Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:17][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)([OH:9])[CH3:17])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(F)c1
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Cl)cc1)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-chlorophenyl)-(3-fluorophenyl)-methanone (200 mg, 0.717 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH:19]([CH3:30])[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH:19]([CH3:30])[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CCNC(=O)OC(C)(C)C)C1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1N=C(c2cccc(F)c2)SC1(c1ccccc1)C(C)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butylcarbamate (50 mg, 116 mmol) in anhydrous DCM (5 mL) was added isobutyryl chloride (16 μL, 151 mmol) followed by triethylamine (21 μL, 151 mmol). After stirring at room temperature for 16 hours the mixture was partitioned between sat. NaHCO3 (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (10 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was chromatographed (19:1, hexanes/ethyl acetate) to afford two diastereomeric pairs, diastereomer pair A (more polar, 13.1 mg) and diastereomer pair B (less polar, 11 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[CH:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl>[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[CH:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])=[CH:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-amino-phenyl)-amide (40 mg, 0.072 mmol) in methylene chloride (5 mL), acetic anhydride (0.072 mmol) was added at room temperature followed by triethylamine (0.10 mL). The mixture was stirred at for 1 hr. and then chromatographed on an ISCO machine (12 g, 40-85% EtOAc/Hexanes) to give a white solid. 34 mg.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=2)[NH:5]1.Cl[C:18]1[N+:23]([O-])=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1.P(Cl)(Cl)Cl>C(=O)([O-])O.[Na+].CN(C)C=O>[OH:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:18]1[CH:19]=[CH:20][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][N:23]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.9 %

Procedure:
To a N,N-dimethylformamide (10 mL) suspension of sodium hydride (97%, 0.784 g, 32.7 mmol) was added methyl 2-oxoindoline-5-carboxylate (2.34 g, 12.3 mmol). The formed mixture was stirred for 10 min at room temperature followed by the addition of 4-[(6-chloro-1-oxidopyridin-3-yl)methyl]morpholine (1.87 g, 8.2 mmol). The resulting reaction mixture was set under N2 atmosphere and stirred for 1 h at 135° C. The N,N-dimethylformamide solution was diluted with saturated aqueous sodium hydrogen carbonate (30 mL) and extracted with chloroform, and ethyl acetate (containing 5% methanol). The combined organic phases were concentrated in vacuo. The remaining N,N-dimethylformamide was removed by co-evaporation with toluene. The residue was dissolved in ethyl acetate/chloroform, (150 mL, 2:1), and phosphorus trichloride (4.5 g, 33 mmol) was added. The reaction mixture was stirred for 1 h at 60° C., and then cooled to room temperature. The mixture was poured into a saturated aqueous sodium hydrogen carbonate solution followed by extraction of the aqueous phase with chloroform (4×). The combined organic extracts were concentrated in vacuo, and the residue was purified on a silica gel column using chloroform/methanol, (10:1), as the eluent to afford 1.05 g (35% yield) of the title compound as a yellow-brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.83 (br s, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.63 (t, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz, 1H), 3.87 (s, 3H), 3.62 (br s, 4H), 3.41 (s, 2H), 2.42 (br s, 4H); MS (EI) m/z 368 (M++1).
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[OH:10][C:11]1[C:20]([CH3:21])=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:22])[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][O:10][C:11]1[C:20]([CH3:21])=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:22])[CH:12]=1)[CH3:6]
Reactant: CCOC(CBr)OCC
Reactant: COC(=O)c1cc(C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(COc1cc(C)c(C(=O)OC)cc1C)OCC
Temperature: 85 °C
Reaction time: 16 h

Procedure:
2-Bromo-1,1-diethoxyethane (0.31 mL) was added to a mixture of methyl 4-hydroxy-2,5-dimethylbenzoate (example 18, step b) (0.25 g) and caesium carbonate (0.68 g) in DMF (20 mL). The resulting mixture was stirred at 85° C. for 16 h. The reaction was partitioned between water (200 mL) and ethyl acetate (100 mL). The aqueous phase was separated and extracted with ethyl acetate (2×100 mL). The combined organic solutions were washed with water (2×100 mL) and brine (100 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with isohexane to 10:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a clear oil. Yield 0.26 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>CS(C)=O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCNCC2)cc1
Temperature: 95 °C
Yield: 93.5 %

Procedure:
Potassium carbonate (20.7 g, 0.15 mol) was added to a solution of 4-fluorobenzonitrile (12.1 g, 0.1 mol) and piperazine (25.8 g, 0.3 mol) in dimethylsulfoxide (75 ml) and heated at 95° C. for 20 hours. The reaction was cooled and poured into water (1100 ml) and extracted into dichloromethane (4×400 ml). The organic solution was dried and the solvent removed in vacuo to yield 4-cyanophenylpiperazine (17.5 g, 93.6% yield):
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[NH2:9][CH2:10][C:11](O)=O>Cl>[NH2:9][CH2:10][C:11]1[NH:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1ccccc1N
Reactant: NCC(=O)O
Agent: Cl
Product: NCc1nc2ccccc2[nH]1
Reaction time: 24 h
Yield: 59.8 %

