Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CO>[N:10]1([C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: C1CNC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(N2CCC2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
In a 25 mL sealable tube were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol), azetidine (0.21 mL, 3.05 mmol), and triethylamine (1.06 mL, 7.62 mmol) in CH3OH (10 mL). The vial was sealed and the reaction mixture was stirred overnight at 50° C. The reaction was concentrated and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (314 mg, 53%) as a yellow solid. LC-MS (ES) m/z=185 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:12][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CCCC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C1(C)CCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a suspension of ethyl 2-oxocyclopentanecarboxylate (20.3 g, 0.130 mol) and K2CO3 (53.8 g, 0.390 mol) in acetone (90 mL) was added MeI (36.9 g, 0.250 mol) at ambient temperature. The reaction mixture was stirred for 30 min at ambient temperature and then heated under reflux for 1 h. Acetone was removed under reduced pressure and diethyl ether (200 mL) was added to the residue. The resulting mixture was stirred for 15 min and filtered. The filtrate was concentrated under reduced pressure followed by distillation under vacuum to afford ethyl 1-methyl-2-oxocyclopentanecarboxylate (20.5 g, 92% yield).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:23][CH2:24][CH:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:26][CH2:27]1)#[N:20]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCCCC2)CC1
Reactant: O=C(O)c1cc2ccccc2s1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCC(N2CCCCC2)CC1
Yield: 27.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1.0 g) and 5-amino-2-(4-piperidinopiperidin-1-yl)benzonitrile (1.4 g), the title compound (0.6 g) was obtained. melting point: 275° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:16])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCNCC1
Reactant: Cc1cccc2c1CCC(=O)N2CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3c(C)cccc32)CC1
Yield: 73 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (107LH27-11,3) (0.057 g, 0.24 mmol), 4-butylpiperidine (0.042 g, 0.30 mmol), KI (0.083 g, 0.50 mmol), and K2CO3 (0.069 g, 0.50 mmol) in MeCN and shaken at 50°. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH28) (0.060 g, 74%). 1H NMR (CD3OD) δ 7.15 (t, J=8.0 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.92 (d, J=7.4 Hz), 4.00 (t, J=7.2 Hz, CH2), 3.10 (d, J=12.1 Hz, 2H), 2.87-2.83 (m, 2H), 2.66-2.62 (m, 2H) 2.59-2.55 (m, 2H), 2.31-2.25 (m, 2H), 2.29 (s, CH3), 1.93-1.87 (m, 2H), 1.76 (d, J=11.7 Hz, 2H), 1.31-1.24 (m, 9H), 0.90 (t, J=6.8 Hz, CH3); 13C NMR (CD3OD) δ 172.7, 140.2, 137.0, 128.1, 126.6, 126.5, 114.5, 56.5, 54.6, 41.2, 37.0, 36.0, 32.2, 32.2, 30.0, 25.0, 23.9, 22.4, 19.7, 14.4; HPLC-MS (ammonium acetate) [M+H+]=343.36.
Reaction SMILES: Cl.C(N=[C:5]1[N:14]([CH2:15][C:16]#[N:17])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:19])[C:11]=2[Cl:18])[NH:6]1)#N.C(=O)([O-])[O-:21].[K+].[K+]>C(O)CO>[Cl:18][C:11]1[C:10]([Cl:19])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][N:14]1[CH2:15][C:16](=[O:21])[NH:17][C:5]1=[N:6]2
Reactant: O=C([O-])[O-]
Reactant: N#CCN1Cc2c(ccc(Cl)c2Cl)NC1=NC#N
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of 10 ml of ethylene glycol in 0.5 ml (0.005 moles) of cc. hydrochloric acid, warmed to 120° C., 0.28 g (0.001 mole) of (2-cyanoimino-5,6-dichloro-1,2,3,4-tetrahydroquinazolin-3-yl) acetonitrile are added, and the solution is stirred at the same temperature for 20 minutes. Then it is cooled to room temperature and made neutral with 10% potassium carbonate solution. The separated crystals are filtered off. Thus 0.27 g (96.4%) of crude 6,7-dichloro-1, 5-dihydroimidazo[2,1-b]quinazolin-2[3H]-one base are obtained (m.p.>300° C., HPLC content: 96.3%), which is dissolved in a hot mixture of 7 ml of methanol and 6 ml of cc. ethanolic hydrogen chloride (hydrogen chloride content: 0.76 moles/1000 ml) and allowed to crystallize. Then it is cooled, the separated product is filtered off and washed with a slight amount of ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[C:17]([CH3:19])([CH3:18])[CH2:16][O:15][C:14]3=[O:20])[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:21][N:22](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[CH3:18][C:17]1([CH3:19])[CH2:16][O:15][C:14](=[O:20])[N:13]1[C:11]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[CH:3][CH:4]=2)[N:12]=1
Reactant: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2)ns1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)ns1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
3-[3-(4-bromophenyl)-1,2,4-thiadiazol-5-yl]-4,4-dimethyl-1,3-oxazolidin-2-one (0.67 g, 1.9 mmol), prepared in step 4 of Example 93, was dissolved in dimethylformamide (19 mL). Zinc cyanide (0.132 g, 1.14 mmol) was added, the mixture was purged with nitrogen for 15 min, and then tetrakis(triphenylphosphine)palladium (0.11 g, 0.095 mmol) was added. The mixture was heated to 120° C. for 2 h, additional tetrakis(triphenylphosphine)palladium (0.11 g, 0.095 mmol) was added and stirring was continued for 45 min. The mixture was cooled, diluted with ethyl acetate, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone in hexane) afforded the title compound (0.48 g, 84%) as a white solid. Analytical HPLC: HPLC purity 100% at 210-370 nm, 9.7 min; 100% at 248 nm, 9.7 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1ncnc2cnccc12
Reactant: NCc1ccccc1
Product: c1ccc(CNc2ncnc3cnccc23)cc1
Temperature: 100 °C
Yield: 20 %

