Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([CH3:13])[NH:5]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]([CH3:13])[NH:5]3)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1Nc2cc(Br)ccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC1Nc2cc(-c3ccc(Cl)cc3)ccc2NC1=O
Temperature: 25 °C

Procedure:
A solution of 6-bromo-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (2.4 g, 10 mmol), 4-chlorophenyl boronic acid (1.6 g, 10 mmol), potassium carbonate (4 g, 30 mmol), and tetrakis-(triphenylphosphine)palladium (0) in dimethoxyethane (150 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours. After cooling to room temperature the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to obtain crude product (0.83 g, 30%). A sample was recrystallized from ethanol to afford the title compound: m.p. 228-230° C. 1H-NMR (DMSO-d6) δ1.28 (d, J=6.63 Hz, 3H), 3.83 (q, J=6.63 Hz, 1H), 6.16 (bs, 1H), 6.81 (d, J=8.00 Hz, 1H), 6.91 (dd, J=8.05, 1.9 Hz, 1H), 6.95 (d, J=1.7 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 10.32 (s, 1H); MS (EI) m/z 272/274.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)=[C:9]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:10]2[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2
Reactant: CCOC(=O)c1c(-c2ccc3[nH]ccc3c2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(-c2ccc3[nH]ccc3c2)c2cc(N)ccc2n1Cc1ccccc1

Procedure:
Ethyl 5-amino-1-benzyl-1H,1′H-3,5′-biindole-2-carboxylate was prepared from ethyl 1-benzyl-5-nitro-1H,1′H-3,5′-biindole-2-carboxylate followed the procedure of Example 1 Step 2 as a white solid: 1H NMR (DMSO-d6) δ 0.89 (t, J=7.1 Hz, 3H, 4.06 (q, J=7.1 Hz, 2H, 5.81 (s, 2H, 6.47 (t, J=2.0 Hz, 1H, 7.08 (d, J=7.1 Hz, 2H, 7.10-7.50 (m, 8H), 7.58 (s, 1H, 7.70 (d, J=8.9 Hz, 1H, 9.28 (br s, 2H, 11.18 (s, 1H; MS (ESI) m/z 410 (MH+); HRMS calcd for C26H24N3O2: 410.1867 found (ESI+): 410.1858; Anal. calcd for C26H23N3O2.1.0 TFA: C, 64.24; H, 4.62; N, 8.03. Found: C, 63.85; H, 4.77; N, 7.91.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[N:7]=1)=[O:5])[CH3:2].Cl.[Cl:18][C:19]1[C:20]([F:27])=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:22]3[C:21](=[C:20]([F:27])[C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:14]=2[CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(SCC(C)=O)n1
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 6-(2-oxo-propylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 3-chloro-2-fluorophenylhydrazine hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.S(=O)(=O)(O)O.[CH2:21](O)[CH:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH2:21]([O:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:4]=1[NH2:1])[CH:22]([CH3:24])[CH3:23]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(C)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)c1ccc(N)cc1N
Temperature: 25 °C

