Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH3:21][C:20]1[C:16]([C:13]2[S:12][C:11]([C:9]([N:5]3[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:4]3)=[O:10])=[CH:15][CH:14]=2)=[N:17][O:18][C:19]=1[C:22]([F:25])([F:24])[F:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](N)C3)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](NS(C)(=O)=O)C3)s2)noc1C(F)(F)F
Reaction time: 48 h
Yield: 69.7 %

Procedure:
A suspension of ((R)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 27, 79 mg, 0.2 mmol) in THF (2 mL) was treated with triethylamine (63 μL, 0.45 mmol) followed by methanesulfonyl chloride (19 μL, 0.24 mmol). The reaction mixture was allowed to stir 48 h, evaporated, and chromatographed on silica gel with EtOAc as eluant to afford product as a colorless foam (61 mg, 70%). 1H NMR (CDCl3) 1.68 (m, 2 H), 1.88 (m, 2 H), 2.02 (m, 1 H), 2.33 (d, J=1.8, 3 H), 2.98 (s, 3 H), 3.46 (m, 2 H), 3.57 (m, 1 H), 3.84 (m, 1 H), 4.05 (d, J=12.7, 1 H), 5.45 (d, J=7.5, 1 H), 7.39 (d, J=4.0, 1 H), 7.43 (d, J=3.5, 1 H). 13C NMR 7.9, 23.4, 31.6, 41.9, 47 (br), 52 (br), 49.9, 114.8, 118.7 (q, J=271), 128.2, 129.8, 131.8, 139.6, 155.2 (q, 40), 157.9, 163.5. 19F NMR −63.1. LC/MS 5.82 min, [M+1]+ 438.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH2:14][CH2:13][CH2:12]2.C([O-])(=O)C.[Na+].Cl.[CH3:37][O:38][NH2:39].O>C(O)C>[CH3:37][O:38][N:39]=[C:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[C:2]([Cl:1])=[CH:23][C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:28])[Cl:29])=[CH:21][C:20]=3[Cl:30])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: O=C1CCCc2cc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)ccc21
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=C1CCCc2cc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)ccc21

Procedure:
1.24 g of 6-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-3,4-dihydro-2H-naphthalen-1-one, 0.23 g of sodium acetate and 0.23 g of O-methylhydroxylamine hydrochloride are stirred in 10 ml of ethanol at 50° C. for 18 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, the title compound is obtained. M.p. 75-77° C.
Reaction SMILES: CC1(C)S[C@@H]2[C@H:7](NC(C(C(O)=O)C3C=CC=CC=3)=O)[C:8](=[O:9])N2[C@H]1C(O)=O.[CH2:27]1[C@H:32](N)[C@@H:31]([O:34][C@H:35]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H:30]([OH:46])[C@@H:29]([O:47][C@H:48]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H:28]1N>>[CH3:7][C:8]([C:27]1[CH:28]=[C:29]([O:47][CH3:48])[C:30]([OH:46])=[C:31]([O:34][CH3:35])[CH:32]=1)=[O:9]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)C(C(=O)O)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Product: COc1cc(C(C)=O)cc(OC)c1O

Procedure:
After four weeks, the segments were transferred to BS-48 regeneration medium containing 200 mg/L carbenicillin and 25 mg/L kanamycin.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][CH:20]2[CH:12]([NH:13][C:14]3[CH:15]=[C:16]([Cl:24])[C:17]([Cl:23])=[CH:18][C:19]=32)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)CO>O>[Cl:24][C:16]1[C:17]([Cl:23])=[CH:18][C:19]2[C@@H:20]3[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C@H:12]3[NH:13][C:14]=2[CH:15]=1
Reactant: O=C(c1ccccc1)N1CCC2Nc3cc(Cl)c(Cl)cc3C2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Clc1cc2c(cc1Cl)[C@@H]1CCNCC[C@H]1N2
Temperature: 170 °C
Yield: 21.8 %

Procedure:
A mixture of 3-benzoyl-8,9-dichloro-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole (0.20 g, 0.55), potassium hydroxide (1.0 g, 17.8 mmol), and ethylene glycol (5 mL) was heated to 170° C. Upon the disappearance of starting material, the reaction was cooled to room temperature, diluted with H2O, and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography and prep HPLC to give the title compound (31 mg, 22%) as a tan solid. 1H NMR (d-MeOH) δ 8.54, 7.02, 6.63, 3.73, 3.08-2.88, 2.40, 2.17, 1.81, 1.65; IR (drift) 2934, 2916, 2866, 2850, 2831, 1627, 1608, 1569, 1481, 1466, 1372, 1365, 953, 775, 662 cm−1; HRMS (FAB) calcd for C12H14Cl2N2+H 257.0612, found 257.0619.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([CH2:27][CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:11][C@@H:10]([C:40](=[O:60])[N:41]([CH:57]2[CH2:59][CH2:58]2)[CH2:42][C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:44]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CS.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][CH2:27][CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:11][C@@H:10]([C:40](=[O:60])[N:41]([CH:57]2[CH2:59][CH2:58]2)[CH2:42][C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:44]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N(CCN3C(=O)c4ccccc4C3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Agent: O=C(O)CS
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCCN3C(=O)c4ccccc4C3=O)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Reaction time: 2.5 h

