Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18]Br)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-:28])(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[K+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:27][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-]C(=S)c1ccccc1
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCNC(=O)OCc1ccccc1)NCCSC(=O)c1ccccc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To the solution of 3-(benzyloxycarbonylamino)-N-(2-bromoethyl)propionamide (10.0 g, 0.03 mol) in acetone (250 ml), acetone (100 ml) solution of potassium thiobenzoate (5.35 g, 0.03 mol) is added. The mixture is stirred for 1 hour and insoluble substance is filtered off. The filtrate is concentrated in vacuo and the residue is dissolved in chloroform. The solution is washed with sodium hydroxide solution, water and then saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solution is concentrated in vacuo to give 7.9 g (68%) of the titled compound.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([S:10][CH3:11])[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:14])=O>>[C:1]([S:4][CH2:5][CH:6]([S:10][CH3:11])[C:7]([Cl:14])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CSC(CSC(C)=O)C(=O)O
Product: CSC(CSC(C)=O)C(=O)Cl

Procedure:
The 3-(acetylthio)-2-(methylthio)propionic acid is refluxed in thionyl chloride for two hours. The reaction mixture is distilled to remove excess thionyl chloride and the product is distilled in vacuo to yield 3-(acetylthio)-2-(methylthio)propionic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:9]([Cl:19])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH:33][CH2:34][CH3:35])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CC(CC)=O>[CH2:34]([N:33]([CH:30]1[CH2:29][CH2:28][N:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:32][CH2:31]1)[C:5](=[O:6])[C:4]1[CH:8]=[C:9]([Cl:19])[C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:11][C:3]=1[O:2][CH3:1])[CH3:35]
Reactant: CCNC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(NC(=O)C(F)(F)F)c(Cl)cc1C(=O)Cl
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCN(C(=O)c1cc(Cl)c(NC(=O)C(F)(F)F)cc1OC)C1CCN(Cc2ccccc2)CC1
Reaction time: 48 h
Yield: 68.3 %

Procedure:
A solution of 2-methoxy-4-trifluoroacetylamino-5-chlorobenzoyl chloride (17.4 g; 0.055 moles) dissolved in anhydrous ethyl methyl ketone (75 ml) was added little by little to another solution of 1-benzyl-4-ethylamino-piperidine (10.9 g; 0.05 moles) and triethylamine (7.0 ml; 0.05 moles) in anhydrous ethyl methyl ketone (75 ml) at room temperature. On completion of the addition, the mixture was left at room temperature and stirred for 48 hours, and then the mixture was concentrated at reduced pressure, poured into water, and extracted with chloroform. The organic solution was dried (Na2SO4) and the solvent removed in vacuo. The residue was recrystallized from a mixture of methanol and diethyl ether to give N-ethyl-N-(1-benzylpiperid-4-yl)-2-methoxy-4-trifluoroacetylamino-5-chlorobenzamide (17 g), m.p. 198°-200° C.
Reaction SMILES: O[CH2:2][C:3]1[NH:7][N:6]=[C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=1.[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=O>C(Cl)(Cl)Cl.C1(C)C(C)=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]1[N:7]2[N:6]=[C:5]([O:8][S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:4]=[C:3]2[CH:2]=[N:25][N:24]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(CO)[nH]n2)cc1
Reactant: NNC(=O)c1ccccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2cc3cnnc(-c4ccccc4F)n3n2)cc1
Temperature: 70 °C
Yield: 92.4 %

