Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[C:13](=O)[N:12]([CH3:15])[CH2:11][C:10](=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:23](=O)([O:29]C(C)(C)C)[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[CH2:1]([CH:8]1[CH2:13][N:12]([CH3:15])[CH2:11][CH2:10][N:9]1[C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CC(=O)NC(Cc2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccccc2)C1

Procedure:
The compound obtained in Step (ii) was subjected to reduction with lithium aluminum hydride in THF. Then, the resultant was subjected to Boc-introducing reaction with di-tert-butyl carbonate to give the subtitle compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][C@:36]([CH2:42][O:43][C:44]([F:47])([F:46])[F:45])([CH:40]=[CH2:41])[C:37]([OH:39])=[O:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:41]=[CH:40]/[C@:36]([CH3:35])([CH2:42][O:43][C:44]([F:45])([F:46])[F:47])[C:37]([OH:39])=[O:38])=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: C=C[C@](C)(COC(F)(F)F)C(=O)O
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/[C@](C)(COC(F)(F)F)C(=O)O)cc3n2)N1
Temperature: 25 °C

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (212 mg, 0.4 mmol), crude (R)-2-methyl-2-trifluoromethoxymethyl-but-3-enoic acid (95 mg), tri(o-tolyl)phosphine (24 mg, 0.08 mmol) and triethylamine (121 mg, 0.17 mL, 1.2 mmol) in 1,4-dioxane (10 mL) was stirred at 50° C. under nitrogen. Trs(dibenzylideneacetone)dipalladium(0) (36 mg, 0.04 mmol) was added and the reaction mixture was heated at reflux for 40 minutes. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-(R)-4-{2-[(R)-1-({(S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carbonyl}-amino)-ethyl]-quinolin-7-yl}-2-methyl-2-trifluoromethoxymethyl-but-3-enoic acid which was used in the next step. LCMS (m/z) 652.1 [M+H], Tr=2.17 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([O:10]CC)=[O:9])=[N:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=[O:9])=[N:3]1
Reactant: CCOC(=O)c1nn(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cn(C)nc1C(=O)O
Yield: 41.4 %

Procedure:
Using ethyl 1,4-dimethyl-1H-pyrazole-3-carboxylate (440 mg, 2.62 mmol), 1N aqueous sodium hydroxide solution (3 mL, 3 mmol) and ethanol (3 mL), and by a reaction in the same manner as in Reference Example 20, the title compound (152 mg, 41%) was obtained as pale-yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:30])=[C:7]([C:13]3[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:18])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.[C:41](O)(C(F)(F)F)=[O:42]>>[CH:41]([C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[O:9][C:8](=[O:12])[C:7]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:18])=[CH:28][CH:29]=1)=[C:6]2[CH3:30])=[O:42]
Reactant: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2cc(O)ccc12
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2c(C=O)c(O)ccc12
Temperature: 115 °C
Yield: 31 %

Procedure:
A mixture of 4-(7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)benzamide (3) (8.17 g, 20.0 mmol) and hexamethylenetetramine (11.22 g, 80.0 mmol) in TFA (200 mL) was heated in a pressure flask in a 115° C. oil bath for 40 minutes. This process was repeated once. Upon cooling, the unified solutions were evaporated to 158 g weight and, after addition of CH2Cl2 (500 mL) and water (100 mL) it was cooled to 0° C. The mixture was neutralized with NaOH (2N, 350 mL) and then close to the end point with NaHCO3 (10%) with cooling and stirring. The product was extracted with CH2Cl2 (5×100 mL), washed with water (backextracted), dried on MgSO4 and evaporated to afford 17.2 g crude product. The crude product was loaded on 40 g silica and purified by medium pressure chromatography (4×100 g columns) using 1-3% MeOH in CH2Cl2 by collecting the front fractions to afford 6.2 g (31%) of the title compound. This product can be turned into its HCl salt by dissolving it in EtOH (100 mL) and adding 6N HCl (10 mL). The salt was filtered and washed with 70% EtOH (2×20 mL), dried on air then at 50° C. under 5 Hgmm vacuum to afford 6.0 g HCl salt of the title compound.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH3:14][OH:15]>CN(C=O)C.C(Cl)(Cl)Cl.[Cu]I>[O:15]1[CH:4]=[CH:2][O:3][CH:14]1[C:6]1[CH:11]=[CH:10][C:9]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])=[CH:8][CH:7]=1
Reactant: CO
Reactant: O=C1Nc2ccccc2C1=O
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1C(=O)N(c2ccc(C3OC=CO3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isatin (1.88 g, 0.0128 mol) in anhydrous DMF (100 mL) was cooled in an ice-bath under nitrogen and treated with sodium hydride (0.3 g, 1 equivalent). The reaction was warmed to room temperature and stirred for 1 hour. It was then treated with 2-(4-bromophenyl)-1,3-dioxalane (2.83 g, 0.0124 mol) followed by CuI (4.71 g, 2 equivalents). This suspension was heated in an oil-bath at 135° C. under nitrogen for 16 hours. It was then cooled to room temperature and diluted with an equal volume of chloroform. The resulting suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in xylenes (100 mL) and evaporated to dryness. A thick, viscous oil was recovered which was used as such for the next reaction. TLC (5% methanol in chloroform) showed clean conversion, Rf (product)=0.91.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=[O:22])[CH:12]([CH3:21])[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:5][CH:4]=1)#[N:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(O)(=O)=O.FC(F)(F)S(O)(=O)=O>C1(C)C(C)=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:12]([CH3:21])[C:11](=[O:22])[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Nc1ccccc1
Reactant: CC(C(=O)CC(=O)c1ccc(C#N)cc1)C(=O)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n(-c2ccccc2)c(-c2ccc(C#N)cc2)cc1=O
Yield: 20.1 %

