Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:4][N:3]1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[O-:23][C:24]#[N:25].[Na+]>O1CCCC1>[N:25]([SiH:2]1[N:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:4][N:3]1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:24]=[O:23]
Reactant: N#C[O-]
Reactant: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1N=C=O
Reaction time: 18 h
Yield: 89 %

Procedure:
In an argon atmosphere, 7.57 g (22.0 mmol) of Si(tOctNCHCHNtOct)(H)Cl was dissolved in 30 mL of tetrahydrofuran and after adding 2.14 g (purity: 96%, 31.6 mmol) of sodium cyanate, the mixture was stirred for 18 hours under heating and refluxing. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 117° C./73 Pa) to obtain 2-isocyanato-1,3-bis(1,1,3,3-tetramethylbutyl)-1,3-diaza-2-silacyclopent-4-ene (Si(tOctNCHCHNtOct)(H)NCO) as a colorless liquid (yielded amount: 6.91 g, yield: 89%).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH2:7]Cl)=[O:4].[C:10]([OH:17])(=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14]>CN1CCCC1=O>[CH3:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH2:7][O:15][C:13](/[CH:12]=[CH:11]/[C:10]([OH:17])=[O:16])=[O:14])=[O:4]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CC(C)C(=O)OCCCl
Solvent: CN1CCCC1=O
Product: CC(C)C(=O)OCCOC(=O)/C=C/C(=O)O
Yield: 12.1 %

Procedure:
Following general procedure A, chloroethyl 2-methylpropanoate (0.24 g, 1.58 mmol) was reacted overnight with the pre-formed bis-dicyclohexylamine salt (DCHA) of fumaric acid (FA) (0.50 g, 1.26 mmol) in N-methylpyrrolidinone (NMP) at ca 100° C. The crude material was purified by mass-guided preparative HPLC to afford (0.035 g, 12% yield) of the title compound (49) as a white, waxy, semi-solid. 1H NMR (CD3CN, 400 MHz): δ 6.89-6.83 (q, J=5.6 Hz, 1H), 6.82-6.81 (d, J=16.0 Hz, 1H), 6.73-6.69 (d, J=16.0 Hz, 1H), 2.58-2.49 (heptet, J=6.8 Hz, 1H), 1.49-1.47 (d, J=5.6 Hz, 3H), 1.12 (d, J=7.2 Hz, 3H), 1.09 (d, J=6.8 Hz, 6H); MS (ESI): m/z=239.01 (M−H)−.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([CH:18]=O)=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.[NH2:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23]>CCO.CCOCC>[CH:1]1[C:9]2[C:8]3[C:10]([CH2:18][NH:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23])=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: O=Cc1c2ccccc2cc2oc3ccccc3c12
Reactant: CC(N)(CO)CO
Solvent: CCO
Solvent: CCOCC
Product: CC(CO)(CO)NCc1c2ccccc2cc2oc3ccccc3c12
Yield: 68.8 %

Procedure:
Using the procedure outlined in Example 1, benzo[b]naphtho[2,3-d]furan-11-carbaldehyde (2B) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 68.8% yield of 2-[[(benzo[b]naphtho[2,3-d]furan-11-yl)methyl]amino]-2-methyl-1,3-propanediol methanesuylfonate, mp 219°-220° (dec), (C,H,N,S), (EtOH/Et2O).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[Br:15]Br>>[Br:15][C:10]1[CH:11]=[CH:12][C:7]2[O:6][C:5]3[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: BrBr
Reactant: Brc1ccc2oc3ccccc3c2c1
Product: Brc1ccc2oc3ccc(Br)cc3c2c1
Yield: 50 %

