Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22].C(N(CC)CC)C>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 7.2 %

Procedure:
A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (22.5 g, 0.1 mole) in 250 ml of tetrahydrofuran was hydrogenated in a small Parr bottle over 5% palladium on carbon (2.5 g) at room temperature for 1 hr. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. Under nitrogen atmosphere, 3,4-dichlorobenzoyl chloride (20.95 g, 0.1 mole) and triethylamine (11.1 g, 0.11 mole) were added dropwise simultaneously to the above stirred filtrate at room temperature. After stirring overnight, the reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was treated with acetone and water to obtain a crystalline solid, which was refrigerated overnight. The solid was collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight (37.1 g). A 4-g sample was recrystallized from acetone/water and dried under high vacuum at 50° C. for 2 days to give 2.66 g of title compound, mp 137°-38° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1.C1O[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH:19](Cl)[CH2:20][CH3:21])[O:17]C1>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]([CH2:19][CH2:20][CH2:21][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][O:7]3)[CH2:3][CH2:2]2)=[O:17])=[CH:28][CH:27]=1
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: CCC(Cl)C1(c2ccc(F)cc2)OCCO1
Product: O=C(CCCN1CCC2(CC1)OCc1ccccc12)c1ccc(F)cc1

Procedure:
Reaction of 1,3-dihydrospiro[isobenzofuran-1,4'-piperidine] and α-chloro-p-fluorobutyrophenone ethylene ketal by the method described in Example 6 provides 1,3-dihydro-1'-[3-(4-fluorobenzoyl)propyl]spiro[isobenzofuran-1,4'-piperidine] as a solid, hydrochloride salt, m.p. 215°-217°.
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:6])[CH3:5].[CH3:7][C:8]1([CH3:31])[CH:17](OS(C)(=O)=O)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26]CC)=[O:25])[C:15]=2[CH3:23])[S:10](=[O:30])(=[O:29])[CH2:9]1>CO.C(OCC)(=O)C>[CH3:7][C:8]1([CH3:31])[CH:17]([S:6][CH2:4][CH3:5])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:24]([OH:26])=[O:25])[C:15]=2[CH3:23])[S:10](=[O:29])(=[O:30])[CH2:9]1
Reactant: CCS
Reactant: CCOC(=O)c1ccc2c(c1C)C(OS(C)(=O)=O)C(C)(C)CS2(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCSC1c2c(ccc(C(=O)O)c2C)S(=O)(=O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
A methanolic solution of 0.8 g (4 mmol, 3 eq.) containing about 28 wt % sodium methoxide was diluted with 5 ml of anhydrous methanol, and 0.5 ml (6.8 mmol, 1.5 eq.) of ethanethiol was added. The mixture was stirred at room temperature for 5 minutes, and then 0.5 g (1.3 mmol) of 3,3,5-trimethyl-4-methanesulfonyloxy-6-ethoxycarbonylthiochroman-1,1-dioxide was added. The mixture was refluxed for 8 hours, and allowed to stand at room temperature for 5 days. The reaction mixture was diluted with 100 ml of ethyl acetate and washed with 50 ml of water twice, and an aqueous layer was separated and cooled in an ice bath. The aqueous layer was acidified with 5 wt % hydrochloric acid and extracted with 100 ml of ethyl acetate, and an organic layer was dried over sodium sulfate. The solvent was distilled off, and the residue was dried under reduced pressure to give 0.32 g (yield 75%) of a yellowish solid.
Reaction SMILES: CCN=C=NCCCN(C)C.[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([OH:20])=O)[CH2:14][CH:15]([CH3:17])[CH3:16].O.Cl.[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C1C=CC2N(O)N=NC=2C=1>ClCCl>[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CCOC(=O)CN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 56.6 %

Procedure:
9.10 Milliliters of WSC was gradually added to 100 ml of a solution of 12.47 g of Boc-Leu-OH.H2O, 6.98 g of HCl.H-Gly-OEt and 6.76 g of HOBT dissolved in dichloromethane, with ice-cooling. The mixture was stirred for 42 hours at room temperature. The reaction mixture was mixed with 100 ml of 1N hydrochloric acid, and the resulting precipitate was removed by filtration. The filtrate was washed with 100 ml of 1N hydrochloric acid, two 100-ml portions of a saturated aqueous sodium bicarbonate solution and 100 ml of a saturated aqueous sodium chloride solution in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added petroleum ether to crystallize the residue. The resulting crystal was recrystallized from ethyl acetate-petroleum ether to obtain 8.68 g (yield: 56.6%) of the above objective compound. Melting point: 79.5°-82.5° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][NH:28][CH2:29][CH2:30][CH3:31].Cl>C(#N)C>[CH3:27][N:28]([CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCNC
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Agent: Cl
Solvent: CC#N
Product: CCCN(C)CC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 14 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.175 g, 0.44 mmol), N-methylpropan-1-amine (0.35 ml) and ACN (2 ml). Yield: 0.11 g, 84%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 222° C. MS m/z (rel. intensity, 70 eV) 299 (M+, 1) 86 (100), 58 (8), 84 (6), 87 (6).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:23]=[C:22]([CH2:24][N:25]([CH3:36])[S:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:21]=[CH:20][C:10]=2[O:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:23]=[C:22]([CH2:24][N:25]([CH3:36])[S:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH:21]=[CH:20][C:10]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2cccc(C#N)c2)c1)S(=O)(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccc(OCC(=O)O)c(-c2cccc(C#N)c2)c1)S(=O)(=O)c1ccc(F)cc1
Yield: 43.6 %