Procedure:
To a solution of (3R*,5S*)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-[[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-(2-nitro-benzenesulfonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.3 mmol) in DMF (1 mL) are added thioglycolic acid (104 uL, 1.5 mmol) and DBU (224 uL, 1.5 mmol) at room temperature. After 2.5 h, the reaction mixture is quenched by H2O (20 mL) and extracted with CH2Cl2 (50 mL). The organic phase is successively washed with H2O and brine, then dried over Na2SO4 and concentrated in reduced pressure. The residue is purified by silica gel column chromatography to afford the title compound. MS: 658 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.60 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[N+]=[N-])[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11].[CH2:29]([OH:31])[CH3:30]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh].C1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([O:31][CH2:29][CH3:30])[C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:20]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)=[N+]=[N-]
Reactant: CCO
Agent: [Rh]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Rhodium (II) acetate dimer (33 mg) was added to a mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-diazopropanoate (2.80 g), ethanol (2.16 mL) and benzene (50 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes, heated at reflux for a further 15 minutes, then cooled and evaporated in vacuo. The residue was chromatographed on silica gel using 1.5% methanol in dichloromethane as eluent to afford the title compound as a gum.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:47]([O:51][C:52]([N:54]1[C@@H:59]([CH3:60])[CH2:58][NH:57][CH2:56][C@H:55]1[CH3:61])=[O:53])([CH3:50])([CH3:49])[CH3:48]>CS(C)=O>[C:47]([O:51][C:52]([N:54]1[C@@H:59]([CH3:60])[CH2:58][N:57]([C:2]2[CH:7]=[N:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][C:13]4[NH:16][C:17]([C:19]5[C:27]6[C:22](=[CH:23][C:24]([C:28]7[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=7[CH2:36][CH3:37])=[CH:25][CH:26]=6)[NH:21][N:20]=5)=[N:18][C:12]=4[CH2:11]3)=[O:9])=[CH:4][N:3]=2)[CH2:56][C@H:55]1[CH3:61])=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C5)cn3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (150 mg, 0.154 mmol) in DMSO (1.5 mL) were added DIPEA (0.143 mL, 0.87 mmol) and (2R,6S)-2,6-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester (124 mg, 0.58 mmol) and the mixture stirred at room temperature for 18 hours. The crude reaction mass was purified by prep-HPLC Method F to afford (3R,5S)-5′-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1H-indazol-3-yl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carbonyl}-3,5-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester as an off white solid (80 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.Br[CH2:48]COCC.BrCCOC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:40][CH2:41][CH2:42][O:43][CH2:44][CH3:48])=[CH:8][CH:7]=2)=[CH:45][CH:46]=1
Reactant: CCOCCBr
Reactant: COCCOc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COCCBr
Product: CCOCCOc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1

Procedure:
The title compound was synthesized as described for Compound 475, except 1-bromo-2-ethoxy ethane was used for alkylation instead of 1-bromo-2-methoxy ethane.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[CH2:17][CH2:16][N:15]([C@@:18]3([CH3:30])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[C:5]=2[N:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:8]=1>O1CCOCC1.C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[C:4]2[CH2:17][CH2:16][N:15]([C@@:18]3([CH3:30])[CH2:22][CH2:21][NH:20][CH2:19]3)[C:5]=2[N:6]=[C:7]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@](C)(N2CCc3c(Cl)nc(N4CCOCC4)nc32)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@]1(N2CCc3c(Cl)nc(N4CCOCC4)nc32)CCNC1
Reaction time: 20 h
Yield: 305.3 %

