Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[Br:22]>N1C=CC=CC=1>[Br:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[CH:13][C:12]([NH:11][S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8])=[CH:21]2
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1cnc2c(Br)cccc2c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cnc2c(Br)cccc2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In pyridine (5 ml) was dissolved 3-amino-8-bromoquinoline (Preparation Example 5) was dissolved in pyridine (5 ml), and 3-pyridinesulfonyl chloride (254 mg) was added thereto, followed by stirring at room temperature for 30 minutes. After the completion of the reaction, the reaction mixture was poured onto brine, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The resulting crude crystals were washed with ethyl acetate and IPA, to give the title compound (270 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[Na].CN(C)C=O.[CH2:26](Br)[C:27]#[CH:28]>C[O-].[Na+].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:28][C:27]#[CH:26])[C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: C#CCBr
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Product: C#CCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 4 h

Procedure:
100 ml. of a 1 N solution in sodium methoxide in methanol were added to a solution of 27.05 g (0.1 mol) of 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one in 500 ml. of anhydrous methanol. The solvent was driven off under reduced pressure, and the resulting sodium derivative was dissolved in 200 ml. of dimethylformamide. The temperature of the solution was maintained at 10°-15° C. while 10 ml. of propargyl bromide were added dropwise; and the mixture was stirred for about 4 hours, and then poured over ice. The product was filtered and dissolved in chloroform; and the chloroform solution was separated from the aqueous layer and dried over sodium sulphate. The chloroform was evaporated off from the solution, and the residue was dissolved in the minimum quantity of a 7:3 (by volume) mixture of benzene and ethyl acetate. This solution was chromatographed on a column of silica gel and eluted with a 7:3 (by volume) mixture of benzene and ethyl acetate. The portion of eluate containing the desired product, as determined by thin-layer chromatography, was collected and evaporated under reduced pressure. The residue was recrystallized from a 1:1 (by volume) mixture of benzene and hexane, giving 14 g of the pure desired product with a melting point of 141°-143° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)[OH:24])[CH2:17][CH2:16]3)=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[S:4][C:3]=1[C:32]([NH2:34])=[O:33].[CH3:35][S:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)(=[O:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH:23]([OH:24])[C:25]4[CH:30]=[CH:29][C:28]([C:43]5[CH:42]=[CH:41][CH:40]=[C:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH:44]=5)=[CH:27][N:26]=4)[CH2:17][CH2:16]3)=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[S:4][C:3]=1[C:32]([NH2:34])=[O:33]
Reactant: NC(=O)c1sc2nc(N3CCC(NCC(O)c4ccc(Br)cn4)CC3)cc(C(F)(F)F)c2c1N
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2ccc(C(O)CNC3CCN(c4cc(C(F)(F)F)c5c(N)c(C(N)=O)sc5n4)CC3)nc2)c1
Temperature: 85 °C
Yield: 42.7 %

Procedure:
A N2-purged suspension of 3-Amino-6-{4-[2-(5-bromo-pyridin-2-yl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (60 mg, 0.107 mmol), (3-methylsulfonylphenyl)boronic acid (24 mg, 0.118 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol), and potassium carbonate (30 mg, 0.214 mmol) in dry DMF (4 ml) and water (1 ml) was sealed and heated to 85° C. for 18h. The crude reaction mixture was applied to a celite plug and purified by SiO2 chromatography (0–25% MeOH/CH2Cl2 with 1% NH4OH). Fractions containing product were pooled and concentrated. The solid yellow residue was dissolved in 1 ml DMF, applied to a 2 mm prep plate (Merck) and eluted twice with 10% MeOH/CH2Cl2 with 1% NH4OH. The recovered yellow residue was dissolved in 0.5 ml water, 2 ml MeOH, 10 ml CH2Cl2, and 10 ml EtOAc and crystallized by the addition of 50 ml hexanes to give 29.0 mg, 42.3% of 3-Amino-6-(4-{2-hydroxy-2-[5-(3-methanesulfonyl-phenyl)-pyridin-2-yl]-ethylamino}-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide product. ES+ 635.1 m/z (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:20]4[CH2:28][CH2:27][NH:26][CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:20]4[CH2:28][CH2:27][N:26]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1
Reactant: Cc1ccc(Nc2ncnc3c2CCNC3)cc1-c1cc2ccccc2cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Nc2ncnc3c2CCN(S(C)(=O)=O)C3)cc1-c1cc2ccccc2cn1
Reaction time: 8 h