Procedure:
A mixture of 4-methylthiopyrido[3,4-d]pyrimidine (74 mg, 0.41 mmol)(see a previous experimental), and benzylamine (1 mL) is heated to 100° C. for 2 h. On cooling the mixture is concentrated under reduced pressure and purified directly by preparative tlc on silica gel eluting with CH2Cl2, to yield 4-(benzylamino)pyrido[3,4-d]pyrimidine (21.2 mg, 20%). 1H NMR (DMSO) δ 9.21 (1H, t, J=5.8 Hz), 9.19 (1H, s), 8.63 (1H, d, J=5.8 Hz), 8.58 (1H, s), 8.20 (1H, d, J=5.1 Hz), 7.41-7.30 (4H, m), 7.26 (1H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CCO.O>[CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
(Scheme 1, Compound B) To a solution of ethyl 4-butoxybenzoate (2.0 g, 9.6 mmol) in EtOH (30 mL) was added NaOH (10 N, 6 mL, 60 mmol). The resulting mixture was stirred at room temperature for 3 hours, diluted with H2O (30 mL), acidified to about pH 1.0 using HCl (6N). The precipitates were filtered off by filter paper, washed by H2O and hexanes. This compound was obtained as a white solid. (1.63 g, 9.1 mmol, 94% yield). 1H NMR (DMSO-d6) δ 12.59 (br. s, 1H), 7.88 (d, 2H, J=9.5 Hz), 6.97 (d, 2H, J=9.5 Hz), 4.01 (t, 2H, J=6.5 Hz), 1.68 (m, 2H), 1.42 (m, 2H), 0.91 (t, 3H, J=6.5 Hz); 13C NMR (DMSO): 166.9, 162.2, 131.2, 122.7, 114.0, 67.3, 30.5, 18.6 and 13.5; Mass Spec.: 195.17 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=O)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:16][CH2:15][CH:14](O)[CH2:13]1.[H-].[Na+]>CN1CCCC1=O>[CH3:11][N:12]1[CH2:16][CH2:15][CH:14]([C:2]2[CH:3]=[CH:4][C:5]([N:8]=[O:10])=[CH:6][CH:7]=2)[CH2:13]1
Reactant: CN1CCC(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN1CCC(c2ccc(N=O)cc2)C1

Procedure:
4-Fluoronitrobenzene and 1-methylpyrrolidin-3-ol were allowed to undergo the reaction in 1-methylpyrrolidone in the presence of sodium hydride. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 4-(1-methylpyrrolidin-3-yl)oxoaniline. F: 193.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:29])=O.CN(C)C=O>CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5]([Cl:29])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl

