Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C([O:22][C:23]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:24])C>C1(C)C=CC=CC=1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([CH2:25][C:23]([OH:24])=[O:22])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)c3ccccc3C2CC(=O)O)cc1
Yield: 87.9 %

Procedure:
A solution of 3-hydroxy-2-(4-methoxyphenyl)isoindolin-1-one (12.0 g) and ethoxycarbonylmethylenetriphenylphosphorane (16.0 g) in toluene (200 ml) was refluxed for 3 hours. After cooling, the toluene was distilled off and the residue was dissolved in 100 ml of methanol. A solution of 10 g of potassium carbonate in 70 ml of water was added to the above methanol solution and the mixture was refluxed gently for an hour. After cooling, 200 ml of water and 300 ml of ether were added and the mixture was shaken well. The aqueous layer was separated and acidified with 5N hydrochloric acid to give 12 g of 3oxo-2-(4-methoxyphenyl)isoindoline-1-acetic acid, which was described in (iv) of Example 2.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[CH3:9][NH:10][CH3:11]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:9][N:10]([CH3:11])[C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[CH2:2]
Reactant: CNC
Reactant: CC(=O)c1ccco1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: C=C(c1ccco1)N(C)C
Reaction time: 3 h

Procedure:
To a solution of 55 g of 2-acetylfuran and 193 g of dimethylamine in 1 liter of dry benzene, stirred at 3° under nitrogen, is added dropwise a solution of 31 mL of titanium tetrachloride in 100 mL benzene over 45 minutes. The mixture is stirred for a further 3 hours at 3°, then at ambient temperature overnight. The brown reaction mixture is filtered through a medium frit glass funnel under nitrogen, and the filtered solids are washed with dry benzene. The combined filtrates are concentrated in vacuo to give the desired enamine as an oil.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.CI>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14]([O:16][CH3:1])=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 94283.6 %

Procedure:
Anhydrous potassium carbonate (20.7 g, 0.15 mmole) was added to a solution of 4-bromocinnamic acid (22.7 g, 0.1 mmole) in dry N,N-dimethylformamide (150 ml) and the mixture was stirred for 30 minutes. Methyl iodide (21.3 g, 9.4 ml, 0.15 mmole) was then added and the total mixture stirred for a further 24 hours at room temperature before the solvent was evaporated in vacuo. Water was added to the residue and the product extracted into ether. The ethereal extracts were washed with saturated aqueous sodium bicarbonate solution, the brine and dried (MgSO4). Evaporation afforded 22.73 g (94%) of the ester as a white solid of mp (methanol) 82°-86° C. (lit mp 80° C., Dictionary of Organic Compounds), υmax (mull), 1718, 1640, 1595, 1495 cm-1. δ(CDCl3) 3.80 (3H, s, ester CH3), 6.37 (1H, d, J 13 Hz, =CHCO2), 7.42 (4H, m, arom), 7.62 (1H, d, J 13 Hz, ArCH=).
Reaction SMILES: [C:1]([Si:5]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=[CH:15][C:16]=2[F:18])[CH2:11][CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Br[C:29]1[C:30]([F:35])=[N:31][CH:32]=[CH:33][CH:34]=1.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[Si:5]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:29]3[C:30]([F:35])=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:14]=[CH:15][C:16]=2[F:18])[CH2:11][CH2:10]1)([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:6])[CH3:7]
Reactant: Fc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(F)c3c2CC[C@@H]3O[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(-c3cccnc3F)ccc(F)c21

Procedure:
The title compound is prepared from (S)-tert-butyl(7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)dimethylsilane and 3-bromo-2-fluoropyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.31 min.; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>>[F:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:21](=[O:22])[C:20]2[CH:19]=[C:18]([C:17]([F:32])([F:31])[F:16])[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ncccc1F
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ncccc1F

Procedure:
The title compound was prepared in analogy to example 55, from (3-fluoro-[2,4]bipyridinyl-3′-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the chromatographic purification. Brown Solid (13%). MS (ESI): m/z=444.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>>[Br:1][C:2]1[S:6][C:5]([S:7]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: c1cc[nH]c1
Product: O=S(=O)(c1ccc(Br)s1)n1cccc1
Yield: 88 %

