Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:13]([CH3:15])[CH3:14])[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]/[CH:27]=[C:28]1/[C:29]2[CH:42]=[C:41]([C:43]([OH:46])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:30]=2[O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:13]([CH3:14])[CH3:15])[CH:8]2[CH2:12][CH2:11][N:10]([CH2:25][CH2:26][CH:27]=[C:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:33]=4[CH2:32][O:31][C:30]4[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]3=4)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)N(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)N(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of (4-chloro-benzyl)-isopropyl-pyrrolidin-3-yl-amine (0.68 mmol, 1.7 eq) in acetonitrile:water (4:1) was added potassium carbonate (0.8 mmol, 2 eq) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.4 mmol, 1.0 eq) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 0.85 (6H, d), 1.50–1.90 (10H, m), 2.10–2.60 (8H, m), 3.50 (3H, m), 5.30 (2H, br, s), 6.10 (1H, t), 6.80 (1H, dd), 7.10–7.40 (8H, m), 7.50 (1H, d), 8.50 (1H, dd). ESI-MS m/z: 546 (M+1), UV retention time: 1.40 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)=[C:8]([CH3:20])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:14]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)=[O:16])[CH:17]=[CH:18][CH:19]=3)=[C:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: Cc1c(-c2cccc(C(=O)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CN1CCNCC1
Product: Cc1c(-c2cccc(C(=O)N3CCN(C)CC3)c2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 1-methylpiperizine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-methylpiperazin-1-yl)methanone. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-methylpiperazin-1-yl)methanone (67 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 19.8 mg of 427. MS (Q1) 554.0 (M)+
Reaction SMILES: [CH:1]1([O:7][C:8]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([O:7][C:8](=[O:9])[NH:10][C@H:11]2[C:12](=[O:14])[O:17][C@H:15]2[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](O)[C@@H](NC(=O)OC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OC1CCCCC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 35.3 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-2-(cyclohexoxycarbonylamino)-3-hydroxy-butanoic acid (0.3 g, 1.22 mmol) in dry CH2Cl2 (16 mL), Et3N (0.51 mL, 3.66 mmol) and subsequently TBTU (0.47 g, 1.46 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 0:100) to afford the title compound (0.098 g, 36%) as white solid. MS (ESI) m/z: 228 [M−H]+; (ESI) m/z: 226 [M−H]−. 1H NMR (DMSO-d6): δ 1.14-1.42 (m, 5H), 1.34 (d, J=6.3 Hz, 3H), 1.44-1.55 (m, 1H), 1.61-1.72 (m, 2H), 1.76-1.89 (m, 2H), 4.47-4.59 (m, 1H), 4.84 (dq, J=6.3 Hz, 1H), 5.40 (dd, J=6.2, 9.3 Hz, 1H), 8.15 (d, J=9.4 Hz, 1H).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].Cl[C:10]1[C:11]2[CH:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])[C:12]=2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=1>CN(C=O)C.O>[CH3:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[N:18]1[C:12]2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=[C:10]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:11]=2[CH:20]=[CH:19]1
Reactant: CC(C)(C)CO
Reactant: Cc1ccc(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccc3c(OCC(C)(C)C)nn(C)c(=O)c32)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To a solution of neopentyl alcohol (39.7 mg, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-(2,4-dimethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (43.2 mg, 0.15 mmol). The mixture was stirred at 60° C. for 2 hours, then diluted with water (30 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 32 mg (63%) of the title compounds as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:44]([C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=1)([O-:46])=[O:45]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:18][CH2:17][CH2:16][N:15]([CH2:51][C:50]2[CH:53]=[CH:54][C:47]([N+:44]([O-:46])=[O:45])=[CH:48][CH:49]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C(CN1CCCNCCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CN1CCCN(Cc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.8 %

