Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[S:5][C:6]([SH:9])=[CH:7][CH:8]=1.[Cl:10][CH2:11][CH2:12]Br>C(OCC)(=O)C>[Cl:3][C:4]1[S:5][C:6]([S:9][CH2:12][CH2:11][Cl:10])=[CH:7][CH:8]=1
Reactant: Sc1ccc(Cl)s1
Reactant: ClCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: ClCCSc1ccc(Cl)s1
Reaction time: 16 h

Procedure:
28 cm3 of a 5N aqueous sodium hydroxide solution were added, with stirring, to a solution, cooled to a temperature in the region of 5° C., of 17.9 g of 2-chloro-5-thiophenethiol in 30 cm3 of 1-chloro-2-bromoethane, and then the temperature was allowed to return to the region of 20° C., while stirring was continued for 16 hours. The reaction mixture was diluted with 300 cm3 of ethyl acetate and washed with 3 times 150 cm3 of water. The organic solution was dried over sodium sulfate, filtered, and evaporated under reduced pressure (5 kPa) at a temperature in the region of 45° C. 20.6 g of 2-chloro-5-(2-chloroethylthio)thiophene were obtained in the form of an oil with a brown color.
Reaction SMILES: [C:1](Cl)(=O)[O:2]C1C=CC([N+]([O-])=O)=CC=1.[NH2:14][C:15]1[CH:44]=[CH:43][C:18]([CH:19]=[C:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.[NH2:45][CH2:46][C:47]([CH3:50])([OH:49])[CH3:48]>O1CCOCC1>[F:37][C:34]([F:35])([F:36])[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:23]2[CH2:22][CH2:21][C:20](=[CH:19][C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:1]([NH:45][CH2:46][C:47]([OH:49])([CH3:50])[CH3:48])=[O:2])=[CH:44][CH:43]=3)[CH2:25][CH2:24]2)=[CH:28][CH:29]=1)([OH:42])[C:38]([F:41])([F:39])[F:40]
Reactant: CC(C)(O)CN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C=C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: C1COCCO1
Product: CC(C)(O)CNC(=O)Nc1ccc(C=C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
4-Nitrophenyl carbonochloridate (0.225 mmol, 45.4 mg) was added to a stirred solution of 2-(4-((4-(4-aminobenzylidene)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.225 mmol, 100 mg) in dioxane (1 mL) and the mixture stirred at room temperature for 1 hour. 1-Amino-2-methylpropan-2-ol (0.675 mmol, 60.2 mg) was added and the mixture stirred at room temperature for 1.5 hours. The mixture was washed with water (1 mL), the organic phase dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by HPLC and treated with strong cation exchange column to afford the title compound (17 mg). MS (ESI) m/z 560.2 [M+H]+
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[F:22][C:23]1[C:24]([CH3:30])=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[F:22][C:23]1[C:24]([CH3:30])=[C:25]([NH:26][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])[CH:27]=[CH:28][CH:29]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: Cc1c(N)cccc1F
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: Cc1c(F)cccc1NS(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 3.4 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 63 μL (0.55 mmol) of 3-fluoro-2-methylaniline. After purification by chromatography on silica (eluent dichloromethane/methanol 96/4) then trituration in diethyl ether, 3.5 mg (2%) of 8-(3-fluoro-2-methyl-phenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:33]=[CH:32][CH:31]=[CH:30][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C@@H:24]([C:26](=O)[NH2:27])[CH3:25])=[CH:19][C:18]=3[F:29])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[CH2:35]Cl.[CH3:37][OH:38].ClCCl>>[CH2:37]([O:38][C:26](=[NH:27])[C@H:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:13]([C:12]2[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:33][CH:32]=[CH:31][CH:30]=2)=[O:14])=[C:18]([F:29])[CH:19]=1)[CH3:25])[CH3:35]
Reactant: CO
Reactant: ClCCl
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(N)=O
Product: CCOC(=N)[C@@H](C)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a stirred solution of (R)-2-(benzo[1,3]dioxol-5-yloxy)-N-[4-(1-carbamoyl-ethoxy)-2-fluoro-benzyl]-nicotinamide (0.4 g, 0.88 mmol) in dichloromethane (20 ml)triethyloxonium tetrafluoroborate (0.17 g, 0.88 mmol) was added. The reaction was stirred at room temperature 16 h. The reaction was adsorbed onto a small amount of silica gel and column chromatography (2% methanol/dichloromethane) afforded 160 mg of the desired product as a colorless oil (38% yield).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)([O:5][CH3:6])=[O:4].Cl.[C:27]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])([CH3:30])([CH3:29])[CH3:28].OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][P:3]([CH2:7][NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[C:10]([NH:35][CH2:34][CH2:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:36])=[O:12])([O:5][CH3:6])=[O:4]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OC(C)(C)C)OC