Procedure:
To a mixture of 212 g of 2,4-dinitrobenzoic acid in 300 ml of toluene were added 38 g of concentrated sulfuric acid and 230 ml of isobutyl alcohol. The mixture was refluxed for 10 hrs and the resulting water removed by azeotropic distillation. After this period the mixture was cooled to room temperature and washed with 1000 ml of an aqueous 5% NaHCO3 solution followed by two 500 ml water washings. The toluene was removed at reduced pressure and the resulting dark oil was washed with hexane to yield 252 g of isobutyl-2,4-diaminobenzoate, a fluffy white crystalline solid, mp 54°-55° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12]C)[CH:7]=[O:8])(=[O:3])[NH2:2].B(Br)(Br)Br>C(Cl)Cl>[CH:7]([C:6]1[CH:9]=[CH:10][C:11]([OH:12])=[C:4]([CH:5]=1)[C:1]([NH2:2])=[O:3])=[O:8]
Reactant: COc1ccc(C=O)cc1C(N)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)c1cc(C=O)ccc1O
Temperature: 23 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
3-Carbamoyl-4-methoxy-benzaldehyde compound 41 (1.065 g, 5.95 mmol) was stirred in dry CH2Cl2 (120 mL) at −78° C. under argon. Boron tribromide (10.71 mL, 1.0 M, 10.71 mmol) was added, and the reaction stirred 18 h while warming to 23° C. The reaction was quenched with 0.05 N HCl (80 mL), and was allowed to stir for 15 min. The organic layer was collected, and the aqueous layer was further extracted with EtOAc (2×50 mL). Organics were combined, dried (Na2SO4), and concentrated. Purification by flash chromatography (60% EtOAc/CHCl3) gave 540 mg (55%) of 5-formyl-2-hydroxy-benzamide 42 as a white solid. 1H NMR (DMSO-d6) δ 14.00 (1 H, s), 9.88 (1 H, s), 8.73 (1 H, br s), 8.55 (1 H, d, J=1.5 Hz), 8.21 (1 H, br s), 8.00 (1 H, dd, J=8.7, 1.5 Hz), 7.13 (1 H, d, J=8.7 Hz); IR (KBr) 3420, 3237, 1686, 1618, 1493, 1375, 1279, 1196 cm−1. Anal. (C8H7NO3) C, H, N.
Reaction SMILES: Cl.[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][CH:39]=[N:40]3)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[C:25]#[N:26]>CN(C)C=O.O>[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:11][CH2:12][N:13]([CH:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:42]=[C:41]6[C:36]([CH:37]=[CH:38][CH:39]=[N:40]6)=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[C:25]#[N:26])[CH2:14][CH2:15]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Reactant: N#CC(Br)c1ccc(-c2ccc3cccnc3c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.101 mmol) in N,N-dimethylformamide (0.5 mL) was treated with potassium carbonate (0.209 mmol) and 2-bromo-2-(4-(quinolin-7-yl)phenyl)acetonitrile (0.070 mmol). The reaction was stirred overnight at room temperature, at which point it was diluted with water (50 mL) and was extracted with three times with dichloromethane. The aqueous layer was further diluted with brine (25 mL) and was extracted twice with tetrahydrofuran. The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (0-9% methanol/dichloromethane). The fractions containing the desired product were combined, concentrated in vacuo, and lyophilized from water to afford the title compound a pale yellow solid (15%). MS(ES)+ m/e 453.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[NH:5][CH:6]=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([Cl:33])=[N:5][CH:6]=[N:7]2
Reactant: O=c1[nH]cnc2cccc(F)c12
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1cccc2ncnc(Cl)c12

Procedure:
Thus, 5-fluoro-3,4-dihydroquinazolin-4-one (2 g) was reacted with triphenylphosphine and carbon tetrachloride to give 5-fluoro-4-chloroquinazoline (1.34 g); NMR Spectrum: (CDCl3) 7.4–7.5 (m, 1H), 7.9–8.0 (m, 2H), 9.1 (s, 1H); and
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=3)[CH:11]=1)[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2.[OH-].[Na+:29]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=3)[CH:11]=1)[O:8][CH:7]([C:21]([F:24])([F:22])[F:23])[C:6]([C:25]([O-:27])=[O:26])=[CH:5]2.[Na+:29]
Reactant: COc1ccc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)O)=C3)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)[O-])=C3)cc1C

Procedure:
A solution of 6-chloro-8-(4-methoxy-3-methylphenyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid 46.6 mg (0.117 mmole) in 2.0 mL of ethanol was treated with 1.160 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide a quantitative yield of a yellow solid: 1H NMR (CD3OD/400 MHz) 2.20 (s, 3H), 3.85 (s, 3H), 5.77 (q, 1H, J=6.8 Hz), 6.93 (d, 1H, J=8.0 Hz), 7.26-7.32 (m, 4H), 7.78 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=1)[CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: CN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN1CCC(c2cn(C(=O)c3ccc(F)cc3)c3ccc(Cl)cc23)CC1