Procedure:
To a solution of compound (4) (1.17 g, 2.36 mmol) in dry CHCl3 (50 ml) were added triethylamine (0.99 ml, 0.72 g, 7.08 mmol) and 4-nitrobenzyl bromide (0.51 g, 2.36 mmol). After stirring at an ambient temperature for 10 hours, the solvent was removed under reduced pressure, and the residue was purified through column chromatography on alumina (basic). Extraction with a mixture of acetate and methanol (10:2) gave a purified clear oil, which was then solidified to obtain compound (15) (1.13 g, 76% yield). 1H NMR (500 MHz, CDCl3): δ 8.12-8.10 (dd, 2H), 7.51-7.49 (dd, 2H), 7.34-7.27 (m, 10H), 5.11 (s, 2H), 5.05 (s, 2H), 3.55 (s, 2H), 3.39 (s, 2H), 3.34 (s, 2H), 2.81 (brs, 2H), 2.74-2.72 (m, 4H), 2.67-2.64 (m, 6H), 2.59-2.57 (m, 2H), 2.46-2.44 (m, 2H), 1.71 (brs, 2H), 1.61-1.59 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 171.3, 170.8, 148.1, 146.9, 135.7, 129.3, 128.5, 128.2, 128.1, 123.3, 66.0, 65.8, 58.1, 55.5, 53.6, 53.1, 52.5, 52.0, 51.2, 49.6, 47.9, 47.2, 25.7; HRMS (FAB) calculated for C35H46N5O6: 632.3448 [(M+H)+], measured value: 632.3447 [(M+H)+].
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:9][CH2:8]1)(C)(C)C.Br[CH2:22][C:23]1[O:24][C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27]=1[CH3:28]>>[OH:6][CH:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:22][C:23]3[O:24][C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[C:27]=3[CH3:28])[C:14]2=[O:18])[CH2:11][CH2:12]1
Reactant: Cc1c(CBr)oc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(N2CCCC2=O)CC1
Product: Cc1c(CC2CCN(C3CCC(O)CC3)C2=O)oc2ccccc12
Yield: 53.6 %

Procedure:
Using the procedure to synthesize Example 3 and using reagents 1-[4-(tert-butyldimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (500 mg, 1.68 mmol) and 2-bromomethyl-3-methyl-benzofuran (567 g, 2.52 mmol) afford the title compound as a tan powder (295 mg, 54%): Mass spectrum (apci) m/z=328.1 (M+H).
Reaction SMILES: Cl[Si:2]([CH3:13])([CH3:12])[C:3]1([CH3:11])[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]1[CH3:10].[CH2:14]([NH-:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li+]>CCOCC>[CH2:14]([NH:21][Si:2]([CH3:13])([CH3:12])[C:3]1([CH3:11])[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]1[CH3:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1=CC(C)([Si](C)(C)Cl)C(C)=C1C
Reactant: [NH-]Cc1ccccc1
Agent: [Li+]
Solvent: CCOCC
Product: CC1=CC(C)([Si](C)(C)NCc2ccccc2)C(C)=C1C
Reaction time: 8 h