Procedure:
A solution of 2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionic acid (2.27 g, 6.25 mmol), β-alanine t-butyl ester hydrochloride (1.36 g, 7.5 mmol), hydroxybenzotriazole (1.05 g, 6.85 mmol), triethylamine (2.41 mL, 17.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.6 g, 8.22 mmol) in dimethylformamide (60 mL) is stirred for 3 hours at room temperature, then diluted with ethyl acetate, washed with ice water, dried (Na2SO4) and chromatographed on silica gel [CH2Cl2 :MeOH:hexanes/76:4:20] to obtain t-butyl N-[2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20].COCCOC>O>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@@:8]2([C:17]3[C:5](=[CH:4][CH:3]=[C:2]([C:25]4[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:20])[CH:18]=3)[CH2:6][CH2:7]2)[N:9]=1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Reactant: N#Cc1cccc(B(O)O)c1
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(-c2ccc3c(c2)[C@@]2(CC3)N=C(N)OCC2(F)F)c1
Yield: 10 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with 3-cyanophenylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (10% yield) as an off-white solid. MS (ISP): m/z=340.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:19][CH:20](Br)[CH3:21]>O1CCCC1.CCCCC>[Br:19][CH2:20][CH2:21][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: BrCCc1cccc2c1Cc1ccccc1-2
Reaction time: 1 h

Procedure:
In this reaction, 8.3 g (0.05 m) of fluorene was dissolved in 150 ml of tetrahydrofuran. Then 31.8 ml (0.05 m) of butyl lithium (1.6 molar in hexane) was added dropwise to this solution. After one hour, this solution was added gradually to a stirred solution of 9 ml (0.1 m) of dibromoethane in 300 ml of pentane within 2 hours. Then the reaction mixture was treated with 50 ml of an
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]1=[S:24].[I:25]I>C1COCC1.[Cl-].[NH4+]>[I:25][C:22]1[N:17]([CH2:16][CH2:15][O:14][CH3:13])[C:18](=[S:24])[NH:19][C:20](=[O:23])[CH:21]=1
Reactant: COCCn1ccc(=O)[nH]c1=S
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCCn1c(I)cc(=O)[nH]c1=S
Temperature: -20 °C
Reaction time: 20 h
Yield: 108 %

Procedure:
To a stirring solution of diisopropylamine (8.3 mL, 59.10 mmol) in THF (50 mL) was added n-butyl lithium (2N in hexanes, 30.0 mL, 60.0 mmol) dropwise at −78° C. under argon. The reaction mixture was slowly warmed to −20° C. and then cooled to −78° C. A solution of 1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (5.0 g, 26.85 mmol) in THF (50 mL) was added dropwise at −78° C. The reaction mixture was slowly warmed to −10° C. over 1 hour and then cooled to −78° C. A solution of iodine (15.0 g, 59.07 mmol) in THF (50 mL) was added at −78° C. and the reaction mixture was stirred at room temperature for 20 hours. Reaction was diluted with saturated aqueous ammonium chloride (200 mL) and the organic solvents were removed under reduced pressure. The aqueous residue was acidified to pH 4 with 1N aqueous HCl and extracted with CH2Cl2 (3×300 mL, 1×200 mL). The combined organic layers were washed with 10% aqueous sodium thiosulfate solution (400 mL), brine (300 mL), dried over MgSO4 and concentrated in vacuo. The resulting residue was stirred in CH2Cl2 at room temperature and solids were collected by filtration to give the title compound (9.05 g, 54%) as a pale brown solid. The filtrate was concentrated and purified by flash chromatography (0-25% CH2Cl2/EtOAc) to afford a second batch of the title compound (3.10 g, 18%) as a cream colored solid (72% combined yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]([NH2:11])=[S:10])=[C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:4][CH:3]=1.[CH3:18][I:19]>CC(C)=O>[IH:19].[CH3:18][S:10][C:9](=[NH:11])[NH:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CI
Reactant: Cc1cccc(N2CCOCC2)c1NC(N)=S
Solvent: CC(C)=O
Product: CSC(=N)Nc1c(C)cccc1N1CCOCC1
Product: I

Procedure:
A mixture of 1-(6-methyl-2-morpholinophenyl)thiourea (9 g) and methyl iodide (2.5 ml) in dry acetone (100 ml) was heated at reflux at 90°-95° C. for 2.5 hours to give 2-methyl-1-(6-methyl-2-morpholinophenyl)-2-thiopseudourea hydroiodide.
Reaction SMILES: [C@@H:1]12[CH2:7][N:6](C(OC(C)(C)C)=O)[C@@H:5]1[CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:2]2.FC(F)(F)C(O)=O>C(Cl)Cl>[C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:2]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(C(=O)OCc3ccccc3)C[C@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Yield: 39.8 %