Procedure:
To a solution of N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (20 mg, 0.055 mmol) in DCM (0.4 ml) is added DIEA (21 mg, 0.121 mmol) and methylsulfonyl chloride (6.2 mg, 0.055 mmol) subsequently. The reaction mixture is stirred overnight. After concentrated by rotary evaporation, the residue is subject to HPLC to afford N-(3-(isoquinolin-3-yl)-4-methylphenyl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine as a white solid. LC-MS m/z: 446.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 9.32 (s, 1H), 8.53 (s, 1H), 8.01 (d, 1H, J=8.0 Hz), 7.85 (d, 1H, J=8.0 Hz), 7.77 (s, 1H), 7.72 (t, 2H, J=6.6 Hz), 7.64-7.60 (m, 2H), 7.31 (d, 1H, J=8.4 Hz), 6.47 (s, 1H), 4.35 (s, 2H), 3.64 (t, 2H, J=6.0 Hz), 2.89 (s, 3H), 2.68 (t, 2H, J=5.6 Hz), 2.39 (s, 3H).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][C:4]#[C:5][CH2:6][CH:7]([OH:10])[CH2:8][CH3:9]>O.OS(O)(=O)=O.[Hg]=O>[CH2:8]([CH:7]1[CH2:6][CH2:5][C:4]2([CH2:3][CH2:2][CH2:1][O:11]2)[O:10]1)[CH3:9]
Reactant: CCC(O)CC#CCCCO
Agent: O=S(=O)(O)O
Agent: O=[Hg]
Solvent: O
Product: CCC1CCC2(CCCO2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
0.540 g of mercury oxide in 100 ml of distilled water and 3.6 ml of concentrated H2SO4 were heated at 60° and at this temperature non-4-yn-1,7-diol (3.0 g) was added to the reaction mixture, which was then left 30 min under stirring. After cooling to room temperature, the mixture was extracted twice with diethyl ether washed with an aqueous solution of NaHCO3 and brine until neutrality, and finally dried over Na2SO4. The volatiles were taken off by evaporation in vacuo and the obtained residue was distilled in a bulb apparatus. 2.3 g (yield 35.2%) of the desired 2-ethyl-1,6-dioxaspiro[4.4]nonane having b.p. 80°-90°/1 Torr were thus obtained. The product had a purity of ca. 97%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27]([C:35](O)=[O:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:35]([C:27]2[C:28]3[O:33][CH2:32][O:31][CH2:30][C:29]=3[CH:34]=[C:25]([F:24])[CH:26]=2)=[O:36])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(F)cc3c2OCOC3)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid. LC-MS (basic): tR=0.79 min; [M+H]+=513.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([S:20]([NH2:23])(=[O:22])=[O:21])=[C:15]2[N:14]=[CH:13][C:12]=1[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].[C:39](O)(=[O:42])[CH2:40][CH3:41]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([S:20]([NH:23][C:39](=[O:42])[CH2:40][CH3:41])(=[O:22])=[O:21])=[C:15]2[N:14]=[CH:13][C:12]=1[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25]
Reactant: Cc1cc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(N)(=O)=O)cnn23)c(Cl)cc1F
Reactant: CCC(=O)O
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(C)c(F)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 94.7 %

Procedure:
Using 7-(2-chloro-4-fluoro-5-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.089 mmol) obtained in step 5 and propionic acid (0.033 mL, 0.446 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.052 g, 95%) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[C:11](N1C=CN=C1)([N:13]1C=CN=C1)=O.CN.C1COCC1.[Cl-].[NH4+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:13][CH3:11])=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(I)c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-iodobenzoic acid (1.5 g, 6 mmol) in anhydrous DMF (10 mL) was added 1,1′-carbonyldiimidazole (1.2 g, 7.2 mmol). The reaction mixture was heated to 50° C. under an atmosphere of nitrogen for 1 h. Upon cooling to room temperature, a solution of methylamine in THF (2 M, 6 mL, 10 mmol) was added. The reaction was stirred at r.t. for 15 min and then transferred into a solution of cold, saturated ammonium chloride (200 mL). The resulting precipitate was collected by filtration and dried to afford the title compound as a white solid, mp 94-97° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([NH:15]C(=O)C)([CH2:11][CH:12]([F:14])[F:13])C(OCC)=O)C.[ClH:20]>>[ClH:20].[NH2:15][CH:5]([CH2:11][CH:12]([F:14])[F:13])[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(CC(F)F)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: NC(CC(F)F)C(=O)O
Temperature: 25 °C
Yield: 97 %

Procedure:
In a flask was placed 2-acetylamino-2-(2,2-difluoro-ethyl)-malonic acid diethyl ester (8.94 g, 31.78 mmol) and 6N aqueous hydrochloric acid (140 mL). This mixture was refluxed overnight. After this time, the mixture was cooled to room temperature and extracted with diethyl ether (100 mL) the aqueous layer was concentrated in vacuo, azeotroped with acetonitrile and dried under high vacuum to afford 2-amino-4,4-difluoro-butyric acid hydrochloride salt (5.39 g, 97%) as a cream colored solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>Cl>[CH3:14][CH:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:17][CH2:16]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC1CCNCC1
Agent: Cl
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)O)CC1

