Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1C=C2OCOC2=C[C:20]=1[C:28](=O)C)=[O:17])(=[O:10])=[O:9].[NH2:32][C:33]1[CH:38]=[CH:37]C(C)=CN=1.NC1C=C2OCOC2=CC=1C(=O)C>>[S:13]1[CH:14]=[CH:15][C:11]([S:8]([NH2:7])(=[O:10])=[O:9])=[CH:12]1.[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[N:32]=[CH:33][C:38]([CH3:37])=[CH:28][CH:20]=1)=[O:17])(=[O:9])=[O:10]
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Reactant: Cc1ccc(N)nc1
Agent: CC(=O)c1cc2c(cc1N)OCO2
Product: Cc1ccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)nc1
Product: NS(=O)(=O)c1ccsc1

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl) 2-{[2-acetyl-4,5-(methylenedioxy)-phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148), except that 2-amino-5-picoline was used in stead of 2′-amino-4′,5′-(methylenedioxy)acetophenone, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was obtained, via HPLC purification of the crude reaction mixture, as a bright yellow powder (17% yield, m.p. 158-160° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][C@@H:11]1[CH2:15][C:14](=[N:16][O:17][CH3:18])[CH2:13][N:12]1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:20].C(O)(=O)C>ClCCl>[CH3:18][O:17][N:16]=[C:14]1[CH2:15][C@@H:11]([CH2:10][C:9]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[N:12]([C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)=[O:20])[CH2:13]1
Reactant: CON=C1C[C@@H](CC(=O)Nc2ccccc2N)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CON=C1C[C@@H](Cc2nc3ccccc3[nH]2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 66 %

Procedure:
A solution of N-(2-aminophenyl)-2-[(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxy imino)pyrrolidin-2-yl]acetamide (Example 11, 21 mg, 0.05 mmol) and acetic acid (0.1 ml) in dichloromethane (1 ml) was stirred overnight. The organic phase was washed with NaHCO3. The organic phase was dried (MgSO4) and concentrated to afford (3EZ,5S)-5-(1H-benzimidazol-2-ylmethyl)-1-(biphenyl-4-ylcarbonyl)pyrrolidin-3-one O-methyloxime (14 mg). Yield: 65%. HPLC purity: 93%
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])C=C.FC(F)(F)S(O[C:41]1[CH:46]=[CH:45][N:44]=[C:43]2[S:47][CH:48]=[CH:49][C:42]=12)(=O)=O>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[CH:12]=[C:11]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]3[S:47][CH:48]=[CH:49][C:42]=23)[S:10][C:9]=1[C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(Oc1ccnc2sccc12)C(F)(F)F
Product: Clc1ccc(-c2cc(-c3ccnc4sccc34)sc2-c2ncc[nH]2)c(Cl)c1

Procedure:
The title compound was prepared from 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole and thieno[2,3-b]pyridin-4-yl trifluoromethanesulfonate using procedures analogous to those described in Example 8-A, Steps 2 and 3. LC/MS (AA) ES+ 428, 430. 1H NMR (400 MHz, d6 DMSO) δ: 11.97-11.69 (m, 1H), 8.73 (d, J=4.97 Hz, 1H), 8.27 (d, J=5.56 Hz, 1H), 7.88 (s, 1H), 7.77-7.73 (m, 2H), 7.68 (d, J=5.56 Hz, 1H), 7.52-7.43 (m, 2H), 7.22-6.89 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.[OH2:25]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:9])(=[O:22])=[O:25])=[C:4]([C:10]([F:13])([F:11])[F:12])[CH:3]=1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Reaction time: 2 h
Yield: 44 %

