmol) and stirred under argon. After 1.5 hrs, the reaction mixture was concentrated and the residue diluted with ethyl acetate, washed with saturated sodium carbonate, water and brine to give chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-amino-ethyl)-phenyl]-amide (40.6 mg, 54.2%) as a white lyophilized solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C@H:10]([C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[C:50]1([S:56](Cl)(=[O:58])=[O:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl>[C:50]1([S:56]([N:8]2[CH2:12][C@@H:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[C@H:10]([C:22]3[C:32]4=[C:33]5[C:28](=[CH:29][CH:30]=[CH:31]4)[CH2:27][CH2:26][CH2:25][N:24]5[CH:23]=3)[CH2:9]2)(=[O:58])=[O:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51909.4 %

Procedure:
To a solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 450 μmol) in DCM (5 mL) under a nitrogen atmosphere was added 4M HCl in dioxane (1.7 mL, 6.8 mmol). The mixture was stirred at room temperature for 2 h. The solvent was then removed under vacuum and the residue dissolved in DCM (5 mL). DIPEA (320 μL, 1.8 mmol) and benzenesulfonyl chloride (95 mg, 0.54 μmol) were added and the mixture stirred at room temperature for 16 h. The solvent was removed under vacuum. The residue was dissolved in DCM, washed with saturated sodium carbonate solution and water and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/hexanes) to yield 1-[(3R,4R)-1-benzenesulfonyl-4-(1H-indol-3-yl)-pyrrolidin-3-yl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline as a white solid (135 mg, 57%). M.p.=115-125° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.81 (s, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.86 (t, J=7.6 Hz, 1H), 7.75 (t, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.09 (d, J=6.4 Hz, 1H), 7.04 (s, 1H), 7.00 (t, J=7.6 Hz, 1H), 6.92 (dd, J=7.2, 2.0 Hz, 1H), 6.86 (t, J=7.6 Hz, 1H), 6.79-6.74 (m, 2H), 4.00-3.90 (m, 4H), 3.78-3.69 (m, 2H), 3.39-3.29 (m, 2H), 2.81 (t, J=6.0 Hz, 2H), 2.01 (m, 2H). LCMS: m/e 482.09 [M+H].
Reaction SMILES: [CH2:1]([N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]([O:19]C)=O)[C:14]([OH:21])=[C:13]([OH:22])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>CO>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=2)=[O:19])[C:14]([OH:21])=[C:13]([OH:22])[N:12]=1)[C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(CCN(Cc2ccccc2)C(=O)OC(C)(C)C)nc(O)c1O
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1)Cc1ccccc1
Temperature: 25 °C

Procedure:
Crude methyl 2-{2-[benzyl(tert-butoxycarbonyl)amino]ethyl}-5,6-dihydroxypyrimidine-4-carboxylate (prepared as described in Step 2) was dissolved in methanol and treated with p-fluorobenzylamine (2.5 equivalents) at 80° C. for 12 hours. The mixture was then cooled to room temperature, volatiles were evaporated and the residue was poured in EtOAc and washed 0.5 N HCl and brine. The organic phase was dried (Na2SO4), filtered and concentrated to a brown solid residue. MS (ES) C26H29FN4O5 requires 496. Found: 497 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:21][C:22]([F:35])([F:34])[C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:25][CH:24]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([C:10]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:27][C:23]([C:22]([F:35])([F:21])[F:34])=[CH:24][N:25]=3)[CH2:29][CH2:30]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ncc(C(F)(F)F)s3)CC2)c1
Yield: 71 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-morpholin-4-yl-benzoic acid (Example A13) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as an off-white crystalline solid (yield 71%). MS (m/e): 505.3 (M+H+, 100%).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH3:36])[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]3[O:29][C:28](C)(C)C(C)(C)[O:26]3)=[C:21](C=O)[CH:20]=2)[N:11]=1)(C)(C)C.[BH4-].[Na+].Cl>CO>[OH:26][B:25]1[C:22]2[CH:23]=[CH:24][C:19]([O:18][C:12]3[N:11]=[C:10]([N:9]([CH2:8][CH2:7][OH:6])[CH3:36])[CH:17]=[CH:16][C:13]=3[C:14]#[N:15])=[CH:20][C:21]=2[CH2:28][O:29]1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)c1ccc(C#N)c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CCO)c1ccc(C#N)c(Oc2ccc3c(c2)COB3O)n1
Reaction time: 8 h
Yield: 17.4 %

