Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH3:24][CH:25]([CH3:29])[CH2:26][CH:27]=[O:28].B(F)(F)F.CCOCC>C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([CH:27]([OH:28])[CH2:26][CH:25]([CH3:29])[CH3:24])[C:19]1=[O:23])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: CC(C)CC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: FB(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(O)C1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add lithium bis(trimethyl silyl)-amide (1.0 M in THF, 148 mL, 148 mmol) to a solution of 2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (25.0 g, 134 mmol) in THF (450 mL) at −78° C. and stir under nitrogen for 2 hours. Add 3-methyl-butyraldehyde (17.5 mL, 162 mmol) followed by boron trifluoride diethyl etherate (20.5 mL, 162 mmol) and continue to stir at −78° C. for 2 hours. Warm the mixture to room temperature, quench with saturated aqueous ammonium chloride (250 mL) and extract with EtOAc (3×). Dry the combined organics (Na2SO4), filter and concentrate under reduced pressure. Divide the crude product into two equal portions and purify each portion by silica gel chromatography, eluting with 0-40% EtOAc in hexanes to provide 3-(1-hydroxy-3-methyl-butyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester, diastereomer 1 (12.5 g, 34%) (D1) as the first eluting isomer, MS (m/z)=216.0 (M−56), and 3-(1-hydroxy-3-methyl-butyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester, diastereomer 2 (3.87 g, 11%) (D2) as the second eluting isomer. MS (m/z)=216.0 (M−56)
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][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](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([CH3:26])=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1([CH3:41])[CH3:40]>>[Cl:1][C:2]1[CH:28]=[CH:27][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:37]5[CH2:38][CH2:39][N:34]([CH3:33])[C:35]([CH3:41])([CH3:40])[CH2:36]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([CH3:26])=[N:8]2)=[C:4]([C:29]([F:31])([F:32])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C)nn3Cc2ccc(Cl)cc2C(F)(F)F)S1
Reactant: CN1CCNCC1(C)C
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=C3SC(N4CCN(C)C(C)(C)C4)=NC3=O)cc12

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,2,2-Trimethyl-piperazine following General Procedure C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH2:34]([NH2:36])[CH3:35]>>[CH2:34]([NH:36][C:30](=[O:32])[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[CH3:35]
Reactant: CCN
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: CCNC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 56 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (250 mg, 0.55 mmol) was reacted with ethylamine to give the title compound as a beige solid (140 mg, 56%); NMR Spectrum 1.09 (t, 3H), 3.23 (m, 2H), 4.87 (s, 2H), 5.77 (s, 2H), 6.97 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.76-7.69 (m, 3H), 7.83 (m, 1H), 8.16 (s, 1H), 8.38 (br t, 1H), 8.56-8.53 (m, 3H), 10.85 (br s, 1H); Mass spectrum MH+ 454.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(F)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B using 5-chloro-1-(3-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 411.2 (M+H)+.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=1)=[CH:5]OCC.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[F:18][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH3:17])[C:9]([C:4]1[C:3](=[O:20])[C:26]2[C:25](=[CH:24][CH:23]=[C:22]([CH3:21])[N:27]=2)[NH:28][CH:5]=1)=[O:19]
Reactant: Cc1ccc(N)cn1
Reactant: CCOC=C(C(=O)OC)C(=O)c1ccc(OC)c(F)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1F
Yield: 40.1 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.50 g (1.86 mmol) of 3-Ethoxy-2-(3-fluoro-4-methoxy-benzoyl) acrylic acid methyl ester, 0.20 g (1.86 mmol) of 6-Methyl-pyridin-3-ylamine, and 15 mL of diphenyl ether to yield 0.233 g of 3-(3-Fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1CC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 29.6 %