Procedure:
Combine 4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene (3.6 g, 15 mmol), mCPBA (7.7 g, 30 mmol) and dichloromethane (100 mL). Stir for 2 hours. Dilute with dichloromethane (300 mL) and water (100 mL). Separate the organic layer and wash with aqueous saturated NaHCO3 (2×100 mL) and brine (100 mL). Dry with MgSO4, filter and concentrate in vacuo. Wash the solid with diethyl ether (2×10 mL) and dichloromethane (10 mL) to give 2.06 g of the title compound (44%).
Reaction SMILES: C[Al](C)C.[C:5]([NH2:9])([CH3:8])([CH3:7])[CH3:6].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1.C(OCC)(=O)C>O1CCOCC1.CCCCCCC>[C:5]([NH:9][C:12](=[O:11])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: CC(C)(C)N
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 798 μL, 1.6 mmol) in dioxane (7.5 mL) was added to tert-butylamine (174 μL, 1.6 mmol) and the mixture was stirred for 1 h at 50° C. 6-[3-(3,4-Difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (150 mg, 0.4 mmol) in dioxane (7.5 mL) was added and stirring was continued overnight at 85° C. Chromatography (silica, ethyl acetate: heptane=1:4 to 1:1) afforded the title compound (20 mg, 13%) as a colourless solid. MS: m/e=416.4 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.O.[NH2:14][NH2:15]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:14][NH2:15])=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(C2CCC2)c(Cl)nn1
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc(C2CCC2)c(Cl)nn1

Procedure:
3,6-Dichloro-4-cyclobutylpyridazine (10 g, 0.049 mol) and hydrazine hydrate (14 ml, 0.30 mol) were heated at reflux in dioxan (125 ml) for 24 hours. Upon cooling the desired isomer crystallized from the reaction and was collected by filtration (4.8 g, 49%). 1H NMR (250 MHz, d6-DMSO) δ1.68-1.86 (1H, m), 2.00-2.11 (3H, m), 2.29-2.38 (2H, m), 3.52-3.61 (1H, m) 4,35 (2H, br), 6.99 (1H, s), 8.06 (1H, br); MS (ES+) m/e 198 [MH]+, 200 [MH]+.
Reaction SMILES: I[C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N([CH2:23][CH3:24])CC)C.[C:25](O)(=[S:27])C>CN(C=O)C.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.[Cu]I>[SH:27][CH2:25][C:23]#[C:24][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: CCN(CC)CC
Reactant: CC(O)=S
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCS
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
A solution of 5-iodo-2′-deoxycytidine (Sigma, 92 mg, 0.260 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) in absolute DMF (1.3 mL) was treated sequentially with triethylamine (0.072 mL, 53 mg, 0.520 mmol), the propargyl S-thioester of thioacetic acid (74 mg, 0.650 mmol), and CuI (10 mg, 0.052 mmol). The mixture was stirred at RT (4 h), the solvents were removed in high vacuum, and the residue was chromatographed (silica, CH2Cl2:MeOH 9:1) to yield the S-acetate of 5-(3-mercaptopropyn-1-yl)-2′-deoxycytidine (77 mg, 0.227 mmol, 88%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: COc1ccc(CN)cc1OC
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1OC

Procedure:
2-Chloro-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine, 3,4-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:21]([CH2:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(=O)C=C1.II.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:30]([C:29]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:47]1[CH:48]=[C:49]2[N:44]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:10]2=[O:20])[CH:45]=[CH:46]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: c1ccncc1
Reactant: COc1ccc(-c2c(-c3ccc(OC)cc3)c2=O)cc1
Agent: II
Agent: O=c1cc1
Product: COc1ccc(C2=C(c3ccc(OC)cc3)N3C=CC(=C(C(=O)c4ccccc4)C(=O)c4ccccc4)C=C3C2=O)cc1
Temperature: 90 °C
Yield: 95 %

Procedure:
A 10 percent solution of 2,3-di(4-methoxyphenyl) cyclopropenone in pyridine was refluxed under nitrogen for 15 minutes. The resulting solution was cooled slightly, and an equivalent amount of dibenzoylmethane based on the cyclopropenone was added to the green solution. The reaction mixture was refluxed for 60 minutes. The resulting reaction mixture was again cooled, and four equivalents of iodine dissolved in a small amount of pyridine was added to the reaction mixture. The mixture was further heated at 90° C. on a steam bath for 15 minutes. The bright blue solution was quenched by pouring it into cold excess dilute hydrochloric acid. The desired dye precipitated and was removed from the solution by filtering. A 95 percent yield of the desired dye was obtained based on the starting cyclopropenone. The dye was chromatographed on silica gel to provide a purified product. The maximum absorption of the dye was at 605 nm in chloroform solution. The structure of the dye was confirmed by mass spectroscopy, nuclear magnetic resonance and infrared analysis.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[Na].BrC1[S:25][CH:26]=[CH:27]N=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[S:25][CH:26]=[CH:27][N:13]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Reactant: Brc1nccs1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(Sc2nccs2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 2.37 g. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide, there is added under nitrogen at less than 30°C., 0.38 g. of sodium borohydrode. The mixture is stirred at 20°-30°C. for 1 hour, then 3.2 ml. of 2-bromothiazole is added. The mixture is heated to 130°-135°C. for 1 hour, then cooled and diluted with water. The crude product is filtered off and recrystallized from methanol yielding 1-acetamido-2-nitro-4-(thiazol-2-ylthio)benzene.
Reaction SMILES: CO[C:3](=[N:13][N+:14]([O-:16])=[O:15])[NH:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1.[CH3:17][NH2:18]>O>[Cl:12][C:9]1[N:8]=[CH:7][C:6]([CH2:5][NH:4][C:3]([NH:18][CH3:17])=[N:13][N+:14]([O-:16])=[O:15])=[CH:11][CH:10]=1
Reactant: COC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CN
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 89.1 %