Procedure:
A mixture of 10.0 g 2-chloro-5-nitro benzoic acid (50 mmol) and 13 mL 4-methyl-piperidine was refluxed for 2 h, 100 mL 1 N aq. HCl solution was added and it was extracted with 100 mL DCM. The organic phase was dried with Na2SO4, concentrated and purified via chromatography (silica gel, eluent: DCM:MeOH 100:1) to furnish the subtitle compound. MS [m+H]+=265.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:19])[NH:10][N:11]([CH:16]([CH3:18])[CH3:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O:23][CH2:24][C@H:25]1[O:30][C@H:29](Br)[C@H:28]([O:32]C(C)=O)[C@@H:27]([O:36]C(C)=O)[C@@H:26]1[O:40]C(C)=O)=O.[OH-].[Na+]>ClCCl>[CH2:1]([C:8]1[C:9]([O:19][C@@H:29]2[O:30][C@H:25]([CH2:24][OH:23])[C@@H:26]([OH:40])[C@H:27]([OH:36])[C@H:28]2[OH:32])=[N:10][N:11]([CH:16]([CH3:18])[CH3:17])[C:12]=1[CH:13]([CH3:14])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)c1c(Cc2ccccc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a suspension of 4-benzyl-1,5-diisopropyl-1,2-dihydro-3H-pyrazole-3-one (0.078 g), acetobromo-α-D-glucose (0.62 g) and benzyl (n-tributyl)ammonium bromide (0.054 g) in dichioromethane (4 mL) was added a sodium hydroxide aqueous solution (5 mol/L, 0.6 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi purified 4-benzyl-1,5diisopropyl-3-(2,3,4,6-tetraacetyl-1β-D-glucopyranosyloxy)-1H-pyrazole was dissolved in methanol (3 mL), and sodium methoxide (28% methanol solution, 0.58 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent of the reaction mixture was removed under reduced pressure, and the residue was acidified by adding 10% citric acid aqueous solution. The mixture was purified by solid phase extraction on ODS (washing solvent: water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) gave the title compound (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([S:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Sc1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2cccc(Cl)c2Cl)ccn1
Yield: 56.4 %

Procedure:
Using the method of Example 3, Step A, 2,3-dichlorobenzenethiol (1.69 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide 2-chloro-4-(2,3-dichlorophenylthio)pyridine (1.55 g, 56% yield) as a white powder. 1H NMR (CDCl3) δ 8.19 (d, 1H), 7.61 (d, 1H), 7.54 (d, 1H), 7.29 (t, 1H), 6.95 (s, 1H), 6.87 (d, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:28]([NH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:36]2[CH:37]=[C:32]([NH:31][C:28](=[O:30])[CH3:29])[CH:33]=[CH:34][CH:35]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(C)n(-c2cccc(NC(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), [3-(acetylamino)phenyl]boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.38 g, 28%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=1>O1CCOCC1.[O-2].[Mn+4].[O-2]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:13]=[O:14]
Reactant: OCc1cccc(CC2OCCO2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1cccc(CC2OCCO2)c1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
To a solution of (3-((1,3-dioxolan-2-yl)methyl)phenyl)methanol (prepared as in Example 22, Step 1 with 3-((1,3-dioxolan-2-yl)methyl)benzoic acid replacing 4-((1,3-dioxolan-2-yl)methyl)benzoic acid; 0.47 g, 2.42 mmol) in 1,4-dioxane (8 mL), manganese (IV) oxide (2.35 g) was added. The resulting suspension was heated at 100° C. for 16 hours. The reaction mixture was allowed to cool, and the suspension was filtered through a pad of celite. The celite pad was washed with ethyl acetate and the filtrate evaporated at reduced pressure to afford the title compound (0.352 g, 76%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:53][O:54][Si:55]([CH:62]([CH3:64])[CH3:63])([CH:59]([CH3:61])[CH3:60])[CH:56]([CH3:58])[CH3:57])=[N:43][N:44]([CH2:46][CH2:47]OS(C)(=O)=O)[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:65][NH:66][CH3:67]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:53][O:54][Si:55]([CH:56]([CH3:57])[CH3:58])([CH:62]([CH3:63])[CH3:64])[CH:59]([CH3:60])[CH3:61])=[N:43][N:44]([CH2:46][CH2:47][N:66]([CH3:67])[CH3:65])[CH:45]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC
Reactant: CC(C)[Si](OCc1nn(CCOS(C)(=O)=O)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1nn(CCN(C)C)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A solution of Intermediate 74j (104 mg, 0.11 mmol) in THF (0.5 mL) was treated with dimethylamine (2M in THF, 0.57 mL, 1.1 mmol) and the mixture was stirred at RT over the weekend. The mixture was evaporated in vacuo and the residue was partitioned between DCM and water. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7% [2M NH3 in MeOH] in DCM, to give the title compound (79 mg, 81%). LCMS (Method 3): Rt 3.46 min, m/z 866.6 [MH+].
Reaction SMILES: [CH2:1]([C:4]1([CH2:18][CH2:19][CH3:20])[CH2:9][CH2:8][C:7]([CH2:14][C:15]([OH:17])=[O:16])([CH2:10][C:11](O)=[O:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C(OC(=O)C)(=O)C>[CH2:18]([C:4]1([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][C:7]2([CH2:10][C:11](=[O:12])[O:17][C:15](=[O:16])[CH2:14]2)[CH2:8][CH2:9]1)[CH2:19][CH3:20]
Reactant: CCCC1(CCC)CCC(CC(=O)O)(CC(=O)O)CC1
Solvent: CC(=O)OC(C)=O
Product: CCCC1(CCC)CCC2(CC1)CC(=O)OC(=O)C2
Yield: 90 %