Procedure:
To a solution of (2S,4S)-4-azido-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester (11.2 g, 42.1 mmol) in tetrahydrofuran (140 mL) were added triphenyl phosphine (22 g, 83.87 mmol) and water (1.9 mL) and the reaction mixture was refluxed at 75° C. for 6 h. The reaction mixture was diluted with ether, quenched with HCl (0.15 N), stirred for 5 min and extracted with ether. The aqueous layer was treated with sodium bicarbonate solution until pH˜10 and then extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester (3 g, 29.6% yield) as a light yellow oil. The compound was used in the next step without further purification. MS calcd. for C13H25N2O2 [(M+H)+] 241.0, obsd. 240.8.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[NH:21][N:20]=2)=[CH:14][C:10]=1[C:11](O)=[O:12].Cl.[CH:31]1([O:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH:31]1([O:36][CH:37]2[CH2:42][CH2:41][N:40]([C:11]([C:10]3[CH:14]=[C:15]([CH:16]=[CH:17][C:9]=3[F:8])[CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:29])[NH:21][N:20]=3)=[O:12])[CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1CCC(OC2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC2CCCC2)CC1
Temperature: 20 °C
Reaction time: 72 h
Yield: 37.2 %

Procedure:
Triethylamine (0.280 ml, 2.01 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (200 mg, 0.67 mmol), 4-(cyclopentyloxy)piperidine hydrochloride (113 mg, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (331 mg, 0.87 mmol) in DMA (2 ml) at 20° C. under air. The resulting mixture was stirred at 20° C. for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (112 mg, 37.2% yield); 1H NMR (400.132 MHz, DMSO) δ 1.23-1.72 (11H, m), 1.81-1.87 (1H, m), 3.00-3.06 (1H, m), 3.22-3.27 (2H, m), 3.52-3.59 (1H, m), 3.96-4.04 (2H, m), 4.33 (2H, s), 7.18-7.23 (1H, m), 7.34 (1H, d), 7.38-7.42 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.26 (1H, d), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=2.30 (M+H 450.1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH2:11][CH3:12])[C:6]=2[CH:5]=[C:4]2[CH2:13][CH:14]([C:16]([O:18]CC)=[O:17])[O:15][C:3]=12.O1CCCC1.CCCCCC>C(O)C.O>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH2:11][CH3:12])[C:6]=2[CH:5]=[C:4]2[CH2:13][CH:14]([C:16]([OH:18])=[O:17])[O:15][C:3]=12
Reactant: CCOC(=O)C1Cc2cc3c(CC)noc3c(Cl)c2O1
Solvent: CCO
Solvent: O
Solvent: CCCCCC
Product: CCc1noc2c(Cl)c3c(cc12)CC(C(=O)O)O3
Yield: 74.8 %

Procedure:
Ester 7b was dissolved in minimal absolute ethanol and treated with excess alcohol potassium hydroxide at room temperature for 20 minutes, then diluted with water. Work-up as in the previous example and recrystallization from tetrahydrofuran/hexane gave white crystals, m.p. 213°-215° C., in 74.8% yield. Anal. (C12H10ClNO4) C,H,N,Cl.
Reaction SMILES: [OH:1][C:2]1([CH:13]2[CH2:18][N:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[CH2:16][CH2:15][NH:14]2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl.O1CCOCC1>CO>[N+:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([N:17]1[CH2:16][CH2:15][NH:14][CH:13]([C:2]2([OH:1])[CH2:5][NH:4][CH2:3]2)[CH2:18]1)(=[O:21])=[O:20])([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CCN2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCNC(C2(O)CNC2)C1
Temperature: 60 °C

