Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=3[CH:38]=2)[C:17]=1[CH3:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1([NH2:48])[CH2:47][CH2:46]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:24]([C:34]([NH:35][CH3:36])=[O:37])[C:23]=3[CH:38]=2)[CH:15]=[C:11]([C:12](=[O:13])[NH:48][C:45]2([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)[CH2:47][CH2:46]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(OCc4ccccc4)c3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)cc(OCc4ccccc4)c3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.40 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (0.064 g, 0.47 mmol, 1.2 eq) (60% purity), HOBT (0.68 g, 0.012 mmol, 1.7 eq), EDC.HCl (0.064 g, 0.72 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.26 g, 2.0 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and preparative HPLC. Yield: 0.17 g (70%). 1H NMR (400 MHz, DMSO-d6): δ 1.26-1.27 (m, 2H), 1.54-1.56 (m, 2H), 2.18 (s, 3H), 2.81-2.82 (s, 3H), 5.26 (s, 2H) 7.13-7.15 (q, 1H, J=4.4 Hz), 7.30-7.43 (m, 6H), 7.58 (d, 4H), 7.65-7.69 (t, 2H, J=3.9 Hz), 7.74-7.79 (d, 1H, J=8.0 Hz), 7.97-8.01 (m, 2H), 8.43-8.48 (dd, 2H, J=4.89 Hz), 9.186 (s, 1H). LCMS: (ES+) m/z=626 (M+H) Ascentis Express C18 (5.0×2.1-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:16][C:9]2=[N:10][CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]2[CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:16][C:6]([CH2:4][OH:3])=[CH:7][C:8]=12
Reactant: CCOC(=O)c1cc2c(OC)ccnc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccnc2[nH]c(CO)cc12

Procedure:
To a suspension of 2-ethoxycarbonyl-4-methoxypyrrolo-[2,3-b]pyridine 3 (1.90 g, 8.62 mmol) in anhydrous THF (25 mL) was added LiAlH4 (0.218 g, 17.2 mmol) in small portions under N2 atmosphere. The mixture was stirred at reflux temperature for 50 min. After cooling, it was poured into cool H2O (20 mL) and extracted with EtOAc (4×15 mL). The combined organic layers were washed with brine (20 mL) and dried (Na2SO4). After filtration, the filtrate was concentrated to dryness and the residue was chromatographed on a silica gel column using 5% methanol in CH2Cl2 to give 4 as white solid. Mp 210-212° C.; Yield: 1.10 g, 71%; ESI MS: m/z 178.9 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13](=[O:25])[NH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[OH:24])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([NH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[OH:24])=[O:25]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(N)C(=O)NC1c2ccccc2CC1O

Procedure:
Compound 17 was kept in DCM-TFA 2:1 (2 mL) for 60 min at RT. The solution was cb-evaporated with toluene to dryness.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (331 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:7][C:4]=1[C:5]#[N:6].C(=O)([O-])[O-:21].[K+].[K+].OO>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:7][C:4]=1[C:5]([NH2:6])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1C#N
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2c[nH]c3ncccc23)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
The de-tosylated nitrile 38 (26.7 mg, 107 μmol) was dissolved in dimethyl sulfoxide (2.49 g). To this was added potassium carbonate (32.7 mg, 237 μmol) and 30% hydrogen peroxide in water (85.5 mg) and the reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was washed with water, acetonitrile and ether to give final product 39 (25.3 mg, 88%). 1H NMR DMSO-d6 11.86 (s, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 8.11 (m, 1H), 7.81 (m, 2H), 7.70 (s, 1H), 7.55 (s, 1H), 7.21 (d, 1H), 7.16 (m, 1H), 3.91 (s, 3H). LC/MS(M+1)=268
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][O:4][CH:5]([CH2:7][OH:8])[CH3:6].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([CH:1]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)[CH:2]([OH:9])[CH2:3][O:4][CH:5]([CH2:7][OH:8])[CH3:6])=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: CC(O)COC(C)CO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CC(CO)OCC(O)C(C(=O)c1ccc([N+](=O)[O-])cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 51.7 %

Procedure:
Dipropylene glycol (40.2 g, 0.3 mole) was treated with p-nitrobenzoyl chloride (116 g, 0.625 mole), following the general procedure described in Example 1, Part A. After treatment with saturated aqueous sodium bicarbonate in the usual manner, the ethyl acetate solution of the product was dried (MgSO4), filtered and crystallization effected by the addition of hexanes. The product, bis-(4-nitrobenzoyl)-dipropylene glycol (67 g), was isolated as a pale yellow solid, m.p. 96°-100° C. which was homogeneous by TLC.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][S:4][C:3]=1[C:13]([O:15]C)=O.C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.Cl>O1CCOCC1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:13](=[O:15])[C:3]3[S:4][CH:5]=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]=3[NH:1][C:32]2=[O:33])=[CH:27][CH:26]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=c1[nH]c2c(-c3ccccc3)csc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
Methyl 3-amino-4-phenylthiophene-2-carboxylate (400 mg, 1.71 mmol), triethylamine (0.04 ml, 0.43 mmol), and 4-chlorophenyl isocyanate (0.39 ml, 3.16 mmol) were dissolved in 1,4-dioxane (10 ml) in a reaction vessel. The mixture was heated with stirring at 90° C. for 3 days. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and filtered. The filtered solid was dissolved in a 10% sodium hydroxide/methanol (3 ml/12 ml) solution and refluxed with stirring at 100° C. overnight. After completion of the reaction, the reaction solution was cooled to room temperature, acidified with 3 N hydrochloric acid, and filtered to give 548 mg (1.54 mmol, 90% yield) of the title compound as a solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:23][CH2:22][C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:25]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:23][CH2:22][C:13]2[N:14]([CH3:25])[C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(F)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c2c(c3cc(F)ccc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.1 %