Procedure:
N-(5-bromothiophene-2-sulfonyl)pyrrole was prepared in the same manner as described in Example 33A from 5-bromothiophene-2-sulfonyl chloride and pyrrole in 88% yield. This was purified by recrystallization using hexane/ethyl acetate as a solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][SH:19])[CH:15]=[N:14]1.[OH-].[Na+].O.[CH2:23]([N:26]1[C:30]([C:31]#[N:32])=[C:29]([C:33]#[N:34])[N:28]=[C:27]1Br)[CH:24]=[CH2:25]>O1CCOCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][S:19][C:27]2[N:26]([CH2:23][CH:24]=[CH2:25])[C:30]([C:31]#[N:32])=[C:29]([C:33]#[N:34])[N:28]=2)[CH:15]=[N:14]1
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CS)n2)c(Cl)c1
Reactant: C=CCn1c(Br)nc(C#N)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1c(SCc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)n2)nc(C#N)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-4-mercaptomethyl-2H-1,2,3-triazole, prepared as in EP No. 350 237, (0.33 g) and sodium hydroxide (0.04 g) were stirred in dioxane (2 ml) and water (1 ml) at ice bath temperature. 1-Allyl-2-bromo-4,5-dicyanoimidazole (0.24 g) in dioxane was added and the mixture stirred at room temperature for 2 hours. Aqueous work up and silica gel column chromatography gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(4,5-dicyano-1-allyl-1H-imidazol-2ylthio)methyl]-2H-1,2,3-triazole, m.p. 125°-127°. (Compound 24a)
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:30][CH2:31][S:32](=[O:36])(=[O:35])[CH2:33][CH2:34]5)=[CH:25][CH:24]=4)=[O:19])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: Nc1ccc(N2CCS(=O)(=O)CC2)cc1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 90.8 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and 4-(4-aminophenyl)thiomorpholine 1,1-dioxide (0.158 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(4-(1,1-dioxidothiomorpholino)phenyl)acetamide as a white solid (0.31 g, 89.8% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)C(C)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(=O)C(C)(C)c1cccc(O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 3-(3-methoxy-phenyl)-3-methyl-butan-2-one (6.570 g, 34.172 mmol) in methylene chloride (100 mL) cooled to −78° C. was added boron tribromide (102 mL, 1 M solution in methylene chloride, Aldrich). The mixture was stirred at −78° C. for 1 h, warmed up to 0° C. for 1 h then put in the freezer (−20° C.) for 72 h. At 0° C., water was added to quench the excess boron tribromide (CAUTION: Violent reaction). The product was extracted with petroleum ether. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by flash chromatography (40 g of silica gel, eluting with 5-20% ethyl acetate in hexane) to give 3-(3-hydroxy-phenyl)-3-methyl-butan-2-one as a yellow oil (5 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH2:33][CH2:34][OH:35])[CH3:31])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCCO
Product: CN(CCO)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2-hydroxy-ethyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and 2-methylamino-ethanol following General Procedure B.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Nc2cccc(Cl)c2)ccc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(c2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2[N+](=O)[O-])CC1
Yield: 78.6 %

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonylchloride (1g, 3.9 mmol), 3-chloroaniline (0.5 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2Cl2 (2 mL) was stirred at room temperature. The reaction was quenched with NaHCO3 (sat aq solution, 30 mL×3). The organic phase was separated, dried (MgSO4), and filtered. The volatiles were evaporated and the residue was purified by column chromatography (SiO2, pentane:EtOAc, 4:1) to give 4-chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide; MS (posESI) m/z=349.2 (M+H+). 1H NMR (CDCl3) δ 7.00-7.40 (m, 3H), 7.60-7.90 (m, 3H), 8.70 (bs, 1H). 4-Chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide (0.45 g, 1.3 mmol), N-methylpiperazine (0.191 mL, 1.73 mmol) and K2CO3 (359 mg, 2.6 mmol) in CH3CN (2.5 mL) as the filtrated was concentrated to give a residue which was purified by column (SiO2, CHCl3:MeOH: NH3 9:1:0.4%) to give 420 mg of N-(3-chlorophenyl)-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide (85%). Purity>95% according to HPLC analysis. The compound was dissolved in THF (1 mL) and ethanol (5 mL) was added. The solution was treated with Raney-Ni (50 mg) and hydrazine monohydrate (0.05 mL) overnight. The Raney-Ni was filtered (celite pad), the volatiles were evaporated and the residue was purified by column chromatography (SiO2, CHCl3:MeOH: NH3 9:1:0.4%). The product was isolated as hydrochloride salt by treatment with HCl gas in diethyl ether to yield 170 mg of final product (32%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]2[C:16]=1[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=1)[CH3:3].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]3[C:16]=2[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)[CH3:3])[C:30]=1[C:31]#[N:32]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COC(=O)c1cccc2nc([C@H](C)N)c(-c3cncc(F)c3)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)c(-c3cncc(F)c3)n12