Procedure:
The procedure for the synthesis of 19 was followed (1 eq. bromine was used) to prepare 20 from 19 as white crystals in a 50% yield. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.04-8.03 (d, J=2.00 Hz, 2H), 7.60-7.59 (d, J=2.00 Hz, 1H), 7.58-7.57 (d, J=2.00 Hz, 1H), 7.47 (s, 1H), 7.44 (s, 1H).
Reaction SMILES: [Na][CH:2]([C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([O:5]C)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.C(O)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([CH2:2][C:3]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[O:5])=[O:16])=[CH:9][CH:10]=1
Reactant: COC(=O)C([Na])C(=O)c1ccc(OC)cc1
Reactant: Cc1ccc(N)cc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: COc1ccc(C(=O)CC(=O)Nc2ccc(C)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of the methyl 2-sodio-2(4′-methoxybenzoyl) acetate salt prepared in Example 1(44.60 g, 0.194 mol) and 4-toluidine (20.85 g, 0.195 mol) in xylene (300 ml) was stirred and heated over 1 hour. Glacial acetic acid (11.7 g, 0.195 mol) in xylene (100 ml) was added which caused the mixture to become viscous. The mixture was then heated at reflux for 6 hours and allowed to cool to room temperature. Xylene (200 ml) was added to reduce the viscosity of the mixture. This solution was heated at reflux for 4 hours and allowed to cool to room temperature. The solid N-(4′-methoxybenzoylacetyl)-4-methylaniline product obtained was collected by filtration and washed with toluene and heptane. After removal of the residual organic solvent by drying, the solid product was re-suspended with water (250 ml) and stirred. The solid product was collected by filtration and dried (7.13 g, 13%); m.p. 122-126° C. The solvent was removed from the filtrate. The residue crystallized upon standing and was recrystallized in ethanol to give an additional purified solid product (6.83 g, 12 wt. %); m.p. 127-130° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]2)[S:13][CH:14]=1)=[O:7].[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:17]1[CH2:16][N:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[N:11]=2)[CH2:18]1)(=[O:27])[CH3:25]
Reactant: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1
Temperature: 90 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
To a solution of 1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (481 mg, 1.34 mmol) (obtained as described in Reference Example 67(3)) in dimethylformamide (14 ml) was added potassium thioacetate (921 mg, 8.07 mmol) at room temperature and the mixture was stirred in an oil bath (90° C.) for 6 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-acetylthio-1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (341 mg, yield 83%) as a pale brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][CH3:6])=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>ClCCl>[C:17](=[O:18])([O:1][CH2:2][C:3]([NH:5][CH3:6])=[O:4])[O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: CNC(=O)CO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h

Procedure:
A suspension of 2.62 g (29.4 mmol) of 2-hydroxy-N-methylacetamide and 16.5 g (58.7 mmol) of supported diisopropylethylamine (Ps-DIEA from Argonaut, loading=3.56 mmol/g) in 250 ml of dichloromethane is admixed in small portions and at ambient temperature with 5.93 g (29.4 mmol) of 4-nitrophenyl chloroformate. Orbital stirring is continued at ambient temperature for 16 hours. The resin is filtered off and rinsed with 150 ml of dichloromethane and the filtrate is concentrated under reduced pressure. This gives 6 g of product in the form or a light yellow solid, which is used as it is in the following step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[CH3:9][C:10]([S@@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].O>C1COCC1>[CH3:9][C:10]([S@@:13](/[N:15]=[CH:7]/[C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:14])([CH3:12])[CH3:11]
Reactant: Cn1cc(C=O)cn1
Reactant: CC(C)(C)[S@@](N)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(/C=N/[S@@](=O)C(C)(C)C)cn1
Temperature: 65 °C
Yield: 97.2 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (3.0 g, 27 mmol) in THF (100 mL) was added (S)-2-methylpropane-2-sulfinamide (6.6 g, 54 mmol) and Ti(OEt)4 (22.3 g, 98.0 mmol). The reaction mixture was heated at 65° C. for 12 h. After cooling, the mixture was poured into water. The solid was filtered, and the filtrate was extracted with EtOAc (3×100 mL). The organic layer was washed with water (3×50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (4:1) to afford 5.6 g (98%) of (S,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide 40 as colorless oil. LCMS (ESI) m/z: 214.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[NH2:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](O)[CH2:20][CH2:21]C>>[CH2:1]([O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[NH2:6])[CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: CCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(=O)c1cc(Cl)ccc1N
Reaction time: 6 h
Yield: 93 %

