Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:6]([Cl:17])[CH:5]=[CH:4][CH:3]=1.[N:18]([O-])=O.[Na+]>O.Cl>[ClH:17].[Cl:17][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][NH2:18])[C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: CC1(C)CON(Cc2c(N)cccc2Cl)C1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CON(Cc2c(Cl)cccc2NN)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a stirred solution of concentrated hydrochloric acid (50 ml) was added 2-[(6-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (4.9 g, 0.019 mole). The reaction mixture was cooled to 0° C., and a solution of sodium nitrite (1.3 g, 0.019 mole) in water (20 ml) was added dropwise, with the tip of the addition funnel below the surface of solution. Upon completion of addition, the reaction mixture was stirred at 0° C. for 30 minutes. A solution of stannous chloride dihydrate (9.5 g, 0.042 mole) in concentrated hydrochloric acid (30 ml) was then added dropwise. Upon completion of addition, the reaction mixture was stirred at 0° C. for one hour, after which time an insoluble material was removed by filtration. Ethyl acetate was added to the filtrate and more insoluble material was removed. The ethyl acetate mixture was concentrated under reduced pressure, made basic with aqueous sodium hydroxide, and extracted with methylene chloride. The methylene chloride extract was concentrated under reduced pressure. Concentrated hydrochloric acid was added to the residue and the mixture was concentrated under reduced pressure to yield 1.8 g of 2-[(2-chloro-6-hydrazinophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone hydrochloride as a yellow solid; m.p. 180°-184° C. (dec). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2SC(NCCF)=N[C:6]=2[CH:14]=1.[CH3:15][N:16](C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)[C:17](=[O:23])[O:18]C(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:6]1([O:23][C:17](=[O:18])[NH:16][CH3:15])[CH:5]=[CH:4][CH:3]=[CH:2][CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FCCNc1nc2cc(Br)ccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1ccccc1
Temperature: 95 °C
Yield: 198.5 %

Procedure:
A mixture of 5-Bromo-N-(2-fluoroethyl)benzo[d]thiazol-2-amine (60 mg, 0.2 mmol), tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (68 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol) in 2 mL dioxane and 0.5 mL of a 1 M Na2CO3 aqueous solution was heated at 95° C. in a microwave reactor for 10 min. After cooling to rt, it was diluted with EtOAc (30 mL) and washed with brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (5% to 50% EtOAc in hexane) to afford tert-butyl 44242-fluoroethylamino)benzo[d]thiazol-5-yl)phenyl(methyl)carbamate as a white solid (60 mg, 75%). MS (ESI) m/z 402 (M+H+).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:20]([NH:22][C:23](=O)[O:24]C1C=CC=CC=1)[CH3:21]>CN(C)C=O>[CH2:20]([NH:22][C:23]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:24])[CH3:21]
Reactant: CCNC(=O)Oc1ccccc1
Reactant: Nc1nccc(Oc2ccc3[nH]ccc3c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(N)n3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Sodium hydride (157 mg, 3.93 mmol) was suspended in N,N-dimethylformamide (10 ml) under nitrogen atmosphere, and 4-(1H-5-indolyloxy)-2-pyrimidinamine (826 mg, 3.65 mmol) was gradually added while the reaction mixture was stirred at room temperature. After 10 minutes, the reaction mixture was cooled with an ice-water bath, phenyl N-ethylcarbamate (633 mg, 3.83 mmol) was added, the reaction mixture was heated to room temperature, and the solution was stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography (eluent; ethyl acetate:hexane=3:1 to 4:1) to yield the title compound (691 mg, 2.32 mmol, 63.7%) as white powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH:37]=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[Br:21][C:20]([Br:24])=[CH:37][C@@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of triphenylphosphine (21.1 g, 80.3 mmol) and carbon tetrabromide (13.32 g, 40.16 mmol) in dichloromethane (300 mL) at 0° C. was treated with a solution of 2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (4.0 g, 20.08 mmol) in dichloromethane (10 mL) dropwise via syringe. The solution was stirred for 1 hour at room temperature, poured into a saturated sodium bicarbonate solution and separated. The organic phase was dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel using 0-1% methanol/dichloromethane to give 6.13 g (86% yield) of the desired product. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.47 (s, 9H), 1.81 (m, 3H), 2.16 (m, 1H), 3.39 (m, 2H), 4.37 (s, 1H), 6.38 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11](F)=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])[N:5]2[N:24]=[CH:25][N:26]=[C:4]2[N:3]=1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][OH:32].[H-].[Na+].O>CS(C)=O>[Br:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:32][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:20])[F:21])[N:5]2[N:24]=[CH:25][N:26]=[C:4]2[N:3]=1
