Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:29][C:30]([O:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[S:40][S:41][CH2:42][CH3:43])=[O:31])[C:17]([O:19][C:20](C1C=CC=CC=1)(C)[CH3:21])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].CC[N:46](C(C)C)C(C)C>ClCCl.BrCC#N>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:29][C:30]([O:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[S:40][S:41][CH2:42][CH3:43])=[O:31])[C:17]([O:19][CH2:20][C:21]#[N:46])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCSSc1cccc(C)c1OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)c1ccccc1
Agent: N#CCBr
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCSSc1cccc(C)c1OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
Trifluoroacetic acid (0.040 ml, 0.519 mmol) was added to a solution of 4-(2-(ethyldisulfanyl)-6-methylphenyl) 1-(2-phenylpropan-2-yl) (S)-2-((tert-butoxycarbonyl)amino)succinate (Compound 110) (240 mg, 0.450 mmol) in dichloromethane (4 ml), and the mixture was stirred at room temperature for 1.5 hours. Trifluoroacetic acid (0.040 ml, 0.519 mmol) was further added and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was then concentrated under reduced pressure. DIPEA (0.259 ml, 1.49 mmol) was added to a solution of the resulting residue in bromoacetonitrile (4.70 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→50/50) to afford 1-(cyanomethyl) 4-(2-(ethyldisulfanyl)-6-methylphenyl) (S)-2-((tert-butoxycarbonyl)amino)succinate (Compound 112) (151 mg, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:21].[Na+].OO>C1COCC1>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C@@H:13]([OH:21])[CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)CC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(F)cc2)[C@@H](O)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Add borane tetrahydrofuran complex (171 mL, 171 mmol) to a solution of tert-butyl 4-(4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (54 g, 186 mmol) in THF (544 mL) under a nitrogen atmosphere. Stir overnight at 40° C., then add 2M sodium hydroxide (36.8 g, 70.8 mmol) and stir for 12 minutes at ambient temperature. Add hydrogen peroxide (31.1 mL, 357.8 mmol) while maintaining the internal temperature at 19-21° C. through the use of an ice-water bath. After addition is complete, remove the ice bath and stir at ambient temperature for 3 hours. Dilute the reaction mixture with water (250 mL) and extract twice with methyl tert-butyl ether (500 mL). Combine organic extracts, and sequentially wash with brine, sodium bisulfate then brine again. Dry the organics over magnesium sulphate; filter; collect the filtrate; and concentrate under vacuum. Purify the crude material via flash column chromatography using hexane/ethyl acetate (4:1, then 3:1) followed by DCM/EtOAc (1:1, then 0:100). Combine product fractions and dry under vacuum to give a white solid. Separate enantiomers using chromatography conditions “L” (see below), collecting the first eluting isomer to give the title compound (20.02 g, 36.4%) as a white solid. MS (m/z): 196 (M+1-Boc).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=3)[CH2:10][C@@H:4]2[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:42]([C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=1)([O-:44])=[O:43].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O.C(OCC)(=O)C>[N+:42]([C:45]1[CH:46]=[CH:47][C:48]([C:49]([O:1][C@@H:2]2[CH2:22][N:5]3[C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][N:12]=4)[CH2:10][C@@H:4]3[CH2:3]2)=[O:50])=[CH:52][CH:53]=1)([O-:44])=[O:43]