Procedure:
186 parts of 5-chloroanthranilic acid methyl ester, 150 parts of n-butanol and 10 parts of potassium carbonate are refluxed for half an hour. The separated methanol is then distilled off over a column. Distillation is continued until the boiling point of n-butanol is reached, then after addition of 4 parts each of bleaching earth and of active charcoal the hot mixture is filtered and agitated with 100 parts of acetone and 200 parts of ice. The reaction lasts for about 6 hours. The precipitate is filtered off, washed with ice-cold water and dried in vacuo at room temperature. There are obtained 211 parts of 5-chloroanthranilic acid-n-butyl ester, melting point 37°-39° C. The yield is 93% of the theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:13])([F:12])[F:11].[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][O:26][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:35][CH:36]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Reactant: COC(=O)Cc1ccc(CBr)cc1
Product: COC(=O)Cc1ccc(COc2ccc(C(C)C(O)(c3cnc4ccccc4c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 140, step 6, 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenol (Example 140, step 5) was reacted with (4-bromomethyl-phenyl)-acetic acid methyl ester to give the title compound as an off-white solid. MS (m/e)=543.7 [M+H+].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C@H:30]([CH3:60])[C@@H:31]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[C:49]([C:55]([F:58])([F:57])[F:56])[C:48]=1[CH3:59])[C:32]([NH:34][NH:35][C:36](=O)[C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=1)=[O:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:22]([O:29][C@H:30]([CH3:60])[C@@H:31]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[C:49]([C:55]([F:58])([F:56])[F:57])[C:48]=1[CH3:59])[C:32]1[O:33][C:36]([C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)=[N:35][N:34]=1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Yield: 83.3 %

Procedure:
Triphenylphosphine (590 mg, 2.25 mmol) was dissolved in 25 mL of DCM followed by addition of I2 (571 mg, 2.25 mmol) and TEA (456 mg, 4.50 mmol) at 0° C. N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (630 mg, 1.13 mmol) in 25 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and extract with EtOAc. The crude mixture was chromatographed to give the product (510 mg, 84%) 1H NMR (400 MHz, acetone-d6, δ in ppm): 8.23 (d, J=9 Hz, 2H), 8.04 (d, J=9 Hz, 2H), 7.67 (d, J=9 Hz, 1H), 7.27 (d, J=9 Hz, 1H), 5.94 (d, J=9 Hz, 1H), 5.19 (m, 1H), 4.74 (m, 1H), 2.39 (m, 3H), 1.48 (d, J=6 Hz, 3H), 0.81 (s, 9H), 0.12 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[CH:5][C:4]=1[C:12]#[N:13])#[N:2].[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][C:4]=1[C:12]#[N:13])#[N:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccccc2)cc1C#N
Yield: 49 %

Procedure:
The procedure of Example 35 was followed except that 1,2-dicyano-4nitrobenzene (1.0 part) was used in place of the 1,2-dicyano-3-nitrobenzene, 1.0 parts instead of 2.79 parts of sodium phenoxide and 20 parts instead of 50 parts of dimethylformamide were used. 1,2-Dicyano-4-phenoxybenzene (0.6 parts, 49%) was obtained as a white solid, m.pt.98°-100° C.
Reaction SMILES: [CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23](=[O:26])[CH2:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:10]=[C:9]([NH:25][CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CC(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)CC(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 3,3-dicyclohexylpropionyl chloride (6.1 g, 0.063 mol) in 70 ml of chloroform was treated portionwise at 7°-12° C. with a solution of 8.3 g (0.063 mol) of glycine tert-butyl ester and 8.9 ml (0.064 mol) of triethylamine in 30 ml of chloroform. After the addition, the solution was stirred at room temperature for 2 hours, kept overnight, refluxed for 0.5 hours, cooled, washed with water (5×25 ml), dried (magnesium sulfate), and the solvent removed on a rotary evaporator, to give a light yellow viscous oil. The latter, which crystallized partly on standing, was dissolved in 50 ml of boiling hexane, cooled, seeded, and rubbed; a crystalline solid gradually separated. After crystallizing at room temperature and cooling overnight, the voluminous colorless solid was filtered, washed with cold hexane and air-dried (13.3 g, melting point 72°-74° C. s, 69° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:32])([C@@H:14]([CH:21]([OH:31])[C:22]4[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=4)[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:32])([C@@H:14]([C:21]([C:22]4[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=4)=[O:31])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
The above methyl 5-(((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(hydroxy)methyl)thiophene-2-carboxylate was dissolved in anhydrous methylene chloride (3 mL). Pyridine (0.1 mL) and then Dess-Martin periodinane (204 mg, 0.48 mmol) were added. The reaction mixture was stirred at RT for 1 hr and quenched by the addition of saturated aqueous sodium bicarbonate solution (5 mL) and saturated aqueous sodium thiosulfate solution (2.5 mL). The mixture was stirred at RT for 30 min. The aqueous layer was separated and extracted with methylene chloride (2×2 mL). The combined organic solutions were dried (Na2SO4). Silica gel flash chromatography (20-100% ethyl acetate in heptanes) gave methyl 5-((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbonyl)thiophene-2-carboxylate (113 mg, 0.25 mmol, 78% yield for steps (b)+(c)) as a solid. MS found: (M+H)+=451.1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=3)[CH:7]=[C:3]([CH2:2][S:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])[N:4]=2)=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2cc(CSc3ccccc3Cl)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656 mmol) and 2-chlorothiophenol (190 mg, 1.31 mmol) in 5 ml of dimethylformamide was added potassium carbonate (226 mg, 1.64 mmol). The mixture was stirred rapidly overnight at room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, the combined organic extracts were washed with brine, and dried over sodium sulfate. The solution was filtered and then concentrated. Chromatography of the residue over silica gel using 50% ethyl acetate in hexane as the eluent followed by crystallization gave the title compound as a pure white crystalline solid (147 mg): mp (DSC) 153° C. Anal. Calc'd. for C23H18Cl2N2O2S2 (MW 489.44): C, 56.44; H, 3.71; N, 5.72. Found: C, 56.51; H, 3.54; N, 5.57.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10](C(O)=O)=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1>Cl>[CH3:14][C:4]1[CH:3]=[C:2]([SH:1])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1
Reactant: Cc1cc(S)n2ncc(C(=O)O)c2n1
Agent: Cl
Product: Cc1cc(S)n2nccc2n1