Procedure:
4,4-Dipropylcyclohexane-1,1 diacetic acid, prepared as described in Example 18, was dissolved in acetic anhydride and refluxed for 1-6h. The excess acetic anhydride was removed by distillation under reduced pressure and the residue was recrystallized form hexanes; m.p. 91-93° ; yield 90-95%.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]#[N:7].[NH3:16]>CO>[CH3:1][S:2][CH2:3][CH2:4][CH:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([CH3:13])([CH3:15])[CH3:14])[C:6]([NH2:16])=[NH:7]
Reactant: CSCCC(C#N)OCCO[Si](C)(C)C
Reactant: N
Solvent: CO
Product: CSCCC(OCCO[Si](C)(C)C)C(=N)N
Temperature: 85 °C

Procedure:
A solution of intermediate 18, 4-(methylthio)-2-(2-(trimethylsilyloxy)ethoxy)butanenitrile, (4.9 g, 0.02 mol) in 30 mL of methanol was saturated with ammonia. The flask was then sealed and heated in an oil bath at 80-90° C. for 16 hrs. After cooling, the flask was opened and the mixture concentrated in vacuo to give the title compound in essentially quantitative yield as a very viscous oil. 1H NMR (300 MHz, CDCl3) δ ppm:3.94-4.02 (1H, m) 3.76-3.94 (3H, m) 3.68-3.77 (2H, m) 3.52-3.62 (2H, m) 2.53-2.67 (2H, m) 2.07 (3H, s) 1.89-2.01 (2H, m); LC/MS193 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:26])[C:18](=[CH:22][N:23]([CH3:25])C)[C:19](=O)[CH3:20])=[CH:11][C:10]=3[F:27])[N:7]=[C:6]([C:28]([F:31])([F:30])[F:29])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(=O)C.C(N)=[NH:37].CC[O-].[Na+]>C(O)C>[CH:1]1([C:4]2[N:8]([C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:18]4[C:19]([CH3:20])=[N:37][CH:25]=[N:23][CH:22]=4)=[O:26])=[CH:11][C:10]=3[F:27])[N:7]=[C:6]([C:28]([F:30])([F:29])[F:31])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)C(=CN(C)C)C(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ncncc1C(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Yield: 5 %

Procedure:
N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3,5-difluorophenyl}-2-[(dimethylamino)methylene]-3-oxobutanamide (700 mg, 1.6 mmol) and formamidine acetate (282 mg, 2.7 mmol) were dissolved in ethanol and added NaOEt (120 mg, 3.4 mmol). The above mixture was refluxed for 3 hr. Ethanol was removed on rotavapour and worked up (H2O/AcOEt) to obtain the crude. Crude was purified by column on 60-120 mesh silica gel using AcOEt and Petether (35:65) as eluent to obtain the title compound (34 mg) as a pale-yellow solid. M.P.: 147-150° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.25 (s, 1H), 9.18 (s, 1H), 8.96 (s, 1H), 7.73 (d, J 9.9, 2H), 6.69 (s, 1H), 2.61 (s, 3H), 1.65-1.56 (m, 1H), 0.95-0.86 (m, 2H), 0.80-0.72 (m, 2H). MS (m/z): 424.09 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)#[N:2]>C1(C)C=CC=CC=1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)/C=C/c1ccc(C#N)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(C#N)cc1
Reaction time: 9 h
Yield: 76.7 %

Procedure:
To a solution of methyl p-cyano-trans-cinnamate (13.6 g, 73 mmol) in toluene (485 mL) was added 5% Pd/BaSO4 (2.7 g). After 9 hours under hydrogen gas at 4 bar (60 psi), the solution was filtered, concentrated in vacuo and chromatographed over silica gel, eluting with a step gradient of hexanes through 30% ethyl acetate/hexanes. The product containing fractions were combined and concentrated to give 10.6 g (77%) of colorless oil.