Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:34].[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:38][CH2:37]1>C1COCC1>[CH3:35][N:36]1[CH2:37][CH2:38][N:39]([C:42]2[CH:47]=[CH:46][C:45]([NH:48][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([C:28]7[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=7)[N:25]=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:34])=[CH:44][CH:43]=2)[CH2:40][CH2:41]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4ccnn4-c4ccccc4)c3)ccc2C1=CO
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6ccnn6-c6ccccc6)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
A small screw cap test tube was charged with 2-Phenyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.222 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (42.2 mg, 0.221 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was redissolved in EtOAc (5 mL) and Hexane (40 mL) was added to the solution. The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (10 mL) to afford the title compound in 81% yield (0.112 g, 0.180 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:16])[C:12](OC)=[O:13]>C1(C)C=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][CH2:10][CH:11]([CH3:16])[C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: COC(=O)C(C)CNc1ccc(F)cc1N
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CC1CNc2ccc(F)cc2NC1=O
Temperature: 90 °C
Reaction time: 15 h
Yield: 75.7 %

Procedure:
To a solution of methyl 3-(2-amino-4-fluorophenylamino)-2-methylpropanoate (10.0 g, 44.2 mmol) in toluene (200 mL) was added titanium tetraisopropanolate (18.8 g, 66.3 mmol). The mixture was stirred at 90° C. for 15 hours. The resultant mixture was concentrated in vacuo, and dissolved in tetrahydrofuran (200 mL), filtered through celite, and washed with tetrahydrofuran (100 mL). The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to afford 8-fluoro-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one as a black solid (6.5 g, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (89.7 mg, 67%)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C.CN(C=O)C>[CH2:29]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCc1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(-c2cn[nH]c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(-c2cnn(CCc3ccccc3)c2)c1
Temperature: 50 °C
Yield: 77.3 %

Procedure:
To a vial was added Intermediate 11B (110 mg, 0.383 mmol) in acetonitrile (0.7 mL) and DMF (0.7 mL) and potassium carbonate (159.0 mg, 1.148 mmol). The reaction was stirred for 10 min before (2-bromoethyl)benzene (106 mg, 0.574 mmol) was added. The resulting mixture was heated at 50° C. for 16 h. The reaction was quenched with water and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated. The crude was purified by flash chromatography to give Intermediate 11C (116 mg, 0.296 mmol, 77.0% yield) as a white solid. LCMS=2.20 min [M+1]=392.3 (Method B).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: ICC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CC3CCCC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and iodomethylcyclopentane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9]2)=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][CH2:43][CH2:44][N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH3:55])([CH3:54])[C:46]1=[O:56]>CC(=O)CC>[CH3:55][C:47]1([CH3:54])[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:45]([CH2:44][CH2:43][CH2:42][N:15]2[CH2:14][CH2:13][C:12]3([N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][N:10]([CH2:19][C:20]4[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=4[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:11]3=[O:18])[CH2:17][CH2:16]2)[C:46]1=[O:56]
