Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C1COCC1.CC1C=CC(S(O[CH2:19][CH2:20][N:21]2[CH:25]=[C:24]([I:26])[CH:23]=[C:22]2[CH2:27][OH:28])(=O)=O)=CC=1>O>[I:26][C:24]1[CH:23]=[C:22]2[N:21]([CH:25]=1)[CH2:20][CH2:19][O:28][CH2:27]2
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(I)cc2CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Ic1cc2n(c1)CCOC2
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a stirred mixture of sodium hydride (0.261 g, 6.53 mmol) and THF (10 mL) was slowly added a solution of 2-(2-(hydroxymethyl)-4-iodo-1H-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (2.75 g, 6.53 mmol) and THF (25 mL). The reaction mixture was stirred at room temperature for 30 hours, then diluted with water (20 mL) and extracted with EtOAc (2×60 mL). The organic phase was dried over sodium sulfate, evaporated, and purified using silica gel column (80 g) chromatography, eluting with a gradient of 0-100% hexane and EtOAc. The pure compound fractions were combined and evaporated to give the title compound as a tan solid, which turned green on standing (1.02 g, 63%). ESI-MS m/z [M+H]+ calc'd for C7H8INO, 250. found, 250.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[OH:16][C@@H:3]1[C:4]([CH3:14])([CH3:15])[C:5]2[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C@H:2]1[NH:1][C:25]([NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: CC1(C)c2ccc([N+](=O)[O-])cc2[C@@H](N)[C@@H]1O
Reactant: O=C=NCc1ccccc1
Solvent: CCO
Product: CC1(C)c2ccc([N+](=O)[O-])cc2[C@@H](NC(=O)NCc2ccccc2)[C@@H]1O
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A solution of trans-3-amino-1,1-dimethyl-2-hydroxy-5-nitro indane (0.75 g, 3.37 mmoles, as prepared in part H of Example 1) and benzyl isocyanate (0.45 g, 3.37 mmoles) in ethanol (6 ml) was heated at reflux for three hours and cooled to room temperature. The reaction product, which had precipitated from solution was collected by suction filtration and dried under vacuum to afford 1.13 g of the title compound as a pure white solid, m.p. 202°-204° C. 1H NMR (DMSO-d6) δ 8.14 (dd, J=2.34 and 8.21 Hz, 1H), 7.91 (s, 1H), 7.50 (d, J=8.21 Hz, 1H), 7.39-7.25 (m, 5H), 6.61 (m, 1H), 5.63 (d, J=5.28 Hz, 1H), 4.93 (dd, J=8.21 and 8.79 Hz, 1H), 4.34 (d, J=5.68 Hz, 2H), 3.79 (dd, J=5.87 and 8.79 Hz, 1H), 1.32 (s, 3H), 1.06 (s, 3H). 13H NMR (DMSO-d6) δ 158.63, 156.50, 146.85, 142.88, 140.81, 128.25, 127.01, 126.61, 123.87, 123.33, 118.66, 84.74, 57.93, 44.05, 44.07, 25.04, 22.42.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>ClCCl>[CH3:26][C:23]([CH3:27])([NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:24][OH:25]
Reactant: CC(C)(N)CO
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 67.1 g (0.322 mole) of 4-chloro-3-nitroquinoline in 800 mL of dichloromethane was added 54 mL (0.38 mole) of triethylamine and 96 mL (0.96 mole) of 2-amino-2-methyl-1-propanol. The mixture was heated at reflux for one hour, then stirred at about 20° C. for about 16 hours. The mixture was concentrated by evaporation in vacuo and the residue was slurred in 1.5 l of water. The product was separated by filtration and dried to provide solid 2,2-dimethyl-2-[(3-nitro-4-quinolinyl)amino]ethanol. The structural assignment was confirmed by comparison of the nuclear magnetic resonance spectrum to that of a sample which was previously used for elemental analysis. Analysis of earlier sample: Calculated for C13H15 N3O2 : % C, 59.8; % H, 5.8; % N, 16.1; Found % C, 59.9; % H, 5.8; % N, 16.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[OH-:24].[Na+].OO.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([NH2:23])=[O:24])[CH:19]=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: COc1ncc(Cn2cc(C#N)cn2)cc1-c1cccc(Cl)c1