Reactant: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@@H](O)CN12
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O[C@H]1C[C@H]2CN(c3ccc(C(F)(F)F)cn3)CCC(=O)N2C1)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
(8R,9aS)-8-Hydroxy-2-[5-(trifluoromethyl)pyridin-2-yl]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one (100 mg, 0.317 mmol, Part B), triphenylphosphine (104 mg, 0.396 mmol), and 4-nitrobenzoic acid (80 mg, 0.476 mmol) were dissolved in tetrahydrofuran (2 mL), and the resulting solution was cooled to −78° C. Diisopropyl azodicarboxylate (77 mg, 0.381 mmol) in tetrahydrofuran (0.5 mL) was added. The mixture was warmed to room temperature and stirred for two hours. Then 1 drop of water was added. The mixture was purified by chromatography on silica gel (ethyl acetate/heptanes=1:1 then 100% ethyl acetate) to give 138 mg (94% yield) of the titled compound as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.20 (m, 1H), 2.77 (m, 3 H), 3.33 (m, 1 H), 3.47 (m, 1 H), 3.88 (m, 1 H), 4.00 (m, 1H), 4.12 (m, 1H), 4.37 (m, 1H), 4.77 (dd, J=14, 4 Hz, 1 H), 5.54 (m, 1H), 6.67 (d, J=8 Hz, 1H), 7.69 (d, J=8 Hz, 1 H), 8.20 (d, J=8 Hz, 2 H), 8.35 (d, J=8 Hz, 2 H), 8.42 (s, 1 H); MS (ESI) m/z 465.0 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][CH:11]([NH:21][C:22]([CH:24]1[N:28]2[C:29](=[O:48])[CH:30]([NH:35][C:36]([C:38]3[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=3)=[O:37])[CH2:31][CH:32]=[CH:33][CH2:34][CH:27]2[CH2:26][CH2:25]1)=[O:23])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])C1C=CC=CC=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH:11]([NH:21][C:22]([CH:24]1[N:28]2[C:29](=[O:48])[CH:30]([NH:35][C:36]([C:38]3[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=3)=[O:37])[CH2:31][CH:32]=[CH:33][CH2:34][CH:27]2[CH2:26][CH2:25]1)=[O:23])[CH2:10][C:9]([OH:49])=[O:8])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC(CC(=O)OCc1ccccc1)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(CC(=O)O)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
A solution containing 4-(tert-Butyl-dimethyl-silanyloxy)-3-({6-[(naphthalene-2-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carbonyl}-amino)-butyric acid benzyl ester (590 mg, 0.86 mmol) in MeOH (10 mL) is treated with 1N NaOH (2.5 mL) and stirred at rt for 12 hrs. The solution was poured into water, acidified to pH=3 with 10% citric acid, and extracted with EtOAc. The combined organic extracts are washed with brine and dried over Na2SO4. The solution is filtered and concentrated to yield 492 mg of desired product that was used without further purification. MS (ESI) 594 (M+1).
Reaction SMILES: Cl[CH:2]([CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:21])([F:20])[CH:17]([Cl:19])[Cl:18])=[CH:11][CH:10]=1)(=[O:8])=[O:7])C#N.[CH2:22]([N:24](CC)CC)C>C1C=CC=CC=1>[Cl:19][CH:17]([Cl:18])[C:16]([F:20])([F:21])[O:15][C:12]1[CH:11]=[CH:10][C:9]([S:6]([C:5](=[CH2:2])[C:22]#[N:24])(=[O:7])=[O:8])=[CH:14][CH:13]=1
Reactant: N#CC(Cl)CS(=O)(=O)c1ccc(OC(F)(F)C(Cl)Cl)cc1
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: C=C(C#N)S(=O)(=O)c1ccc(OC(F)(F)C(Cl)Cl)cc1

Procedure:
To 3.0 g (0.079 mol) of 2-chloro-3-((4-(2,2-dichloro-1,1-difluoroethoxy)phenyl)sulfonyl)propanenitrile in 100 ml of benzene was added a slight molar excess of triethylamine. The reaction mixture was filtered to remove the triethylamine hydrochloride produced. The benzene was removed in vacuo from the filtrate, and the residue which remained was crystallized from methanol/ water to give 1.5 g of the title compound as a tan solid, mp 89°-90° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[CH2:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]3[CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[CH:3]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Reactant: CCc1cccc(B(O)O)c1