Reactant: CC1(C)C(=O)N(CCCCl)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(CCCN3C(=O)C(C)(C)c4ccccc43)CC2)C1=O
Temperature: 78 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of tert-butyl 2-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.15 g, 0.34 mmol), sodium iodide (0.015 g, 0.1 mmol) and potassium carbonate (0.081 g, 0.51 mmol) in 2-butanone (4 mL), was added 1-(3-chloropropyl)-3,3-dimethylindolin-2-one (0.081 g, 0.34 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered and isolated by Biotage flash chromatography (1-10% methanol/dichloromethane) and preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.18 g, 83%); 1H NMR (DMSO-d6): δ 1.25 (s, 6H), 1.56 (s, 9H), 1.67-1.75 (m, 4H), 2.31 (br, 4H), 2.64-2.66 (m, 4H), 3.72 (t, 2H, J=7.2 Hz), 4.58 (s, 2H), 4.82 (s, 2H), 6.90-6.91 (m, 2H), 7.02 (t, 1H, J=7.6 Hz), 7.08-7.12 (m, 3H), 7.19-7.27 (m, 2H), 7.33 (d, 1H, J=6.8 Hz), 7.40 (t, 1H, J=7.2 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.82 (dd, 1H, J=7.2 and 1.2 Hz); MS for C38H45FN4O4 m/z 641.17 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].[CH:23]1([S:26]([C:29]2[N:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:30]=2[C:31](O)=[O:32])(=[O:28])=[O:27])[CH2:25][CH2:24]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>[NH4+].[Cl-].CN(C)C=O>[CH:23]1([S:26]([C:29]2[C:30]([C:31]([N:20]3[CH2:21][CH2:22][CH:17]([C:2]([CH3:1])([S:4]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=4)(=[O:5])=[O:6])[CH3:3])[CH2:18][CH2:19]3)=[O:32])=[CH:34][CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[N:37]=2)(=[O:27])=[O:28])[CH2:25][CH2:24]1
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1S(=O)(=O)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C1CCN(C(=O)c2ccc(C(F)(F)F)nc2S(=O)(=O)C2CC2)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 50 ml round bottom flask was added 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine (1.64 g, 4.88 mmol), 2-(cyclopropylsulfonyl)-6-(trifluoromethyl)nicotinic acid (1.2 g, 4.06 mmol), Bop reagent (2.16 g, 4.88 mmol), diisopropylethyl amine (1.42 ml, 8.13 mmol) and 10 ml dimethylformamide. The resulting solution was stirred at room temperature 10 minutes. It was diluted with 60 ml NH4Cl solution and extracted with 60 ml ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated. The sesidue was purified on silica gel column eluted with 2:1 ethyl acetate/hexane. The desired fraction was collected and concentrated. The residue was further purified on prep-TLC to give title compound as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][C@H:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:31]([F:34])([F:33])[F:32])([CH3:3])[CH3:2].C1C(=O)N([Cl:42])C(=O)C1>C(Cl)Cl>[Cl:42][C:14]1[C:13]2[CH:12]=[C:11]([O:10][CH2:9][C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([C:31]([F:34])([F:32])[F:33])[CH:7]=3)[CH:19]=[CH:18][C:17]=2[N:16]2[CH2:20][CH2:21][C@H:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]=12
Reactant: CCOC(=O)C[C@H]1CCn2c1cc1cc(OCc3ccc(OC(C)C)c(C(F)(F)F)c3)ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CCn2c1c(Cl)c1cc(OCc3ccc(OC(C)C)c(C(F)(F)F)c3)ccc12