Procedure:
To a mixture of O-methyl-N-(6-chloro-3-pyridylmethyl)-N'-nitroisourea (970 mg, 3.96 mmol) and water (30 ml) was added 40% aqueous solution of methylamine (0.7 ml, 7.92 mmol, 2.0 equivalents) at room temperature with stirring. After 1.5 hours of stirring at room temperature, the resulting crystals were collected. The crystals were washed with water and methanol, and dried. As a result, 860 mg (89.1% yield) of 1-(6-chloro-3-pyridylmethyl)-3-methyl-2-nitroguanidine.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(#N)C>[S:1]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: OCCCCc1ccccc1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)OCCCCc1ccccc1
Yield: 63 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride in acetonitrile solution prepared in (a) was reacted as in Example 12 with 17.7 g (0.118 mole) of 4-phenylbutanol, 46.4 g (0.459 mole) of triethylamine in 100 ml additional acetonitrile followed by using extracting, washing and concentration procedures of Example 12 through the first evaporation. The viscous residue was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A Prep Pak 500® silica. Eluting solvent used was methylene chloride at a flow rate of 200 ml/min). Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give 19.3 g of colorless, viscous oil which solidified on standing. The solid was recrystallized from ethyl ether-petroleum ether (bp range 30°-60° C.) to give 16.9 g (63%) of title compound as white solid, mp 79°-81° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([CH:13]([CH3:15])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:17][CH2:18]Cl>[Cl-].[Al+3].[Cl-].[Cl-]>[CH:13]([C:7]1([CH2:17][CH2:18][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)([CH3:15])[CH3:14]
Reactant: ClCCCl
Reactant: c1ccccc1
Reactant: CC(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)C1(CCc2ccccc2)C=CC=CC1

Procedure:
Benzene and cumen are brought into reaction with 1,2-dichloroethane in the presence of aluminum chloride as a catalyst to obtain 1-isopropylphenyl-2-phenylethane.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)/[CH:10]=[CH2:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:29][CH2:30][CH3:31])(=[O:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Si:5]([O:8][C:9]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:21]([C:20]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH:10]=1)([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:7])[CH3:6]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: C=C/C(=C/c1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Product: CCOC(=O)C1CC=C(O[Si](C)(C)C(C)(C)C)C(c2ccc(F)cc2)C1C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 37 g (˜80% pure, 133.1 mmol, 1 equiv.) of 1E and 1Z-tert-butyl{[1-(4-fluorobenzylidene)prop-2-en-1-yl]oxy}dimethylsilane (Example 1, step C) and 17 mL (18 g, 104.6 mmol) diethyl(2E)-but-2-enedioate in 200 mL xylenes under nitrogen atmosphere was heated at 160° C. for 5 hr then cooled to RT. The solvent was evaporated under vacuum to give an oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=2)[C@@H:9]1[CH:20]([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:24]1C=C2C(C)N(C(OC(C)(C)C)=O)[C@@H](C(C)C)C2=NC=1>>[C:1]([O:5][C:6]([N:8]1[CH:16]([CH3:24])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=2)[C@@H:9]1[CH:20]([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1c2ncc(C(=O)O)cc2CN1C(=O)OC(C)(C)C
Reactant: CC(C)[C@H]1c2ncc(Cl)cc2C(C)N1C(=O)OC(C)(C)C
Product: CC(C)[C@H]1c2ncc(C(=O)O)cc2C(C)N1C(=O)OC(C)(C)C
Reaction time: 0.02 h