Procedure:
In 400 ml of xylene were dissolved 10.0 g (0.033 mole) of 5-(4-cyanophenyl)-2-methyl-1-phenyl-1,3,5-pentanetrione, 25.0 g (0.26 mole) of aniline and 7.0 g (0.073 mole) of methanesulfonic acid. The solution obtained was heated under reflux for 30 minutes in a reactor fitted with a Dean-Stark apparatus. After cooling, 6.5 g (0.043 mole) of trifluoromethanesulfonic acid was added further to the reaction mixture and the resultant mixture was similarly heated under reflux for 30 minutes. After cooling, solid matter was removed from the reaction mixture, followed by concentration under pressure. The concentrate was extracted with dichloromethane. The organic layer was washed successively with 100 ml of 10% hydrochloric acid, 100 ml of a 10% aqueous solution of sodium hydroxide and water. The organic layer was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). The resultant crystals were washed with acetone to afford 2.4 g of 6-(4-cyanophenyl)-3-methyl-1,2-diphenyl-4(1H)-pyridinone having a melting point of 229°-233° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].O[CH:15]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)S([O-])(=O)=O.[Na+].C(O)C>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:15]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:3]=2[CH:4]=1
Reactant: O=S(=O)([O-])C(O)C1CCCCC1
Reactant: Nc1ccc(Cl)cc1NCCCO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCCCn1c(C2CCCCC2)nc2ccc(Cl)cc21
Yield: 58 %

Procedure:
A mixture of 40 parts of 3-[(2-amino-5-chlorophenyl)amino]-1-propanol, 87 parts of sodium α-hydroxycyclohexanemethanesulfonate and 200 parts of ethanol is stirred and refluxed for 10 minutes. The reaction mixture is diluted with water and the solvent is evaporated. The residue is extracted a few times with trichloromethane. The combined extracts are dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane: a sticky tar precipitates. The 2,2'-oxybispropane is decanted and upon stirring at room temperature, the product is allowed to precipitate. It is filtered off and dried, yielding 34 parts (58%) of 6-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol; mp. 120.1° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.O.[NH3:22]>C(Cl)(Cl)Cl>[NH2:22][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: N
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1OCC(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2ccc(N)nn2)cc1OCC(C)C
Yield: 53.8 %

