Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:34][NH:35][O:36][CH3:37].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]([CH3:17])[CH2:13][C:14]([N:35]([O:36][CH3:37])[CH3:34])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: CC(CC(=O)O)NC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)CC(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 3-{[(benzyloxy)carbonyl]amino}-butanoic acid (Step A; 9.0 g; 38 mmol) in CH2Cl2 (90 mL) at 0° C. under N2 were added N-methylmorpholine (10.4 mL; 95 mmol) and isobutyl chloroformate (6.2 ml; 47.5 mmol). The resultant yellow solution was stirred at 0° C. for 5 min prior to portionwise addition of N,O-dimethylhydroxylamine hydrochloride (4.45 g; 45.6 mmol) over 5 min. The reaction was allowed to warm to room temperature and stirred for 14 h, then poured into 1 N HCl (200 mL) and extracted with CH2Cl2 (3×100 mL). The combined extracts were washed with 1 N HCl (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford benzyl-{3-[methoxy(methyl)amino]-1-methyl-3-oxopropyl}carbamate as a clear oil. LCMS=281.3 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.35-7.29 (m, 5H), 5.61 (br s, 1H), 5.09 (s, 2H), 4.16-4.10 (m, 1H), 3.66 (s, 3H), 3.16 (s, 3H), 2.77-2.72 (m, 1H), 2.59-2.54 (m, 1H), 1.27 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH2:3][OH:4].[OH-].[Na+].[CH3:16][O:17][CH2:18]Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl>[CH3:1][C@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:16][O:17][CH3:18])[CH2:3][OH:4]
Reactant: COCCl
Reactant: C[C@@H](CO)CSc1ccccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccccc1SC[C@@H](C)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
2.47 g (0.012 mol) of 2-(S)-methyl-3-(2-hydroxyphenylthio)propan-1-ol (XXh), 25 ml of dichloromethane, 12.5 ml (0.024 mol) of an aqueous sodium hydroxide solution (2N), 0.55 ml (0.0012 mol) of Aliquat 336 and 0.9 ml (0.012 mol) of chloromethyl methyl ether are introduced into a 100 ml round-bottomed flask. The mixture is stirred at ambient temperature for 24 hours and then the phases are separated. The organic phase is washed successively with an aqueous hydrochloric acid solution (1N), an aqueous sodium hydroxide solution (1N), water and brine and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/acetone=96:4). 1.1 g (0.0045 mol) of the title compound (XXIa) are recovered in the form of a white oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C1C(=O)N([Br:25])C(=O)C1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:25][C:10]1[C:2]([Cl:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2c(Cl)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c1ccc(Br)c2Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 1,1-dimethylethyl 4-chloro-2,3-dihydro-1H-indole-1-carboxylate (6.36 g, 25.07 mmol) in Dichloromethane (DCM) (100 mL) was added a solution of NBS (4.91 g, 27.6 mmol) in Dichloromethane (DCM) (200 mL). The reaction was stirred at room temperature for 2 hours. LCMS indicated good conversion, so the reaction mixture was poured into sodium bicarbonate (sat., 300 mL), and separated. The aqueous layer was extracted with ethyl acetate (2×300 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-30% EtOAc in hexanes, 200 g silica gel column) to afford 1,1-dimethylethyl 5-bromo-4-chloro-2,3-dihydro-1H-indole-1-carboxylate (5.5 g) as an off-white solid. LC-MS (ES) m/z=276, 278 [M+H-t-Bu]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (s, 9H), 3.01-3.18 (m, 2H), 3.88-4.03 (m, 2H), 7.50-7.58 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Br)c2)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3-Bromo-benzoic acid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:24])[N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:4]1[N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=2)[N:3]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cc(Br)nc2C)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cc(-c3ccc(N)nc3)nc2C)n1

Procedure:
The title compound was prepared from 2-(4-bromo-2-methyl-imidazol-1-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.64) (0.2 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.11 g, 55%). MS (ISP) 411.0 [(M+H)+]; mp 227.5° C.