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of (R)-ethyl 2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (52.8 g, 111 mmol) in DCM (350 mL) at −5° C. (ice-salt bath) was added a solution of NCS (14.8 g, 111 mmol) in DCM (350 mL) slowly over 20 min via addition funnel. After stirring for 0.5 h the mixture was washed w/sat. aq. sodium thiosulfate (300 mL). The organics were concentrated to about 300 mL and filtered using a column (60 cm×80 cm) containing sodium sulfate (top layer), sand (middle layer), and silica gel (bottom) using DCM as the eluant. The filtrate was concentrated to give (R)-ethyl 2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (54.6 g, 107 mmol, 96% yield) as a white/mildly yellow solid. Exact mass calculated for C26H27ClF3NO4: 509.2, found: LCMS m/z=510.3, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (t, J=7.1 Hz, 3 H), 1.37 (d, J=6.1 Hz, 6 H), 2.34 (m, 1 H), 2.52 (dd, J1=16.3, J2=10.2 Hz, 1 H), 2.93 (m, 1 H), 3.22 (dd, J1=16.3, J2=4.0 Hz, 1 H), 3.81 (m, 1 H), 4.00 (m, 1 H), 4.12 (m, 1 H), 4.20 (qd, J1=7.1, J2=1.7 Hz, 2 H), 4.65 (sep, J=6.1 Hz, 1 H), 5.04 (s, 2 H), 6.89 (dd, J1=8.8, J2=2.4 Hz, 1 H), 7.01 (d, J=8.6 Hz, 1 H), 7.06 (d, J=2.4 Hz, 1 H), 7.12 (d, J=8.8 Hz, 1 H), 7.56 (dd, J1=8.5, J2=1.9 Hz, 1 H), 7.67 (d, J=1.9 Hz, 1 H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[CH:17]OC(C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:23]([NH2:33])(=[O:32])([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)=[O:24]>Cl.C(O)C>[O:16]=[C:11]1[C:10](=[CH:17][NH:31][C:28]2[CH:29]=[CH:30][C:25]([S:23]([NH2:33])(=[O:24])=[O:32])=[CH:26][CH:27]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:12]1
Reactant: CC(C)(C)OC=C1C(=O)Nc2ccc(-c3ccccc3)cc21
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc(-c4ccccc4)cc32)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of 0.09 g (0.31 mmol) of 5-phenyl-3-tert-butoxymethylene-1,3-dihydro-indol-2-one, 0.053 g (0.31 mmol) of sulfanilamide, and 2 drops of conc. HCl in 15 mL of ethanol was refluxed for 1 h and cooled to rt. The resulting yellow solid was isolated by filtration, washed with ethanol and dried to give 0.068 g (56%) of the title compound: 1H NMR (DMSO-d6): δ 6.90 (d, J=8.2 Hz, 1H), 7.25 (s, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.34 (dd, J=1.6, 8.2Hz, 1H), 7.43 (d, J=7.5 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.64 (d, J=7.5 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.99 (d, J=1.6 Hz, 1H), 8.74 (d, J=12.5 Hz, 1H), 10.62 (s, 1H), 10.76 (d, J=12.5 Hz,1H); APCI−MS m/z 390 (M−H)−.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[C:20]([C:36]#[N:37])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=[O:17])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[C:20]([C:36]#[N:37])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=[O:17])[C:10]([OH:12])=[O:11].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(C(=O)NCC[C@H](N)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)butanoic acid (20 mg, 0.03 mmol) was dissolved in TFA (2 mL) and CH2Cl2 (2 mL). The resulting mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was dissolved again in CH2Cl2 (2 mL). The volatiles were removed again in vacuo to give the title compound as its TFA salt in 14 mg. MS: (−) m/z 404.91 (M−1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:21]([CH3:33])[CH:22]=[C:23]([NH:25]C(=O)OC(C)(C)C)[N:24]=3)=[C:18]3[C:13]([N:14]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:15](=[O:36])[N:16]([CH3:35])[C:17]3=[O:34])=[N:12]2)=[CH:2]1.Cl>O1CCOCC1>[NH2:25][C:23]1[N:24]=[C:20]([C:19]2[N:11]([CH2:10][C:3]3[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[S:1][CH:2]=3)[N:12]=[C:13]3[C:18]=2[C:17](=[O:34])[N:16]([CH3:35])[C:15](=[O:36])[N:14]3[CH2:37][CH:38]([CH3:40])[CH3:39])[N:21]([CH3:33])[CH:22]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nc(NC(=O)OC(C)(C)C)cn3C)n(Cc3csc4ccccc34)nc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nc(N)cn3C)n(Cc3csc4ccccc34)nc21

Procedure:
This compound was synthesized by treating tert-butyl 2-[2-(1-benzothien-3-ylmethyl)-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-imidazol-4-ylcarbamate with 4M HCl in dioxane at room temperature for 3 hours. Mass: 464.10 (M+H).
