Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][C:4]#[C:5][NH2:6].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH3:1][Si:2]([CH3:8])([CH3:7])[C:3]#[C:4][CH2:5][NH:6][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[Si](C)(C)CC#CN
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)C#CCNC(=O)c1ccccc1

Procedure:
To 8.2 g (0.07 M) of 3-trimethylsilylprop-1-ynylamine in 150 ml of diethyl ether containing 6.6 g (9.1 ml) of triethylamine at 0° C is added 9.1 g (0.07 M) of benzoyl chloride in 30 ml of ether. After 1 hour at 25° C the solution is washed well with brine and the ether extract dried over magnesium sulfate, filtered and the filtrate concentrated. The residue is recrystallized from methanol to give N-(3-trimethylsilylprop-2-ynyl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[C:23]([N:27]1[N:31]=[N:30][C:29]([C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH:34]=O)=[N:28]1)([CH3:26])([CH3:25])[CH3:24]>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:34][C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[C:29]4[N:30]=[N:31][N:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:28]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)n1nnc(-c2ccccc2C=O)n1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)n1nnc(-c2ccccc2C=Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)n1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 691 mg (3.0 mmol) of 2-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde to form 4-(3-chloro-phenylamino)-3-[(2-(2-tert-butyl-tetrazol-5-yl)-phenyl}-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H and analogous working-up yield 4-(3-chloro-phenylamino)-3-[2-(2-tert-butyl-tetrazol-5-yl)-benzylamino]-1H-pyrazolo[3,4d]pyrimidine; TLC: Rf=0.64 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=10.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12](=[O:16])[CH:13]([CH3:15])[CH3:14].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12](=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: C1COCCN1
Reactant: COc1cc(F)cc(OC)c1C(=O)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(N2CCOCC2)cc(OC)c1C(=O)C(C)C

Procedure:
Into a 1-liter, three-necked round-bottom flask was placed 15.0 g (0.07 mole) of 1-(2,6-dimethoxy-4-fluorophenyl)-2-methylpropan-1-one produced in Example 12, 5.8 g (0.07 mole) of morpholine, and 19.0 g (0.14 mole) of K2CO3 in 100 ml. of dimethylsulfoxide (DMSO). The mixture was flushed with argon and heated to reflux overnight. The reaction mixture was cooled and then mixed with about 100 ml of distilled water and extracted with dichloromethane. The organic layer was washed with NaHCO3 solution, salt water, and then dried. The solvent was removed by vacuum to yield the final product, 1-(2,6-dimethoxy-4-morpholinophenyl)-2-methylpropan-1-one. The yield of the reaction was 18.1 g of product (88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1
Reactant: OCCC1CCNCC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCC(CCO)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 95.7 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, Step B) (21.5 g, 116 mmol) in DMSO (100 mL) was added 2-(4-piperidinyl)ethanol (15 g, 116 mmol) and K2CO3 (48.1 g, 348 mmol). The reaction was heated in a sealed tube at 80° C. overnight. The reaction mixture was cooled to rt and poured into H2O. The resultant solid was filtered, air dried, dissolved in DCM, dried (Na2SO4), filtered, and rotovapped down to give the title compound of Step F (32.6 g, 111 mmol, 95%). 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 6.63 (s, 1H), 4.33 (t, J=5.0 Hz, 1H), 3.85 (s, 3H), 3.39-3.49 (m, 2H), 3.23 (d, J=12.2 Hz, 2H), 2.65 (t, J=11.3 Hz, 2H), 2.14 (s, 3H), 1.72 (d, J=11.4 Hz, 2H), 1.46-1.61 (m, 1H), 1.39 (q, J=6.6 Hz, 2H), 1.25 (qd, J=12.0, 3.4 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[CH:23]([NH:26][CH3:27])([CH3:25])[CH3:24]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][N:26]([CH:23]([CH3:25])[CH3:24])[CH3:27])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: CNC(C)C
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: CC(C)N(C)Cc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with N-Isopropylmethylamine similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide afford 10-bromo-9-fluoro-3-((isopropyl(methyl)amino)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 31 mg (35%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[[isopropyl(methyl)amino]methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:15])=[C:6]([NH:11]C(=O)C)[C:7]([CH3:10])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Cl.[OH-].[NH4+]>>[NH2:11][C:6]1[C:5]([CH3:15])=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[CH3:10]
Reactant: CC(=O)Nc1c(C)ccc(C(C)=O)c1C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CC(=O)c1ccc(C)c(N)c1C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of 40 parts of N-(3-acetyl-2,6-dimethylphenyl)acetamide and 300 parts of concentrated hydrochloric acid was stirred for 20 hours at reflux temperature. After cooling, the reaction mixture was treated with ammonium hydroxide. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated, yielding 35.5 parts (100%) of 1-(3-amino-2,4-dimethylphenyl)ethanone as a residue (int. 111).
Reaction SMILES: Cl.C1C2C(=CC=CC=2)CCN1CCC[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[CH:27]=[CH:28][CH:29]=[C:22]3[C:23]=2[C:18](=[CH:19][CH:20]=[CH:21]3)[C:17]1=[O:30].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]CBr.BrCCCCBr>>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:15][N:16]1[C:17](=[O:30])[C:18]2[CH:19]=[CH:20][CH:21]=[C:28]3[C:27]=2[C:24](=[CH:23][CH:22]=[CH:29]3)[C:25]1=[O:26]
Reactant: BrCCCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCc2ccccc2C1
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr