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])#[CH:16].C(N(CC)CC)C.O>O1CCCC1>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([C:2]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=[O:21])[O:14][N:13]=2)=[CH:4][CH:5]=1
Reactant: ON=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C#Cc1cccc(C=O)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1cccc(-c2cc(-c3ccc(C(F)(F)F)cc3)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution (20 ml) of 1-[chloro(hydroxyimino)methyl]-4-trifluoromethylbenzene (0.849 g) and 3-ethynylbenzaldehyde (0.521 g) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (1.12 ml) in tetrahydrofuran at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1, volume ratio) and recrystallized from hexane-ethyl acetate to give 3-[3-(4-trifluoromethylphenyl)-5-isoxazolyl]benzaldehyde (0.660 g, yield 52%) as colorless needle crystals. melting point: 151–152° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[F:26][C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33]>>[F:26][C:27]1[CH:28]=[C:29]([O:34][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Fc1ccc(Oc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1F

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 3,4-difluorophenol according to the procedure described in Example 74 to afford 2-(3,4-difluorophenyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=463 (M++1); Rt=4.60 min; 1H-NMR 400 MHz (CDCl3): δ 7.05. (m, 3H), 7.19-7.30 (m, 6H), 7.39 (d, J=2 Hz, 1H), 8.60 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:17])=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[N:7]=2)[CH:14]=[CH:13][CH:12]=1)#[N:16]
Reactant: N#Cc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1cccc(O)c1
Product: N#Cc1cccc(Nc2nc(Nc3cccc(O)c3)ncc2F)c1
Yield: 62.2 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 3-aminobenzonitrile (142 mg, 1.2 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave 2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (128 mg, 86%) as a white solid. The reaction of 2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol) and 3-aminophenol (66 mg, 0.6 mmol) gave N4-(3-cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (acetone-d6): δ 6.48 (ddd, J=0.9, 2.4 and 7.8 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.18 (ddd, J=1.2, 2.1 and 8.1 Hz, 1H), 7.33 (t, J=2.1 Hz, 1H), 7.45 (dt, J=1.2 and 7.8 Hz, 1H), 7.54 (t, J=8.1 Hz, 1H), 8.08 (d, J=3.3 Hz, 1H), 8.14 (ddd, J=1.5, 2.7 and 8.4 Hz, 1H), 8.39 (t, J=2.1 Hz, 1H), 8.58 (s, 1H, NH), 8.84 (s, 1H, NH); 19F NMR (282 MHz, acetone-d6): δ −167.41; LCMS: ret. time: 17.75 min.; purity: 92.39%; MS (m/e): 322.59 (MH+).
Reaction SMILES: [C-:1]#[N:2].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[Co:13].[Cl-].[Zn+2:15].[Cl-]>O>[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[Co+3:13].[Co+3:13].[Zn+2:15].[Zn+2:15].[Zn+2:15]
Reactant: [Co]
Agent: [C-]#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: [Co+3]
Reaction time: 0.17 h

Procedure:
Potassium hexacyanocobaltate (4.0 g) is dissolved in deionized water (150 mL) in a beaker. Zinc chloride (10 g) is dissolved in deionized water (15 mL) in a second beaker. The aqueous solutions are quickly combined and magnetically stirred for 10 min. The precipitated solids are isolated by centrifugation. The solids are reslurried in deionized water (100 mL) for 10 min. with stirring, and are again recovered by centrifugation. The catalyst is dried in a vacuum oven at 50° C. and 30 in. (Hg) to constant weight. This catalyst is identified as Catalyst A.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C@@H:7]([CH2:10][CH2:11][CH2:12][OH:13])[C@H:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:15]=3[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:5]2)[O:3]C1.Cl>O1CCCC1>[CH2:29]([O:28][C:15]1[CH:16]=[C:17]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:19][C:14]=1[C@H:6]1[C@H:7]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][C:4](=[O:3])[CH2:5]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OCCC[C@@H]1CCC2(C[C@H]1c1ccc(OCc3ccccc3)cc1OCc1ccccc1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CC[C@@H](CCCO)[C@H](c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Yield: 92 %

Procedure:
A mixture of 5.17 g. (10.6 mmole) of trans-3-(2,4-dibenzyloxyphenyl)-4-(3-hydroxypropyl)cyclohexanone ethylene ketal, 50 ml. 1N hydrochloric acid and 100 ml. tetrahydrofuran was heated at reflux for one hour. The reaction was cooled, partially evaporated on a rotovapor and the residue diluted with 300 ml. saturated sodium chloride-300 ml. ether. The ether extract was washed with 300 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue was crystallized from diisopropyl ether to yield 4.32 g. (92%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=O)=O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=2)[CH:32]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)O