Procedure:
The product of Example 38I (1.0 g, 6.92 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (5 mL) at room temperature for 1 hour. The mixture was concentrated and the residue was diluted with CHCl3 (50 mL). The brown chloroform solution was washed with saturated aqueous NaHCO3 (2×20 mL, pH=8-9) and brine (5 mL), dried (MgSO4), filtered, and the filtrate concentrated to provide the title compound as a brown oil (0.64 g, 97% yield) which was used in the next step without purification. 1H NMR (MeOH-d4, 300 MHz) δ 3.30-3.16 (m, 3H), 3.36 (m, 1H), 3.80 (m, 3H), 4.45 (dd, J=6.4 Hz, 4.8 Hz, 1H), 5.16 (s, 2H), 7.36 (m, 5H); MS (DCI/NH3) m/z 250 (M+NH4)+. 233 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([CH:20](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:33][S-:34].[Na+]>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH:18]([CH:20]([S:34][CH3:33])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C[S-]
Reactant: Cc1ccc(S(=O)(=O)OC(C)C(C)n2c(C)c(C(=O)OC(C)(C)C)c3ccccc32)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
A mixture of compound tert-butyl 2-methyl-1-(3-(tosyloxy)butan-2-yl)-1H-indole-3-carboxylate (200 mg, 0.43 mmol) in N,N-dimethyl formamide (2 mL) was added sodium methanethiolate (994 mg, 1.44 mmol). The reaction mixture was stirred at 110° C. for 4 hours. The reaction was quenched by adding water (6 mL). The aqueous layer was extracted with ethyl acetate (30 mL×3), and the organic layer was concentrated. The crude product was purified by preparative TLC (elute: petroleum/ethyl acetate:5:1) to give product tert-butyl 2-methyl-1-(3-(methylthio)butan-2-yl)-1H-indole-3-carboxylate (100 mg, yield: 68%). LRMS (M+H+) m/z: calc'd 333.18. found 334.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([OH:26])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=C(F)C=1.[S:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:56]3[CH2:57][CH2:58][S:54][CH2:55]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Reactant: C1CSCN1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1

Procedure:
130 mg (0.30 mmol) of the compound of Example 39A is reacted analogously to the synthesis of the compound of Example 1 with 0.03 ml (0.33 mmol) of thiazolidine. 116 mg (77% of theory) of the title compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S1C=CC=C1[Cl:17].CCOCC>CN(C)C=O>[N+:1]([C:4]1[O:8][C:7]([C:9]([Cl:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: Clc1cccs1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc([N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3.00 g. of 5-nitro-2-furan-carboxylic acid and 2.06 ml. of thienyl chloride in 50 ml. ether is added 0.45 ml. of dimethyl formamide. The reaction mixture is stirred overnight, under nitrogen, at room temperature. The ether solution is then decanted and the solvent removed to yield 5-nitro-2-furancarboxylic acid chloride, which is then dissolved in 50 ml. ether at 0° . To this solution is added, under nitrogen, 2.06 g. of cyclopropanemethyl alcohol and 3.1 of pyridine. The reaction mixture is allowed to warm to room temperature and is stirred for six days. Ether and water is added to the reaction mixture, the ether layer is decanted, and the aqueous phase is extracted once with ether. The combined organic phases are washed with 2N sulfuric acid, sodium carbonate, water, saturated copper sulfate, and brine, dried over calcium sulfate and the solvent removed to give 3.36 g. of cyclopropanemethyl 5-nitro-2-furancarboxylate, melting point 78°-80°.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.N1C=CN=C1.[Cl:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:25]=2)[N:20]=1.[OH:34][CH:35]([CH2:44][CH3:45])[CH2:36][NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH2:30][CH2:31][CH2:32][NH:33][C:6]([N:37]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:36][CH:35]([OH:34])[CH2:44][CH3:45])=[O:7])[CH:25]=2)[N:20]=1
Reactant: CCC(O)CNC1CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCOc1ccc2nc(Cl)ccc2c1
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CCC(O)CN(C(=O)NCCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.6 %