Procedure:
Following the procedure of part (a) of example 39 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 95°-96°.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:22]1[N:27]=[CH:26][C:25]([C:28]([NH:30][CH3:31])=[O:29])=[CH:24][CH:23]=1>CS(C)=O>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([O:18][C:22]4[N:27]=[CH:26][C:25]([C:28]([NH:30][CH3:31])=[O:29])=[CH:24][CH:23]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.6 %

Procedure:
To a stirred solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (40 mg, 0.158 mmol) in DMSO (2 ml) was added NaH (14 mg, 0.316 mmol, 60 in mineral oil) at RT in one portion. The suspension was stirred for 2 h at RT then 6-chloro-N-methylpyridine-3-carboxamide (54 mg, 0.316 mmol) was added in one portion. The mixture was heated at 80-100° C. in a sealed tube over night. After cooling to RT, the solution was partitioned between brine/water (1:1 mixture, 15 ml) and DCM (20 ml). The organic layer was separated, washed with brine (2×20 ml), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was purified by preparative HPLC to provide the title compound as white solid (83 mg, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:27]([F:30])([F:29])[F:28])/[CH:11]=[CH:12]/[C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([O:22][C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH2:31][CH2:32][C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:27]([F:30])([F:29])[F:28])/[CH:11]=[CH:12]/[C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:31][CH2:32][C:33](=[O:34])[NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:18])=[C:15]([O:22][C:23]([F:24])([F:25])[F:26])[CH:14]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1OC(F)(F)F
Reactant: NCC(=O)NCC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1OC(F)(F)F)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoic acid (0.25 g, 0.52 mmol), 2-amino-N-(2,2,2-trifluoroethyl)acetamide (0.158 g, 0.62 mmol), PyBOP (0.40 g, 0.78 mmol) and DIPEA (0.134 g, 1.04 mmol) in DCM (10.0 mL) were stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with DCM. The combined DCM layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 20% ethyl acetate/pet ether) afforded the title compound as a pale yellow gummy material (0.15 g, 47%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[NH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O.[OH-].[Na+]>[CH2:1]([N:16]1[C:17]2[C@@:18]3([CH3:28])[C:25]([CH3:27])([CH3:26])[C@H:21]([CH2:20][CH2:19]3)[C:22]=2[C:23](=[O:24])[N:15]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2)n1Cc1ccccc1
Temperature: 78 °C
Yield: 7.8 %