Procedure:
To a stirred solution of 2-Methoxy-6-pentadecylbenzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Methoxy -6-pentadecylbenzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:22][NH:23][C:24](=[S:27])[NH:25][NH2:26].O>CN(C)C=O>[CH3:22][N:23]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:26][N:25]=[C:24]1[SH:27]
Reactant: CNC(=S)NN
Reactant: O=C(O)c1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(S)nnc1-c1ccccn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
15 g of pyridine-2-carboxylic acid (121.8 mmol) were dissolved in 150 ml of dimethylformamide. At room temperature, 29.6 g (181.8 mmol) of carbonyldiimidazole were slowly added, during which gas was evolved. Reaction was allowed to take place at 100° C. for 30 min, and then 25.6 g (242.7 mmol) of 4-methyl-3-thiosemicarbazide were added, and the mixture was stirred at 100° C. for a further 2 h. The reaction mixture was mixed with 300 ml of water. After cooling in an ice bath, the precipitated crystals were filtered off with suction and washed with a little water. The crystals were taken up in 390 ml of 1M sodium bicarbonate solution and heated to reflux for 3 h.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(N(C(C)C)CC)(C)C>CC#N>[Br:13][CH2:14][CH2:15][CH2:16][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCCCBr
Temperature: 25 °C

Procedure:
To a solution of N-hydroxyphthalimide (2.0 g) and 1,3-dibromopropane (2.49 ml) in 50 ml of dry CH3CN was added diisopropylethylamine (4.27 ml). The mixture was stirred at room temperature. After 4 hours the volatiles were removed in vacuo. The residue was triturated with Et2O to provide 2.53 g of while solid, homogeneous by TLC.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](Cl)=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>N1C=CC=CC=1>[N:17]1([C:13]2[CH:14]=[CH:15][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[N:11][CH:12]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Cl)cn1
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)c1ccc(N2CCNCC2)cn1
Temperature: 120 °C
Yield: 48.3 %

Procedure:
To a mixture of 5-chloro-2-pyridinyl phenyl sulfone (10.2 g, 40.2 mmol) in pyridine (100 mL) was added piperazine (13.8 g, 161 mmol). The mixture was heated to 120° C. in a preheated oil bath for 18 h. The mixture then was removed from heat and cooled to room temperature. The mixture was partitioned between water and ethyl acetate. The layers were separated and the organic layer washed twice with water (2×50 mL). The organic layer was dried with anhydrous magnesium sulfate and concentrated. The solids obtained after concentration were recrystallized from water and dried to give 5.89 g of the title compound; m.p. 126-127° C.; IR (drift) 1568, 1479, 1447, 1306, 1290, 1254, 1175, 1154, 1145, 1104, 830, 756, 715, 688, 602 cm−1. 1H NMR (CDCl3) δ 3.0, 3.29, 7.13, 7.53, 8.01, 8.26.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([O:22]CC)=[O:21])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>CO>[Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([OH:22])=[O:21])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A mixture of ethyl 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.00 g), 4N aqueous sodium hydroxide solution (2.3 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated and acidified with 10% aqueous citric acid solution. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.88 g, yield 95%) as colorless crystals. melting point>290° C. (decomposition).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([C:8]2[C:13]3[N:14]4[CH2:20][CH2:19][CH2:18][N:17]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])[C:15]4=[N:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[OH:7])[CH2:5][CH2:4]1.[CH3:29]I>CN(C)C=O.O>[CH:3]1([CH:6]([O:7][CH3:29])[C:8]2[C:13]3[N:14]4[CH2:20][CH2:19][CH2:18][N:17]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])[C:15]4=[N:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4]1
Reactant: CI
Reactant: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 0.08 h
Yield: 64 %

Procedure:
Sodium hydride (60% in oil, 45.3 mg, 1.13 mmol) was added to a stirred solution of cyclopropyl[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (400 mg, 1.03 mmol) in N,N-dimethylformamide (3.0 mL) at 0° C. After stirring 5 min, methyl iodide (219 mg, 1.55 mmol) was added to the mixture, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (265 mg, 0.659 mmol, 64%).
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:4]1=[O:33])=[CH:22][CH:21]=[CH:20][CH:19]=3.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[ClH:1].[C:34]([O:2][C@@H:3]1[C@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:4]1=[O:33])=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:36])[CH3:35]
Reactant: CCN(CC)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CCN(CC)CCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Yield: 93 %

Procedure:
A mixture of 2.5 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(diethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one hydrochloride and 25 mL of acetic anhydride was stirred and heated at 100° for 17 hours. The excess of reagent was removed under reduced pressure and the residue was crystallized from ethyl acetate to give 2.5 g (93%) of (±)-cis-3-(acetyloxy)-5-[2-(diethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one hydrochloride, mp 211°-212°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8]2)=[CH:2]1.C[O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[O:32][CH2:33][CH2:34]Cl>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([OH:36])=[O:23])=[C:26]([O:32][CH2:33][CH2:34][N:19]2[CH2:18][CH2:17][CH:16]([C:9]3[C:10]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:7]([CH2:6][C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[CH:8]=3)[CH2:21][CH2:20]2)[CH:27]=1
Reactant: c1cnc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Reactant: COC(=O)c1ccc(Cl)cc1OCCCl
Product: O=C(O)c1ccc(Cl)cc1OCCN1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1
Yield: 11.8 %