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ncc(Cn2cc(C(N)=O)cn2)cc1-c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A solution of 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbonitrile (Example 170, 25.00 mg, 0.08 mmol) in MeOH (1.54 mL) was heated to 50° C., until the starting material dissolved. Sodium hydroxide (0.23 mL, 1.00 mol/L, 0.23 mmol) and hydrogen peroxide (0.23 mL, 1.00 mol/L, 0.23 mmol) were added and the reaction stirred at 50° C. for 2 h. Water was added (5 mL), and the mixture was filtered and washed with water (3×5 mL) to afford the title compound as a solid (25.0 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=13.69 Hz, 2H), 7.80 (d, J=14.48 Hz, 2H), 7.65-7.37 (m, 5H), 6.95 (br s, 1H), 5.32 (br s, 2H), 3.87 (br s, 3H). [M+H]=343.33.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:49][C:48]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)[O:19][C:45](=[O:46])[C:44]=1[S:43][CH2:42][CH2:41][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCCCc2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCCCc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(3-phenylpropoxy)acetophenone (1.28 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 139-142° C.; 1H NMR (400 MHz, DMSO-d6) δ2.04 (m, 2 H), 2.84 (m, 4 H), 2.98 (t, 2 H), 4.40 (t, 2 H), 6.68 (s, 1 H), 7.18 (m, 12 H), 7.75 (d, 2 H), 11.86 (bs, 1 H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:9])[CH2:4][CH2:5][C:6](O)=[O:7].[NH2:10][C@@H:11]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:13]>>[CH2:31]([O:30][CH2:29][C@H:11]([NH:10][C:6](=[O:7])[CH2:5][CH2:4][N:3]([CH3:9])[CH3:2])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CN(C)CCC(=O)O
Agent: Cl
Product: CN(C)CCC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 10 %

Procedure:
Proceeding as in Example 1, but substituting 3-dimethylaminopropionic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-chlorophenoxy)phenyl)propanamide, gave Compound 209, (S)-3-(benzyloxy)-N-(4-(4-chlorophenoxy)phenyl)-2-(3-(dimethylamino)propanamido)propanamide (6 mg, 10%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.15 (br s, 1H), 8.48-8.47 (d, 1H), 7.65-7.61 (d, 2H), 7.42-7.39 (d, 2H), 7.43-7.39 (m, 2H), 7.32-7.26 (m, 5H), 7.06-6.96 (m, 4H), 4.72-4.67 (m, 1H), 4.52 (s, 2H), 3.65-3.64 (d, 2H), 2.47-2.43 (m, 2H), 2.33-2.30 (m, 2H), 2.12 (s, 6H). MS (EI) for C27H30ClN3O4. found 496.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[F:53][C:54]([F:65])([F:64])[O:55][C:56]1[CH:57]=[C:58]([NH2:63])[C:59]([NH2:62])=[CH:60][CH:61]=1>CN(C)C=O>[NH2:63][C:58]1[CH:57]=[C:56]([O:55][C:54]([F:53])([F:64])[F:65])[CH:61]=[CH:60][C:59]=1[NH:62][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH3:37])[CH2:29]1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(OC(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 124 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.2 g, 3.2 mmol) added to a solution 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (1.25 g, 2.10 mmol) and N,N-Diisopropylethylamine (1.2 mL, 6.9 mmol) and 4-(trifluoromethoxy)benzene-1,2-diamine (0.48 g, 2.5 mmol) in N,N-Dimethylformamide (10 mL). The mixture was stirred overnight at RT, partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to give the desired compound (2 g) as an oil.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)=[N:4][CH:5]=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])=[CH:27][CH:26]=1)#[N:24]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cc(C(=O)N[C@@H]3CCCC[C@H]3O)cnc2OCC2CC2)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31, using 5-bromo-6-cyclopropylmethoxy-N-(trans-2-hydroxy-cyclohexyl)-nicotinamide and 4-cyanophenylboronic acid (commercially available) as starting materials. MS (ISP): 392.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1N
Yield: 98.7 %

Procedure:
[1-(3-Methyl-4-nitrophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (1.744 g, Example 35a), iron powder (1.52 g), ammonium chloride (1.45 g), ethanol (50 ml) and water (50 ml) were refluxed together under nitrogen for 2 h. The mixture was cooled and the iron was filtered off. Water (200 ml) was added to the residue and the product extracted into ethyl acetate (3×200 ml), dried (MgSO4), and concentrated to give the subtitle compound (1.56 g).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:17]([CH3:18])=[N:16][C:15]2[N:11]([N:12]=[C:13]3[CH2:21][N:20]([C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[O:31][C@@H:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)=[O:23])[CH2:19][C:14]3=2)[C:10]=1[CH3:37].C=O.[BH4-].[Na+]>C1COCC1.CC(=O)OCC>[Cl:8][C:9]1[C:17]([CH3:18])=[N:16][C:15]2[N:11]([N:12]=[C:13]3[CH2:21][N:20]([C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[O:31][C@@H:32]4[CH2:36][CH2:35][N:34]([CH3:1])[CH2:33]4)=[O:23])[CH2:19][C:14]3=2)[C:10]=1[CH3:37]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCNC1)C3
