Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH:15]([CH3:17])[CH3:16].[OH2:18].[CH2:19]([O:21][CH2:22][CH3:23])[CH3:20]>COCCOC>[CH2:14]([N:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]1[CH2:20][C:19]([O:21][CH2:22][CH3:23])=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CN1C(=O)c2ccccc2C1O
Reactant: CCOCC
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CC1c2ccccc2C(=O)N1CC(C)C
Temperature: 0 °C

Procedure:
7.7 cm3 of triethyl phosphonoacetate are added dropwise, while keeping the temperature below 10° C., to a suspension of 1.6 g of 60% sodium hydride in 60 cm3 of 1,2-dimethoxyethane under an inert atmosphere and cooled to 0° C., with stirring. The reaction mixture is allowed to warm to a temperature in the region of 20° C. and is then stirred for 45 minutes. 5.3 g of 3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are then added and the mixture is refluxed for 3.5 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 40 cm3 of distilled water and then 100 cm3 of diethyl ether. After separation of the phases by settling, the aqueous phase is extracted twice with 100 cm3 of diethyl ether. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 18° C., to give a pale yellow oil, which is purified by chromatography under argon pressure (60 kPa), on a column of silica gel (particle size 15-40 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (60/40 and then 50/50 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. 6.3 g of ethyl (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a pale yellow oil. (Rf=0.56, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:11][C:12]#[CH:13])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.C([Li])CCC.CN(C)[C:21](=[O:23])[CH3:22].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCCCCC>[CH3:1][C@H:2]([CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[CH2:11][C:12]#[C:13][C:21](=[O:23])[CH3:22]
Reactant: C#CC[C@H](C)COC1CCCCO1
Reactant: CC(=O)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)C#CC[C@H](C)COC1CCCCO1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a solution of 100.0 g (RS)-2-{[(S)-2-Methylpent-4-in-1-yl]oxy}3,4,5,6-tetrahydro-2H-pyran (Ireland, Robert E. et al., Tetrahedron, 1997, 53, 39, 13221-13256) in 200 ml THF were added, dropwise at −30° C., 439 ml n-butyllithium (15% in hexane). The solution was stirred for 20 minutes at −30° C. and 20 minutes at −20° C. After cooling to −30° C., a solution of 95.6 g N,N-dimethylacetamide in 200 ml THF was added during 15 minutes and the reaction mixture was stirred for 30 minutes at −20°. The reaction mixture was then poured into a stirred precooled (0° C.) mixture of 1000 ml hexane and a solution of 104,8 g citric acid monohydrate in 700 ml water. The aqueous phase was separated and the organic phase was washed with 300 ml water and then filtered over 100 g silica gel. The silica gel was washed with 1000 ml hexane. The combined eluates were reduced to an oil by vacuum distillation.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])([CH3:5])[CH3:4])#[N:2].O.[OH-].[Li+].CO.O>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: COC(=O)c1cccc(C(C)(C)C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of methyl 3-(1-cyano-1-methylethyl)benzoate (2.8 g, 14 mmol) in tetrahydrofuran (30 mL) were added lithium hydroxide-monohydrate (0.98 g, 24 mmol), methanol (10 mL) and water (10 mL), and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (15 mL). The mixture was adjusted to pH 3 by slowly adding 1N hydrochloric acid. The precipitated white precipitate was collected by filtration, washed with water, and air-dried to give the title compound (2.5 g, 98%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([O:18]C)[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.B(Br)(Br)[Br:24]>C(Cl)Cl>[BrH:24].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([OH:18])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:21][CH:22]=1
Reactant: COc1cc2c(cc1O)CCNC2COc1ccc(Cl)cc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: Oc1cc2c(cc1O)C(COc1ccc(Cl)cc1)NCC2
Reaction time: 22 h
Yield: 67 %

Procedure:
To a solution of 1-(4-chlorophenoxy)methyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (100 mg) in anhydrous methylene chloride (5 ml) was added boron tribromide (140 mg) at -60° C. under cooling and stirring, and then the reaction temperature was gradually elevated to at 15° C. over 22 hours. After the reaction, the reaction mixture was concentrated, and oily residue was dissolved in methanol (5 ml) and water (0.5 ml). The solution was refluxed for 10 minutes, and then the solvent was distilled off. The amorphous residue was dissolved in acetone, and to the solution was added ether, and the mixture was allowed to stand. The precipitated crystals were collected by filtration and dried to give 1-(4-chlorophenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (81 mg), mp 232° to 233° C. The product was identified with a sample by I.R. spectrum and N.M.R. spectrum.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:35])=[C:16]([C@@:18]23[O:26][CH2:25][CH2:24][C@@H:23]2[CH2:22][S:21][C:20]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:19]3)[CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:35][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:8](=[O:10])[C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:17][C:16]=1[C@@:18]12[O:26][CH2:25][CH2:24][C@@H:23]1[CH2:22][S:21][C:20]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:19]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(N)ccc3F)OCC[C@@H]2CS1