Procedure:
Procedure same as that for (S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylic acid, using tert-butyl(7S)-3-chloro-7-isopropyl-5-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate as a starting material. LC-MS tR=0.99 min in 1 min chromatography, MS (ESI) m/z 321.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:12]2[O:16]C(C)(C)C(C)(C)[O:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O1CCCC1.O.Cl>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([B:12]([OH:16])[OH:13])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)c(F)c2)OC1(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(B(O)O)cc1F
Reaction time: 2 h
Yield: 42.2 %

Procedure:
Combine 2-(3-fluoro-4-methanesulfonyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (222 mg, 0.74 mmol), NaIO4 (474 mg, 2.2 mmol), tetrahydrofuran (THF, 4 mL) and water (1 mL). Stir for 2 hours and add 2M HCl in diethyl ether (0.2 mL). Stir another 12 hours and filter away the solid. Wash the filtrate with brine (10 mL), dry with MgSO4 and evaporate the solvent. Wash the solid with hexane (2×10 mL) and ether (10 mL). Dry the solid under vacuum to obtain 68 mg of the title compound (42%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino 1-N-methyl piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.93 (m, 2 H) 1.18-1.31 (m, 2 H) 1.50-1.80 (m, 6 H) 1.83-2.00 (m, 4 H) 2.17 (s, 3 H) 2.71-2.95 (m, 2 H) 3.29 (s, 3 H) 3.67-3.87 (m, 3 H) 3.94 (s, 3 H) 4.89 (d, J=8.59 Hz, 1 H) 5.30-5.47 (m, 2 H) 6.01 (ddd, J=17.49, 12.69, 10.74 Hz, 1 H) 7.41-7.54 (m, 2 H) 7.82 (s, 1 H) 8.12 (s, 2 H) 8.30 (d, J=8.34 Hz, 1 H). [M+H] calc'd for C29H38FN7O3, 552; found 552.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[F:30][C:31]([F:35])([F:34])[CH2:32]I.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:28][CH:29]=3)=[N:9][N:10]([CH2:32][C:31]([F:35])([F:34])[F:30])[CH:11]=2)=[CH:5][CH:6]=1
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 60 °C

Procedure:
To a solution of 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (26.5 g) in dimethyl formamide (140 mL) was added 1,1,1-Trifluoro-2-iodo-ethane (21 mL, 2.0 eq.) and cesium carbonate (68.3 g, 3 eq.) and the reaction mixture heated at 60° C. for 24 h. The reaction mixture was diluted with water, extracted 3× methylene chloride, dried with magnesium sulfate, filtered and concentrated. Purification via flash chromatography eluting with 5% methanol/70% ethyl acetate/hexanes provided the title compound 20.85 g as an 8:1 regioisomeric mixture. Preparative HPLC eluting with acetonitrile/methanol (98:2) on a chiralpak AD column with a flow rate of 430 ml/Min provided the pure title compound as a free base 13.4 g. 1H NMR (400 MHz, CDCl3) δ 8.45 (m, 2H), 8.16 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.69 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.50 (m, 1H), 7.36 (d, J=8.7 Hz, 2H), 7.14 (d, J=6.2 Hz, 2H), 6.98 (d, J=9.1 Hz, 2H), 5.35 (s, 2H), 4.75 (q, J=8.3 Hz, 2H); MS: (M+H m/z=427.1). MS: (M+H m/z=461.2).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:7]=1)[CH3:4].Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:29]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:29]=3)=[CH:23][CH:24]=2)[N:7]=1)[CH3:4]
Reactant: ClCc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccc(-c4ccccc4)n3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (478 mg) and 2-chloromethyl-6-phenylpyridine (306 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(6-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (689 mg, yield: 95%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:28])[CH2:27][CH2:26][N:25]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:24][CH2:23]1
Reactant: FC1(F)CCNCC1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CCC(F)(F)CC2)ncn1

Procedure:
100 mg (0.3 mmol) of the compound from Example 13A, 63 mg (0.4 mmol) of 4,4-difluoropiperidine hydrochloride and 116 μl (86 mg, 0.7 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 2.5 h. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 82 mg (71% of theory)