Reactant: CN(C)CCCO
Reactant: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Br)nc2ncnn12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](Nc1c(-c2c(F)cc(OCCCN(C)C)cc2F)c(Br)nc2ncnn12)C(F)(F)F
Temperature: 60 °C
Yield: 78.3 %

Procedure:
To a solution of 5-bromo-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine (44 mg, 0.1 mmol) and 3-dimethylamino-1-propanol (51 m g, 0.5 mmol) in 1 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 20 mg, 0.5 mmol). The mixture is heated at 60° C. for 2 h, and cooled to room temperature. Water is added to quench the reaction, and the product is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride (x3), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 30% methyl alcohol in ethyl acetate. Concentration provides 5-bromo-6-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a light tan solid (41 mg, mp 40-42° C.). MS: m/z 523.1, 525.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=O)[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][C:9]3[C:10]=2[O:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[N:14]([CH3:17])[C:15]=3[N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[CH:7]=1
Reactant: CCNCC
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCN(CC)C1=C2N=c3cc(Cl)ccc3=C2Oc2ccccc2N1C

Procedure:
In the same way as described in example 1, 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepine-6(5H)-one, phosphorous pentachloride and diethylamine were reacted and the solid product recrystallized from methanol for analysis, mp. 127°-8°.
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[O:32][C:31]([CH3:34])([CH3:33])[CH:30]=[CH:29][C:12]2=[C:13]2[C:22]=1[C:21](=[O:23])[C:20]1[C:15](=[CH:16][CH:17]=[C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]3=1)[N:14]2[CH3:28].[OH2:35]>CC(C)=O>[OH:35][CH:30]1[C:31]([CH3:34])([CH3:33])[O:32][C:11]2[C:12](=[C:13]3[C:22](=[C:9]([O:8][CH3:7])[CH:10]=2)[C:21](=[O:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]4[CH:27]=[CH:26][CH:25]=[CH:24][C:19]4=2)[N:14]3[CH3:28])[C:29]1=[O:1]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C=CC(C)(C)O2
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(=O)C(O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Over a period of 30 minutes, add a suspension of 1.28 g of KMnO4 in 15 ml of water dropwise to a solution of 0.5 g of the product of Example 3 dissolved in 25 ml of acetone. The reaction mixture is stirred at ambient temperature for 8 hours and then, after extraction and conventional treatment, the expected product is isolated by chromatography of the residue over silica gel (dichloromethane/methanol: 98/2).
Reaction SMILES: C(O)(=O)C(O)=O.[OH:7][CH2:8][CH:9]1[C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12][NH:11][CH2:10]1.[C:22](=[S:24])=[S:23].CI.[CH2:27](N(CC)CC)C>CS(C)=O>[OH:7][CH2:8][CH:9]1[C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12][N:11]([C:22]([S:24][CH3:27])=[S:23])[CH2:10]1
Reactant: S=C=S
Reactant: CCN(CC)CC
Reactant: OCC1CNCc2[nH]c3ccccc3c21
Agent: O=C(O)C(=O)O
Solvent: CS(C)=O
Solvent: CI
Product: CSC(=S)N1Cc2[nH]c3ccccc3c2C(CO)C1
Yield: 58 %

Procedure:
146 mg of (4RS)-4-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline oxalate, 0.06 ml of carbon disulfide, 0.06 ml of methyl iodide, 0.14 ml of triethylamine and 2 ml of dimethylsulfoxide are treated in the same manner as described in Example 17. 85 mg of methyl (4RS)-4-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-2-carbodithioate are obtained as pale yellow powder. Yield: 58%
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[F:25][C:26]([F:44])([F:43])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]2)=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:43][C:26]([F:25])([F:44])[C:27]1[CH:28]=[CH:29][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:41])[CH2:36][CH2:35]2)=[CH:31][CH:32]=1