Procedure:
To a solution of 1,1-dimethylethyl 3-hydroxy-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidine-1-carboxylate (308 mg, 0.70 mmol) in methanol (10 mL) was added HCl in dioxane (4 N, 1.75 mL, 7.0 mmol), and the mixture was heated to 60° C. for 30 minutes. The solution was concentrated to provide 3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol as a sticky white solid. This material was dissolved in dichloromethane (7 mL). To the solution was added N,N-diisopropylethylamine (1.16 mL, 7.0 mmol) followed by 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (277 mg, 0.7 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 16 hours. The solution was concentrated and the residue was purified by column chromatography (95% dichloromethane: 5% methanol) to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol as a pale yellow foam (453 mg, 0.63 mmol, 90% yield). 1H NMR (400 MHz, CDCl3): 8.49 (s, 1H), 7.96 (dd, 1H), 7.71 (m, 2H), 7.53 (dd, 1H), 7.39 (dd, 1H), 7.33 (d, 1H), 7.15 (m, 1H), 6.84 (br s, 1H), 6.62 (m, 1H), 4.29-3.97 (br m, 4H), 3.79-3.62 (m, 3H), 3.26-2.99 (br m, 3H), 2.92-2.62 (br m, 3H); MS (EI) for C26H23F3IN5O6S: 718 (MH+).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[CH3:31])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1.C(N(CC)CC)C.[CH3:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46]>ClCCl>[CH3:43][C:44]([CH3:49])([CH3:48])[C:45]([N:22]1[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]2[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[CH2:10][CH:9]([N:8]2[C:7]4[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=4[N:5]=[C:4]2[CH3:3])[CH2:15]3)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:24][CH2:23]1)=[O:46]
Reactant: Cc1ccccc1C1(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C1(CCN2[C@@H]3CC[C@H]2CC(n2c(C)nc4ccccc42)C3)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A mixture of 2-methyl-1-(8-{2-[4-(2-methylphenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1H-benzimidazole dihydrochloride (0.15 g, 0.31 mmol), triethylamine (0.087 mL, 0.62 mmol) and trimethylacetyl chloride (0.043 mL, 0.34 mmol) in dichloromethane (3 mL) was stirred at rt for 1 h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried, concentrated and purified by chromatography on silica gel eluting with 33:1 dichloromethane:methanol to give 1-((1R,5S)-8-{2-[1-(2,2-dimethylpropanoyl)-4-(2-methylphenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a white solid (0.073 g, 45%). 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 1H), 7.13-7.31 (m, 7H), 4.62 (m, 1H), 3.86 (m, 2H), 3.48 (m, 2H), 3.24 (m, 2H), 2.56 (m, 6H), 2.34 (m, 4H), 10.93 (m, 8H), 1.60 (m, 4H), 1.27 (s, 9H). HRMS C34H46N4O m/z 527.3750 (M+H)Cal., 527.3749 (M+H)Obs..
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:40]([O:42][CH3:43])=[O:41])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 70.2 %

Procedure:
To a solution of 25 mg of amine prepared in Example 11 and 0.05 mL of DIPEA in 0.5 mL of methylene chloride was added 12 mg of methyl chloroformate. After 1.5 h in a sealed vial, the volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with ethyl acetate to afford 20 mg of title compound. Mass spec (NH3 /CI): 476 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[CH2:10][CH:11]([CH2:18][CH2:19][OH:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[CH2:10][CH:11]([CH2:18][CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)CC(CCO)c1ccccc1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccccc1)c1ccc(Cl)cc1
Yield: 92.5 %

Procedure:
N-(4-Chlorophenyl)-beta-(2-hydroxyethyl)-N-methyl-benzenepropanamide (1.25 g) in CH2Cl2 (25 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (0.497 g), and methanesulfonyl chloride (0.563 g). After two hours the reaction mixture was washed with water (3×25 mL), sat. NaHCO3 (20 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (1.44 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:38][O:39][C:40]([C:42]1[C:50]2[NH:49][C:48]([NH2:51])=[N:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)=[O:41]>>[CH3:38][O:39][C:40]([C:42]1[C:50]2[N:49]=[C:48]([NH:51][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)=[O:41]
Reactant: COC(=O)c1cccc2nc(N)[nH]c12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cccc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc12
Yield: 75.5 %