Procedure:
A mixture of benzyl bromide (0.54 mL, 4.5 mmol) and (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 1.11 g, 4.1 mmol) in N,N-dimethylformamide was heated at 78° C. for 2.5 h. The reaction mixture was diluted with 1 M NaOH (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with 1 M NaOH and brine, dried (magnesium sulfate), filtered and evaporated. The residue was recrystallized from ethyl acetate/hexanes to give (4S,7R)-1-benzyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (114 mg, 8%) as a tan solid. APCI-MS (M+H) 359.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]=[C:20]([C:2]2[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1cc(F)cnc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ncc(F)cc2N)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A degassed solution of 2-chloro-5-fluoro-3-amino-pyridine (3.5 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8.89 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)palladium(II) chloride (0.84 g) in dioxane (157 ml) was treated with a degassed solution of sodium carbonate (7.6 g) in water (72 ml). The reaction mixture was stirred at reflux for 1 hour, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was diluted with ethyl acetate, washed with water then brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane/ethyl acetate 8:2) afforded 3-amino-5-fluoro-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (4.6 g) as a solid. MS (ES+) 294 (MH+), 238 (M-isoprene); 1H NMR (400 MHz, CDCl3) 1.48 (s, 9H), 2.53 (m, 2H), 3.64 (t, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 5.99 (m, 1H), 6.70 (dd, 1H), 7.85 (d, 1H).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:26]1([CH:36]=[CH:35][CH:34]=[CH:33][CH2:32]1)[CH:27]=[N:28][C:29](=O)[CH3:30])C>O>[CH3:30][C:29]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:10])[N:9]=[C:27]([C:26]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]=1
Reactant: CCOC1(C=NC(C)=O)C=CC=CC1
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1-n1nc(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Next, 9.1 g of o-tolyl hydrazine hydrochloride and 100 mL of carbon tetrachloride were put into a 300-mL three-neck flask, 12 mL of triethylamine (Et3N) was added dropwise to the mixture little by little, and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 10 g of N-(1-ethoxybenzylidene)acetamide was added, and the mixture was stirred at room temperature for 19 hours. Then, water was added to this reacted solution and the aqueous layer was subjected to extraction with chloroform. The obtained solution of the extract and the organic layer were combined and washed with saturated saline, and anhydrous magnesium sulfate was added to the organic layer for drying. The obtained mixture was gravity-filtered, and the filtrate was concentrated to give an oily substance. The obtained oily substance was purified by silica gel column chromatography. As the developing solvent, dichloromethane was used. The obtained fraction was concentrated, so that 5-methyl-1-(2-methylphenyl)-3-phenyl-1H-1,2,4-triazole (abbreviation: HMp3tz1-mp) was obtained (a red oily substance, 64% yield). The synthesis scheme of Step 2 is shown in (B-2) below.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>ClCCl>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Yield: 52.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-octadecanol (36 grams, 210 mmol), pyridine (20 milliliters), and dichloromethane (500 milliliters) was heated to reflux. The alcohol dissolved and the solution was allowed to cool 5° C. 4-Nitrobenzoyl chloride (39.0 grams, 210 mmol) was added in portions over a twenty minute period. The reaction mixture was heated to reflux for sixteen hours. The reaction mixture was washed with 250 milliliters of water. The aqueous layer was washed with 250 milliliters of dichloromethane. The organic layers were combined and concentrated under reduced pressure to a light tan solid. Added 500 milliliters of hexane and heated to reflux. A white precipitate formed as the solution was cooled to room temperature. Filtered off the white precipitate and concentrated the filtrate to a light tan solid. The solid was recrystallized from ethanol (500 milliliters) to obtain 46 grams of octadecyl 4-nitrobenzoate as a white solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:1](=[O:4])[CH3:2])=[CH:8][CH:7]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
Acetic acid (1.321 g, 22.000 mmol) was dissolved in DMF (10 ml), 1-(4-chlorophenyl)methanamine (2.804 g, 19.800 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (7.770 g, 24.200 mmol) and N-ethyl-N,N-diisopropylamine (5.971 g, 46.200 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by preparative HPLC (the initial mobile phase was isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product-containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation and gave 2.337 g of N-(4-chlorobenzyl)acetamide (yield 57.8%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH:11]1([O:14][C:15]2[CH:16]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12]1>>[CH:11]1([O:14][C:15]2[CH:20]=[C:19]([C:2]3[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=3)[CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12]1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CC1(C)OB(c2cccc(OC3CC3)c2)OC1(C)C
Product: Nc1c(F)cc(-c2cccc(OC3CC3)c2)cc1F
Yield: 11.3 %