Procedure:
To a solution of toluene-4-sulfonic acid 5-hydroxymethyl-1H-pyrazol-3-yl ester (25 g, 93 mmol) in chloroform (800 ml) was added manganese dioxide (40.3 g, 465 mmol) and the suspension was heated at 70° C. for 14 h. The reaction mixture was filtered through sand/silica and the plug of silica was then washed several times with 10% methanol/dichloromethane. The combined filtrates were concentrated under vacuum to give crude aldehyde (25 g). Some of the crude aldehyde (2 g, 7.6 mmol) and 2-fluorobenzoic hydrazide (1.16 g, 7.6 mmol) were suspended in xylene (60 ml) and heated together at reflux for 3 h. After cooling, the solid formed was collected by filtration and dried under vacuum at 80° C. to afford 2.7 g (94%) of the condensation product as a light brown solid. Some of this condensation product, which existed in nmr solution as a mixture of isomers (1 g, 2.5 mmol), was dissolved in Dowtherm A (100 ml) and heated at 180° C. for 72 h. The whole reaction solution was cooled and eluted through a silica gel column using 0 to 15% ethyl acetate/dichloromethane to give the title compound as a light tan solid (0.614 g, 64%); 1H NMR (360 MHz, CDCl3) δ 2.46 (3H, s), 6.73 (1H, s), 7.18-7.35 (4H, m), 7.61 (1H, m), 7.71 (1H, m), 7.82 (2H, d, J 8.3 Hz), 9.33 (1H, s).
Reaction SMILES: O.[O:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:12][CH:13]([OH:15])[CH3:14])[CH:6]=[CH:5][C:4]1=2>[Pd].COCCOCCOC>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH:13]([OH:15])[CH3:14]
Reactant: CC(O)Cn1ccc2c1CCCC2=O
Agent: [Pd]
Solvent: COCCOCCOC
Solvent: O
Product: CC(O)Cn1ccc2c(O)cccc21
Yield: 78.5 %

Procedure:
10 g of palladium on carbon at 5% by weight and containing 50% water were added to a solution of 19.3 g of 4-oxo-4,5,6,7-tetrahydro-1-N-(β-hydroxypropyl)indole, obtained in the preceding stage, in 300 cm3 of diglyme. The temperature of the reaction medium was raised to the reflux temperature of diglyme for 5 hours, after removing the water by azeotropy. The catalyst was then filtered off on celite and then the diglyme was evaporated off. 17 g of crude product were obtained. After chromatography on silica gel (heptane/ethyl acetate=1/4), 15 g of viscous product were obtained, which product was crystallized by the addition of 15 cm3 of dichloromethane.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:9][C@H:8]([CH3:10])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To D-alanine tert-butyl ester hydrochloride (1 g) in methylene chloride (35 ml) solution, triethylamine (1.7 ml) and 4-chlorobenzenesulfonyl chloride (1.1 g) were added under ice cooling and the mixture was stirred at room temperature for 2 hours. The methylene chloride was distilled off in vacuo, then the residue was diluted with ethyl acetate. The obtained solution was successively washed with distilled water, saturated potassium hydrogensulfate aqueous solution, and saturated saline, dried over with anhydrous sodium sulfate, then concentrated. The residue was recrystallized from ethyl acetate/hexane to obtain the title compound (1.47 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][C:16]#[N:17].Br[CH2:22][C:23]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[N:25]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[N:24]=1>O1CCCC1>[Cl:35][C:30]1[CH:29]=[C:28]([C:26]2[N:25]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[N:24]=[C:23]([CH2:22][CH:15]([C:14]3[CH:13]=[C:12]([CH3:11])[CH:20]=[CH:19][CH:18]=3)[C:16]#[N:17])[CH:27]=2)[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: Cc1cccc(CC#N)c1
Reactant: COc1ccc(-n2nc(CBr)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CC(C#N)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a solution of sodium bis(trimethylsilyl)amide (14.0 mL, 1.0 M solution in THF, 1.0 equiv) in tetrahydrofuran (56.0 mL) at 0° C. was added 3-methylbenzyl cyanide (1.84 g, 14.0 mmol, 1.0 equiv). This mixture was stirred at 0° C. for 30 min then was added to a solution of 3-bromomethyl-5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole (prepared as in Method 1; 5.78 g, 14.0 mmol, 1.0 equiv) in tetrahydrofuran (56.0 mL) and allowed to stir for 2 h. The reaction was quenched with satd aq ammonium chloride (10.0 mL), and the resulting mixture was diluted with water (200 mL), and extracted with diethyl ether (2×100 mL). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by flash chromatography (25% ethyl acetate/hexanes) to yield the title intermediate (2.76 g, 43%). HPLC: Rt=13.44 (Method G). MS (ESI): mass calculated for C26H21Cl2N3O, 461.11; m/z found, 462.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.36 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.28 (t, J=7.4 Hz, 1H), 7.24 (s, 1H), 7.23-7.21 (m, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.19-7.16 (m, 1H), 6.95 (dd, J=8.5, 2.2 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 6.42 (s, 1H), 4.22 (dd, J=9.6, 6.0 Hz, 1H), 3.83 (s, 3H), 3.30-3.21 (m, 2H), 2.38 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C-:15]#[N:16].[K+]>CN(C)C=O.O>[NH2:1][C:2]1[N:10]=[C:9]([C:15]#[N:16])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1nc(Cl)c([N+](=O)[O-])cc1C(=O)O
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nc(N)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 84.4 %