Reactant: O=C(O)c1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(NC(=O)c4ncccc4F)ccc3F)OCC[C@@H]2CS1
Yield: 40 %

Procedure:
A solution of 3-fluoropicolinic acid (6.34 mg, 0.045 mmol), tert-butyl ((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (11 mg, 0.030 mmol), HATU (17.07 mg, 0.045 mmol), and Hunig's Base (10.46 μL, 0.060 mmol) in DMF (299 μL) was stirred at rt for 10 h. The crude product was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 95% eater/5% MeCN/10 nM NH4OAc, B: 5% water/95% MeCN/10 mM NH4OAc) over 12 min to give tert-butyl ((4aS,7aS)-7a-(2-fluoro-5-(3-fluoropicolinamido)phenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.012 mmol, 40.9% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.91 (br. s., 1H), 8.49 (br. s., 1H), 8.11-7.97 (m, 1H), 7.71 (d, J=5.2 Hz, 1H), 7.68-7.61 (m, 1H), 7.61-7.55 (m, 1H), 7.17-7.10 (m, 1H), 4.27-4.06 (m, 2H), 3.33 (d, J=13.4 Hz, 1H), 3.03 (d, J=13.7 Hz, 1H), 2.90 (dd, J=13.0, 4.5 Hz, 1H), 2.47-2.33 (m, 1H), 2.29-2.15 (m, 1H), 1.51 (s, 9H). MS (M+H)+: 491.19.
Reaction SMILES: C[Al](C)C.[C:5]1([NH2:12])[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1.C.C(OC([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35](OCC)=O)[CH:29]=2)[CH2:23][CH2:22]1)=O)(C)(C)C>C1(C)C=CC=CC=1.CO.O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:24]2[CH2:25][CH2:26][CH2:27][NH:21][CH2:22][CH2:23]2)=[CH:29][C:30]=1[C:35]1[NH:12][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=1
Reactant: CCOC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Reactant: Nc1ccccc1N
Agent: C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Clc1ccc(N2CCCNCC2)cc1-c1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of trimethylaluminium (2.0 M solution in toluene) (90 mL, 180 mmol) in toluene (300 mL) cooled to 0° C. under nitrogen was added benzene-1,2-diamine (6.5 g, 60 mmol) portionwise. The solution was stirred for 30 minutes at 0° C. then at 15-20° C. until evolution of methane ceased. 4-(4-chloro-3-ethoxycarbonyl-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (15.2 g, 40 mmol) was added in one portion to the resulting solution. The reaction was heated to reflux for 24 h then cooled to 0° C. Water (70 mL) was added carefully followed by MeOH (700 mL) The solid precipitated was filtered and the filtrate was concentrated under reduced pressure. The precipitate was washed with hot DCM:MeOH 1:1 (400 mL) followed by AcOEt (200 mL) The solution was concentrated under reduced pressure. Two extracts were combined and purified by flash chromatography (eluent: AcOEt:MeOH:NH3 gradient from 100% AcOEt to AcOEt:MeOH:NH3 73:25:2) to afford 9.3 g of a mixture of 2-(2-Chloro-5-[1,4]diazepan-1-yl-phenyl)-1H-benzoimidazole and N-(2-amino-phenyl)-2-chlorodiazepan-1-yl-benzamide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:6]#N.S(=O)(=O)(O)[OH:23].[OH2:27]>C(O)(=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:4][CH2:3][CH2:2][O:27][C:6]2=[O:23])=[CH:9][CH:10]=1
Reactant: O
Reactant: N#CC(CCCCl)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1OCCCC1(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
A mixture of 3 parts of α-(3-chloropropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetonitrile, 92 parts of concentrated sulfuric acid, 50 parts of water and 50 parts of acetic acid was stirred and refluxed for 24 hours. The reaction mixture was concentrated to about 100 parts and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was suspended in petroleumether. The product was filtered off and crystallized from 2,2'-oxybispropane, yielding 1.41 parts of 3,3-bis(4-fluorophenyl)tetrahydro-2H-pyran-2-one; mp. 122.4° C. (intermediate 15).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:13][C:14]1[C:19](C)=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][S:22](=[O:25])(=O)[O-:23].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:28]>C1(C)C=CC=CC=1>[Cl:28][C:19]1[C:14]([CH3:13])=[C:15]([NH:21][S:22]([NH:12][C:9]2[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)(=[O:25])=[O:23])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cccc(NS(=O)(=O)[O-])c1C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cccc1NS(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 5.5 %

Procedure:
In the similar fashion using route 19 general procedure 42, 5-chloroquinolin-8-amine (Intermediate 27) (155 mg, 1.15 mmol), sodium (2,3-dimethylphenyl)sulfamate (Intermediate 21) (300 mg, 1.23 mmol), PCl5 (771 mg, 3.70 mmol), TEA (1.67 ml, 12.3 mmol) and toluene (10 ml) gave the title compound (24 mg, 7%) after purification by column chromatography with n-hexane/EtOAc (1:0-17:3) as the eluent followed by trituration from n-pentane.
