Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][CH2:6][C:7]([NH2:9])=[O:8].C(O)(=O)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CO>[NH2:9][C:7](=[O:8])[CH2:6][NH:5]/[C:24](/[C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[O:15][CH3:14])=[CH:25]\[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC(=O)c1cc(OC)ccc1OC
Reactant: NCC(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\NCC(N)=O)c1cc(OC)ccc1OC
Temperature: 65 °C
Yield: 106.9 %

Procedure:
A 5-L reaction vessel was charged with methanol (3.3 L), sodium methoxide (102.4 g, 1.8 moles), and glycinamide hydrochloride (202 g, 1.8 moles). The mixture was heated at 65° C. for 1 hour before cooling to 50° C. and adding acetic acid (514.25 mmoles, 30.88 g, 29.47 mL) and ethyl 3-(2,5-dimethoxyphenyl)-3-oxopropanoate (300 g, 1.03 mole). After heating at reflux for 16 hours, the reaction mixture was stirred as it was cooled to 10° C. After 30 min the resulting solid was collected by vacuum filtration, pulling dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65° C.) for 14 hours to afford the title compound (339.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+].O>CO.[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(N)c1C
Temperature: 70 °C
Yield: 95.2 %

Procedure:
To a solution of methyl 5-chloro-2-methyl-3-nitrobenzoate (9.19 g, 40 mmol) in methanol (200 ml) at room temperature was added ammonium chloride (21 g, 400 mmol) followed by deionized water (100 ml). The mixture was heated to 70° C. before the addition of iron (13.4 g, 240 mmol). The reaction turned to a dark colour over the 2.5 hours it was stirred at 70° C. This mixture was allowed to cool to room temperature and was filtered through Kieselgel. The filter pad was washed with MeOH (100 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in deionized water (100 ml) and EtOAc (100 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic extracts were washed with brine (100 ml), dried over MgSO4, filtered and concentrated under reduced pressure to give 7.6 g of the title compound as a viscous orange oil that solidified upon standing. This material was used without further purification. LC-MS 63%, m/z=200.3/202.0, 1H NMR (500 MHz, Chloroform-d) δ 7.20 (1H, d, J=2.21 Hz), 6.80 (1H, d, J=2.05 Hz), 3.89 (3H, s), 3.74-3.87 (2H, m), 2.30 (3H, s).
Reaction SMILES: C(O[C:6]1[C:7](=[O:25])[C:8](=[O:24])[C:9]=1[NH:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=2[CH:16]=1)CCC.[C:26]([NH2:31])([CH2:29][CH3:30])([CH3:28])[CH3:27]>C(O)C>[CH3:27][C:26]([NH:31][C:6]1[C:7](=[O:25])[C:8](=[O:24])[C:9]=1[NH:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=2[CH:16]=1)([CH3:28])[CH2:29][CH3:30]
Reactant: CCCCOc1c(NCc2cc3cc([N+](=O)[O-])ccc3o2)c(=O)c1=O
Reactant: CCC(C)(C)N
Solvent: CCO
Product: CCC(C)(C)Nc1c(NCc2cc3cc([N+](=O)[O-])ccc3o2)c(=O)c1=O
Temperature: 70 °C
Reaction time: 18 h
Yield: 84.7 %

Procedure:
To 3-butoxy-4-[(5-nitro-benzofuran-2-ylmethyl)-amino]-cyclobut-3-ene-1,2-dione (0.25 g, 0.727 mmol), as prepared in Example 8, in ethanol (5 mL) was added tert-amylamine (0.53 mL, 4.54 mmol). The reaction was stirred at 70° C. for 18 hours and then at room temperature for 48 hours. The precipitated product was filtered and washed with ethyl acetate, diethyl ether, and petroleum ether to afford 0.22 g (85%) of 3-(1,1-dimethyl-propylamino)-4-[(5-nitro-benzofuran-2-ylmethyl)-amino]-cyclobut-3-ene-1,2-dione as an off-white solid: mp 283.5°-287.5° C. (dec); 1H NMR (DMSO-d6): δ 8.61 (d, 1H), 8.18 (dd, 1H), 7.96 (br t, 1H), 7.81 (d, 1H), 7.46 (br s, 1H), 7.07 (s, 1H), 4.99 (d, 2H), 1.66 (q, 2H), 1.30 (s, 6H), 0.82 (t, 3H). IR (KBr): 3220, 2950, 1800 cm-1 ; MS (m/z) 357 (M+).