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
To 50 ml of anhydrous pyridine, was added 2.4 g of 2-methylbenzoic acid followed by 4.4 g of DCC under cooling in ice. After stirring for 30 minute and adding 5.0 g of 6-amidino-2-naphthol methanesulfonate, the mixture was stirred overnight at room temperature. The precipitate was collected by filtration and washed with a small volume of pyridine, then successively with ethylether and acetone. The precipitate was dissolved in DMF and the insolubles were removed by filtration. Ethylether was added to the filtrate and the precipitated crystals were recrystallized from ethanol to obtain 1.4 g of flaky colorless crystals of 6-amidino-2-naphthyl 2-methyl benzoate methanesulfonate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](OCC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)C>O1CCCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH:11]=[O:12]
Reactant: CCOC(=O)c1cnc2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A solution of ethyl 2-quinoxalinecarboxylate (10-1) (2.34 g, 11.6 mmol) in tetrahydrofuran (22 mL) was cooled to −78° C. This solution was treated with a 1.0 molar THF solution of lithium aluminum hydride (5.80 mL, 5.80 mmol) added over a period of 6 min. After 30 min, the reaction was quenched with glacial acetic acid (1.30 mL, 22.71 mmol). The reaction mixture was warmed to room temperature and diluted with water (14 mL). The water was extracted five times with ethyl acetate and the combined organics washed with brine and dried (Na2SO4). The solvent was removed in vacuo. Preparative centrifugal TLC (SiO2, 5 mm, CH2Cl2) afforded solid 10-2 (874 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[C@@H:21]2[CH2:25][C@H:24]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:23]([OH:31])[C@H:22]2[OH:32])=[C:14]([NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:13]=1.[N:48]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=2)[CH2:53][CH2:52][CH:51]([NH:54][C:55](N2C=CN=C2)=[O:56])[CH2:50][CH2:49]1>CC(O)C.C(Cl)Cl>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:42]1([CH:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][NH:33][C:14]2[N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:55]([NH:54][CH:51]3[CH2:50][CH2:49][N:48]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=4)[CH2:53][CH2:52]3)=[O:56])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[C@@H:21]2[CH2:25][C@H:24]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:23]([OH:31])[C@H:22]2[OH:32])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A solution of N-{(1S,2R,3S,4R)-4-[2-(2-amino-ethylamino)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide trifluoroacetate (Example 100) (27 mg, 37 μmol) in IPA (0.5 ml) is treated with imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (Intermediate C) (1.1 ml of a 10 mg/ml solution in DCM, 40 μmol). After stirring at room temperature for 7 days, the solvent is removed in vacuo and purification of the residue by C-18 reverse phase column chromatography eluting with acetonitrile:water:TFA (0.1%) (gradient of 0 to 100% acetonitrile) yields the title compound. (MH+ 748.6)
Reaction SMILES: [H-].[Na+].C1([O:9][C:10](=[O:34])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[C:14]([CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH:13]=2)C=CC=CC=1.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43]O)=[C:38]([CH2:45][CH3:46])[CH:37]=1>C1COCC1>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][O:9][C:10](=[O:34])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[C:14]([CH2:24][N:25]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH3:26])[CH:13]=2)=[C:38]([CH2:45][CH3:46])[CH:37]=1
Reactant: CCc1cc(Br)ccc1CCO
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1CCOC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
NaH (190 mg, 4.7 mmol) was added in one portion to a solution of 16G (547 mg, 1.2 mmol) and 36B (1000 mg, 4.4 mmol) in THF (20 mL) at −40° C. The reaction was warmed slowly to ambient temperature over 2 h and stirred for 15 h. The reaction was quenched with saturated citric acid and diluted with EtOAc. The mixture washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (0% to 100% EtOAc in hexanes) to afford 43A (650 mg, 92%) as a yellow solid. MS (ESI) m/z 597.1/599.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN1CCN(c2cccc(C(=O)Nc3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)n2)CC1
Temperature: 160 °C
Yield: 10.9 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). 1-methylpiperazine (0.029 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 4 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by using Mass Directed Automated Preparative HPLC (Method E). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (12.8 mg).