Procedure:
The compound prepared in Example 238 (0.130 g) and potassium cyanide (0.195 g) were combined in N,N-dimethylformamide (3 mL) and water (0.5 mL) was added. The reaction mixture was heated at 90° C. for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was cautiously acidified with 1N hydrochloric acid to pH 1 to 2. It was then extracted with ethyl acetate. These extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated to obtain the title compound (0.105 g) having the following physical data.
Reaction SMILES: C([O:4][N:5]1[C:10]([NH2:11])=[CH:9][C:8](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:7][C:6]1=[NH:23])(=O)C.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[NH2:11][C:10]1[N:5]([OH:4])[C:6](=[NH:23])[N:7]=[C:8]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:9]=1
Reactant: C1CCNCC1
Reactant: CC(=O)On1c(N)cc(OS(=O)(=O)c2ccc(C)cc2)nc1=N
Solvent: ClC(Cl)Cl
Product: N=c1nc(N2CCCCC2)cc(N)n1O
Reaction time: 1 h
Yield: 75 %

Procedure:
0.3 g (0.88 mmole) of 1-acetoxy-6-amino-1,2-dihydro-2-imino-4-(4-toluenesulfonyloxy)pyrimidine is added to a solution containing 10 ml of chloroform and 2 ml of piperidine while stirring. The mixture is refluxed under stirring for 30 minutes, then evaporated under reduced pressure. To the residue, 5 ml of ethanol and 1 ml of 1N aqueous sodium hydroxide solution are added. The mixture is set aside at room temperature for one hour, then evaporated under reduced pressure. The residue is triturated with 10 ml of water, the crystals are filtered, washed with water and dried to give 0.14 g (75% yield) of the aimed compound which shows no melting point depression when mixed with the product of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:7]=1
Reactant: BrCCc1ccccc1
Reactant: OCc1ccc(F)cc1O
Product: CC(Oc1cc(F)ccc1CO)c1ccccc1