Reaction SMILES: [BH4-].[K+].[F:3][C:4]([F:17])([F:16])[C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH:14]=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.O1CCCC1.O>CCOCC>[F:17][C:4]([F:3])([F:16])[C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][OH:15])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=Cc1c(C(F)(F)F)[nH]c2ccccc12
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1c(C(F)(F)F)[nH]c2ccccc12
Reaction time: 1 h
Yield: 64.6 %

Procedure:
2 g of potassium borohydride were added in small fractions at +5° C. to a solution of 4.6 g of the product of Step A, 150 ml of tetrahydrofuran and 30 ml of water and the mixture was stirred for one hour. The mixture was allowed to return to ambient temperature and the tetrahydrofuran was eliminated under reduced pressure. The resulting mixture was diluted with ether, washed with water, dried and concentrated under reduced pressure. The residue was chromatographed over silica (eluent: hexaneethyl acetate 7-3) to obtain 3 g of 2-trifluoromethyl-(1H)-indol-3-yl methanol melting at 106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32]O.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][O:24][C:23]([C:18]1([C:20]([O:22][CH2:30][C:31]([CH3:35])([CH3:34])[CH3:32])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(C)(C)CO
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)C)(C(=O)OCC(C)(C)C)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2,2-dimethylpropanol according to the procedure of Example 1 as an off-white foam (HCl salt); 1H NMR (CDCl3) δ 0.924 (s, 18H), 1.45 (d, 2H), 1.75 (s, 2H), 2.80 (m, 1H), 3.17 (m, 1H), 3.45 (m, 1H), 3.98 (s, 4H), 5.45-5.55 (bd, 1H), 5.63-5.67 (bs, 1H), 6.75-6.80 (m, 2H), 6.80-6.89 (m, 2H), 7.25-7.35 (m, 3H), 7.440 (s, 1H), 8.75 (bs, 1H), 10.10 (bs, 1H); IR (KBr) 3355 cm-1 (--OH), 1767 cm-1 (C=O); MS (ES) m/z 562.3 (MH+); [α]D25 -23° (c, 1.0, CHCl3). Anal. Calcd. for C30H40ClNO7 : C, 60.20; H, 6.90; N, 2.34; Cl, 11.85. Found: C, 59.74; H, 6.97; N, 2.23; Cl, 11.60.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:14]([C:16]3[O:17][CH:18]=[CH:19][N:20]=3)[OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:3]=12.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:14]([C:16]3[O:17][CH:18]=[CH:19][N:20]=3)[OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[NH:21][CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:3]=12
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccccc2F)c2c(Cl)c(-c3cccc(C(O)c4ncco4)c3)cnc21
Solvent: O=C(O)C(F)(F)F
Product: OC(c1cccc(-c2cnc3[nH]cc(-c4ccccc4F)c3c2Cl)c1)c1ncco1
Reaction time: 1 h
Yield: 16.1 %

Procedure:
{3-[4-Chloro-3-(2-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-oxazol-2-yl-methanol (0.040 mmol) was treated with 1 mL neat TFA. After 1 h, the TFA was removed in vacuo. The residue was treated with ethylene diamine (0.5 mL) and THF (1 mL) for 20 min. The mixture was concentrated and purified by preparative LCMS to afford {3-[4-chloro-3-(2-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-oxazol-2-yl-methanol (2.7 mg, 16%) MS: m/z 420 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 5.88 (d, 1H), 6.48 (d, 1H), 7.15 (d, 1H), 7.23 (m, 2H), 7.38-7.46 (m, 5H), 7.52 (br s, 1H), 7.71 (s, 1H), 8.04 (s, 1H), 8.19 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[N:5]=1
Reactant: Cc1ccc(CO)c(Nc2cccc([N+](=O)[O-])c2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C=O)c(Nc2cccc([N+](=O)[O-])c2)n1
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a suspension of 3-hydroxymethyl-6-methyl-2-(3-nitrophenylamino)pyridine (11.05 g, 42.62 mmol) in chloroform (200 ml) was added manganese dioxide (50 g), and the mixture was stirred overnight and filtered to remove an insoluble. Evaporation of the solvent from the filtrate gave a residue. Recrystallization of the resultant residue from acetonitrile gave 6-methyl-2-(3-nitrophenylamino)nicotinaldehyde (7.90 g, 72%).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][N:5]=[C:6]([C:26](=[N:28][O:29][CH3:30])[CH3:27])[C:7](=[N:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19][N:20]=[CH:21][C:22]([O:24]C)=O)[CH3:8]>O1CCCC1>[CH3:1][NH:2][C:22](=[O:24])[CH:21]=[N:20][O:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][N:9]=[C:7]([CH3:8])[C:6](=[N:5][O:4][CH3:3])[C:26](=[N:28][O:29][CH3:30])[CH3:27]
Reactant: CN