Procedure:
To a solution of 1.000 g (4.651 mmol) (chloro)(dimethyl)(tetramethylcyclopentadienyl)silane in 70 mL ether was slowly added 0.526 g (4.651 mmol) lithium benzylamide. The reaction mixture was stirred overnight, then the solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed under reduced pressure to give the product as a pale yellow oil. The yield was 1.234 g (93.3%). Mass spec. m/e 285 (18%). 1H NMR (C6D6) δ 7.0-7.24 (m, 5H), 3.71 (d, 2H), 2.73 (br s, 1H), 1.88 (s, 6H), 1.76 (s, 6H), 0.43 (br t, 1H), -0.07 (s, 6H). 13C NMR (C6D6) δ 144.5, 135.7, 132.0, 128.5, 127.3, 126.7, 56.7, 46.4, 14.6, 11.4, -2.3.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[N:11]=[CH:10][N:9]([CH2:12][C:13]3[CH:29]=[CH:28][C:16]4[N:17]=[C:18]([NH:20][C@@H:21]5[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]5[OH:27])[S:19][C:15]=4[CH:14]=3)[C:6]2=[N:7][CH:8]=1)=[CH2:2]>[Ni].CO.C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[N:11]=[CH:10][N:9]([CH2:12][C:13]3[CH:29]=[CH:28][C:16]4[N:17]=[C:18]([NH:20][C@@H:21]5[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]5[OH:27])[S:19][C:15]=4[CH:14]=3)[C:6]2=[N:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (20 mg, 0.049 mmol) from Example 98 in 1:1 MeOH/THF (2 mL) was added Raney Ni (10 mg). The resulting mixture was stirred under a H2 balloon at rt for 4 h. LCMS analysis showed that the reaction was complete. The reaction mixture was filtered through a Celite plug and the filtrate was purified with preparative TLC to give (1R,2R)-2-((6-((6-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (6 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 8.53 (br s, 1H), 8.26 (br s, 1H), 7.95 (d, J=12.4 Hz, 2H), 7.66 (br s, 1H), 7.25-7.42 (m, 1H), 7.06-7.25 (m, 1H), 5.45 (br s, 2H), 4.74 (d, J=4.5 Hz, 1H), 3.51 (br s, 1H), 2.73 (d, J=7.2 Hz, 2H), 2.04 (br s, 1H), 1.86 (br s, 1H), 1.62 (br s, 2H), 1.23 (t, J=6.8 Hz, 7H). LCMS (ESI) m/z 408 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[C:13]([C:14]2[N:19]=[C:18]([OH:20])[C:17]([OH:21])=[C:16]([C:22]([O:24][CH3:25])=[O:23])[N:15]=2)=[CH:12][S:11][CH:10]=1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:8][C:9]1[C:13]([C:14]2[N:19]=[C:18]([OH:20])[C:17]([OH:21])=[C:16]([C:22]([O:24][CH3:25])=[O:23])[N:15]=2)=[CH:12][S:11][CH:10]=1
Reactant: COC(=O)c1nc(-c2cscc2NC(=O)OC(C)(C)C)nc(O)c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(-c2cscc2N)nc(O)c1O
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Ester 40 (828 mg, 2.25 mmol), prepared as described above, was treated with a 6:4 mixture of methylene chloride:trifluoroacetic acid (8 ml). The solution was stirred for 20 min then concentrated in vacuo and the residue dried to give methyl 2-(3-amino-4-thienyl)-4,5-dihydroxy-pyrimidine-6-carboxylate trifluoroacetate (860 mg, 99%) as a solid. 1H NMR (DMSO-d6): δ 8.32 (1H, s), 6.75 (1H, s), 3.87 (3H, s). MS m/z (MH)+ 268.0.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:5][CH2:4]1.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>CO.C(N(CC)CC)C>[Br:1][CH2:2][CH:3]([OH:5])[CH2:4][S:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:11][CH:12]=1
Reactant: BrCC1CO1
Reactant: CC(C)(C)c1ccc(S)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(SCC(O)CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a stirred solution of 64.9 ml [103.67 g (0.758 mole)] 1-bromo-2,3-epoxypropane dissolved in 18 ml methanol/triethylamine (1:1) cooled to 5°-10° C. in a water-ice bath, 124.5 g (0.75 mole) p-tert-butylthiophenol was added dropwise. After the addition was complete (about 21/4 hours), the reaction mixture was allowed to come to room temperature and was allowed to stir at room temperature for about 2 hours. Volatiles were removed in vacuo to give 233.1 g of crude product as a viscous oil.
Reaction SMILES: C(O[CH:5]1[C:14]2[C:9](=[CH:10][C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])=[C:12]([O:15][C:16](=[O:18])[CH3:17])[CH:13]=2)[O:8][C:7]([CH3:34])([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[CH2:6]1)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:16]([O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[C:19]([CH3:22])([CH3:21])[CH3:20])[O:8][C:7]([CH3:34])([CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=1)[CH:6]=[CH:5]2)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2