Procedure:
A solution of (S)-methyl 2-(1-aminoethyl)-3-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylate (0.151 g, 0.480 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.089 g, 0.576 mmol) and DIEA (0.252 mL, 1.441 mmol) in n-butanol (2.40 mL) was stirred at 110° C. for 2 h. The mixture was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-7% MeOH in DCM) to afford the methyl 2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(5-fluoro-3-pyridinyl)imidazo[1,2-a]pyridine-5-carboxylate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.65 Hz, 3H) 3.33 (s, 3H) 5.41 (quin, J=6.65 Hz, 1H) 7.16 (d, J=7.24 Hz, 1H) 7.23 (br. s., 2H) 7.38-7.50 (m, 2H) 7.75-7.90 (m, 2H) 7.95 (dd, J=8.61, 1.57 Hz, 1H) 8.42 (br. s., 1H) 8.62 (d, J=2.74 Hz, 1H). LC-MS (ESI) m/z 433.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([O:9][CH3:10])([CH2:7][CH3:8])[C:4]([OH:6])=[O:5])[CH3:2].[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27](O)[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:33]2)=[CH:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>>[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27]([O:5][C:4](=[O:6])[C:3]([CH2:7][CH3:8])([O:9][CH3:10])[CH2:1][CH3:2])[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:33]2)=[CH:20]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(CC)(OC)C(=O)O
Product: CCC(CC)(OC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 45.3 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 1.28 g of 2-ethyl-2-methoxybutyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 558 mg of the title compound as a colorless foam.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])=[N+:2]=[N-:3].[Cl:13][C:14]1[C:21]([F:22])=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1.[H-].[Na+].O>CN(C=O)C>[N:1]([CH2:4][C@@H:5]([O:6][C:16]1[CH:15]=[C:14]([Cl:13])[C:21]([F:22])=[CH:20][C:17]=1[C:18]#[N:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: [N-]=[N+]=NC[C@@H](O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CN=[N+]=[N-])c1ccccc1
Yield: 69.8 %

Procedure:
The product from step (a) (1.75 g) and 4-chloro-2,5-difluorobenzonitrile (1.86 g) in dry DMF (40 ml) were treated with 60% sodium hydride in mineral oil (470 mg) with stirring under nitrogen. The reaction mixture was stirred for 2.5 h, poured into water, and extracted with ethyl acetate. The extract was washed with water (5×) then brine and dried (MgSO4). The solvent was evaporated and the residue purified by chromatography (silica, 10% ether/isohexane as eluent) to give the sub-title compound (2.37 g) as a pale yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:3]([C:5]2[CH:9]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[NH:7][N:6]=2)=[O:4])[CH2:26][CH2:27]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n[nH]1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC2CCOCC2)n[nH]1
Yield: 99 %

Procedure:
As described for example 14e, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.22 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine to the title compound (85 mg, 99%), which was obtained as a colorless oil. MS: m/e=384.2 [M+H]+.
Reaction SMILES: Br[CH:2]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:15][C:16]([NH2:18])=[S:17].C(=O)([O-])O.[Na+]>C(O)C>[NH2:18][C:16]1[S:17][C:2]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:3]([C:4]([CH3:7])([CH3:6])[CH3:5])[N:15]=1
Reactant: NC(N)=S
Reactant: CC(C)(C)C(=O)C(Br)C(=O)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)c1sc(N)nc1C(C)(C)C
Yield: 94.8 %