Reaction SMILES: CCOCC.[C:6]1([C@H:12]([NH:14][C:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:16]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(#N)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C>[C:6]1([C@H:12]([NH:14][C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][C@@H:16]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
A 1L 3-neck round bottom flask equipped with a mechanical stirrer and addition funnel was charged with 252B (14.7 g, 39 mmol) and acetonitrile (200 mL) and acetic acid (100 mL). The solution was cooled to 0° C. and Na(OAc)3BH (33.3 g, 157 mmol) was added in three portions over 2 hours. The reaction was stirred for two hours at this temperature after the final addition. The mixture was then cooled to −10° C. and slowly quenched by addition of 1 N NaOH (100 mL), 4 N NaOH (100 mL), 6 N NaOH (100 mL) followed by 50% NaOH (50 mL). The reaction was warmed to room temperature and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×250 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (10% to 30% EtOAc/hexane gradient) on silica gel afforded 6.0 g (yield: 41%) of Compound 252C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](CCC(O)=O)[NH:8]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:22]1C[O:25][CH2:24][CH2:23]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)CCc1cc2ccc(F)cc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1c[nH]c2cc(F)ccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a solution of 3-(6-fluoroindolyl)propionic acid (235 mg, 1.13 mmol) in THF (5.3 mL) was added LiAlH4 (86 mg, 2.26 mmol) slowly at 0° C. under N1. The reaction mixture was warmed to 20° C. and stirred for 15 h. The reaction was quenched by addition of H2O (0.5 mL) and diluted with EtOAc. The resulting solution was dried over MgSO4, filtered through Celite and concentrated in vacuo. The residue was chromatographed to give 6-fluoro-3-(3-hydroxypropyl)indole (142 mg, 65%) as a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1(C2C=CC(N)=CC=2)CC1>[CH:29]1([C:30]2[CH:6]=[CH:7][C:8]([N:9]3[CH2:20][CH2:19][C:6]4([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:32][CH:31]=2)[CH2:27][CH2:28]1
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCCCCC
Agent: C[Al+]C
Agent: Nc1ccc(C2CC2)cc1
Agent: [Cl-]
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2

Procedure:
This material was prepared in analogy to example 1 step D) from 4-(2-Methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, dimethylaluminium chloride in hexane and 4-cyclopropyl-phenylamine, with concomitant cleavage of the Boc protecting group under the reaction conditions. MS (ESI): 271.2 (MH+).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:34])[N:21]([CH3:33])[C@@H:22]([C:29](=[O:32])[NH:30][CH3:31])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:33][N:21]([C@@H:22]([C:29](=[O:32])[NH:30][CH3:31])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[C:20](=[O:34])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl) carbamic acid tert butylester (1.38 g ; 2.71 mmol) was dissolved in methylene chloride (6 ml) and triflouroacetic acid (4 ml) was added. The reaction mixture was stirred for 1 hour at room temperature. Water (30 ml) and solid sodium hydrogencarbonate were added to pH 8. The phases were separated and the aqueous phase was extracted with methylene chloride (4×20 ml). The organic phase was dried over magnesium sulfate and the solvent was removed over vacuo to afford 1.06 g of (2R)-N-methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)-3-(2-naphthyl)propionamide.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:20])[N:8]=2)[CH:6]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.12) (0.14 g, 0.4 mmol) and commercially available 3-pyridyl-boronic acid (0.049 g, 0.4 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.027 g, 19%). MS (ISN) 346.1 [(M−H)−]; mp 179-181° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](OC(F)(F)F)=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[C:10]([O:30][CH3:31])[CH:9]=2)[CH:7]=1.[F:34]C1C=CC(S(Cl)(=O)=O)=CC=1.FC1C=CC(OC)=C(C2C=CC(CN)=C(OC)C=2)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([F:34])=[CH:23][CH:24]=3)(=[O:17])=[O:18])=[C:10]([O:30][CH3:31])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1cc(-c2cc(F)ccc2OC)ccc1CNS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Agent: COc1cc(-c2cc(F)ccc2OC)ccc1CN
Product: COc1cc(-c2cc(F)ccc2OC)ccc1CNS(=O)(=O)c1ccc(F)cc1

Procedure:
Prepared in a similar manner to N-(5′-Fluoro-3,2′-dimethoxy-biphenyl-4ylmethyl)-4-trifluoromethoxy-benzenesulfonamide (Example 16) starting with 4-fluorobenzene sulfonyl chloride and C-(5′-fluoro-3,2′-dimethoxy-biphenyl-4-yl)-methylamine. Title compound: 1H NMR (400 MHz, CDCl3): 7.7-7.8 (m, 2H), 7.0-7.1 (m, 2H), 6.85-7.15 (m, 6H), 5.06-5.15 (m, 1H), 4.21 (d, 2H), 3.76 (s, 3H), 3.77 (s, 3H) ppm; MS (ESI) m/z: 442.0 [M+Na]+.