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN(C)C1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
TFA (15 μL) was added to a cold (0° C.) mixture of Example 80 (150 mg; 0.35 mmol; 1 eq.), formaldehyde (0.26 mL; 3.49 mmol; 10 eq.) and NaBH4 (66 mg; 1.74 mmol; 5 eq.) in THF (12 mL) and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EA, washed with 0.1M NaOH, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to EA/MeOH/TEA, 90/10/2) afforded the title compound (50 mg, 32%) as yellow foam. 1H NMR (DMSO-d6) δ 7.39-7.30 (m, 1H), 6.98 (dd, J=11.5, 2.3 Hz, 1H), 6.87 (td, J=8.4, 2.3 Hz, 1H), 5.01-4.92 (m, 1H), 4.85-4.78 (m, 2H), 4.66-4.45 (m, 2H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.79-2.70 (m, 1H), 2.62 (s, 1.5H), 2.60-2.52 (m, 2H), 2.55 (s, 1.5H), 2.35-2.2.20 (m, 2H), 2.17 (s, 1.5H), 2.16 (s, 1.5H), 1.81-1.60 (m, 1H). HPLC (max plot) 96.7%, Rt 2.74 min. UPLC/MS: (MS+) 444.5 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:23]([O:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1)([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH:23]([CH3:25])[CH3:24])[CH:28]=3)[CH2:38][CH2:37]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: CC(C)Oc1cccc(N2CCNCC2)c1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc(OC(C)C)c2)CC1
Yield: 93 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3-isopropoxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[C:13]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32].CN1CCOCC1.Cl>ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[C:13]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Hexanoylchloride (0.029 g.) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.05 g.) and N-methylmorpholine (0.05 g.) in dichloromethane (3 ml.), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (15 ml.). This mixture was extracted with ethyl acetate (2×20 ml.). The combined extracts were dried (MgSO4), and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluting with 4:6 v/v ethyl acetate:hexane, to give a colorless oil, which was crystallized from a mixture of toluene and hexane to give the title compound (0.05 g, 65%) as a white powder; NMR: 0.86(t, 3H, CH2.CH3), 1.28(m,4H, CH2.CH2.CH3), 1.57(quintet, 2H, CH2.CH2.CON), 2.25(t,2H, CH2.CH2.CON), 3.69(s,3H, NCH3), 3.82(s,3H, CO.OCH3), 3.92(s,3H, OCH3), 3.97(s, 2H, CH2.Ar), 7.05 (s,1H), 7.13(d,1H), 7.27(d,1H), 7.28(d,1H), 7.40(dd,1H), 7.48(s,1H), 7.74(s,1H), 9.61(s,1H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([Br:13])=[CH:5]2.[OH-:14].[Na+]>O.P(=O)(O)(O)O>[Br:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([OH:14])=[CH:11][C:10]=2[CH3:12]
Reactant: Cc1cc(N)cc2cc(Br)cnc12
Reactant: [OH-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)cc2cc(Br)cnc12
Temperature: 180 °C

Procedure:
6-Amino-3-bromo-8-methylquinoline (12 g) was suspended in a mixture of water (5 ml) and phosphoric acid (60 ml) and heated in a sealed glass tube to 180° C. for 3 days. The mixture was cooled to ambient temperature, diluted with water then taken to pH 3-4 with aqueous (2M) sodium hydroxide. The precipitate formed was filtered from solution, washed with cold water and sucked to dryness to give 3-bromo-6-hydroxy-8-methylquinoline, 11.0 g, as a grey solid.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)[C:6](=[O:27])[C:5]=1O)(=O)[CH3:2].[NH:29]([C:31]1[C:32]([O:37][CH3:38])=[N:33][CH:34]=[CH:35][CH:36]=1)[NH2:30]>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:30][N:29]([C:31]4[C:32]([O:37][CH3:38])=[N:33][CH:34]=[CH:35][CH:36]=4)[C:5]=3[C:6](=[O:27])[N:7]2[C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)=[CH:14][CH:13]=1
Reactant: COc1ncccc1NN
