Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH:12]([NH:17][C:18]1[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[N:22]=[CH:21]3)[CH2:13]2)[CH2:7][CH3:8].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH2:6]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH:12]([N:17]([C:18]1[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[N:22]=[CH:21]3)[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13]2)[CH2:7][CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN1C2CCC1CC(Nc1ccc3c(cnn3C3CCCCO3)c1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCN1C2CCC1CC(N(c1ccc3c(cnn3C3CCCCO3)c1)S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
Methanesulfonyl chloride (0.10 ml, 1.29 mmol) was added to a solution of N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (37 mg, 0.100 mmol) in pyridine (1 ml), and the resulting mixture was stirred at room temperature for 3 days. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a preparative thin-layer chromatography (200×200×0.5 mm, 2 plates, eluent: chloroform/methanol=20/1) to obtain N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-methanesulfonamide (20 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])[CH:5]=[C:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[C:7]=1F.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:3]=[C:4]([S:27]([NH:30][CH3:31])(=[O:28])=[O:29])[CH:5]=[C:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[C:7]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: CNS(=O)(=O)c1cc(F)c(F)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Product: CNS(=O)(=O)c1cc(F)c(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example 202 from 3,4-Difluoro-N-methyl-5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide (example CC) and morpholine to yield the title compound as a colourless foam, MS (m/e): 531.1 (M+H, 100%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([CH2:27][OH:28])[CH2:25][OH:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:35])=[N:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)([CH2:27][O:28][S:44]([CH3:43])(=[O:46])=[O:45])[CH2:25][O:26][S:44]([CH3:43])(=[O:46])=[O:45])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:35])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)(CO)c4ccccc4)cc2OCC3)n(C(C)C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)(COS(C)(=O)=O)c4ccccc4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-phenylpropane-1,3-diol (115 mg, 0.242 mmol) and Et3N (101 μL, 0.725 mmol) in DCM (15 mL) cooled at 0° C. was added methanesulfonyl chloride (47 μL, 0.605 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording the title compound (124.5 mg, 81%) as a colourless gum. LCMS (Method J): RT 3.26 min [M+H]+ 632
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.Cl.C[NH:33][O:34][CH3:35].C(N(CC)CC)C>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:33][O:34][CH3:35])=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.2 %

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoyl chloride hydrochloride (100 mg; 0.23 mmol) was suspended in dichloromethane (10 ml), N,O-dimethyl hydroxylamine hydrochloride (38 mg; 0.45 mmol) added followed by triethylamine (0.16 ml; 1.1 mmol). The resulting mixture was stirred at ambient temperature for 18 h. The mixture was evaporated to dryness under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, dried (MgSO4) and evaporated to dryness under reduced pressure. The title compound (4 mg; 4%) was obtained by high performance liquid chromatography. 1H NMR (250 MHz; CD3OD) δ: 3.74 (3H, s), 6.00 (2H, s), 6.94 (1H, d,), 7.04-7.08 (2H, m), 7.50-7.70 (2H, m), 7.85 (2H, d), 8.00-8.20 (3H, m), 8.59 (1H, d); m/z (ESMS): 415.1 [M+H]⊕.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:45])[C:32]=1[O:33][C:34]1[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][N:35]=1)[C:28]#[N:29].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:29]=[C:28]([C:27]2[CH:26]=[C:25]([Cl:24])[C:32]([O:33][C:34]3[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][N:35]=3)=[C:31]([Cl:45])[CH:30]=2)[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.00 g), 3,5-dichloro-4-(3-chloro-5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.00 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[NH:2]1.O=P(Cl)(Cl)[Cl:13].Cl>O>[Cl:13][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]sc2ccccc12
Agent: Cl
Solvent: O
Product: Clc1nsc2ccccc12
Reaction time: 1.5 h