Procedure:
110 g of 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid were heated to reflux temperature for 2.5 hours in 500 ml of 20 percent hydrochloric acid. The reaction mixture was cooled, the product was filtered off under suction and then recrystallized from water/ethanol at a pH of 6. There was obtained 5-methylpyrazolo [1,5-a]pyrimidine-7-thiol as yellow crystals of a melting point above 250°.
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH2:5][CH2:6]2)=O.[C:11]([CH2:13]C(O)=O)#[N:12].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:11]([CH2:13][CH:1]=[C:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH2:5][CH2:6]2)#[N:12]
Reactant: N#CCC(=O)O
Reactant: CC1C2CCC(C2)C1C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC1C(=CCC#N)C2CCC1C2
Yield: 77 %

Procedure:
A stirred solution of 97 g (0.7 mol) of 2-formyl-3-methylbicyclo[2.2.1]heptane 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evolution of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 87 g (77% yield) of 2-(2-cyanoethylidene)-3-methylbicyclo[2.2.1]heptane: b.p. 72°-85° C./1 mm; ir 2940, 2870, 2220, 1610, 1450, 1380, 830, 740; nmr 0.9-1.1 (3H, m), 1.2-2.8 (9H, m), 2.85-3.2 (2H, m), 4.8-5.4 (1H, m); ms 161.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[N:3]=1
Reactant: Cc1nc(Br)ccc1[N+](=O)[O-]
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(-n2cncn2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 36 h
Yield: 71 %

Procedure:
A mixture of 2-bromo-6-methyl-5-nitropyridine (ECA International Corporation, Palatine, Ill., USA; 2 g, 9.2 mmol), 1,2,4-triazole (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 0.64 g, 9.2 mmol) and potassium carbonate (1.27 g, 9.2 mmol) in dimethylsulfoxide (4 mL) was stirred at room temperature for 1.5 days and then poured into a mixture of ice and water (400 mL). The resulting mixture was stirred until all of the ice melted to give a dark purple slurry. The solid was filtered off to give 2-methyl-3-nitro-6-[1,2,4]triazol-1-yl-pyridine (1.34 g, 71%) as a purple solid with a purity estimated at 93% by LC-MS. This was used directly in the next step without further purification.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][NH:5]1)#[N:2].[H-].[Na+].[O:11]1[CH:17]2[CH:12]1[C:13]([CH3:25])([CH3:24])[O:14][C:15]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:16]=12>CS(C)=O>[C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C@@H:17]1[C:16]2[CH:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:15]=2[O:14][C:13]([CH3:24])([CH3:25])[C@H:12]1[OH:11])#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: N#CN=C1NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-cyanoiminoimidazolidine (0.42 g) in dimethyl sulfoxide (12.5 ml) was added 60% sodium hydride (0.15 g) under water-cooling and the mixture was stirred at room temperature for 0.5 hours. 3,4-Epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.50 g) was added portionwise thereto. After being stirred at room temperature overnight, the mixture was poured into ice-brine (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was pulverized with chloroform and recrystallized from ethanol to give trans-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.15
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:30][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCC1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 71 at rt but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as a white powder (3 mg, 5%). HPLC, Rt: 3.78 min. (purity 100%). LC/MS, M+(ESI): 405.3, M−(ESI): 403.2.