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(C)c3nnc(C)n3c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 90.1) and 3-hydrazinyl-2-methoxypyridine (Step 71.1). The crude material was purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2) followed by preparative achiral SFC (column Propyl-pyridyl-urea, gradient 12-17% in 6 min_total 11 min) and triturated in Et2O. tR: 0.99 min (LC-MS 2); ESI-MS: 500 [M+H]+ (LC-MS 2); Rf=0.33 (1% ammonia/5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07 (s, 3H) 2.45 (s, 3H) 2.62 (s, 3H) 3.92 (s, 3H) 6.59 (s, 1H) 7.21 (dd, J=7.6, 5.01 Hz, 1H) 7.34 (s, 1H) 7.37-7.48 (m, 4H) 8.00 (dd, J=7.6, 1.71 Hz, 1H) 8.33 (dd, J=4.9, 1.6 Hz, 1H) 8.47 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH:20][CH2:21][CH2:22][NH2:23])[CH3:19]>>[CH2:18]([N:20]1[C:1]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]3[C:10]([C:11](=[O:13])[N:23]2[CH2:22][CH2:21]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:19]
Reactant: CCNCCN
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Product: CCN1CCN2C(=O)c3ccccc3C12c1ccccc1

Procedure:
Condense o-benzoylbenzoic acid (10 g.) and N-ethylethylene-diamine (15 ml.) by the procedure of Example 1 to obtain 1-ethyl-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 122°-4° C. (elemental analysis confirms the empirical formula C18H18N2O).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[CH2:18][O:17][C:9]([CH3:16])([CH2:10][C:11](OCC)=[O:12])[O:8]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH2:7]1[CH2:18][O:17][C:9]([CH2:10][CH2:11][OH:12])([CH3:16])[O:8]1
Reactant: CCOC(=O)CC1(C)OCCO1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC1(CCO)OCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
Lithium aluminium hydride (2 g, 51 mmol) is added in small portions to anhydrous ethyl ether (200 cc). The mixture is cooled to 0° C. and ethyl 3,3-ethylenedioxybutanoate (3 g, 17 mmol) is then added over 10 minutes as a solution in anhydrous ethyl ether (10 cc). The mixture is stirred for 2 hours 30 minutes at a temperature in the region of 20° C. and is then hydrolysed by adding a saturated sodium sulphate solution (12 cc). After 2 hours the white precipitate is separated off by filtration. The organic phases are dried over magnesium sulphate. 2,2-Ethylenedioxy-4-hydroxybutane (2.22 g) is thus obtained.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CO[C:17](OC)([CH3:22])[C:18](OC)=[O:19]>C(O)(=O)C>[C:1]([N:5]1[C:9]2[NH:10][C:18](=[O:19])[CH:17]=[CH:22][C:8]=2[C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C2CCC2)cc1N
Reactant: COC(=O)C(C)(OC)OC
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CCC2)c2ccc(=O)[nH]c21
Temperature: 110 °C
Reaction time: 24 h
Yield: 31.5 %

Procedure:
To 2-tert-butyl-5-cyclobutyl-2H-pyrazol-3-ylamine (5.0 g, 25.9 mmol) in acetic acid (25 mL) was added methyl dimethoxypropionate (7.4 mL, 51.8 mmol), and then the reaction was heated to 110° C. After 24 hr, the reaction mixture was cooled to room temperature, and concentrated to a viscous oil that was diluted with EtOAc. The organic layer was washed with aqueous NaHCO3 and then the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of this material was accomplished by MPLC using a 45 L Biotage® column eluting with 20% EtOAc/hexanes. The product-containing fractions were collected and concentrated under reduced pressure, and the resulting solid was washed with hexanes and dried to afford the title compound (2.0 g, 32% yield) as a colorless solid. Rf=0.33 (10% MeOH/CH2Cl2). 400 MHz 1H NMR (CDCl3) d 7.72 (d, J=9.1 Hz, 1H), 6.26 (d, J=9.1 Hz, 1H), 3.68 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 2.46-2.32 (m, 4H), 2.14-1.89 (m, 2H), 1.71 (s, 9H). LRMS m/z (APCI+) 246 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:14][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=S(=O)(NCc1ccncn1)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(NCc1ccncn1)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
The sulphonamide from example 2 (1.0 eq), 4-fluorophenylboronic acid and Pd(PPh3)4 were dissolved in dioxane (3 mL/mmol) and an aqueous solution of sodium carbonate (2 mL/mmol) was added. The reaction mixture was heated under reflux overnight and after completion of the reaction the solvent was removed under reduced pressure. The residue was purified by chromatography to yield the title compound as beige solid.