Procedure:
This compound was prepared following the procedure described in example 4, parts E and F, starting with 1.5 g (5.3 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 1.7 g (6.9 mmol) of 2-(2-chloroethoxy)-4-chlorobenzoic acid methyl ester. After standard work-up and purification, 0.3 g (10% yield) of 4-chloro-2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid were obtained.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][CH:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[C:23]1([C:29]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[C:36]3[C:31](=[CH:32][C:33](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:35]=3)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>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.O>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH:14]2[CH2:15][CH:12]([C:4]3[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]4=[C:2]([C:33]4[CH:32]=[C:31]5[C:36]([C:37]([C:39]([F:42])([F:40])[F:41])=[CH:38][C:29]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)=[N:30]5)=[CH:35][CH:34]=4)[N:3]=3)[CH2:13]2)[CH2:17][CH2:18]1
Reactant: CN1CCN(C2CC(c3nc(I)c4c(N)nccn34)C2)CC1
Reactant: CC1(C)OB(c2ccc3c(C(F)(F)F)cc(-c4ccccc4)nc3c2)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN(C2CC(c3nc(-c4ccc5c(C(F)(F)F)cc(-c6ccccc6)nc5c4)c4c(N)nccn34)C2)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine (120 mg, 0.00029 mole), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-quinoline (230 mg, 0.00058 mole), cesium carbonate (330 mg, 0.0010 mole), 1,2-dimethoxyethane (6 mL, 0.06 mole) and water (1 mL) were combined in a 25 ml round bottom flask with a magnetic stir bar. The flask was subjected to three vacuum, argon cycles and charged with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.000030 mole). The flask was subjected to three vacuum, argon cycles again. The reaction was stirred under argon at 75° C. (external temperature) overnight. The product mixture was concentrated in vacuo, then allowed to stand under vacuum for 1 h. The product mixture was then chromatographed on silica gel with methylene chloride, methanol, concentrated ammonium:hydroxide (140:10:1). Only the purest fractions were combined and concentration in vacuo, and placement under high vacuum for 30 minutes afforded the title compound as a yellow solid. The solid was re-crystallized from hexanes/ether to afford the title compound as a yellow solid; 1H NMR (CD3OD, 400 MHz) δ 2.14-2.62 (m, 15H), 2.78-2.82 (Q, 1H, J=7.9 Hz), 3.62-3.67 (Q, 1H, J=7.9H), 6.32 (bs, 2H), 7.12-7.14 (d, 1H, J=4.8 Hz), 7.58-7.64 (m, 4H), 8.16-8.22 (m, 2H), 8.39-8.42 (m, 3H), 8.48 (s, 1H); 19F NMR (DMSO, 400 MHz) δ 60.15; MS (ES+): 557.98 (10) [MH+]; HPLC TR 3.408 min. (100%) (polar—15 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C1C(=O)N([I:18])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:18])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)c1ccccc1N
Solvent: ClCCl
Product: CC(=O)c1cc(I)ccc1N
Temperature: 0 °C

Procedure:
A flask charged with 1-(2-aminophenyl)ethanone (405 mg) and DCM (20 mL) was cooled in an ice/water bath and NIS (675 mg) was added in three portions. The reaction was stirred at 0° C. The reaction mixture was diluted with 30 mL DCM, washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by preparative RP-HPLC, affording the title compound. MS (ESI+): m/z 262.06 (MH+). 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.44 (d, J=8.8 Hz, 1H), 6.43 (d, J=8.8 Hz, 1H), 6.32 (br, 2H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([C:8]([F:11])([F:10])[F:9])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:12][C:13]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[Li+].[Li+]>>[F:12][C:13]1[CH:20]=[C:19]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([C:8]([F:9])([F:11])[F:10])[C@@H:2]2[CH3:1])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(F)cc1F
Reactant: C[C@@H]1NCC[C@@]1(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@@]1(O)C(F)(F)F

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-methyl-3-(trifluoromethyl)pyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4-difluorobenzonitrile (258 mg) and lithium carbonate (138 mg), the title compound was obtained as a colorless solid (yield: 120 mg, yield: 45%).