Procedure:
7.0 g (24 mmol) of 3-chloro-6-[4-methoxy-3-(2-methylpropoxy)phenyl]pyridazine are reacted as described in Example 1 in 40 ml of ammonia-saturated ethylene glycol. The crude product obtained by precipitation with water is dissolved in chloroform, the solution is dried with potassium carbonate, and the product is precipitated with petroleum ether (b.p. 50°-70° C.). 3.5 g (53.8%) of the title compound of m.p. 187° C. are obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:33])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:5][CH:4]=1.Cl.[NH2:36][OH:37]>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:36][OH:37])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:33])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=C(CCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(CCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 15 g (0.033 mole) of 4'-fluoro-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone hydrochloride and 15 g of hydroxylamine hydrochloride in 120 ml of pyridine is stirred on a steam bath for about 4 hours then cooled to room temperature. The pyridine is removed at reduced pressure on a steam bath, and the residue is triturated with a dilute sodium hydroxide solution and extracted with chloroform. The chloroform extract is washed with water, dried over magnesium sulfate, filtered and concentrated to a residue which is triturated with hexane. The resulting solid is filtered off and recrystallized from ethanol to give 4'-fluoro-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone oxime.
Reaction SMILES: [CH3:1][C:2]1([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1>CN(C)C=O>[CH3:1][C:2]1([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:4][N:5]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)[CH2:6][CH2:7]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(NC(=O)OC(C)(C)C)CCN(c2cnccn2)CC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a mixture of tert-butyl (4-methyl-4-piperidinyl)carbamate obtained in Example 10–5 (415 mg) and potassium carbonate (321 mg) in N,N-dimethylformamide (4.5 mL), was added chloropyrazine (665 mg). The mixture was heated at 100° C. with stirring for 24 hrs. The resulting mixture was partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (2:1) to give the title compound as a pale yellow oil (566 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.3 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-(4-fluorophenyl)acetic acid (I49) (725 mg, 2.69 mmol) in THF (20 ml), were added N,N′-methanediylidenedicyclohexanamine (667 mg, 3.23 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (437 mg, 3.23 mmol), and (R)-quinuclidin-3-ol (411 mg, 3.23 mmol). The reaction was stirred at RT for 15 hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 93/7) to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(4-fluorophenyl)acetate (410 mg; 40% yield).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)(=[O:36])[CH3:35]>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]
Reactant: [Br-]
Reactant: CC(=O)c1csc2ccccc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
Phenyltrimethylammonium tribromide (26.32 g) was added in portions over 45 minutes at -5° C. under nitrogen to a stirred solution of 3-acetylbenzo[b]thiophen (12.34 g) in tetrahydrofuran (100 ml), then the mixture was stirred at ambient temperature for 1 hour. The resulting solid was collected by filtration, washed with ether (100 ml), dried in vacuo at ambient temperature, and crystallised from ethanol to give 3-(2-bromoacetyl)benzo[b]thiophen as a white solid (10.9 g).
Reaction SMILES: CN(C)C=O.C[O-].[Na+].[SH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].Cl[C:17]1[C:22]([C:23]#[N:24])=[CH:21][CH:20]=[CH:19][N:18]=1>O>[C:23]([C:22]1[C:17]([S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:18][CH:19]=[CH:20][CH:21]=1)#[N:24]
Reactant: COC(=O)CCS
Reactant: N#Cc1cccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCSc1ncccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A mixture of anhydrous N,N-dimethylformamide (30 ml), sodium methoxide (0.54 g, 10 mmol), methyl 3-mercaptopropionate (1.20 g, 10 mmol) and 2-chloro-3-cyanopyridine (1.38 g, 10 mmol) was stirred at room temperature for 1 h. The reaction mixture was poured into water (200 ml), the product filtered, washed with water and recrystallized from ethyl acetate/hexanes to yield methyl 3-(3-cyanopyridin-2-ylthio)propanoate (1.60 g). mp 101-102° C. as heavy colorless prisms. 1H NMR (300 MHz, CDCl3): 8.45 (dd, 1H), 7.02 (dd, 1H), 3.68 (s, 3H), 3.49 (t, 2H), 2.78 ppm (t, 2H).
Reaction SMILES: [N+:1]([O-])([O:3]C(=O)C)=[O:2].[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][CH:11]([F:26])[C:10]1=[O:27].C(Cl)(Cl)(Cl)Cl>C(#N)C>[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([N+:1]([O-:3])=[O:2])=[CH:19][C:14]=2[C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][CH:11]([F:26])[C:10]1=[O:27]
Reactant: CC(=O)O[N+](=O)[O-]
Reactant: CN1C(=O)C(F)N=C(c2ccccc2)c2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Reaction time: 3 h

Procedure:
1.2 g. of acetyl nitrate are added dropwise, at 10° to a stirred solution of 2.67 g. of 1-methyl-3-fluoro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one in 70 ml. of CCl4 and 20 ml. of acetonitrile. The mixture is stirred for 1 hour more at 10° and for 3 hours at 20° and is poured into ice cold sodium carbonate solution and worked up in the customary manner to give 1-methyl-3-fluoro-5-phenyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazapin-2-one.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[CH2:5]([O:9][C:10](=[O:17])[C:11]([CH2:15][OH:16])([CH2:13][OH:14])[CH3:12])[CH2:6][CH2:7][CH3:8].O.N#N>C1(C)C=CC=CC=1>[Cl:4][P:1]1[O:14][CH2:13][C:11]([CH3:12])([C:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:17])[CH2:15][O:16]1
Reactant: ClP(Cl)Cl
Reactant: CCCCOC(=O)C(C)(CO)CO
Agent: N#N
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C1(C)COP(Cl)OC1
Reaction time: 1 h