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([O:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCNCC1
Reaction time: 12 h

Procedure:
Crude piperazine-1,4-dicarboxylic acid tert-butyl ester phenyl ester was dissolved in 10 ml dichloromethane and treated with 4 ml TFA. After stirring for 12 h the solution was concentrated and the residue codistilled twice with toluene. Yield: 3.0 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][C@@H:19]([N:21]([CH2:32][CH3:33])[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:42]1C=CC(OC(=O)N([C@H]2[C@H](C3C=CC(Cl)=CC=3)CN(CC3C=CC=CC=3)C2)C(C)C)=CC=1.C(OC(N1CCC(C(O)=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:16]2[CH2:20][C@@H:19]([N:21]([C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[O:23])[CH:32]([CH3:42])[CH3:33])[C@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)N(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CC(C)N(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester the title compounds were prepared from rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid 4-fluoro-phenyl ester by cleavage of the benzyl group and subsequent coupling with 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. The resulting rac-4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was subjected to separation by chiral HPLC on CHIRALPAK AD eluting with i-propanol/heptane. After evaporation of the product containing fractions 4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was obtained as yellow viscous oil. MS m/e: 588.3 [M+H]+. 4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was obtained as yellow viscous oil. MS m/e: 588.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]([NH2:50])[CH:47]([CH3:49])[CH3:48]>CN(C=O)C>[CH3:45][CH:46]([NH:50][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:21])[CH:47]([CH3:49])[CH3:48]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC(C)C(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC(C)C(C)C)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 1,2-dimethylpropylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(1,2-dimethylpropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])C>C(O)=O>[CH:13]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Solvent: O=CO
Product: O=CNc1ccc2c(c1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a solution of 7-amino-1-tetralone (1.70 g, 10.5 mmol) in formic acid (3 ml) was added a mixture of formic acid (8 ml) and acetic anhydride (3 ml), followed by stirring for 10 minutes at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with ethyl acetate. The extract solution was washed with brine and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from ethyl acetate/isopropyl ether to give 1.80 g (yield 91%) of the above-titled compound, m.p.137-138° C.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16]C)[CH:11]=2)=[O:8])=[C:5]([F:20])[CH:4]=1)#[N:2].[Si](I)(C)(C)C>C(#N)C>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[O:8])=[C:5]([F:20])[CH:4]=1)#[N:2]
Reactant: COc1cc(NC(=O)c2ccc(C#N)cc2F)ccn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: N#Cc1ccc(C(=O)Nc2cc[nH]c(=O)c2)c(F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 4-cyano-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (7.3 g, 26.99 mmol) in acetonitrile (244.0 mL) was added TMSI (9.99 mL, 70.17 mmol). The reaction was stirred at 50° C. overnight. The acetonitrile was evaporated and the crude solid was triturated with ethyl acetate. The solid was isolated by filtration and washed with ethyl acetate to give 4-cyano-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide as a tan solid. ESI-MS m/z calc. 257.06. found 258.1 (M+1)+; Retention time: 1.08 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.11 (t, J=11.4 Hz, 1H), 7.88 (m, 2H), 7.53 (d, J=7.1 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.60 (dd, J=7.2, 2.1 Hz, 1H) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)Cc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 47 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (4-chlorophenyl)acetyl chloride and conditions outlined in procedure N. M.p.=120-125° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.91 (m, 2H), 7.74 (t, 1H), 7.56 (t, 1H), 7.35 (m, 2H), 7.25 (m, 2H), 4.10 (dd, 1H), 3.94 (m, 1H), 3.77 (dd, J=3.3 Hz, 2H), 3.57 (s, 2H), 3.09 (s, 2H), 2.05 (m, 2H), 1.67 (m, 2H); LCMS: 454 [M+H].
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:12]1[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=1>>[CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:12]2[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: OB(O)c1cnc(Cl)nc1
Product: CS(=O)(=O)C1CCN(c2ncc(B(O)O)cn2)CC1

Procedure:
Prepared from 4-(methylsulfonyl)piperidine (0.515 g, 3.16 mmol) and (2-chloropyrimidin-5-yl)boronic acid (0.5 g, 3.16 mmol) in accordance with General Method C to give the title compound as an off-white semi-solid. HPLC-MS: m/z MH+ 286.2, RT 0.17 minutes.