Reactant: O=C(Cl)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@](O)(COC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (1.54 g, 7.01 mmol), N,N-diisopropylethylamine (1.63 ml, 9.34 mmol) and 4-dimethylaminopyridine (0.11 g, 0.93 mmol) were added to a suspension of 4-(4-trifluoromethylphenylamino)piperidine-1-carbonylchloride (1.43 g, 4.67 mmol) in toluene (30 ml) followed by stirring at 100° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenylamino)piperidine-1-carboxylate (1.44 g, yield 61%) as a light yellow oil.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[CH:32]=1.[C:39]([BH3-])#[N:40].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:40]([CH2:39][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)[CH2:37][C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: O=Cc1cccnc1
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: [BH3-]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3cccnc3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
The compound (100 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with pyridin-3-aldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (44.8 μl), followed by the addition of sodium cyanoborohydride (44.9 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 65 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (95.8 mg) of the subject compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:11]=[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:29])[C:25]([F:28])([F:26])[F:27])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:9][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7]
Reactant: N#Cc1ccc[nH]1
Reactant: O=C(CBr)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cccn1CC(=O)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1H-Pyrrole-2-carbonitrile (0.84 ml; 9.42 mmol) and 1-{4-[4-(2-bromo-acetyl)phenyl]-piperidin-1-yl}-2,2,2-trifluoro-ethanone (2.74 g; 7.25 mmol) are dissolved in acetone (25 ml). To this clear brown solution potassium carbonate (2 g; 14.49 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is filtered off by suction and washed with acetone. The filtrate is evaporated to dryness. The residue is purified by flash chromatography to afford 1-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carbonitrile as pale off-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH2:26])[CH:20]=[CH:19]2.[S:27]1[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:32]([C:29]1[CH:30]=[CH:31][S:27][CH:28]=1)=[O:33])[CH:20]=[CH:19]2
Reactant: O=C(O)c1ccsc1
Reactant: COc1cc2nccc(Cc3ccc4cc(N)ccc4c3)c2cc1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Cc3ccc4cc(NC(=O)c5ccsc5)ccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(6,7-dimethoxy-quinolin-4-ylmethyl)-naphthalen-2-ylamine (Step g, 36 mg, 0.10 mmol) and 3-thiophenecarboxylic acid (15 mg, 0.115 mmol) in CH2Cl2 (1 mL), was added PyBop (163 mg, 0.314 mmol) and Et3N (44 μL, 0.314 mmol). The mixture was stirred at RT overnight. The solvent was evaporated and the crude material was purified by Prep-TLC with EtOAc/CH2Cl2 (3:2) to give the desired product. MS (ESI, pos. ion) m/z: 455.1 (M+1). Calc'd for C27H22N2O3S: 454.14.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4]1.CN(C)C=O.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:21][CH:22]=1>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:9][CH:5]3[CH2:6][CH2:7][CH2:8][CH:3]([OH:10])[CH2:4]3)[N:19]=2)=[CH:28][CH:27]=1
Reactant: OC1CCCC(O)C1
Reactant: Fc1ccc(-c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OC1CCCC(OCc2coc(-c3ccc(F)cc3)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
With ice-cooling, initially 2.25 g of an 80 percent suspension of sodium hydride and then 5.8 g of 1,3-cyclohexanediol were added to a mixture of 50 ml of dimethylformamide and 50 ml of tetrahydrofuran. The mixture was stirred at about 25° C. for 3 hours. 10.5 g of 4-chloromethyl-2-(4-fluorophenyl)oxazole (1) was then added, the mixture was heated at 70° C. and the reaction was monitored by thin-layer chromatography. After the reaction ended, the mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was separated off, dried and concentrated and the residue was purified on silica gel by flash chromatography (ethyl acetate/n-heptane=1:1). This gave the alcohol 3 as an oil. C16H18FNO3 (291.33) MS(ESI): 292 (M+H+). Methyl 2-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-6-methylbenzoate 5