Procedure:
A mixture of 1,2-benzisothiazole-3(2H)-one (Example 1, 818 g, 5.414 moles) and POCl3 (1114 g, 7.26 moles) was heated to 120° over about two hours. HCl evolution began at about 70°. Heat was continued at 120° for another 1.5 hours. The hot solution was poured into 8 liter of H2O at 25°. The temperature was not allowed to exceed 50°. After 30 minutes, the mixture was cooled to 25° (ice addition) and extracted with methylene chloride (4 liter). A dark oil was obtained by evaporation of the methylene chloride in vacuo. This oil was extracted with Skelly B (3×1 liter and 2×500 mL). The turbid extract was treated with Darco G-60 (30 g) and Celite A-545 (20 g) before filtering. The filtrate was evaporated in vacuo to give 743.9 g, 81%, of a yellow oil which readily crystallized. Distillation of the oil at reduced pressure gave 707 g, 77%, b.p. 80°-85° at 0.75 Torr., of colorless distillate which readily crystallized, m.p. 39°-41°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[CH3:30][N:31]([CH2:33][C:34]1[O:38][C:37]([CH2:39][OH:40])=[CH:36][CH:35]=1)[CH3:32]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:28][CH3:29])=[N:3][C:2]([O:40][CH2:39][C:37]2[O:38][C:34]([CH2:33][N:31]([CH3:32])[CH3:30])=[CH:35][CH:36]=2)=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Product: COc1nc(OCc2ccc(CN(C)C)o2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 115b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.3 g) and (5-dimethylaminomethyl-2-furanyl)methanol (0.2 g). After removal of the SEM (2-[trimethylsilyl]ethoxymethyl) group the title compound was purified by silica gel chromatography eluting with methanol/dichloromethane mixtures Yield 0.23 g
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1.N[C@H:23](C1C=NC=C(Br)C=1)[C@@](C1C=C(F)C=CC=1F)(O)C>>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])([CH3:23])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@@](O)(c1cc(F)ccc1F)[C@H](N)c1cncc(Br)c1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Product: C[C@]1(c2cc(F)ccc2F)OC(=O)N[C@@H]1c1cncc(Br)c1