Procedure:
The title compound (170 mg) was prepared from 4-bromo-2,6-difluoroaniline (1.2 g, 5.76 mmol) and 2-(3-cyclopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 5.76 mmol) as a yellow liquid.
Reaction SMILES: BrCC(=O)CCCCC.BrC(C(=O)CCC)CC.BrC(C(C)C)C(=O)C(C)C.NC1SC=C(CCCCC)N=1.[NH2:40][C:41]1[S:42][C:43]([CH2:48]CC)=[C:44]([CH2:46][CH3:47])[N:45]=1.NC1SC(C(C)C)=C(C(C)C)N=1>>[NH2:40][C:41]1[S:42][C:43]([CH3:48])=[C:44]([CH2:46][CH3:47])[N:45]=1
Reactant: CCCc1sc(N)nc1CC
Agent: CC(C)C(=O)C(Br)C(C)C
Agent: CC(C)c1nc(N)sc1C(C)C
Agent: CCCC(=O)C(Br)CC
Product: CCc1nc(N)sc1C

Procedure:
By the same method, 1-bromo-2-heptanone, 3-bromo-4-heptanone and 4-bromo-2,5-dimethyl-3-hexanone are converted to 2-amino-4-pentylthiazole, 2-amino-4-ethyl-5-propylthiazole and 2-amino-4,5-diisopropylthiazole, respectively.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Br:1][C:2]1[C:3]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CCNCCO
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 22.1 using 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 25.2) and 2-ethylamino-ethanol to afford a white crystalline solid. HPLC (Condition 4) tR=6.33 min, UPLC-MS (Condition 3) tR=1.25 min, m/z=466.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:20]=2[CH2:21]Br)=[O:15])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1.[NH3:32].CO>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:20]=2[CH2:21][NH2:32])=[O:15])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1CBr)c1cccc(C(F)(F)F)c1
Reactant: N
Solvent: CO
Product: CCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1CN)c1cccc(C(F)(F)F)c1
Yield: 61 %

Procedure:
5-Bromomethyl-1-(4-chloro-phenyl)-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-butyl]-amide (47 mg, 0.091 mmol) is treated with ammonia in methanol (7.0 N solution, 2.0 mL, 14 mmol) and the resultant solution is heated in a microwave at 120° C. for 3 min. The crude reaction mixture is concentrated in vacuo and purified by preparative reverse phase HPLC (eluted with 10 to 90% CH3CN/H2O and 0.1% TFA as additive) to afford 5-aminomethyl-1-(4-chloro-phenyl)-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-butyl]-amide (25 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>ClCCl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([Cl:17])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)Cl)c2ccccc12

Procedure:
To a solution of 0.35 g (1.89 mmol) of 4-methyl-1-napthoic acid in 3 mL of dry dichloromethane under argon, was added 2.5 ml (34.3 mmol) of thionyl chloride. The solution was refluxed for 4 hrs and the solvent and excess thionyl chloride were removed by vacuum distillation to give a red oil, which was used without further purification.