Procedure:
2.6 g (75%) of the 2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester was synthesized from isoquinoline-3-carboxylic acid (1.7 g, 10 mmol), HBTU (4.6 g, 12 mmol), and the above synthesized 2-amino-3H-benzoimidazole-4-carboxylic acid methyl ester (1.9 g, 10 ml) as described in general procedure A. This ester was then hydrolyzed according to general procedure B to give 2.2 g (88%) of acid. LCMS: 333 (M+1)+.
Reaction SMILES: C([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:16][CH2:17][CH2:18][Cl:19])[C:9]1=[O:20])C1C=CC=CC=1>[Pd].C([O-])=O.[NH4+].CO>[Cl:19][CH2:18][CH2:17][CH2:16][N:10]1[C:11](=[O:15])[C:12]([CH3:14])=[CH:13][NH:8][C:9]1=[O:20]
Reactant: Cc1cn(Cc2ccccc2)c(=O)n(CCCCl)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c[nH]c(=O)n(CCCCl)c1=O
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture of 1-benzyl-3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (1 g, 3.41 mmol), prepared as in Example 19, 10% palladium on carbon (1 g) and 0.1M ammonium formate/methanol (340 mL) was heated 3 hours at reflux under argon. The reaction mixture was allowed to cool to 25° C., then filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (1:1) to give 3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (0.52 g, 2.57 mmol), m.p. 117°-121° C.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[C:23]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[C:44]([F:46])[C:43]([O:47]C)=[CH:42][C:41]=2[F:49])[CH2:36][CH2:35]1)(=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:23]([N:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:45]=[C:44]([F:46])[C:43]([OH:47])=[CH:42][C:41]=2[F:49])[CH2:38][CH2:39]1)(=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCC(=O)N1CCN(c2cc(F)c(OC)cc2F)CC1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: CCCCCCCCCC(=O)N1CCN(c2cc(F)c(O)cc2F)CC1
Yield: 75 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 1-decanoyl-4-(2,5-difluoro-4-methoxyphenyl)piperazine (371 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=19:1) to provide 1-decanoyl-4-(2,5-difluoro-4-hydroxyphenyl)piperazine (268 mg).
Reaction SMILES: [Na:1].C(C1(C[CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.[CH3:47][C:48]1(CO)[O:52][CH2:51][CH2:50][O:49]1>>[Na:1].[CH3:35][C:18]1[C:19]([CH2:23][S:24]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]=2)=[O:25])=[N:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:48]1([CH3:47])[O:52][CH2:51][CH2:50][O:49]1
Reactant: CC1(CO)OCCO1
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: Cc1c(OCC2(C)OCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 12.9 %

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using (2-methyl-1,3-dioxolan-2-yl)methanol obtained in the step (67b) above to obtain the title compound (263 mg, total 12.9% yield) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Br:18]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:18][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
To a DMF (50 ml) solution of 1-Amino-2-[2-(tert-butyldimethylsilyloxy)ethyl]benzene (3.96 g, 0.015 mol) [European journal of organic chemistry, 2001, issue 48, 2447-2462] was added N-bromosuccinimide (2.67 g, 0.015 mol) and the mixture was stirred at ambient temperature for 24 hours. Then, the reaction was poured onto saturated aqueous sodium bicarbonate water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtration and evaporation. The crude material was purified through silica gel column chromatography eluting with hexane/ethyl acetate (10:1 to 5:1) to afford 3.62 g (73% yield) of the title compound as brown oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[N:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[N:24]=1>>[CH3:30][C:25]1[CH:26]=[C:27]([CH3:29])[N:28]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[N:24]=1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4,6-dimethyl-pyrimidine. MS (ESI) mass calcd. for C23H24N4OS, 404.53; m/z found, 405.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH2:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)CCC=C2
Temperature: 130 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
4 g of 7-nitro-1,2,3,4-tetrahydro-1-naphthalenol [J. Pharm. Soc. Japan, Vol. 64, (1944), p. 153], 53 ml of toluene and 180 mg of p-toluene sulfonic acid were mixed together and then stirred for 2 hours at 130° C. while distilling off ≃20 ml of solvent. Then, at 20° C. 50 ml of water were added and extraction was done with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium bicarbonate, and with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness. The residue was crystallized from ethanol to obtain 2.75 g of the expected product melting at ≃35° C. and after crystallizing from isopropanol melting at 37° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:25](B(O)O)[CH:26]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[C:25]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:26]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1cc(F)ccc1OCC1CCOCC1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cc(F)ccc3OCC3CCOCC3)n2)c1

Procedure:
Example 21 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and [5-fluoro-2-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]boronic acid (FCH Group Company). The batch was purified by preparative HPLC.