Procedure:
To a clear solution of 6-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-2-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (11) (485 mg, 0.903 mmol) in MeOH (anhydrous, 100 mL) was slowly added NaBH4 (101 mg, 2.65 mmol). The reaction was stirred at room temperature for 4 hours, before the addition of HCl solution (1 M, 60 mL). The stirring was kept at room temperature overnight. Then the solution was slowly evaporated in vacuo. Purification was accomplished by reverse phase Biotage with 10%-100% MeOH/H2O gradient to afford 51 mg (13.8% yield) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (s, 1 H), 7.92 (d, J=8.6 Hz, 1 H), 7.75 (d, J=8.2 Hz, 1 H), 7.24 (s, 1 H), 7.16 (dd, J=7.8, 2.0 Hz, 1 H), 6.43 (br. s., 1 H), 4.98 (s, 2 H), 3.90 (br. s., 1 H), 3.47 (br. s., 2 H), 3.39 (s, 2H, masked), 2.95 (br. s., 3 H); HPLC: 98.18% (220 nm), 99.15% (254 nm), 99.16 (MaxPlot).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[N:21]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([N:21]2[CH:22]=[CH:23][CH:24]=[CH:25]2)=[N:27][CH:28]=1
Reactant: O=C(O)c1ccc(-n2cccc2)nc1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2cccc2)nc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 6-pyrrol-1-yl-nicotinic acid. MS: 444.5 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:21][C:22]1[CH:23]=[C:24]([CH:29]2[CH2:34][C:33](=[O:35])[NH:32][C:31]([CH3:36])=[C:30]2[C:37](O)=[O:38])[CH:25]=[CH:26][C:27]=1[F:28]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:37]([C:30]3[CH:29]([C:24]4[CH:25]=[CH:26][C:27]([F:28])=[C:22]([F:21])[CH:23]=4)[CH2:34][C:33](=[O:35])[NH:32][C:31]=3[CH3:36])=[O:38])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)CC(=O)N1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3=C(C)NC(=O)CC3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure AC and Scheme AM using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide and 4-(3,4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid: ESMS m/e: 525.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=3)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (161) (100 mg, 0.27 mmol) was coupled to 3-fluoro-phenylboronic acid (34 mg, 0.24 mmol) using Method E. The residue was purified by column chromatography eluting with 15% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1([CH3:24])[C:21](=[O:22])[N:12]2[CH2:13][CH:14]=[CH:15][CH:16]([C:17]([O:19][CH3:20])=[O:18])[N:11]2[C:10]1=[O:23].Cl>N1C=CC=CC=1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1([CH3:24])[C:21](=[O:22])[N:12]2[CH2:13][CH:14]=[CH:15][CH:16]([C:17]([O:19][CH3:20])=[O:18])[N:11]2[C:10]1=[O:23])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1C=CCN2C(=O)C(C)(CCO)C(=O)N12
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C1C=CCN2C(=O)C(C)(CCOS(C)(=O)=O)C(=O)N12
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
3.45 g (30 mmol) of methanesulfonyl chloride were added dropwise to a stirred solution, cooled at 0° C., of 6.7 g (25 mmol) of methyl 2,3,5,8-tetrahydro-2-(2-hydroxyethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylate in 20 ml of dry pyridine. After 2 hours, the resulting suspension was poured on to ice/water and acidified with 2M hydrochloric acid. Extraction with dichloromethane then yielded 7.84 g (75%) of methyl 2,3,5,8-tetrahydro-2-(2-methanesulfonyloxyethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate having a melting point of 104°-105° C. (from diethyl ether).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])[CH:7]=[C:8]([N+:20]([O-])=O)[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH3:2].C(O)(=O)C>C1COCC1.[Zn]>[NH2:20][C:8]1[CH:7]=[C:6]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(OCC)c(OCc2cccc(OC)c2)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(OCc2cccc(OC)c2)c(OCC)c1
Reaction time: 1 h

Procedure:
A solution of 4-[3-ethoxy-4-(3-methoxy-benzyloxy)-5-nitro-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile and acetic acid (1.3 ml) in THF (33 ml) was cooled to 0° C. Zinc dust (3.02 g) was added in portions under vigorous stirring. The mixture was allowed to reach room temperature and stirred for 1 h. The mixture was then filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with sat. aq. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
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.[NH:31]1[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:39])[CH3:38])[CH2:32]1>CN1CCCC1=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:31]3[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:39])[CH3:38])[CH2:32]3)[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: CC(=O)NC1CCNC1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc3c2C(C)(C)C(=O)N3)C1
Temperature: 150 °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 4 ml of absolute 1-methyl-2-pyrrolidone and 618 mg (4.82 mmol) of N-(pyrrolidin-3-yl)acetamide was added. The mixture was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 122 mg (98% of theor.) of the target compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][Cl:26])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(Cc2ccccc2OCc2ccccc2)cc1

Procedure:
To a solution of 4-(2-benzyloxybenzyl)benzyl alcohol (0.67 g) in dichloromethane (30 mL) was added thionyl chloride (0.48 mL), and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 4-(2-benzyloxybenzyl)benzyl chloride (0.68 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>>[CH3:38][N:39]([CH3:43])[C:40]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1)=[O:41]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)N(C)C)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with dimethylcarbamic chloride to give the title compound. LC/MS (M+H)+: 606. Ret. time: 1.53 min. (Condition G); analytical HPLC Ret. time: 7.53 min (Condition H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](SC)=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.[CH3:23][NH2:24]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:24][CH3:23])=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CSC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21
Reactant: CN
Solvent: C1CCOC1
Product: CNC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21

Procedure:
400 mg of 6-chloro-1-methylthio-4-(4-nitrophenyl)-3,4-dihydroisoquinoline (see compound 1e) were heated with 2 g of methylamine in THF at 120° C. in a shaking autoclave under inert gas for 20 hours. Removal of the solvent by distillation was followed by MPLC chromatography on an MPRC cartridge with a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane, 5 parts by volume of methanol and 1 part by volume of concentrated aqueous ammonia solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C@H:29]1[OH:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C@H:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][C@H:29]2[OH:37])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(N[C@H]1c2ccccc2C[C@H]1O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)terephthalamide. MS (Q1) 518.2 (M)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])=[CH:8][CH:9]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(CCO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(N3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-(4-(2-hydroxyethyl)phenyl)isoindoline-1,3-dione (926 mg, 3.46 mmol) was dissolved in dichloromethane (15 mL), cooled to 0° C. and p-toluenesulfonyl chloride (991 mg, 5.2 mmol) was added, followed by pyridine (0.56 ml, 6.93 mmol). The reaction was stirred at room temperature for 16 h and concentrated. The residue was dissolved in ethyl acetate (60 ml), washed with water (20 ml), saturated aqueous NaHCO3 (2×15 ml), brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude tosylate was used without further purification.