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([OH:13])=[O:12].[Cl:14][CH2:15][CH2:16][CH3:17].[N:18]1([C:24](=[O:26])[CH3:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>ClCCl>[Cl:14][CH2:15][CH2:16][CH2:17][O:13][C:11]([N:21]1[CH2:22][CH2:23][N:18]([C:24](=[O:26])[CH3:25])[CH2:19][CH2:20]1)=[O:12]
Reactant: CCCCl
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)OCCCCl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N′-diisopropylethylamine (0.10 mL, 6 mmol), followed by 3-chloropropane chloroformate (47.1 mg, 0.3 mmol) was added to a 5 mL glass vial containing 1-piperazin-1-yl-ethanone (38 mg, 0.3 mmol) dissolved in dichloromethane (1 mL). The reaction mixture was shaken at room temperature for about 0.5 h, then evaporated in vacuo to yield the title intermediate as an oily residue which was used without further treatment.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9]O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][N:3]=1.C(Cl)(Cl)[Cl:18]>O(Cl)Cl.[P]>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][Cl:18])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][N:3]=1
Reactant: ClC(Cl)Cl
Reactant: OCCc1c(Cl)ncnc1-c1ccccc1
Agent: ClOCl
Agent: [P]
Product: ClCCc1c(Cl)ncnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4-chloro-6-phenylpyrimidin-5-yl)ethanol (340 mg) in dry chloroform (10 mL), phosphorus oxy chloride (2 mL) was slowly added under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours and solvents were removed under reduced pressure. The resulting oil was diluted with dichloromethane (50 mL), washed with 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to gave crude 4-chloro-5-(2-chloroethyl)-6-phenylpyrimidine (150 mg) as viscous liquid, which was used as was. 1H NMR (DMSO-d6): δ 2.89-2.94 (t, 2H), 3.54-3.55 (t, 2H), 7.48-7.59 (m, 5H), 8.91 (s, 1H).
Reaction SMILES: [C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[N:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[C@:22]([CH3:26])([CH2:24][CH3:25])[NH2:23])=[CH:16][N:15]=3)[O:6][CH2:5][CH2:4]1)[CH2:3][CH2:2]2.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[N:19]=[CH:18][C:17]([N:20]4[C:21](=[O:27])[C@:22]([CH2:24][CH3:25])([CH3:26])[NH:23][C:29]4=[O:31])=[CH:16][N:15]=3)[O:6][CH2:5][CH2:4]1)[CH2:2][CH2:3]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@](C)(N)C(=O)Nc1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2cnc(Oc3cccc4c3C3(CCO4)CC3)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 155.5 %

Procedure:
To a solution of N1-[2-(2,3-dihydrospiro[chromene-4,1′-cyclopropan]-5-yloxy)-5-pyrimidinyl]-D-isovalinamide (Intermediate 225, 4 mg, 10.86 μmol) in dry Dichloromethane (1 mL) TEA (3.78 μL, 0.027 mmol) was added. The reaction was cooled in an ice-bath, then a solution of triphosgene (1.450 mg, 4.89 μmol) in dry Dichloromethane (0.250 mL) was added once then two other times with 10 minutes in between. The reaction was stirred at 0° C. for 40 minutes, then it was quenched with water (5 mL) maintaining the reaction in the ice-bath. The organic layer was separated, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using a column isolute 2 g and cyclohexane to cyclohexane/ethyl acetate 1:1 as eluent affording the title compound (3 mg,) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>CO>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH:29][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:3]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CO
Product: COc1ccc(CCNc2nc(N3CCOCC3)c3nc[nH]c3n2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
As shown in Scheme 3 above, a mixture of 2,6-dichloropurine (1.90 g, 10 mmol) and morpholine (2.34 g, 30 mmol) in water (25 mL) was heated under reflux for 15 min. Solidified reaction mixture was cooled to room temperature. Solid was filtered out and washed with water, methanol and ether. The 2-chloro-6-morpholin-4-yl-9H-purine was obtained in 96% yield (2.30 g). A mixture of 2-chloro-6-morpholin-4-yl-9H-purine (1.92 g, 8 mmol) and 2-(3,4-dimethoxyphenyl)ethylamine (4.35 g, 24 mmol) in sealed tube and under nitrogen was stirred at 190–195° C. for 1 hour. The reaction mixture turned to clear solution initially and then formed a slurry. The reaction mixture was cooled to room temperature diluted with methanol (8 mL) and the solid was collected by filtration, washed with methanol and Et2O and dried to afford 2.30 g (74% yield) of [2-(3,4-dimethoxy-phenyl)-ethyl]-(6-morpholin-4-yl-9H-purin-2-yl)amine.