Product: CCc1cccc(-c2cccc(NC(=O)OC3CN4CCC3CC4)c2)c1
Yield: 56 %

Procedure:
Using general procedure E, quinuclidin-3-yl 3-bromophenylcarbamate, 3-ethylphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (78 mg, 56%). 1H NMR (500 MHz, CDCl3) δ 7.64 (br s, 1H), 7.43-7.27 (m, 6H), 7.24 (br s, 1H), 7.18 (d, J=8.0 Hz, 1H), 4.85 (m, 1H), 3.30 (m, 1H), 2.99-2.73 (m, 5H), 2.70 (q, J=7.5 Hz, 2H), 2.12 (m, 1H), 1.92-1.84 (m, 1H), 1.75-1.67 (m, 1H), 1.62-1.55 (m, 1H), 1.48-1.38 (m, 1H), 1.27 (t, J=7.5 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 153.5, 144.8, 142.4, 140.8, 138.4, 129.4, 128.8, 127.1, 126.8, 124.6, 122.3, 117.4, 72.1, 55.4, 47.4, 46.5, 29.0, 25.4, 24.5, 19.5, 15.7 ppm. Purity: >98% LCMS (214 nm & 254 nm); retention time 1.66 min: (M+1) 351.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(O)[CH2:39]C[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH:24]2[CH2:37][CH2:36][CH2:35][CH2:39]2)=[CH:18][CH:17]=1
Reactant: OC1CCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCCC4)cc3)c2cc1OC
Yield: 58 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclopentanol (22 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (40 mg, yield 53%).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])=[CH:19][CH3:20])[CH:15]=[CH:14][C:5]=1[O:6][CH2:7][C:8](=[O:13])C(C)(C)C)(=O)[CH3:2].[CH2:23]1[CH2:33]CN2C(=NCCC2)CC1.[OH2:34]>CN(C=O)C>[CH2:33]([O:34][C:8]([C:7]1[O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([CH2:21][CH3:22])=[CH:19][CH3:20])=[CH:17][C:4]=2[C:1]=1[CH3:2])=[O:13])[CH3:23]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O
Reactant: CC=C(CC)c1ccc(OCC(=O)C(C)(C)C)c(C(C)=O)c1
Solvent: CN(C)C=O
Product: CC=C(CC)c1ccc2oc(C(=O)OCC)c(C)c2c1
Temperature: 140 °C
Yield: 71 %

Procedure:
A solution of 1-[2-acetyl-4-(1-ethyl-propenyl)-phenoxy]-3,3-dimethyl-butan-2-one (4.80 g, 16.5 mmol) in DMF (40 mL) is treated with DBU (2.51 g, 16.5 mmol) and the solution is heated to 140° C. for 2 h. The reaction mixture is cooled down and poured into water (400 mL) and extracted with EtOAc (2×100 mL). The organic layer is dried over Na2SO4, concentrated, purified on column chromatography (5% EtOAc/Hex) to give the title compound as an oil (3.20 g, 71%)
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[C:24](O)=[O:25])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27]([O:31][C:32](=[O:44])[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=1[CH2:42][NH2:43])([CH3:30])([CH3:29])[CH3:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[C:24](=[O:25])[NH:43][CH2:42][C:36]3[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:35]=3[CH2:34][NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:44])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A mixture of crude (S)-1-[{(9H-Fluoren-9-yl)methoxy}carbonyl]piperidine-2-carboxylic acid (0.75 g, 2.21 mmol), tert-butyl[2-(aminomethyl)-4-chlorobenzyl]carbamate (0.52 g, 1.93 mmol), HOBT (0.26 g, 1.93 mmol), and EDC.HCl (0.48 g, 2.51 mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for 16 h. The reaction mixture was quenched with water (20 mL) and diluted with EtOAc (50 mL). The organic layer was washed sequentially with saturated aqueous NaHCO3 solution (50 mL) and brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water) to