Procedure:
A solution of 2-aminoaniline (27 g, 0.25 mol), glycine (27.7 g, 0.37 mol) and 250 ml of 5.5M hydrochloric acid is refluxed for 30 hours and then stored in a refrigerator for 24 hours. The precipitate formed is filtered off with suction and then taken up in 400 ml of methanol and treated with carbon black. The mixture is filtered and the solvent is removed to give 22 g (49%) of a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:10][NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31][N:11]([CH2:10][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Cc1cccnc1CNCc1ncccc1C(C)C
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1C(C)C

Procedure:
Using General Procedure A: Reaction of (3-isopropyl-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester, and DIPEA in CH3CN gave 5-Cyano-2-{[(3-isopropyl-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[N:9]1([C:15]2[N:16]=[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH:18][C:19](=[O:21])[CH:20]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O1CCOCC1>[CH3:1][N:18]1[C:19](=[O:21])[CH:20]=[C:15]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:16]=[C:17]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CI
Product: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Temperature: 40 °C
Yield: 38 %

Procedure:
330 mg of potassium carbonate and 150 ml of methyl iodide are added to a solution of 500 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (prepared in step 1c of example 1c) in 1.5 ml of dioxane. The reaction mixture is heated at 40° C. for 16 and then cooled to ambient temperature. The suspension is filtered through sintered glass and then rinsed with dioxane, and the filtrate is concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane, acetonitrile and methanol (98/01/01, 96/02/02, then 90/05/05 V/V/V). 200 mg of ethyl [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C@H:11]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][C@H:15]1[C:20](=[O:39])[NH:21][CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:13])(=O)C.Cl>CO.CCOC(C)=O>[Cl:29][C:27]1[CH:26]=[CH:25][C:24]([CH2:30][NH:31][C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[C:23]([CH2:22][NH:21][C:20]([C@@H:15]2[CH2:16][O:17][CH2:18][CH2:19][N:14]2[C:12](=[O:13])[C@H:11]([OH:10])[C:40]([CH3:43])([CH3:42])[CH3:41])=[O:39])[CH:28]=1
Reactant: CC(=O)O[C@@H](C(=O)N1CCOC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1C(=O)[C@H](O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
K2CO3 (0.016 g, 0.11 mmol) was added to a solution of (R)-1-{(S)-3-[2-{(tert-Butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]morpholino}-3,3-dimethyl-1-oxo-butan-2-yl acetate (0.28 g, 0.51 mmol) in MeOH (3 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (20 mL), acidified with 1N aqueous HCl (5 mL) and the extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel; eluent: 70% EtOAc/hexanes) to afford the title compound as a pale yellow oil (0.25 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=C)=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([NH2:23])=[O:22])=[CH:9]2)=[CH:4][CH:3]=1.CC(C)=[O:26].O.I([O-])(=O)(=O)=O.[Na+]>CCOC(C)=O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:26])=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([NH2:23])=[O:22])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: C=Cc1ccc2c(c1)c(=O)c(C(N)=O)cn2-c1ccc(F)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C=O)cc2c1=O
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of compound F (385 mg, 1.25 mmol) in 3:1 acetone/water (8 mL) was added N-oxide-4-methylmorpholine (220 mg, 1.87 mmol) and osmium tetroxide (254 μL, 0.025 mmol). After the reaction stirred for one hour, sodium periodate (294 mg, 1.37 mmol) was added. After another two hours, the reaction was diluted with EtOAc and washed well with a 10% NaS2O3 solution. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 365 mg (94%) of the title compound that was used without further purification. ES-MS [M+1]+: 311.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[CH:4][N:3]=1.CO[C:13](OC)(OC)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:10][N:9]1[C:7](=[S:8])[N:6]2[N:5]=[CH:4][N:3]=[C:2]2[N:1]=[C:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNC(=S)n1ncnc1N
Reactant: COC(OC)(OC)c1ccccc1
Product: Cn1c(-c2ccccc2)nc2ncnn2c1=S
Yield: 66 %

Procedure:
The synthesis method of Example 96 was applied. The compound (1.50 g) obtained in Example 29 and trimethylorthobenzoate (5.0 ml) were used. The mixture was reacted at 150° C. for 2 hours. The resulting crystals were collected by filtration and purified by a method similar to the method of Example 98, whereby crystals (1.53 mg) were obtained (yield 66%). The crystals were recrystallized from methanol to give colorless transparent plate crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:18]1>N1C=CC=CC=1>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:16][C@@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:18]2)[N:11]=1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: NC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)c1nc(N[C@H]2CC[C@@H](C(N)=O)CC2)nc2ccccc12
Yield: 43.8 %