Procedure:
A solution of 4 M hydrochloric acid in dioxane (5 mL) was added to a solution of the product of Example 4, step 2, tert-butyl(3S)-3-[4-chloro-2-(morpholin-4-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate (424 mg, 1.00 mmol) in DCM (5 mL) at room temperature, and the mixture was stirred for 20 h. The reaction mixture was concentrated to give 4-chloro-7-[(3S)-3-methylpyrrolidin-3-yl]-2-(morpholin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine hydrochloride (550 mg). This material was dissolved in a biphasic mixture of DCM (10 mL) and saturated aqueous
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[CH:25][C:21]4[CH:22]=[N:23][O:24][C:20]=4[CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[O:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:10]3[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]5[CH:45]=[CH:46][C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:39][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)[N:9]=3)[CH:26]=[CH:25][C:21]=2[CH:22]=[N:23]1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4cnoc4c3)n2)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5cnoc5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.34 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-benzo[d]isoxazol-6-yl-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure N-{3-[8-(benzo[d]isoxazol-6-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}4-tert-butyl-benzamide.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:10]Cl)([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[Na].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CN(C)C=O.O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:9])([CH3:8])[CH2:10][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Yield: 78.4 %

Procedure:
A mixture of 2.6 g (0.010 mol) of (1,1'-biphenyl-4-yl)chloromethyldimethylsilane and 1.1 g (0.012 mol) of 1,2,4-triazole sodium salt in 5 ml of dimethylformamide was warmed to 80°-90° for 2 hours, cooled, diluted with water, and extracted with ether. The ether solution was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2.3 g of colorless solid, m.p. 79°-86°. Recrystallization from a mixture of 25 ml of hexanes and 2 ml of ethyl acetate gave 1.1 g (38%) of the title compound: m.p. 92°-93°; ir (Nujol®) 1255, 1130, 1000, 825, 760, 695 cm-1 ; nmr (CDCl3) 0.4 (6H, s), 3.9 (2H, s), 7.2-7.7 (9H, m), 7.8 (1H, s), 7.9 (1H, s); analysis for C17H19N3Si (mw 293.43):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35].C(N(CC)CC)C>ClCCl>[CH2:33]([N:36]([CH2:37][CH2:38][CH3:39])[C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:10])[CH2:34][CH3:35]
Reactant: CCCNCCC
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(Cl)ccn1
Yield: 67.3 %

Procedure:
Stir a solution of 4-chloro-2-pyridine carboxylic acid (1.0 g, 6.3 mmol), 1-hydroxybenzotriazole (850 mg, 6.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.21 g, 6.3 mmol), dipropyl amine (862 μL, 6.3 mmol), and triethylamine (1.75 mL, 12.6 mmol) in dichloromethane (63 mL) at room temperature over the weekend. Wash the solution with 0.1 N citric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes)to give the title compound (1.02 g, 67%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[N:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:13]([CH3:24])=[N:12][CH:11]=2)[CH2:5][CH2:4]1.B1([O-])O[O:38]1.O.O.O.O.[Na+]>CO.O>[OH:1][CH2:2][C:3]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=2)[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[N:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH2:21])=[O:38])=[CH:22][CH:23]=3)[C:13]([CH3:24])=[N:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: Cc1ncc(CN2CCC(CO)(Cc3cccc(OC(F)(F)F)c3)CC2)n1Cc1ccc(C#N)cc1
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ncc(CN2CCC(CO)(Cc3cccc(OC(F)(F)F)c3)CC2)n1Cc1ccc(C(N)=O)cc1
Temperature: 50 °C

Procedure:
A solution of 4-{5-[4-hydroxymethyl-4-(3-trifluoromethoxy-benzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile (71 mg, 0.142 mmol; Example 31) and sodium perborate tetrahydrate (92.8 mg, 0.6 mmol) in a mixture of methanol (2.5 mL) and water (1 mL) was heated at 50° C. for 7 h. The resultant mixture was concentrated under vacuum, and the residue was partitioned between chloroform and dilute hydrochloric acid (0.5M). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][NH:11]1)([O-])=O.[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>COCCOC.C(Cl)(Cl)Cl>[C:17]1([N:14]2[CH2:15][CH2:16][N:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:23](=[S:24])[N:11]3[CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(c2ccccc2)CCN1
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: S=C1Nc2ccccc2N2CCN(c3ccccc3)CCN12