Procedure:
Prepared according to the same procedure as (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one, starting with (1R,2R)-1-amino-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol. 1H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J=2.4 Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 7.95 (t, J=2.0 Hz, 1H), 7.46 (ddd, J=10.9, 9.1, 4.4 Hz, 1H), 7.40-7.33 (m, 1H), 7.25 (ddd, J=9.3, 6.1, 3.2 Hz, 1H), 5.15 (d, J=1.5 Hz, 1H), 1.85 (s, 1H) 1.25 (s, 3H), Mass spec.: 371.1 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:3].C([Li])CCC.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>O1CCCC1.CCOCC>[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:21](=[O:22])[C:20]([F:27])([F:26])[F:19])=[CH:9][CH:8]=1)[CH3:3]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CN(C)CCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
To a solution of N,N-dimethyl-2-(4bromophenoxy)ethylamine (1.0 g, 4.1 mmol) in tetrahydrofuran (10 ml) at −78° C. was added dropwise n-butyllithium (1.5M in hexane, 2.7 ml, 4.1 mmol). The mixture was stirred at this temperature for 15 min. and then transferred via a cannula into a pre-cooled solution of ethyl trifluoroacetate (0.64 g, 4.5 mmol) in ether (8 ml) at −78° C. The resulting mixture was stirred and the temperature allowed to rise gradually to r.t. over a period of 1.5 h. The reaction mixture was then quenched with water (5 ml) and diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Bulb-to-bulb distillation (82-84° C./0.01 mmHg) afforded the title compound (423 mg, 39%) as a pale yellow oil. Analysis for C12H14F3NO2.0.3H2O calcd. C 54.05%, H 5.52%, N 5.25%; Found: C 54.12%, H 5.39%, N 5.28%.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:25])[CH3:24]>C1COCC1.[Cl-].[Na+].O>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:9]2[S:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:18][CH2:19]1)(=[O:25])[CH3:24]
Reactant: CCOC(=O)c1sc(C2CCNCC2)nc1-c1ccccc1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(C2CCN(C(C)=O)CC2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To prepare compound 90, the procedure was followed as outlined in Scheme 10, Step 2 replacing compounds 77 and 78 with compounds tent-butyl 4-carbamothioylpiperidine-1-carboxylate and ethyl 2-bromo-3-oxo-3-phenylpropanoate to afford compound 90 (0.790 g, 21% yield) as a white solid. To a stirring solution of ethyl 4-phenyl-2-(piperidin-4-yl)thiazole-5-carboxylate 90 (0.235 g, 0.743 mmol) in THF (8 mL) was added acetyl chloride (1.11 mL, 0.891 mmol) and the reaction was stirred at room temperature for 2 h. The solution was diluted with brine and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 2-(1-acetylpiperidin-4-yl)-4-phenylthiazole-5-carboxylate 91 as a light yellow oil (0.196 g, 74% yield) after purification by flash chromatography (0 to 10% MeOH in ethyl acetate). LRMS (ESI): (calc) 358.45 (found) 359.3 (MH)+
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH2:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH2:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: CCc1cc(C(=O)Cl)cc(C#N)c1OC
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)N2CSc3ccccc32)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (318 mg) and 37% formalin (0.21 mL) in the same manner as in Example 1 was dissolved in dichloromethane (6 mL), and triethylamine (0.71 mL) and 3-cyano-5-ethyl-4-methoxybenzoyl chloride (387 mg) were added to the solution, and then the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (498 mg) as a yellow oily substance.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH3:11])[CH:6]=[C:7]([CH:9]=O)[N:8]=2)[CH2:3][CH2:2]1.C1(C2N(C)C(C=O)=CN=2)CC1.N(C1C=C(C=CC=1C)C(NC1C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=1OC)=O)=[N+]=[N-].[C:53]([C:57]1[CH:58]=[C:59]([NH:89][S:90]([CH3:93])(=[O:92])=[O:91])[C:60]([O:87][CH3:88])=[C:61]([NH:63][C:64](=[O:86])[C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[C:67]([N:72]3[CH:76]=C(C4N(C)C(C5CC5)=NC=4)[N:74]=[N:73]3)[CH:66]=2)[CH:62]=1)([CH3:56])([CH3:55])[CH3:54]>>[C:53]([C:57]1[CH:58]=[C:59]([NH:89][S:90]([CH3:93])(=[O:91])=[O:92])[C:60]([O:87][CH3:88])=[C:61]([NH:63][C:64](=[O:86])[C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[C:67]([N:72]3[CH:76]=[C:9]([C:7]4[N:8]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]([CH3:11])[CH:6]=4)[N:74]=[N:73]3)[CH:66]=2)[CH:62]=1)([CH3:56])([CH3:54])[CH3:55]
Reactant: Cn1cc(C=O)nc1C1CC1
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C5CC5)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cn1c(C=O)cnc1C1CC1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cn(C)c(C5CC5)n4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 47 was prepared from 2-cyclopropyl-1-methyl-1H-imidazole-4-carbaldehyde (as a 1:1 mixture with 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde) and 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide in the same manner as Example 39. Chromatography allowed separation of Example 47 from Example 46. ESI MS m/z 578 [C29H35N7O4S+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[OH:30]>>[OH:30][CH:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCCC1O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCC2O)cn1
Yield: 31 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 2-amino cyclopentanol instead of 2-aminoethyl isopropylether, to the title compound (80 mg, 31%) which was obtained as a white solid. MS: m/e=494.2 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:9][CH:4]([CH2:5][C:6]1=NO)[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]2=1.[Na].[OH2:15]>C(O)C.C(Cl)(Cl)Cl>[CH:1]12[CH2:9][CH:4]([CH2:5][C:6]1=[O:15])[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]2=1
Reactant: ON=C1CC2CC1c1ccccc12
Reactant: O
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1CC2CC1c1ccccc12
Temperature: 25 °C

Procedure:
A solution of benzonorbornen-2-one oxime (2g.) in absolute ethanol (120ml.) was heated to reflux under nitrogen and sodium metal (12 g.) was added in small portions with continuous stirring. The reaction mixture was then refluxed for 30 minutes. This viscous suspension was then cooled to room temperature, 100 ml. of water added and the reaction mixture agitated until a clear solution was obtained. This was extracted with ether and the ether extract worked up to give an oil which was dissolved in chloroform and extracted with 10% HCl solution. Removal of water and excess HCl under vacuum from this extract gave a white solid (1g., 40%). The white solid was analyzed by infra-red, nuclear magnetic resonance and elemental analysis techniques and was determined to be the 1,2,3,4-tetrahydro-1,4-methanonaphthalen-endo-2-amine hydrochloride, C11H14NCl (m.p. 230°-231°C). Basification of a sample of this material with 10% NaOH gave, on ether extraction, the required amine as a pale yellow oil which was also analyzed by infra-red, and nuclear magnetic resonance techniques, and the empirical formula was determined to be C11H13N.
Reaction SMILES: Cl[CH:2]([C:7]1([C:16]([F:19])([F:18])[F:17])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[H][H]>C1COCC1.[Pd]>[F:6][C:3]([F:4])([F:5])[CH2:2][C:7]1([C:16]([F:17])([F:19])[F:18])[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[O:11]1
Reactant: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccccc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1