afford the title compound (0.89 g) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH:13]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nc(-c3ccccc3)cs2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2nc(-c3ccccc3)cs2)CCNC1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of tert-butyl 4-(4-phenylthiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (206 mg, 0.602 mmol) in CH2Cl2 (2.4 mL) was added TFA (0.232 mL). The solution turned bright red immediately, and after stirring overnight the color had become orange. The solution was concentrated under reduced pressure and the crude oil obtained purified with a 5 g SCX-2 column washing first with MeOH, then with 2M NH3 in MeOH leading to elution of basic materials. Upon drying, 4-phenyl-2-(1,2,3,6-tetrahydropyridin-4-yl)thiazole (121 mg, 0.499 mmol, 83%) was obtained as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:13][C:14](Cl)=[O:15])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[O:3]1.[CH3:21][NH:22][CH2:23][C:24]([OH:26])=[O:25]>>[CH3:21][N:22]([C:14](=[O:15])[CH2:13][C:6]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[O:3][C:2]1=[O:1])[CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C(Cl)CC1(c2ccccc2)C(=O)Oc2ccccc21
Reactant: CNCC(=O)O
Product: CN(CC(=O)O)C(=O)CC1(c2ccccc2)C(=O)Oc2ccccc21

Procedure:
This compound was prepared according to the process described in Example 11, starting with 2-(2,3-dihydro-2-oxo-3-phenyl-3-benzofuranyl)acetyl chloride and N-methyl glycine.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C=O)C>[NH2:26][C:27]1[C:28]([C:29](=[O:30])[NH2:31])=[CH:32][CH:33]=[CH:34][C:35]=1[NH:36][C:9]([C:7]1[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC(=O)c1ccc(C(=O)O)s1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(N)=O)c2N)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 5-acetylthiophene-2-carboxylic acid (1.80 g, 10.55 mmol) in pyridine (12 mL) and N,N′-dimethylformamide (12 mL) was treated with 1,1′-carbonyldiimidazole (1.88 g, 11.60 mmol) at 45° C. for 4 hours. 2,3-Diaminobenzamide dihydrochloride (2.36 g, 10.55 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the residue stirred in ethyl acetate and water, filtered, and the yellow solid washed with water and ethyl acetate and dried to give the title compound (2.91 g, 91%). MS(APCI): 304 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13](O)[CH2:14][OH:15]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]1([O:15][CH2:14][CH2:13][O:12]1)[CH2:6][CH2:5]2
Reactant: OCCO
Reactant: O=C1CCc2cc(Br)ccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)CCC1(C2)OCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a solution of 6-bromo-2-tetralone (5.36 g, 23.8 mmol) in benzene (5 mL) was added ethylene glycol (1.46 mL, 26.1 mmol, 1.1 eq) and p-toluenesulfonic acid (1.5 mg, catalyst). The mixture was heated at reflux and a Dean-Stark trap was used to collect the water produced. After 6 hours, TLC (25% EtOAc/hexanes) showed no 6-bromo-2-tetralone (Rf˜0.5) left and a new spot (Rf˜0.6) formed. The reaction mixture was cooled to room temperature, washed with 10% aqueous NaOH (2 mL) and H2O (5×2 mL), dried (Na2SO4), and concentrated in vacuo. The crude residue was chromatographed on silica gel by eluting with 10% EtOAc/hexanes to give 5.0 g (78%) of 6′-bromo-3′,4′-dihydro-1′H-spiro[[1,3]dioxoiane-2,2′-naphthalene] as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.27 (s, 1H), 7.23 (d, 1H, J=8.1 Hz), 6.92 (d, 1H, J=8.1 Hz), 4.02 (s, 4H), 2.96 (t, 2H, J=6.9 Hz), 2.92 (s, 2H), 1.93 (t, 2H, J=6.9 Hz).