Procedure:
To a suspension of NaH (80% in oil, 0.0190 g, 0.633 mmol) in dry THF (1 mL), was added a solution of 8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (0.114 g, 0.393 mmol) in THF (4 mL) via cannula. The reaction mixture was allowed to stir at room temperature for 5 min and then iodomethane (0.098 mL, 1.57 mmol) was added. The resulting mixture was stirred for 2 h and then it was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was separated, dried (MgSO4), filtered and concentrated to dryness to give the title compound (0.109 g, 91%) as a yellow oil which was used without further purification. LCMS: m/e 305 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([N:17]1[CH2:22][CH2:21][N:20]([C:10]([C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N1CCNCC1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: CC(C)(C)N1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1

Procedure:
This example was prepared according to Example 1 employing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-tert-butylpiperazine, which is commercially available from, for example, Beta Pharma. m/z (ES+) M+1=287.2; HPLC tR=1.60 min. 1H NMR (500 MHz, CDCl3) δ 7.34-7.23 (m, 2H), 7.23-7.15 (m, 1H), 7.11 (d, J=7.0 Hz, 2H), 3.73-3.53 (m, 4H), 2.64-2.50 (m, 4H), 2.47 (ddd, J=8.9, 6.4, 4.3 Hz, 1H), 1.96 (td, J=4.5, 3.5 Hz, 1H), 1.65 (ddd, J=9.2, 5.2, 4.3 Hz, 1H), 1.25 (ddd, J=8.2, 6.4, 4.3 Hz, 1H), 1.06 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1.CCCCCC>CCOCC>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:17]=[C:18]([NH:22][C:23]([N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][C:6]2=3)=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2c(c1)CCCCN2
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc2c(c1)CCCCN2C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.0 g (11.3 mMol) of 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine [Monatsheft Chemie, 97 (1966),150] and 2.28 g (97%; 11.8 mMol) of 3-trifluoromethyl-phenyl-isocyanate in 20 ml ether is stirred for 30 min in a icebath. After addition of hexane, the mixture is concentrated partially in vacuo and the crystallized product filtered off: m.p.: 108° C.; MS: [M+1]+=365; Anal.: C,H,N,F.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2Cl)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35]C1C=CC(CO)=CC=1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:35][CH3:34])=[CH:29][CH:28]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CO)cc1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3ccccc3)c2cc1F
Product: COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2ccccc2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate c, from 1-benzyl-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 6, intermediate) and (4-methoxy-phenyl)-methanol (CAS Reg. No. 105-13-5). Colorless solid (72%). MS (Turbo Spray): m/z=458.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][CH:25]([OH:28])[CH:26]=[CH2:27]>>[CH3:24][CH:25]([O:28][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH:26]=[CH2:27]
Reactant: C=CC(C)O
Reactant: COc1cc(-c2cc3ncccc3c(Cl)n2)cc(OC)c1OC
Product: C=CC(C)Oc1nc(-c2cc(OC)c(OC)c(OC)c2)cc2ncccc12

Procedure:
5-(1-Methyl-allyloxy)-7-(3,4,5-trimethoxy-phenyl)-[1,6]naphthyridine (for Example 31) was prepared from 5-chloro-7-(3,4,5-trimethoxy-phenyl)-[1,6]naphthyridine and (R/S)-but-3-en-2-ol using an analogous procedure
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[Si:25]([O:32][CH2:33][CH2:34][CH:35]=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[BH3-]C#N.[Na+]>C(Cl)Cl.CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH2:35][CH2:34][CH2:33][O:32][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH:17]=2)=[CH:3]1
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(C2=C(c3cccc(NCCCO[Si](C)(C)C(C)(C)C)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3.3 %