Procedure:
306.5 g of 2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole of Example 2a were dissolved in 500 ml of THF and the solution was treated with 101 g of triethylamine and 30 g of palladium on charcoal (5% strength by weight). The mixture was then hydrogenated for 48 hours at 110° C. under 100 bar hydrogen. The mixture was subsequently filtered, the solvent was stripped off, and the residue was subjected to fractionation in vacuo. The yield was 126 g (46% of theory), and the boiling point was 60° C. at 10 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -59.0 and -84.6 ppm. 1H-NMR: 3.02 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([C:5]2[C:4]([OH:10])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([CH3:9])[CH:6]=2)[C:4]=1[OH:10]
Reactant: COc1cc(C)ccc1O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)cc(-c2cc(C)cc(OC)c2O)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Bu3MeNMnO4 (10.9 g, 34.1 mmol) was dissolved in CH2Cl2 (250 mL) placed in an ice bath and allowed to cool. Then 2-methoxy-4-methylphenol (9.95 g, 72.0 mmol) was added dropwise to the CH2Cl2 solution and allowed to react with stirring for 1 h at 0° C. under N2. The reaction mixture was diluted with H2O (˜200 mL) and the mixture stirred for an additional 30 min. The mixture was filtered through a glass-wool plug to remove the MnO2 and the organic layer separated. The organic layer was washed with 0.1 M HCl (3×150 mL), brine (50 mL), and then dried over MgSO4. Removal of the solvent under reduced pressure afforded 1 as a yellow powder (5.97 g, 60% yield). Purification of 1 was achieved using column chromatography on silica gel and elution with ethyl acetate/hexanes (1/4, v/v) to afford a 50% overall yield.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:33]=[CH:32][C:27]4[C:28](=[O:31])[O:29][CH2:30][C:26]=4[CH:25]=3)[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.[C:34]([Cu])#[N:35].O>CN(C=O)C>[O:15]=[C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]3[C:28](=[O:31])[O:29][CH2:30][C:26]=3[CH:25]=2)[CH2:18][CH2:17]1)[CH2:13][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)=[C:2]([CH:3]=1)[C:34]#[N:35]
Reactant: N#C[Cu]
Reactant: O=C1OCc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)c(I)c4)CC3)ccc21
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(CC(=O)N2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1-n1cnnn1
Temperature: 110 °C

Procedure:
A mixture of 5-[2-(4-{[3-iodo-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (190 mg, 034 mmol) and CuCN (47 mg, 0.52 mmol) in 2 ml of anhydrous DMF was heated to 110° C. under N2 for 30 min. The reaction was cooled to ambient temperature, and then 15 ml of water was added. Extracted with DCM and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified via prep-TLC to afford 5-(2-oxo-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(1H-tetrazol-1-yl)benzonitrile. 1H-NMR (400 MHz, CD3CN) δ ppm 9.36 (s, 1H), 7.85 (s, 1H), 7.72˜7.79 (m, 3H), 7.44˜7.50 (m, 2H), 5.30 (s, 2H), 3.87 (s, 2H), 2.49 (t, J=7.5 Hz, 21H), 2.64 (t, J=7.2 Hz, 2H), 2.65˜2.70 (m, 2H), 2.46˜2.53 (m, 4H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].I[CH:13]([CH2:15][CH3:16])[CH3:14]>C(#N)C>[CH:13]([N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)([CH2:15][CH3:16])[CH3:14]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCC(C)I
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCC(C)n1nc2ccccc2n1
Yield: 34 %

Procedure:
To a stirred solution of 96.0 grams of benzotriazole in 800 milliliters of acetonitrile at 50° C. is added 33.6 grams of sodium hydroxide pels. After most of the sodium hydroxide has reacted with the benzotriazole, 190 grams of 2-iodobutane is added in one portion and the resulting solution is refluxed for 15 hours. The acetonitrile is then evaporated and 300 milliliters of concentrated hydrochloric acid is added to the residual oil followed by the addition of 800 milliliters of benzene. The precipitated sodium iodide is removed by filtration. The acid layer is separated from the benzene layer and then washed three more times with 300 milliliters of benzene. The benzene washings are combined, dried over MgSO4 and evaporated to yield 48 grams (34%) of the 2-sec-butyl-2H-benzotriazole as an oil. The material is purified by distillation, b.p. 0.25 mm Hg=63° C.