Procedure:
Hexahydro-1-(2-nitrophenyl)-5-phenyl-1H-1,2,5-triazepine (22.4 g) was hydrogenated in 1,2-dimethoxyethane (800 ml) as in Example 11 and the volume reduced to 250 ml. 1,1'-Thiocarbonyldiimidazole (27 g) was added and the mixture, protected from moisture, was heated under reflux on a steam bath overnight. The solution was evaporated to dryness. The residue was dissolved in toluene and applied to a column (63×8.0 cm) of dry column grade neutral alumina prepacked in toluene. Elution with toluene (several liters) removed a faster moving yellow component from the column. The eluting solvent was changed to toluene-chloroform (4:1, 2 l) and then to chloroform. Monitoring of fractions was by t.l.c. on Alox-25 uv254 plates (Brinkmann) with chloroform as developer and on silica gel GF (Analtech) plates with chloroform as developer. A slightly faster moving minor purple component was eluted in the earlier fractions containing the major component. In later fractions a slower moving yellow component contaminated the major component. The first fraction (having none of the slower yellow minor component) were evaporated to smaller volume. Coevaporation with toluene caused crystallization. Addition of heptane completed the process; wt. 12.46 g (crop 1), mp=206°-208°. The later yellow fractions similarly gave 5.33 g (crop 2), mp=203°-208° of crude titled product. Recrystallization of crop 2 (from chloroform-toluene-heptane) gave material which was combined with crop 1. This material was dissolved in chloroform and the solution was decolorized. Evaporation to smaller volume followed by coevaporation with toluene and addition of heptane gave 17.6 g (76%) of crude titled product, mp=205°-209°. Recrystallization from the same solvent system gave titled product, mp=205°-208°.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Br:14][C:15]1[CH:16]=[C:17]2[C:27](=[CH:28][CH:29]=1)[O:26][C:20]1([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:19]/[C:18]/2=[N:30]\[S:31]([C:34]([CH3:37])([CH3:36])[CH3:35])(=O)=[O:32]>C1COCC1>[Br:14][C:15]1[CH:16]=[C:17]2[C:27](=[CH:28][CH:29]=1)[O:26][C:20]1([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:19][C:18]2([CH2:2][C:1]([O:4][CH3:5])=[O:3])[NH:30][S:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: COC(C)=O
Reactant: CC(C)(C)S(=O)(=O)/N=C1\CC2(CCCCC2)Oc2ccc(Br)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC1(NS(=O)C(C)(C)C)CC2(CCCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a solution of methyl acetate (1.86 g, 0.025 mol) in THF (18 mL) was added LDA (2 M in THF) was added dropwise via a syring at −78. After stirring at −78 for 30 minutes, a solution of (E)-N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)-2-methylpropane-2-sulfonamide (5.0 g, 0.0126 mol) in THF (7.4 mL) was added dropwise via a syring. The mixture was stirring at −78 for 3 h. The reaction was quenched with aqueous NH4Cl solution and allowed to warming to room temperature. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to give the product, which was purified by chromatography to afford methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)spiro[chroman-2,1′-cyclohexane]-4-yl)acetate (1.4 g, 33%). 1H NMR (CDCl3): 1.23 (s, 9H), 1.36-1.52 (m, 4H), 1.57 (m, 1H), 1.66 (m, 3H), 1.86 (d, 2H), 2.24 (d, 1H), 2.67 (d, 1H), 2.93 (s, 3H), 3.71 (s, 3H), 5.34 (s, 1H), 6.79 (d, 1H), 7.26 (s, 1H), 7.39 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29]Br>CC(C)=O>[Br:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1OCCCBr)c1cccc2[nH]ccc12

Procedure:
A suspension of 2 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide and 2.18 g of potassium carbonate in 20 ml of acetone was admixed with 3.2 ml of 1,3-dibromopropane and the mixture was refluxed for 90 minutes and was filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica (eluant: chloroform/ethyl acetate/triethylamine 6:3:1 to obtain 2.37 g of N-[2-[3-bromopropoxy)phenyl]-1H-indole-4-carboxamide melting at 145° C.
Reaction SMILES: C([S@@]([NH:7][C@H:8]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)[CH2:9][CH2:10][CH2:11][C:12](OCC)=[O:13])=O)(C)(C)C.C(N(CC)CC)C>CO>[F:24][C:19]1[CH:18]=[C:17]([C@H:8]2[NH:7][C:12](=[O:13])[CH2:11][CH2:10][CH2:9]2)[CH:22]=[C:21]([F:23])[CH:20]=1
Reactant: CCOC(=O)CCC[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1CCC[C@@H](c2cc(F)cc(F)c2)N1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl (5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)pentanoate from Step A (4.42 g, 12.2 mmol) in MeOH (200 mL) was cooled to 0° C. Hydrogen chloride gas (anhydrous) was bubbled through this cold solution for about 1 minute, after which time the reaction vessel was sealed and allowed to sit in the ice bath for 15 minutes. Dry nitrogen was then bubbled through the solution for 30 minutes, prior to removal of solvent in vacuo. More MeOH (˜50 mL) was added, and then removed in vacuo. After dissolving in a third volume of MeOH (100 mL), triethylamine (6.78 mL, 48.9 mmol) was introduced and the mixture was heated to 65° C. for 3 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between diethyl ether (100 mL) and 1 M HCl (50 mL). The organics were washed with additional 1 M HCl (50 mL), water (50 mL) and saturated brine (50 mL). The ethereal solution was dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: m/z=212 (M+1).