Procedure:
The title compound was prepared from 5-fluoro-2-(hydroxymethyl)phenol and (bromoethyl)benzene according to the procedure for the preparation of Example 136, part A.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[N:7]([CH3:35])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].Cl.Cl>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[N:7]([CH3:35])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4C)c3)c(=O)n(C)c2n1
Agent: Cl
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4C)c3)c(=O)n(C)c2n1
Yield: 26 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.180 g, 0.363 mmol) and MeNH2.HCl (0.0502 g, 0.743 mmol, 2.00 eq) were combined to afford 1-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.0451 g, 24% yield) as the HCl salt. 1H NMR (400 MHz, DMSO-d6): δ 9.49 (brs, 1H), 9.07 (s, 1H), 8.44-8.41 (m, 1H), 7.97 (brs, 1H), 7.92 (s, 1H), 7.33-7.27 (m, 2H), 6.23 (s, 1H), 3.71 (s, 3H), 3.63 (brs, 3H), 2.94 (s, 3H), 1.24 (s, 9H); MS (ESI) m/z: 479.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[C:19](/[CH2:23][C:24](O)=[O:25])\[C:20](O)=[O:21])/[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](=[C:19](/[CH2:23][CH2:24][OH:25])\[CH2:20][OH:21])/[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(/C(=C(\CC(=O)O)C(=O)O)c2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C(/CO)CCO)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a solution of 7.85 g (0.0199 mole) of (Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)methylene]succinic acid, prepared in example 28, in 40 ml of tetrahydrofuran are added dropwise 5.65 ml (0.0596 mole) of borane/dimethyl sulphide complex. The mixture is then stirred for 3 hours at ambient temperature and then 1 hour at 50° C. After returning to ambient temperature, 5 ml of ethanol are added dropwise. The mixture is then concentrated to half its volume and then taken up into water. The crystals obtained are filtered off under suction and washed with pentane and dried giving 6.92 g of (Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)-methylene]-1,4-butanediol in the form of crystals with a melting point of 159-160° C.
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:17]2[N:18]=[CH:19][C:20]3[N:21]([C:22]([C:25]45[CH2:32][CH2:31][C:28]([NH:33][S:34]([CH:37]6[CH2:39][CH2:38]6)(=[O:36])=[O:35])([CH2:29][CH2:30]4)[CH2:27][CH2:26]5)=[N:23][N:24]=3)[C:16]=2[CH:15]=[CH:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].I[CH3:41]>CN(C=O)C>[CH3:41][N:33]([C:28]12[CH2:27][CH2:26][C:25]([C:22]3[N:21]4[C:16]5[CH:15]=[CH:14][N:13]([S:3]([C:6]6[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=6)(=[O:4])=[O:5])[C:17]=5[N:18]=[CH:19][C:20]4=[N:24][N:23]=3)([CH2:30][CH2:29]1)[CH2:32][CH2:31]2)[S:34]([CH:37]1[CH2:38][CH2:39]1)(=[O:36])=[O:35]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N(C)S(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.4 %

Procedure:
A round bottom flask was charged with sodium hydride (60% dispersion in mineral oil, 0.013 g, 0.33 mmol) and DMF (1 mL) to give a white suspension. The suspension was cooled to about 0° C. followed by the addition of a solution of N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.15 g, 0.27 mmol, Example #7, Step C) in DMF (2 mL). The reaction mixture was stirred for about 15 min and iodomethane (0.06 g, 0.41 mmol) was added. The reaction mixture was stirred at about 0° C. for about 30 min, warmed to room temperature, and stirring was continued for about 2 h. The solvent was removed under reduced pressure. The residue was dissolved in DCM (5 mL) then purified by flash silica gel chromatography using EtOAc as the eluant to give N-methyl-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.068 g, 45%) as a yellow solid: LC/MS (Table 1, Method a) Rt=2.35 min; LC/MS m/z 555 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:21]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:8][CH:9]=1)=[O:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)O)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)OCc3ccccc3)cc2)cc1

Procedure:
A solution of 11.64 g (40 mmol) of N-(4-carboxyphenyl)-4-toluenesulfonamide, 5.06 g (40 mmol) of benzyl chloride and 5.20 g (44 mmol) of di-i-propylethylamine in 100 ml of dimethylformamide is heated at 140° C. for 4 hours. After the reaction is complete, the mixture is evaporated in vacuo, the residue is taken up in propyl acetate, and the solution is washed 2× with 2N hydrochloric acid and ##STR22## 2× with saturated NaHCO3 solution, dried over sodium sulfate and evaporated. 11.8 g (78% of theory) of N-(4-benzyloxycarbonylphenyl)-4-toluenesulfonamide, which are recrystallized from methanol, are obtained.
Reaction SMILES: [C:1]([O:9]C)(=[O:8])[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:11]([Si:15]([CH3:26])([CH3:25])[O:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[K+].C(O)(C)(C)C.Cl>>[CH3:7][O:6][C:4](=[O:5])[C:3](=[CH:23][CH:20]1[CH2:19][CH2:18][CH:17]([O:16][Si:15]([C:11]([CH3:12])([CH3:14])[CH3:13])([CH3:26])[CH3:25])[CH2:22][CH2:21]1)[CH2:2][C:1]([OH:9])=[O:8]
Reactant: COC(=O)CCC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)CC(=O)O
Temperature: 50 °C
Yield: 38.3 %