Procedure:
A mixture of 2.4 g of 4,6-diacetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman (prepared as described in Preparation 56), 0.1 g of p-toluenesulfonic acid monohydrate and 50 ml of benzene was heated under reflux for 1 hour. The reaction solution was cooled, washed with a saturated aqueous solution of sodium bicarbonate, and then with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27]N4C5C=CC=CC=5N=N4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.[C:39]1(O)[C:48]2[CH2:47][CH2:46][CH2:45][CH2:44][C:43]=2[CH:42]=[CH:41][CH:40]=1>>[CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:47]4[C:48]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[CH:45][CH:46]=4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]2)[CH2:4][O:3]1
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(On2nnc3ccccc32)cc1=O
Reactant: Oc1cccc2c1CCCC2
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2cccc3c2CCCC3)cc1=O

Procedure:
Using the method described in Example 109, Step 2, 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Example 109, Step 1) and 5,6,7,8-tetrahydro-naphthalen-1-ol afforded 4-methyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white solid as a mixture of diastereomers (197.3 mg, 77%).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]2[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:6]=2[N:7]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([NH:2][C:3]1[S:4][C:5]2[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:6]=2[N:7]=1)(=[O:26])=[O:25]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Agent: Br
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc2c(s1)C(=O)CC(C)(C)C2

Procedure:
The title compound was prepared from 2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one hydrobromide and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (26 mg) with purity >90%: MS (pos) m/z 419.1, 421.1; HRMS m/z 417.9979 (calc. of monoisotopic mass for C16H16Cl2N2O3S2 gives 417.9979).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:28][NH2:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH2:28][C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[C:16]([Cl:15])[CH:17]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: NCc1cnc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (134 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (148 mg, 0.57 mmol, Amine-23) in a similar manner to Intermediate-2.
Reaction SMILES: O[CH2:2][C:3]1[C:11]2[S:10][C:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.P(Br)(Br)[Br:29]>ClCCl>[Br:29][CH2:2][C:3]1[C:11]2[S:10][C:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(C)c(Nc2nc3cccc(CO)c3s2)c(C)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)c(Nc2nc3cccc(CBr)c3s2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To 0.065 g (0.22 mmol) of 7-(hydroxymethyl)-N-mesityl-1,3-benzothiazol-2-amine in 2 mL of dichloromethane was added 58 μL (0.72 mmol) of pyridine and 0.24 mL (0.24 mmol) of phosphorous tribromide (1 M in dichloromethane). The reaction was stirred at room temperature for 8 h and quenched with saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.045 g (57%) of the title compound that was used without further purification.
Reaction SMILES: C(O[C:4]1[S:5][C:6]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:7]=2[C:8](=[O:10])[N:9]=1)C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C>[CH2:22]([NH:29][C:4]1[S:5][C:6]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([C:18]([F:19])([F:20])[F:21])=[CH:11][C:7]=2[C:8](=[O:10])[N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CCOc1nc(=O)c2cc(C(F)(F)F)cc([N+](=O)[O-])c2s1
Solvent: CC(=O)O
Product: O=c1nc(NCc2ccccc2)sc2c([N+](=O)[O-])cc(C(F)(F)F)cc12
Yield: 73 %