Procedure:
(22.5 mg, 61%); from 5-chloro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5e, 25 mg, 0.10 mmol) and 4-fluorobenzoyl chloride (23.8 mg, 0.15 mmol), HRMS-FAB+ for C21H20N2OClF, calculated MH+ : 371.13263; found: 371.13063.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]([F:37])([F:36])[F:35])[CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[N:7]=[CH:6][N:5]=1)=[N+]=[N-]>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[C:23]([C:34]([F:37])([F:36])[F:35])[CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[N:7]=[CH:6][N:5]=1
Reactant: [N-]=[N+]=Nc1cc(Oc2ccc(NC(=O)Nc3ccc(CN4CCCCC4)c(C(F)(F)F)c3)cc2)ncn1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccc(NC(=O)Nc3ccc(CN4CCCCC4)c(C(F)(F)F)c3)cc2)ncn1

Procedure:
Hydrogenation of N-(4-(4-azidopyrimidin-6-yl-oxy)-phenyl)-N′-(3-trifluoromethyl-4-(piperidin-1-ylmethyl)-phenyl)-urea (Example 130; 213 mg, 0.41 mmol) in the presence of 10% Pd/C (40 mg) in 10 ml of THF during 2 h at rt, filtration and concentration of the filtrate affords the title compound: MS: [M+1]+=487; 1H-NMR (DMSO-d6): 9.09 & 8.92 (2s, 2HN), 8.03 & 7.93 (2s, 2H), 7.69 & 7.65 (2m, 2H), 7.47 & 7.03 (2d, 2×2H), 6.79 (s, 2H), 5.6 (s, 1H), 3.46 (s, 2H), 2.31 (m, 4H), 1.49 (m, 4H), 1.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C([O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[C:39]([F:44])[CH:38]=1)C>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:43][C:40]3[CH:41]=[CH:42][C:37]([C:36]([OH:35])=[O:45])=[CH:38][C:39]=3[F:44])=[O:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(O)c1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 6, [rac]-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 24.7) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-3-fluoro-benzoic acid ethyl ester (CAS Reg. No. 73792-12-8) in the presence of DMAP to give the title compound as yellow liquid. MS: m/e=570.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:20]=[C:21]([C:22]([O:24]C)=[O:23])[C:16]=2[N:15]=[C:14]1[C:32]([F:35])([F:34])[F:33].[OH-].[Li+]>C1COCC1>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:16]=2[N:15]=[C:14]1[C:32]([F:34])([F:33])[F:35]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(C(F)(F)F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C(F)(F)F)nc3c(C(=O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of methyl 1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 46 (510 mg, 1.017 mmol) and 2 M lithium hydroxide (6 mL, 12.00 mmol) in THF (12 mL) was stirred at 50° C. for 2 h. The reaction was cooled to room temperature. The organic solvent was removed under reduced pressure and the aqueous was diluted with water and acidified by the addition of 1 N HCl. The precipitate formed was collected by filtration. The solid was washed with ether and turned into a gummy residue. The residue was washed with MeOH until all the material was transferred into the collection flask. The organics were evaporated and a white solid formed upon standing. The precipitate was collected by filtration, washed with water and dried to give the desired product (438 mg, 0.881 mmol, 87% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (d, J=2.02 Hz, 1H), 7.61 (d, J=8.08 Hz, 1H), 7.23 (t, J=7.83 Hz, 1H), 7.08 (d, J=2.02 Hz, 1H), 6.27 (d, J=7.58 Hz, 1H), 5.74 (s, 2H), 3.63-3.82 (m, 4H), 3.05-3.21 (m, 4H), 2.52 (br. s., 3H). MS (ES+) m/e 488 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19](O)=[O:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]1([C:59]2[N:64]=[CH:63][CH:62]=[CH:61][N:60]=2)[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:9]([CH2:18][C:19]([N:56]3[CH2:57][CH2:58][N:53]([C:59]4[N:60]=[CH:61][CH:62]=[CH:63][N:64]=4)[CH2:54][CH2:55]3)=[O:20])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)Cn1nc(-c2ccccc2)cc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccccc2)cc1-c1ccccc1)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
278 mg (3,5-diphenyl-pyrazol-1-yl)-acetic acid was dissolved in 5 mL DMF. 321 mg TBTU and 172 μL DIPEA were added to this solution and the mixture was stirred for a few minutes at RT. 164 mg 2-(1-piperazinyl)-pyrimidine was added and stiffing was continued for 30 min. Then 10 mL of a 1M NaOH solution and 50 mL CH2Cl2 were added, the organic phase was separated. The solvent was removed and the residue was purified by flash chromatography (silica gel, DCM/MeOH/NH3 0-5%). Diethylether was given to the residue and the precipitate was filtered to yield 310 mg of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]1[CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([N:10]4[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:28]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: C[C@@H](COC1CCN(c2nc3cc(O)ccc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](COC1CCN(c2nc3cc(OCC4CCC4)ccc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 83.2 %