Reactant: CON=C(C)C(=NOC)C(C)=NOCc1ccccc1CON=CC(=O)OC
Solvent: C1CCOC1
Product: CNC(=O)C=NOCc1ccccc1CON=C(C)C(=NOC)C(C)=NOC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2 ml of 40% strength aqueous methylamine solution are added to a solution of 0.6 g (1.5 mmol) of methyl (2-(2,3-bismethoxyimino-1-methylbutylideneaminooxymethyl)phenyl]methoxyiminoacetate in 10 ml of tetrahydrofuran, and the mixture is stirred for 12 hours at room temperature. For working up, the reaction mixture is evaporated in vacuo, taken up in 20 ml of diethyl ether, washed using 20 ml of water, dried over sodium sulfate and evaporated in vacuo. This gives 0.6 g (98%) of an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:47])[CH2:10][C:11]1[CH:46]=[CH:45][CH:44]=[CH:43][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:42]=[CH:41][C:26]([O:27][CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)=[CH:25][CH:24]=2)[N:16]=1>C(Cl)Cl>[CH3:21][C:20]1[C:15]([CH2:14][CH2:13][C:12]2[CH:43]=[CH:44][CH:45]=[CH:46][C:11]=2[CH2:10][C:9]([NH2:8])=[O:47])=[N:16][C:17]([NH:22][C:23]2[CH:42]=[CH:41][C:26]([O:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:25][CH:24]=2)=[N:18][CH:19]=1
Reactant: Cc1cnc(Nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(OC3CCNCC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
TFA (0.5 mL) was added to a cooled (water/ice bath 6° C.) solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenoxy)piperidine-1-carboxylate (A113) (0.050 g, 0.092 mmol) in DCM (2 mL) and the resulting mixture was stirred at room temperature for 4 hours. The volatiles were removed in vacuo then 2 M aqueous K2CO3 solution (10 mL) and water (10 mL) were added to the residue. The resulting suspension was sonicated for 1 minute, filtered and the filter cake dried to give the title compound 26 as a light pink solid (0.034 g, 83%); 1H NMR (300 MHz, d6-DMSO) δ 9.17 (s, 1H), 8.12 (s, 1H), 7.62 (d, J=8.9 Hz, 2H), 7.43 (s, 1H), 7.12-7.27 (m, 4H), 6.93 (s, 1H), 6.84 (d, J=8.9 Hz, 2H), 4.23-4.29 (m, 1H), 3.49 (s, 2H), 3.30-3.34 (m, 2H), 2.83-3.05 (m, 7H), 2.05 (s, 3H), 1.86-1.90 (m, 2H), 1.39-1.42 (m, 2H). LCMS-B: rt 4.717 min; m/z 446 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.O.[Cu]I>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:21][CH2:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)c2cc(I)ccc2n1
Reactant: OCc1cccnc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Cl)c2cc(OCc3cccnc3)ccc2n1

Procedure:
4-Chloro-6-iodo-2-methylquinoline (0.61 g; see Preparation 6(ii) below), 3-pyridyl-carbinol (0.26 g), copper (I) iodide (0.038 g), caesium carbonate (0.78 g), 1,10-phenanthroline (0.072 g) in toluene (3 mL) was heated in a microwave at 160° C. for 40 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica eluting with a mixture of methanol and dichloromethane. Evaporation of the desired fractions gave the title compound as a pale pink solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[Cu][C:17]#[N:18].C(OCC)(=O)C>CN1CCCC1=O.O>[C:17]([C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1)#[N:18]
Reactant: CCC(Oc1cncc(Br)c1)C(=O)OC
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(Oc1cncc(C#N)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of methyl 2-(5-bromo-3-pyridyloxy)butyrate (1.37 g) and copper (1) cyanide (0.67 g) in dry N-methylpyrollidin-2-one (5 ml) was stirred at 150° C. under an atmosphere of nitrogen for 3.25 hours then cooled to ambient temperature and stored for 18 hours. The mixture was diluted with water and extracted with ethyl acetate (four times). The extracts were combined, washed with water (three times), dried over magnesium sulphate and evaporated under reduced pressure to give a liquid which was fractionated by chromatography (silica; ethyl acetate) to give the required product, 0.29 g, as an orange oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:19][C:20]1[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][C:21]=1[C:22]#[N:23]>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:19][C:20]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: N#Cc1cc(CO)ccc1Oc1cc(F)cc(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3cc(F)cc(F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.269 mmol), sodium hydride (21.55 mg, 0.539 mmol) and 2-(3,5-difluorophenoxy)-5-(hydroxymethyl)benzonitrile (70.4 mg, 0.269 mmol) in DMF (2 mL).