Procedure:
68.70 g (0.50 mol) of phosphorus trichloride in 50 ml of toluene were added dropwise with vigorous stirring, in the course of 1 hour, to a solution of 95.15 g (0.50 mol) of 2,2-bis-hydroxymethylpropionic acid butyl ester in 250 ml of toluene at 5°-10° C. The reaction mixture was subsequently stirred for 1 hour without cooling in a water-jet vacuum, during which time a gentle flow of N2 was fed in; the solvent was then distilled off in vacuo (bath temperature=50° C./15-20 mm Hg), and the residue was purified by vacuum distillation. The product obtained was in the form of a colourless liquid; nD20 =1.4701; b.p. 113°-115° C./0.1 mm Hg.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([OH:22])=O)=[CH:14]3)[CH2:6][CH2:5]1.[N:25]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:34][O:33][C:31]([N:25]1[CH2:30][CH2:29][N:28]([C:20]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][CH:7]2[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:23])([F:1])[F:24])[CH2:9][CH2:8]2)=[CH:19][CH:18]=3)=[O:22])[CH2:27][CH2:26]1)=[O:32]
Reactant: O=C(O)c1cc2cc(OC3CCN(CC(F)(F)F)CC3)ccc2[nH]1
Reactant: COC(=O)N1CCNCC1
Product: COC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(CC(F)(F)F)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was prepared in analogy to example 40b), from 5-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yloxy]-1H-indole-2-carboxylic acid and methyl piperazine-1-carboxylate. Light yellow solid. MS (m/z): 469.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH3:14])=[C:12]([CH3:15])[C:5]2[C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[C:3]=1[CH3:16].[CH:17](O)=[O:18]>>[CH3:10][C:7]1([CH3:9])[C:6](=[O:11])[C:5]2[C:12]([CH3:15])=[C:13]([CH3:14])[C:2]([NH:1][CH:17]=[O:18])=[C:3]([CH3:16])[C:4]=2[O:8]1
Reactant: O=CO
Reactant: Cc1c(C)c2c(c(C)c1N)OC(C)(C)C2=O
Product: Cc1c(C)c2c(c(C)c1NC=O)OC(C)(C)C2=O
Yield: 81 %

Procedure:
A mixture of formic acid (5 mL) with 6-amino-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one (700 mg, 3.19 mmol) obtained in Reference Example 72, was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, water and ethyl acetate were added to the residue, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 640 mg (yield 81%) of the title compound. Melting point: 191-192° C.
Reaction SMILES: C[O-].[Na+].[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]([C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=1>CO.CN(C)C=O>[C:9]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:10]=[CH:11][C:12]([C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:18])[CH2:16][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)(c1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: OC(Cn1ccnc1)(c1ccccc1)c1ccc(-c2ccccc2)cc1
Yield: 12.2 %

Procedure:
2.45 g (0.045 mol) of sodium methylate are dissolved in 20 ml of methanol, and 5.25 g (0.077 mol) of imidazole are added. A solution of 11.1 g (0.077 mol) of 1-(4-biphenylyl)-2-chloro-1-phenyl-ethanol in 50 ml of dimethylformamide is added dropwise to this mixture and the reaction mixture is heated under reflux for 16 hours. Thereafter, it is poured onto water and the crystals which form are extracted with hot acetonitrile. 3.2 g (21% of theory) of 1-(4-biphenylyl)-2-(imidazol-1-yl)-1-phenyl-ethanol of melting point 224° C. are obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=[O:4].C(OC(=O)C)C.[N:22]12CN3CN(CN(C3)C1)C2.C(O)C.[ClH:35]>>[ClH:35].[NH2:22][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=[O:4]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CBr)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCC(=O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone (60.00 g 1.00 equiv; 210.50 mmoles (mmol)) in ethylacetate (EA) (450 mL; 4.60 moles (mol)), add 1,3,5,7-tetraazatricyclo-[3.3.1.13,7]decane (Methenamine, 1.10 equiv; 231.55 mmol; 32.46 g) and stir at RT overnight. Remove the solvent in vacuo and triturate the solid with methyl-t-butylether (MTBE), filter and dry in vacuo. Add ethanol (450 mL; 7.73 mol) followed by hydrogen chloride (36.5 wt/wt % in water) (150 mL; 8.30 equiv; 1.75 mol) and stir the mixture overnight. Remove the solvent in vacuo and dry the solid in vacuo at 50° C. for 1 week to give the title compound (54.23 g; 100% yield) as a white solid with some amount of ammonium salt. 1H NMR (300 MHz, DMSO): 8.69-8.59 (m, 4H), 8.07-8.01 (m, 1H), 4.95 (d, J=5.2 Hz, 2H). Use the solid as is.