Procedure:
A mixture of 4-bromo-2,2,6,6-tetramethyl-3,5-heptanedione(α-bromo-dipivaloylmethane; 1.42 g, 5.40 mmol), thiourea (451.8 mg, 5.94 mmol) and ethanol (15 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was crystallized (dichloromethane/hexane) to give the title compound (1.23 g, 94.5%) as a white crystal.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:15]=3[N:16]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(=O)([O-])[O-].[K+].[K+].Cl[C:39]1[CH:44]=[CH:43][N:42]=[C:41]([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)=[O:47])[CH:40]=1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([O:21][C:39]4[CH:44]=[CH:43][N:42]=[C:41]([NH:45][C:46]([CH:48]5[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]5)=[O:47])[CH:40]=4)=[CH:17][C:15]=3[N:16]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(C(=O)Nc2cc(Cl)ccn2)CC1
Reactant: CC(C)(C)c1cccc(Nc2nc3cc(O)ccc3s2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc4sc(Nc5cccc(C(C)(C)C)c5)nc4c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The mixture containing 2-(3-tert-butylphenylamino)benzo[d]thiazol-5-ol (1 eq), potassium bis(trimethylsilyl)amide (4 eq), and potassium carbonate (1.2 eq) in dimethylformamide was stirred at room temperature for 10 minutes. N-(4-chloropyridin-2-yl)-1-methylpiperidine-4-carboxamide (1.4 eq) was then added and mixture subjected to microwave at 220° C. for 20 minutes. Reaction partitioned between ethyl acetate and water. Organic layer separated, washed with brine, dried over sodium sulfate and concentrated to give crude product. Purification by HPLC to yield N-[4-({2-[(3-tert-butylphenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]-1-methylpiperidine-4-carboxamide. HPLC=4.74 min; MS: MH+=516.
Reaction SMILES: [C:1]([NH:9][C:10](N)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-]C#N.[NH4+].C(Cl)(=O)C1C=CC=CC=1>ClCCl>[C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)NC(=O)c1ccccc1
Agent: N#C[S-]
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(N=C=S)c1ccccc1
Temperature: 12.5 °C

Procedure:
Benzoyl isothiocyanate was prepared as a starting material for benzoyl thiourea and derivates thereof. In a 500 mL three-neck round-bottom flask (“RBF”), fitted with a condenser, thermo-probe, sealed system nitrogen purge, pressure-equilibrated addition funnel and mechanical stirrer, were placed solid ammonium thiocyanate (16.9 g, 0.22 mol) and dichloromethane (100 mL). The stirred mixture was cooled in an ice-water bath to a temperature of about 10-15° C. To the stirred mixture was added a solution of benzoyl chloride (28.4 g, 0.2 mol) in dichloromethane (50 mL) over a period of time of 20 minutes and the reaction mixture was warmed to a temperature near reflux (39° C.) for a period of time of 1 hour. Reaction completion was confirmed by FT-IR analysis. The solution was then cooled to a temperature of about 10-15° C. The solution can be concentrated to an oil to provide the benzoyl isothiocyanate. A boiling point of 128-131° C. at 15 mm Hg was measured.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O>CCOC(C)=O.C(=O)([O-])O.[Na+]>[CH:28]1([C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH:9]=3)=[CH:4][CH:3]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN(Cc1cccc(-c2ccc(N)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(Cc1cccc(-c2ccc(NC(=O)C3CCCCC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
tert-Butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino]-2-oxoethyl}carbamate (240 mg) was dissolved in a mixed solution of EtOAc (10 ml)/saturated aqueous sodium hydrogen carbonate solution (10 ml), followed by ice-cooling. A solution of cyclohexanecarbonyl chloride (142 mg) in EtOAc (5 ml) was added dropwise thereto. The reaction mixture was returned to room temperature and stirred for 24 hours, and then to the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane=2/1) to obtain tert-butyl {2-[({4′-[(cyclohexylcarbonyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (311 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=O)[C:3]=1[NH2:4].[N:13]#[C:14][NH2:15]>C(O)(=O)C.Cl>[NH2:15][C:14]1[N:13]=[N+:10]([O-:12])[C:5]2[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([Br:1])[C:3]=2[N:4]=1
Reactant: Cc1cc(Br)c(N)c([N+](=O)[O-])c1
Reactant: N#CN
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(Br)c2nc(N)n[n+]([O-])c2c1
Temperature: 50 °C
Yield: 51.5 %

Procedure:
To 13.0 g (56.3 mmol) of 2-bromo-4-methyl-6-nitroaniline stirring in a mixture of 25 ml glacial acetic acid and 5 ml of concentrated hydrochloric acid at 80° C., 29.0 g (690.5 mmol) of cyanamide and 25 ml of concentrated hydrochloric acid were added simultaneously, separately, and very slowly. At one point during the addition, a vigorous exotherm occurred and the external heat immediately removed. After the addition, the reaction was heated at reflux for 15 minutes. On cooling to about 50° C., 100 ml of 25% aqueous sodium hydroxide were added dropwise and the mixture heated at reflux 15 minutes. The reaction was cooled to room temperature, the insoluble orange solid filtered and washed with water followed by ethyl acetate to afford 7.4 g of yellow 3-amino-5-bromo-7-methyl-1,2,4-benzotriazine-1-oxide after drying.