Reaction SMILES: [C:1]1([C:6]([CH2:8][C:9]#[N:10])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[Cl-].C([NH+](CC)CC)C>C1(C)C=CC=CC=1>[NH:11]1[C:9]([CH2:8][C:6]([C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)=[O:7])=[N:10][N:13]=[N:12]1
Reactant: N#CCC(=O)c1cccs1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(Cc1nnn[nH]1)c1cccs1
Yield: 43.5 %

Procedure:
A mixture of 2-thenoylacetonitrile (9 g, 59.3 mmol), Sodium azide (4.33 g, 66.7 mmol) and triethylammoniumchloride (9.14 g, 66.9 mmol) was stirred in dry toluene (139 mL) under argon atmosphere at 90° C. for 18 hrs. A two-phase system was formed, cooled and extracted with NaOH (2M, 3×500 mL), and the aqueous solution was poured into hydrochloric acid (4M, 300 mL) and the crude tetrazole was filtered off and recrystalised from acetonitrile. Yield: 43.5%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH3:14])[C:7]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:6]=3[C:5]=2[CH:4]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].[OH-].[Na+]>>[CH3:1][N:2]([C:3]1[CH:11]=[CH:10][C:9]2[N:8](/[CH:12]=[C:13](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:14])[C:7]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:6]=3[C:5]=2[CH:4]=1)[C:26](=[O:28])[CH3:27]
Reactant: CNc1ccc2c(c1)c1c(n2C=C(C)c2ccncc2)CCN(C)C1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(C)c1ccc2c(c1)c1c(n2/C=C(\C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,3,4,5-Tetrahydro-N, 2-dimethyl-5-(2-(pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indol-8-amine (23 mg) was charged in round bottom flask and acetic anhydride (0.7 mL) was added. The contents were stirred at RT for 30 min. The reaction mixture was basified with 1N NaOH and compound extracted with EtOAc (2×25 mL). The organic layer was concentrated under vacuum and recrystallized in DCM:Hexane (1:3) to yield 2.38 mg of desired compound. 1H NMR (CDCl3, free base) δ (ppm): 8.62 (d, 2H), 7.42 (d, 2H), 7.25 (s, 1H), 7.10 (dd, 2H), 6.98 (d, 1H), 3.70 (s, 2H), 3.30 (s, 3H), 2.82 (m, 4H), 3.60 (s, 3H), 2.04 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]#N)=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:30][Si:31]([C:34]#C)([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>CC#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][Si:31]([C:34]#[C:28][C:26]1[CH:25]=[CH:24][C:23]2[N:19]([CH2:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:20]=[N:21][C:22]=2[CH:27]=1)([CH3:33])[CH3:32]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (109 mg, 0.24 mmol) from Step 6 of Example 108, (trimethylsilyl)acetylene (68 μL, 0.48 mmol), and DIEA (62 μL, 0.36 mmol) in CH3CN (2 mL), was purged with a stream of argon for 5 min. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.05 mmol) and argon was bubbled into the mixture for an additional 5 min. The reaction vessel was sealed and the mixture was heated at 80° C. for 5 h. The mixture was cooled to rt and was partitioned between EtOAc (100 mL) and 1 M aq NaHCO3 (50 mL). The organic layer was washed with brine (50 mL), dried over Mg2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford (1R,2R)-2-((6-((5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (61 mg, 54%) as an amber oil. LCMS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:16](OCC)(=[O:20])[C:17]([CH3:19])=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:15]=[C:17]([CH3:19])[C:16]2=[O:20])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Nc2ccccc2N)cc1
Reactant: CCOC(=O)C(C)=O
Product: Cc1nc2ccccc2n(-c2ccc(N)cc2)c1=O

Procedure:
Preparation as in Example 1 but using N-(4-aminophenyl)benzene-1,2-diamine and ethyl pyruvate gave the title compound mp 269°-271° C.