Reaction SMILES: [I-].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:18])[CH3:17])[CH:13]=[C:12]([C:19](=[O:21])[CH3:20])[CH:11]=2)[CH:6]=[C:5]([CH3:22])[N+:4]=1[CH3:23].CO.O.[OH-].[Na+]>O>[NH2:2][C:3]1[N:4]([CH3:23])[C:5]([CH3:22])=[CH:6][C:7](=[N:9][C:10]2[CH:11]=[C:12]([C:19](=[O:21])[CH3:20])[CH:13]=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=2)[N:8]=1
Reactant: CC(=O)c1cc(Nc2cc(C)[n+](C)c(N)n2)cc(C(C)=O)c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)c1cc(N=c2cc(C)n(C)c(N)n2)cc(C(C)=O)c1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
A suspension of 21 g (49.3 mmole) of 2-amino-4-(3,5-diacetylphenyl)amino-1,6-dimethylpyrimidinium iodide (compound No. 2, synthesized as described in section 6.1) in 1:1 methanol/water (750 mL) at 60° C. was treated with excess 2N NaOH with cooling to maintain about 60° C. An additional 200 mL of water was added and the mixture was cooled in ice and filtered to give 14.69 g 2-amino-4-(3,5-diacetylphenyl)imino-1,4-dihydro-1,6-dimethylpyrimidine as yellow crystals, mp 219-220°.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:17]=[N:16]2)[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].Br[C:30]1[C:31]([CH3:36])=[N:32][NH:33][C:34]=1[CH3:35].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:30]3[C:31]([CH3:36])=[N:32][NH:33][C:34]=3[CH3:35])[CH:17]=[N:16]2)[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1)#[N:2]
Reactant: Cc1n[nH]c(C)c1Br
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1n[nH]c(C)c1-c1cnn(C2(CC#N)CN(C(=O)OC(C)(C)C)C2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
A mixture of tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (381 mg, 0.981 mmol, from Example 1, step 2), 4-bromo-3,5-dimethyl-1H-pyrazole (206 mg, 1.18 mmol), tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.098 mmol) and sodium carbonate (310 mg, 2.9 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was purged with N2 and stirred at 110° C. for 2 h. The reaction mixture was filtered, diluted with EtOAc, then washed with water. The organic layer was concentrated and purified on silica gel (eluting with 0-100% EtOAc/hexanes followed by 0-10% MeOH/dichloromethane) to give tert-butyl 3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine-1-carboxylate (90 mg, 26%). LCMS calculated for C18H25N6O2 (M+H)+: m/z=357.2. Found: 357.2. This intermediate was treated with 4.0 M hydrogen chloride in dioxane (1.2 mL, 4.9 mmol) in methylene chloride (1 mL) at rt for 2 h. The mixture was stripped to dryness to give the desired product. LCMS calculated for C13H17N6 (M+H)+: m/z=257.1. Found: 257.1.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>C(O)C>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccccc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
2-Mercaptobenzimidazole (4.73 g) was dissolved in 150 ml of ethanol, and to the solution was added 6.18 g of 2-dimethylaminobenzyl chloride hydrochloride. The mixture was stirred at room temperature for 30 minutes. Precipitated crystals were collected by filtration. A saturated aqueous NaHCO3 solution was added to the crystals, and the resulting mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from a mixture of chloroform and acetonitrile to obtain 5.39 g of 2-(2-dimethylaminobenzylthio)benzimidazole as a colorless crystalline product (m.p. 164° C.).