Procedure:
A solution of 0.7 g of 2-ethoxy-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one in 15 ml acetic acid was treated with 0.4 ml of benzylamine and refluxed for 14 h. The reaction mixture was evaporated and the residue was treated by 10 ml water, the yellow precipitate was filtered off and washed with 50 ml water. Pure final product was obtained after recrystallization twice from ethanol/DMF. 2-(Benzylamino)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one is a light yellow crystalline solid. Yield 73%. mp 192-194° C.
Reaction SMILES: O1[CH:6]2[CH:2]1[C:3](=[O:34])[CH:4]([CH:23]([OH:33])[C:24]#[C:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:5]2[CH:7]=[CH:8][CH:9]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.[OH:42][CH:43]([CH2:46][OH:47])[CH2:44][SH:45].S([O-])(O)(=O)=O.[K+]>CO>[OH:42][CH:43]([CH2:46][OH:47])[CH2:44][S:45][C:2]1[C:3](=[O:34])[CH:4]([CH:23]([OH:33])[C:24]#[C:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:5]([CH:7]=[CH:8][CH:9]([O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17])[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=1
Reactant: OCC(O)CS
Reactant: COC(=O)CCCC#CC(O)C1C(=O)C2OC2C1C=CC(O[Si](C)(C)C(C)(C)C)C1CCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCCC#CC(O)C1C(=O)C(SCC(O)CO)=CC1C=CC(O[Si](C)(C)C(C)(C)C)C1CCCC1
Reaction time: 2 h
Yield: 62 %

Procedure:
A 49 mg amount of 2,3-epoxy-5-(1-hydroxy-6-methoxycarbonyl-2-hexynyl}-4-(3-t-butyldimethylsilyloxy-3-cyclopentyl-1-propenyl)cyclopentanone was dissolved in 1 ml of methanol and 21 μl of triethylamine was added. Then, 12 mg of 2,3-dihydroxypropanethiol was added thereto, followed by stirring for 2 hours. The reaction mixture was poured on an aqueous saturated solution of potassium hydrogen sulfate, followed by extracting with ethyl acetate. The extracted solution was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering and concentrating, the concentrate was subjected to silica gel chromatography to give 36 mg (yield 62%) of 2-(2,3-dihydroxypropylthio)-5-(1-hydroxy-6-methoxycarbonyl-2-hexynyl)-4-(3-t-butyldimethylsilyloxy-3-cyclopentyl-1-propenyl)-2-cyclopentenone.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:26][C:27]([NH2:29])=[O:28].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH2:26][C:27]([NH2:29])=[O:28])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.4 %

Procedure:
A mixture of 1-benzyl-3-(4-chloro-phenyl)-1-pyridin-3-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.05 mmol), 2-bromo-acetamide (8 mg), and Na2CO3 (15 mg) in acetone (2 mL) was stirred at 25° C. for 16 h. After concentration, purification by flash chromatography (2 M NH3/MeOH in CH2Cl2) provided the desired compound (6 mg). MS (ESI): exact mass calculated for C22H23ClN4O, 394.16; found, m/z 395.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49-8.48 (m, 1H), 7.56-7.54 (m, 1H), 7.44-7.42 (m, 2H), 7.32-7.30 (m, 2H), 7.19-7.11 (m, 1H), 6.84-6.82 (m, 1H), 5.39 (s, 2H), 2.93-2.87 (m, 2H), 2.76-2.74 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30](=[O:32])[CH3:31])=[C:24]([OH:33])[CH:23]=1.C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30](=[O:32])[CH3:31])=[C:24]([OH:33])[CH:23]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)c(O)cc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(C(C)=O)c(O)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 13.1 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.2 g, 19 mmol), 1-[4-(3-chloropropoxy)-2-hydroxy-5-methoxyphenyl]ethanone (5.0 g, 19 mmol), NaHCO3 (1.8 g, 20 mmol) and acetronitrile (120 mL) was stirred and refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to a dark oil. The oil was taken up in anhydrous ether and ethereal HCl was added to precipitate 8.7 g of an off-white hydrochloride salt. A 2.0 g sample of the salt was converted to its free base and chromatographed by preparative HPLC (silica gel with 5% MeOH/CH2Cl2 as eluent). Concentration of the desired fractions gave 1.1 g of a white solid, which was recrystallized from EtOH to yield 0.85 g of the product, m.p. 122°-124° C.