Procedure:
To a solution of N,N-carbonyldimidazole (2.1 g) and imidazole (1.9 g) in chloroform (100 ml) is added dropwise with stirring a solution of 2-chloro-6-(3-aminopropoxy)quinoline (3 g) in chloroform (40 ml) at -10° C. The mixture is stirred at room temperature overnight, and thereto is added dropwise a solution of N-(2-hydroxybutyl)-N-cyclohexylamine (2.9 g) in chloroform (10 ml). The mixture is stirred at room temperature for one hour, and refluxed for 2.5 hours. The mixture is allowed to cool, and the chloroform layer is washed successively with diluted hydrochloric acid, water and a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and evaporated to remove the solvent to give 2-chloro-6-{3-[3-cyclohexyl-3-(2-hydroxybutyl)ureido]propoxy}quinoline (6.8 g) as a colorless oil.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22])#N.C1C=CC2N(O)N=[N:33][C:31]=2C=1.CCN=C=NCCCN(C)C.[C:48]([NH2:52])([CH3:51])([CH3:50])[CH3:49]>>[C:48]([NH:52][C:21]([C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:3][CH:4]=3)[N:8]([CH:12]3[CH2:17][CH2:16][CH:15]([C:31]#[N:33])[CH2:14][O:13]3)[N:7]=2)[CH:19]=1)=[O:22])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)N
Reactant: On1nnc2ccccc21
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(C(=O)O)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)NC(=O)c1cccc(-c2nn(C3CCC(C#N)CO3)c3ccccc23)c1
Yield: 77.8 %

Procedure:
Following Example 357, the reaction of 3-(5-cyano-1-perhydro-2H-pyran-2-yl-1H-indazol-3-yl)benzoic acid (0.8 g, 2.3 mmol), HOBT (1.16 g, 8.62 mmol), EDCI (1.64 g, 8.62 mmol) and tert-butylamine (0.73 mL, 0.5 g, 6.9 mmol) furnished 0.72 g (74% yield) of the title compound. ES-MS (m/z) 403 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:18]#[N:19])=[CH:6]3.[N-:21]=[N+:22]=[N-:23].[Na+]>C(O)(C)C.O.[Cl-].[Zn+2].[Cl-]>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:18]1[NH:23][N:22]=[N:21][N:19]=1)=[CH:6]3
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: O
Product: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(-c4nnn[nH]4)cn1c23
Temperature: 110 °C
Yield: 60.2 %

Procedure:
To a mixture of nitrile 5 (40 mg, 0.14 mmol) in isopropanol and water (1:1 v/v, 15 ml) were added 20 mg of sodium azide (0.29 mmole) and 22 mg of zinc chloride (0.29 mmole). The mixture was heated to 110° C. for 18 h. The precipitates were collected by filtration and washed with water. The solid was dried under vacuum to give 27 mg (60% yield) of 13. This title compound was used without further purification in the next step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[CH:41]=[C:40]([C:42]([OH:44])=[O:43])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:45][CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:61][N:62]([CH3:67])[CH2:63][CH2:64][CH2:65][NH2:66]>CN(C=O)C>[CH:42]([OH:44])=[O:43].[CH3:61][N:62]([CH3:67])[CH2:63][CH2:64][CH2:65][NH:66][C:42]([C:40]1[S:39][C:35]2[N:36]=[CH:37][N:38]=[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[O:45][CH:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)[C:34]=2[CH:41]=1)=[O:43]
Reactant: CN(C)CCCN
Reactant: O=C(O)c1cc2c(Nc3ccc(F)cc3OC3CCOCC3)ncnc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1cc2c(Nc3ccc(F)cc3OC3CCOCC3)ncnc2s1
Product: O=CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
HATU (0.054 g, 0.14 mmol) was added into a solution of 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.050 g, 0.13 mmol) and Hünig's base (22 μL, 0.13 mmol) in anhydrous DMF (1.0 mL) at 0° C. After 0.5 hours, 3-dimethylamino-1-propylamine (71 μL, 0.64 mmol) was added and the solution allowed to warm to ambient temperature over night. The reaction was concentrated in vacuo and the residue redissolved in dimethyl sulfoxide. The sample was purified by reverse phase preparative HPLC to yield off-white solid (0.007 g, 11%) as the mono-formate salt.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Nc1nc(NCc2ccccc2)nc2c1ncn2Cc1ccccc1
Yield: 67.2 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and benzylamine (825 mg, 7.70 mmol) in 1-butanol (10 ml) were refluxed on heating for 8 hours. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (171 mg, yield 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][NH:27][CH:28]=[CH:29][C:30](=[O:32])[CH3:31])[CH:23]=[CH:24][CH:25]=1>>[C:30]([C:29]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:27]([CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=2)[CH:28]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)C=CNCc1cccc(Cl)c1
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3cccc(Cl)c3)C=C1C(C)=O)C2=O

Procedure:
The title compound 63 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 64 (90 mg, 0.42 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 63 as a yellow solid. (Yield 70 mg, 39%).