Procedure:
A solution of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (31.05 g, 150 mmol) and cis-4-amino-cyclohexanecarboxylic acid amide hydrochloride (26.7 g, 150 mmol) in pyridine (150 mL) was stirred at reflux for overnight. The reaction mixture was concentrated and residue was dissolve in CH2Cl2. The organic layer was washed with saturated aqueous NaHCO3 and the aqueous layer was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 2% to 10% 2 M NH3/MeOH in CH2Cl2) to give a slightly brown solid and the solid was recrystallized from CH2Cl2 to give cis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexanecarboxylic acid amide (20.6 g, 44%) as yellow crystals.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[Cl:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:28])[N:22]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][CH2:3][C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:22]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Product: Cc1cc(Cl)nc(NCc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4-chloro-6-methylpyrimidin-2-amine. M/e+, 384.1, 386 for C19H15C12N5. 1H-NMR (400 MHz, CDCl3, δ) 8.25 (m, 1H), 7.74 (d, J=6.598 Hz, 2H), 7.63 (m, 1H), 7.42 (d, J=6.599 Hz, 2H), 7.24 (m, 1H), 6.84 (m, 1H), 6.55 (s, 1H), 5.41 (s, NH), 5.05 (d, J=5.13 Hz, 2H, D, CH2), 2.318 (s, 3H, D, CH3) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=O)[C:9]#[CH:10])[C:5]2[C:12]([O:34][CH3:35])=[N:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.Cl.[C:37]([NH2:40])(=[NH:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][N:40]=[C:37]([CH3:38])[N:39]=2)[C:5]2[C:12]([O:34][CH3:35])=[N:13][N:14]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[CH:3]=1
Reactant: C#CC(=O)c1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3ccnc(C)n3)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
1-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)prop-2-yn-1-one (60B, 63 mg, 0.132 mmol) was dissolved in acetonitrile (3 ml), charged with acetamidine hydrochloride (14.95 mg, 0.158 mmol) and sodium carbonate (34.9 mg, 0.330 mmol) and allowed to stir at 70° C. for 2 h. The solution was filtered through a syringe filter and the solvents were removed in vacuo. The residue was purified on silica gel 2-25% EtOAc/DCM to afford 6-chloro-3-methoxy-4-(2-methylpyrimidin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (63B, 58 mg, 0.112 mmol, 85% yield). MS: [M+H]+ m/z 518.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.N1(C2CCNCC2)C[CH2:35][CH2:34]1>>[N:8]1([CH:9]2[CH2:35][CH2:34][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:11][CH2:10]2)[CH2:15][CH2:14][CH2:13]1
Reactant: C1CN(C2CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 4-azetidin-1-yl-piperidine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a cream solid (54 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)c2cccnc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-5-(3-pyridinyl) -2,4-pentadienoic acid (5.7 g) and 4-nitrophenol (3.06 g) in 80 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (4.2 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up. the ester was crystallized from 2-propanol to give 7.3 g of (E,E)-5-(4-methoxyphenyl)-5-(3-Pyridinyl)-2,4-pentadienoic acid 4-nitrophenyl ester 129.5°-131° C. The analytical specimen was obtained from the same solvent, mp 130°-131° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[CH2:31][C:30]6[C:25](=[CH:26][C:27]([O:32][CH3:33])=[CH:28][CH:29]=6)[C:24]5=[O:34])[C:18]=4[CH3:35])=[N:15][N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2].[CH3:39][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[CH2:31][C:30]6[C:25](=[CH:26][C:27]([O:32][CH3:33])=[CH:28][CH:29]=6)[C:24]5=[O:34])[C:18]=4[CH3:35])=[N:15][N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10][C:11]=2[CH:12]=1)([CH3:39])[CH3:2]
Reactant: COc1ccc2c(c1)C(=O)N(c1cccc(-c3nnc(C(N)=O)c4[nH]c5cc(C(C)=O)ccc5c34)c1C)C2
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N(c1cccc(-c3nnc(C(N)=O)c4[nH]c5cc(C(C)(C)O)ccc5c34)c1C)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of 7-acetyl-1-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide (36.0 mg, 0.071 mmol) in tetrahydrofuran (8 mL) at 0° C. was added methylmagnesium bromide (0.119 mL, 0.356 mmol). The mixture was stirred at room temperature for 20 min. Additional methylmagnesium bromide (0.119 mL, 0.356 mmol) was added at 0° C. and the mixture was stirred at room temperature for another 20 min. The reaction was quenched with water (15 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. After solvent was removed under vacuum, the residue was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (11.4 mg, 0.021 mmol, 30.1% yield) as a white solid. LCMS (M+H)+=522.20. 1H NMR (500 MHz, DMSO-d6) δ: 12.34 (s, 1H), 8.75 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.73 (d, J=6.9 Hz, 1H), 7.61-7.57 (m, 2H), 7.51 (d, J=6.4 Hz, 1H), 7.35-7.33 (m, 2H), 7.27-7.25 (m, 2H), 5.19 (s, 1H), 4.98 (d, J=16.9 Hz, 1H), 4.90 (d, J=16.9 Hz, 1H), 3.86 (s, 3H), 1.90 (s, 3H), 1.49 (s, 6H).