Reaction SMILES: [IH+][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]([OH:23])([C:21]#[CH:22])[CH3:20]>>[NH2:17][C:13]1[N:14]=[CH:15][N:16]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:22]#[C:21][C:19]([CH3:20])([OH:23])[CH3:18])[CH:10]=3)[CH:6]=[N:7]2)[CH:12]=1
Reactant: Nc1cc(-n2ncc3ccc([IH+])cc32)ncn1
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1ccc2cnn(-c3cc(N)ncn3)c2c1

Procedure:
The title compound was prepared by the procedure described in Example 1-b by reacting 6-(6-iodomoindazol-1-yl)pyrimidin-4-amine with 2-methylbut-3-yn-2-ol: 1H NMR (500 MHz, DMSO) delta 1.50 (6H, s), 5.56 (1H, s), 6.95 (1H, s), 7.10 (2H, br. s.), 7.29 (1H, dd, J=8.20, 1.26 Hz), 7.86 (1H, d, J=8.20 Hz), 8.46 (2H, d, J=9.30 Hz), 8.81 (1H, s); LC-MS: m/z=+294.50.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:52])[N:29]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38](B4OC(C)(C)C(C)(C)O4)[C:37]=3[CH3:51])[C:30](=[O:35])[N:31]2[CH3:34])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([N:29]2[C:28](=[O:52])[C:27]4[C:32](=[CH:33][C:24]([F:23])=[CH:25][CH:26]=4)[N:31]([CH3:34])[C:30]2=[O:35])[C:37]=1[CH3:51])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)c2ccc(F)cc2n(C)c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)c2ccc(F)cc2n(C)c1=O
Temperature: 90 °C
Yield: 53.5 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (200 mg, 0.524 mmol), 7-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 15] (215 mg, 0.524 mmol), Cs2CO3 (512 mg, 1.57 mmol) and PdCl2(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and water (0.50 mL) was heated at 90° C. for 4 h. The cooled mixture was concentrated, and the residue was purified by column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (gradient from 0-40%), to provide a mixture of four atropisomers of 3-chloro-4-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (164 mg, 53% yield). The material was separated by chiral super-critical fluid chromatography as follows: column: Lux Cel2 (3×25 cm, 5 μm); Mobile Phase: CO2-MeOH-MeCN (62:19:19) at 85 mL/min; sample preparation: 30 mg/mL in MeOH; injection: 0.5 mL. The material isolated from the third peak eluting from the column was again separated by chiral super-critical fluid chromatography as follows: column. CHIRALPAK® AS (3×25 cm, 5 μm); Mobile Phase: CO2-MeOH-MeCN (68:16:16) at 85 mL/min; sample preparation: 11.4 mg/mL in MeOH; injection: 3.5 mL. The first peak eluting from the column provided a single atropisomer of 3-chloro-4-(R)-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (25 mg, 15% yield). The isomeric purity was determined to be greater than 98%. Mass spectrum m/z 567 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 8.31 (dd, J=8.6, 6.2 Hz, 1H), 7.76 (s, 1H), 7.68 (d, J=1.1 Hz, 1H), 7.58-7.52 (m, 1H), 7.38 (ddd, J=14.1, 7.8, 1.0 Hz, 2H), 7.24 (dd, J=8.4, 1.5 Hz, 1H), 7.06-6.95 (m, 3H), 3.67 (s, 4H), 1.86 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:17]=[C:16]([CH2:18][CH2:19][CH3:20])[NH:15][N:14]=1)(=O)C.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:18]([C:16]1[NH:15][N:14]=[C:13]([CH:5]2[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4]2)[N:17]=1)[CH2:19][CH3:20]
Reactant: CCCc1nc(C2Cc3ccccc3N2C(C)=O)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1nc(C2Cc3ccccc3N2)n[nH]1

Procedure:
A solution of the compound 91 (0.42 g) in ethanol (25 ml) was treated with an aqueous NaOH solution (3 M, 25 mL) and the reaction mix was refluxed for 24 hours. The reaction was cooled, diluted with ethyl acetate, and treated with cold distilled water. The layers were separated and the aqueous fraction was extracted 5 times with ethyl acetate and the combined organic fractions were dried, concentrated and purified by preparatory column chromatography yielding 2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indole. b) A solution of 2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indole (0.00017 mole) in DCM (5 ml) was treated with N-ethyl-N-(1-methylethyl)-2-propanamine (0.00072 mole) then (2-fluoro-2-oxoethyl)-9H-fluoren-9-yl-carbamic acid methyl ester (0.00070 mole). The reaction was stirred at room temperature for 15 hours. The reaction was diluted with DCM, treated twice with saturated NaHCO3, and dried over Na2SO4 and concentrated. The residue was subjected to reverse phase prep column chromatography to obtain 0.02 g of the desired mono-adduct and 0.02 g of a bis-adduct that was completely converted to the desired mono-adduct by treatment with the prep chromatography eluent (0.1% trifluoroacetic acid in water/acetonitrile). These were combined, yielding 0.03 g of H-fluoren-9-ylmethyl[2-[2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl]-2-oxoethyl]-carbamate. c) A solution of H-fluoren-9-ylmethyl[2-[2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl]-2-oxoethyl]-carbamate (0.00006 mole) in DCM (10 ml) was treated with piperidine (0.010 mole) and stirred at room temperature for 1 hour. The completed reaction was concentrated in vacuo and subjected to reverse phase prep column chromatography, yielding 0.02 g of 2,3-dihydro-β-oxo-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indole-1-ethanamine trifluoroacetate (1:1) (compound 92).
Reaction SMILES: Cl.[C:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1)(=[O:4])[CH3:3].[BH4-].[Na+].Cl>CO>[OH:4][CH:2]([CH3:3])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1
Reactant: CC(=O)CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.76 Grams of 6-(4-acetylmethyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril monohydrochloride was dissolved in 50 ml of methanol, under ice-cooled condition, 0.44 g of sodium borohydride (NaBH4) was added slowly and then stirred at a room temperature for 1 hour. After the reaction was completed, a concentrated hydrochloric acid was added to ajust the pH of the reaction mixture to about pH 1, then most portion of the solvent was removed by distillation under a reduced pressure and the residue was extracted with 1N-NaOH-chloroform. The organic layer was washed with water and dried with anhydrous sodium sulfate, then the solvent was removed by distillation. The residue obtained was treated by means of a column chromatography and recrystallized from ethanol to obtain 2.26 g of 6-[4-(2-hydroxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless flake-like crystals. Melting point: 156°-157.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.C[Si](C)(C)Cl.[C:41](Cl)(=[O:47])[CH2:42][CH2:43][C:44](Cl)=[O:45]>N1C=CC=CC=1>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:18]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([N:8]([C:5]2[CH:6]=[N:7][C:2]([N:1]3[C:44](=[O:45])[CH2:43][CH2:42][C:41]3=[O:47])=[CH:3][C:4]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH3:28])=[O:27])[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)CCC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1-c1cc(N2C(=O)CCC2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml pyridine were added 54 mg (0.50 mmol) trimethylchlorosilane at room temperature. After stirring for 15 min, this mixture was added slowly under stirring to 155 mg (1.0 mmol) succinyl chloride and stirring was continued overnight. The solvent was removed in vacuo and the residue was purified by flash-chromatography to give 29 mg (25%) of the title compound as white solid.