Procedure:
A solution of dimethyl succinate (730 mg, 5.0 mmol) and 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanecarbaldehyde (1.00 g, 4.1 mmol) was added over 25 min to a 1.0 M solution of potassium tert-butoxide in tert-butanol (4.4 mL. 4.4 mmol). The reaction mixture was heated at 50° C. for 50 min, cooled to RT and concentrated under vacuum. The residue was dissolved in water (25 mL) and washed with EtOAc (2×10 mL). The aqueous layer was acidified with 6 N HCl (2.0 mL, 12 mmol) and extracted with EtOAc (2×20 mL), dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (25% EtOAc/DCM) to give the title compound (560 mg) as a mixture of olefin isomers (˜1:1) and a mixture of cis and trans isomers at the cyclohexyl ring (˜1:1). 1H NMR (CDCl3, 400 mHz) δ (ppm) olefin peaks at 6.88 (d, J=10.2 Hz) 6.77 (d, J=10.0 Hz) CHOTBS peaks at 3.96 ppm (br s) (cis isomer, hydrogen equitorial, 3.55 (m) (trans isomer, hydrogen axial).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=3)[CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)C1CNCCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: O=C(O)C1CNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 137 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 434. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.47 (s, 1H) 8.36 (d, 2H) 7.88 (d, 1H) 7.74 (t, 1H) 7.61 (d, 1H) 7.15 (d, 2H) 6.68 (d, 2H) 4.68 (dd, 1H) 4.39 (s, 2H) 3.96 (t, 2H) 3.84 (dd, 2H) 3.52 (t, 2H) 3.44 (t, 2H) 2.95 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:24][C@@H:25]2[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26]2)=[N:6][CH:7]=1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Reactant: N[C@@H]1CC[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: 100 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (75 mg, 0.226 mmol), was added (1S,3R)-3-aminocyclopentanol (68.6 mg, 0.678 mmol), NMP (0.75 ml) and triethylamine (0.158 ml, 1.130 mmol). The crude reaction mixture was stirred at 100° C. for 18 hr, and the reaction progress followed by LCMS. The crude reaction mixture was cooled, filtered, and purified by prep LC. The product fractions were collected, 50 mL of 1 M NaOH and 50 mL of EtOAc were added. The aqueous layer was removed, the organic layer was washed with 50 mL of saturated salt solution, dried over sodium sulfate, and reduced to constant mass. 28 mg of the desired compound was obtained. LCMS (m/z): 413.1 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, CHLOROFORM-d, 25° C.) δ ppm 1.71 (d, J=14.09 Hz, 1H) 1.75-1.91 (m, 2H) 1.97-2.05 (m, 1H) 2.10-2.16 (m, 1H) 2.61 (br. s., 1H) 4.03-4.18 (m, 1H) 4.39 (tt, J=4.84, 2.59 Hz, 1H) 4.55 (d, J=5.09 Hz, 2H) 5.19 (br. s., 2H) 6.41 (d, J=8.22 Hz, 1H) 6.55 (s, 1H) 6.90-7.02 (m, 2H) 7.05-7.18 (m, 2H) 7.24-7.34 (m, 1H) 7.43-7.55 (m, 1H) 8.07 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](N)=[CH:9][CH:8]=[CH:7]2.N([O-])=O.[Na+].[S-:17][C:18]#[N:19].[K+]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[S:17][C:18]#[N:19])[CH:5]=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: Nc1cccc2cccc(Cl)c12
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#CSc1cccc2cccc(Cl)c12

Procedure:
3.92 parts 8-chloro-1-naphthylamine were stirred in dilute hydrochloric at room temperature and diazotised by the careful addition of a solution of 1.52 parts sodium nitrite in water. The diazo solution was then added, at 10° C., to a stirred suspension of 3.5 parts potassium thiocyanate, 4.5 parts cuprous thiocyanate and 0.1 parts ferrous sulphate in water. After stirring the mixture for several hours, the product was filtered off and recrystallised several times from ethanol to yield 1 part of pure product, m.pt 77°-8° C. The I.R. spectrum contained a band at 2160 cm-1 due to the thiocyanate group.