Reaction SMILES: [C:1]1([P:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]([CH3:28])([CH2:26][NH2:27])[CH2:24][NH2:25]>C1(C)C=CC=CC=1>[C:1]1([P:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[N:25][CH2:24][C:23]([CH3:28])([CH3:22])[CH2:26][N:27]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(CN)CN
Reactant: O=Cc1ccccc1P(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(CN=Cc1ccccc1P(c1ccccc1)c1ccccc1)CN=Cc1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
Under argon, a solution of 2-(diphenylphosphino)benzaldehyde (522.7 mg, 1.8 mmol) and 2,2-dimethyl-1,3-propanediamine (93.3 mg, 0.9 mmol) in toluene (15 mL) was stirred at room temperature for 15 h. Then the reaction mixture was heated at 80° C. (oil bath) for 2 h 30 min. Next, the solvent was removed in vacuo, and an orange solid was recovered (476.8 mg, 0.74 mmol, 82%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]3[CH2:11][N:10]([CH3:22])[C:9](=[O:23])[C:8]=2[CH:24]=1.[CH3:25]C(O)C>>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][CH:20]([CH3:25])[CH3:21])=[O:18])=[C:12]3[CH2:11][N:10]([CH3:22])[C:9](=[O:23])[C:8]=2[CH:24]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Temperature: 25 °C

Procedure:
100 ml of 2-propanol are treated with 100 mg of sodium hydride. 5 g of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate are added thereto and the mixture is heated to boiling under reflux for 1 hour. Subsequently, the mixture is left to cool to room temperature, the separated crystals are filtered off and washed with 2-propanol and water, there being obtained isopropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 243°-244° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[H-].[Na+].Cl[CH2:13][C:14]1[N:18]=[C:17]([CH3:19])[O:16][N:15]=1>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:13][C:14]1[N:18]=[C:17]([CH3:19])[O:16][N:15]=1
Reactant: Sc1cccc(Cl)c1Cl
Reactant: Cc1nc(CCl)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(CSc2cccc(Cl)c2Cl)no1
Reaction time: 2 h
Yield: 40.7 %

Procedure:
7.0 g (39.1 mmol) of 2,3-dichloro-thiophenol are introduced into 50 ml of absolute tetrahydrofuran, the mixture is treated with 1.2 g (0.039 mmol) of 80% sodium hydride dispersion in portions and stirred for 2 hours at reflux temperature. The mixture is subsequently treated with 4.5 g (33.9 mmol) of 3-chloromethyl-5-methyl-1,2,4-oxadiazole at room temperature and stirred until the reaction is complete (approximately 10 to 15 hours). The sodium chloride which has precipitated is subsequently separated off and the entire batch is concentrated in vacuo. The crude product which remains can be chromatographed over a silica gel column (silica gel 60-Merck, particle size: 0.040 to 0.063 mm) using toluene as the eluent. 3.8 g (36.5% of theory) of 3-(2,3-dichlorophenylthiomethyl)-5-methyl-1,2,4-oxadiazole are obtained.
Reaction SMILES: [Li]CCCC.[CH2:6]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=2)[C:10]1=[O:22])[CH2:7][CH3:8].[CH3:23][C:24]([O:27][C:28](/[N:30]=[N:31]/[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:26])[CH3:25].O>O1CCCC1>[CH3:26][C:24]([O:27][C:28]([NH:30][N:31]([C:9]1([CH2:6][CH2:7][CH3:8])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:15]=2)[C:10]1=[O:22])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:23])[CH3:25]
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Reactant: CCCC1Cc2cc(C(F)(F)F)ccc2C1=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2cc(C(F)(F)F)ccc2C1=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of diisopropropylamine (1.3 mL, 9.1 mmol) in 30 mL tetrahydrofuran cooled to −78° C. was added 6.0 mL n-BuLi (1.6M, 9.5 mmol). The mixture was allowed to warm to −20° C. over 20 min, then re-cooled to −78° C. A solution of the product from Step C (2.0 g, 8.3 mmol) in 15 mL tetrahydrofuran was added dropwise. After 30 min, a solution of di-tert-butylazodicarboxylate (2.1 g, 9.1 mmol) in 20 mL tetrahydrofuran was added dropwise. The reaction was allowed to slowly warm to RT and stirred overnight. Water was added and the mixture was extracted with ethyl acetate, dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 10% ethyl acetate/hexane to afford 2.92 g of a white solid, m.p. 135-137° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A solution of 3-chloro-2-(2,4-difluorophenyl)4,5,6,7-tetrahydro-2H-indazole (217 g) in conc. sulfuric acid (1 kg) was cooled to 5° C., and 99% nitric acid (67 g) was dropwise added thereto at a temperature below about 10° C., followed by stirring for 3 hours. After completion of the reaction, the reaction mixture was added to ice-water (10 kg), and the precipitated crystals were collected by filtration, washed and dried to give 3-chloro-2-(2,4-difluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole (227 g). m.p., 117°-118° C. (decomp.).