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(5-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (389 mg) in DMF (5 mL) were added potassium carbonate (413 mg) and (bromomethyl)cyclobutane (297 mg), and the mixture was stirred with heating at 60° C. for 6 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (380 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.Cl.[NH2:41][C@@H:42]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:39]=[CH:38][C:34]([C:35]([NH:41][C@@H:42]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[O:37])=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (42 μL, 0.24 mmol) was added to a mixture of 4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoic acid (33 mg, 0.080 mmol), tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (23 mg, 0.10 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (42 mg, 0.096 mmol) in DMF (1 mL). The mixture was stirred at RT overnight, and quenched with saturated sodium bicarbonate (5 mL). The reaction mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column with ethyl acetate in hexanes (40%) to afford the desired product. Analytical LCMS: (M+H)+=584.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:17]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=2[CH3:26])[C:10]2[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CC(O)=O.CO.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:18]([CH3:26])=[C:17]([N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]2[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=2)[CH:22]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N(c1ccc(F)c(Cl)c1)c1cc(N)ncn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(N)cc1N(c1ccc(F)c(Cl)c1)c1cc(N)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
Synthesis of N-(5-Amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-F) A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stifling, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)([Cl:13])=O>CCCCCC.N1C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1O

Procedure:
Salicylic acid (5.0 g, 36.2 mmol) was suspended in dry hexane (40 ml) and thionyl chloride (4.52 g, 38 mmol) was added under nitrogen atmosphere followed by one drop of pyridine. The mixture was refluxed for two hours while stirring. The clear yellow solution was cooled and concentrated in vacuum, giving a dense oil to be used in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CN1CCN(C(=O)CCc2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)CCc2cccc(N)c2)CC1
Reaction time: 18 h

Procedure:
To a nitrogen-degassed solution of 3-(3-nitrophenyl)-1-(4-methylpiperazinyl)propan-1-one (3.67 g, 13.330 mmol, Step A) in MeOH (50 ml) was added 10% by weight Pd/C (500 mg). The mix was stirred under H2 atmosphere for 18 h then filtered through Celite® and concentrated in vacuo, yielding a thick amber oil which eventually solidified into a dark pink solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[K+]>CCO.O.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc([N+](=O)[O-])ccc1C(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(N)ccc1C(C)(C)C
Temperature: 25 °C
Yield: 72.5 %

Procedure:
To a refluxing solution of 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 0.4 mmol) in EtOH (2 mL) was added potassium formate (300 mg, 3.6 mmol) in water (1 mL), followed by 10% Pd—C (15 mg). The reaction mixture was refluxed for additional 60 min, cooled to room temperature and filtered through Celite. The filtrate was concentrated to dryness to give 4-tert-butyl-3-methoxyaniline (C-2) (52 mg, 72%) that was used without further purification. HPLC ret. time 2.29 min, 10-99% CH3CN, 5 min run; ESI-MS 180.0 m/z (MH+).