Procedure:
A mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (0.2 g, 6 mmol) and 3-(tert-butyldimethylsilyloxy)propionaldehyde (0.25 g, 13 mmol) in CH2Cl2 (10 mL) and MeOH (5 mL) was stirred at room temperature for 15 min and then NaCNBH3 (57 mg, 1.5 eq) was added. The reaction mixture was stirred at RT overnight and then concentrated under vacuo. The residue was purified by preparatory TLC to give 98 mg 3-(1-methylindol-3-yl)-4-[3-(3-tert-butyldimethylsilyloxypropylamino)phenyl]-1H-pyrrole-2,5-dione (32%) MS (LSIMS): (M+H)+ 490, MP: 58-65° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[NH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Reactant: CC(C)(C)OC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CNCCC(=O)OC(C)(C)C)cc2C)ncn1
Reaction time: 18 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with tert-butyl 3-aminopropanoate hydrochloride (Bachem, 227.1 mg; 1.24 mmol) and polymer supported carbonate (150 mg) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 3-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylbenzylamino)propanoate which was used directly without any further purification. The residue was taken up into DCM (4.5 ml) and TFA (0.5 ml) added. After stirring at RT for 2 hours the solvent was removed in vacuo. The residue was taken up into dilute HCl and precipitated by basification to pH 3-4. The solid was removed by filtration, washed with water and dried to give the title compound as a white solid.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([O:29]C)=O)=[CH:20][C:14]=3[C:15]=2[C:16](=[O:19])[NH:17][CH3:18])=[CH:7][CH:6]=1.O/[N:35]=[C:36](\[NH2:40])/[CH:37]([CH3:39])[CH3:38]>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:33]=[CH:32][CH:31]=[C:26]([C:27]5[O:29][N:40]=[C:36]([CH:37]([CH3:39])[CH3:38])[N:35]=5)[CH:25]=4)=[CH:20][C:14]=3[C:15]=2[C:16]([NH:17][CH3:18])=[O:19])=[CH:7][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)OC)c3)cc12
Reactant: CC(C)/C(N)=N/O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nc(C(C)C)no4)c3)cc12
Yield: 19.5 %

Procedure:
Sodium methoxide (33 mg, 0.620 mmol) was added to a stirring slurry of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (50 mg, 0.124 mmol) and (Z)—N′-hydroxyisobutyrimidamide (38 mg, 0.372 mmol) in EtOH (2.5 mL) at rt. The mixture was subjected to microwave irradiation for 5 min at 160° C. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (11 mg, 20%). 1H NMR (400 MHz, DMSO-d6) d ppm 8.46-8.54 (1H, m), 8.35 (1H, s), 8.11 (1H, d, J=7.78 Hz), 7.97-8.08 (3H, m), 7.92-7.97 (1 H, m), 7.73-7.84 (3H, m), 7.40 (2H, t, J=8.91 Hz), 3.12-3.23 (1H, m), 2.87 (3H, d, J=4.52 Hz), 1.36 (6H, d, J=7.03 Hz). LC-MS retention time: 1.80 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=16.33 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=13.72 min, purity=99%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][OH:4])(=[O:20])=[O:21])=[C:15]([F:23])[CH:14]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
To a solution of 2-aminoethanol (0.24 mL, 4.0 mmol), and triethylamine (1.5 mL, 11 mmol) in anhydrous THF (15 mL) was added 4-bromo-2-fluorobenzene-1-sulfonyl chloride (1.0 g, 3.7 mmol) portion wise and the reaction mixture stirred at room temperature for 16 h. The reaction was filtered, the filtrate was concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (850 mg, 77%): ESI MS m/z 298 [C8H9BrFNO3S+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH3:14].C1C=CC=CC=1>O>[C:1]1([O:7][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCBr
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCOc1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml four-neck flask, load 115 g phenol (1.223 mol) and 82.2 g (1.468 mol) of dry KOH. A mass is heated up to 90° C. while mixing. Then by dropping during 0.5 h add 184.7 g (1.223 mol) of amylbromide. Maintain the mixture at a temperature of 95-100° C. for 45 minutes while mixing. After cooling, 200 ml of benzene and 300 ml of water are added to the mixture. The water layer is decanted. Then the benzene layer is washed with 200 ml of 5% solution of NaOH The benzene layer is then washed a few times with water until the reaction mixture is neutral.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([CH:15]=O)=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.Cl[CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:15][C:11]2=[CH:10][C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: CC(C)(C)C(=O)c1cc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2o1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 0.38 g of the product of Step A dissolved in 3 mL of DW, was added 0.14 mL (1.07 mmol) of 1-chloropinacolone and 0.65 g of Cs2CO3. After stirring for 2 h, another 0.05 mL (0.38 mmol) of 1-chloropinacolone was added and the stirring was continued for another 1 h. Additional 0.325 g (1 mmol) of Cs2CO3 was added and the solution was heated in a 60° C. bath for 3 h. The solution was cooled, diluted with Et2O, washed with water, brine, dried and concentrated. The residue was purified on a prep TLC plate using 20% EtOAc/hexane as eluant to afford the title compound. HPLC/MS: 424 (M+1), 426 (M+3); Rt=4.49 min.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].I[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)CI
Reactant: Nc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CNc1ccccc1Cl
Temperature: 100 °C
Yield: 69.7 %

Procedure:
A mixture of 2-chloroaniline (13.2 ml, 0.125 mol), iodoacetone (26.6 g, 0.145 mol) and potassium carbonate (18.1 g, 0.13 mol) in DMF (200 ml) was heated under nitrogen at 100° C. overnight. After cooling to rt, water was added and the mixture extracted with ether (×3). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography (Heptane:EtOAc 80:20) afforded 16.0 g (70%) of the title compound as a brown liquid.