Procedure:
t-butyl 2-(2-(3-cyanophenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (4) (780 mg; 1.53 mmol) was stirred in a mixture of TFA (15 mL) and DCM (30 mL) for 1 h. After concentration in vacuo, the residue was purified via reversed phase semi-preparative HPLC to yield 303 mg (43.6%) of 2-(2-(3-cyanophenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetic acid (Example 5) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 7.84 (m, 3H), 7.75 (m, 1H), 7.61 (m, 1H), 7.50 (t, 1H), 7.24 (m, 3H), 6.85 (d, 1H), 4.69 (s, 2H), 4.13 (s, 2H), 2.63 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:28])[CH2:11][N:12]3[C:17]4=[N:18][C:19](Cl)=[CH:20][C:21](=[O:22])[N:16]4[CH2:15][CH2:14][C@H:13]3[C:24]([F:27])([F:26])[F:25])=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.[C@H:30]12[CH2:36][C@H:33]([NH:34][CH2:35]1)[CH2:32][O:31]2>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:28])[CH2:11][N:12]3[C:17]4=[N:18][C:19]([N:34]5[CH2:35][C@@H:30]6[CH2:36][C@H:33]5[CH2:32][O:31]6)=[CH:20][C:21](=[O:22])[N:16]4[CH2:15][CH2:14][C@H:13]3[C:24]([F:27])([F:26])[F:25])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccc2snnc2c1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Product: O=C(CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccc2snnc2c1

Procedure:
210 mg (0.49 mmol) of (8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 79.50 mg (0.58 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 100 mg of (8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CN=3)=NOC=2C)=NC=1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Yield: 84.1 %

Procedure:
As described for example 283, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (53 mg, 0.16 mmol) was converted, instead of 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (42 mg, 83%) which was obtained as a white solid. MS: m/e=311.5
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:18][CH2:17][C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1)=O.[C:21](Cl)(=[O:25])[C:22](Cl)=[O:23].[CH3:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl>[CH3:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:21](=[O:25])[C:22](=[O:23])[C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:8]3[CH2:7][CH2:6][NH:5][CH2:18][CH2:17][C:9]=23)=[CH:31][CH:30]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(N1CCc2cc3ccccc3n2CC1)C(F)(F)F
Reactant: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)C(=O)c2c3n(c4ccccc24)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
(Chart B, Step 1): A solution 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole in dichloromethane (20 mL) is cooled to 0° C. and treated with oxalylchloride (0.17 mL, 2.0 mmol) instantly becoming a yellow color. After 40 min, the reaction mixture is warmed to rt and volatiles are removed under reduced pressure. The resulting solid is diluted with toluene (20 mL) and dichloromethane (5 mL) and treated with the 4-methoxy aniline (160 mg, 1.3 mmol) and triethylamine (0.42 mL, 3.0 mmol) with immediate smoke/haze forming. After 18 hrs, the reaction mixture is concentrated, diluted with methanol (10 mL) and THF (10 mL) and treated with 1N sodium hydroxide (10 mL). After 15 min, reaction mixture is concentrated, diluted with 1N sodium hydroxide (20 mL), and extracted twice with dichloromethane (25 mL). The combined organics are washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to give a crude solid. This material is purified by LC (230-400 silica gel) eluting with 10% methanol/dichloromethane to afford 359 mg of N-(4-methoxyphenyl)-2-oxo-2-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)acetamide as a light yellow solid, mp 177-180° C. IR (drift) 1670, 1621, 1559, 1507, 1465, 1416, 1333, 1264, 1242, 1221, 1211, 1073, 838, 789, 762 cm−1; OAMS supporting ions at: ESI+364.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][CH2:18][NH:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21].Br[CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]1>CC(C)=O>[CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][NH:19][C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])[CH:27]=1
Reactant: O=C(NCCc1c[nH]c2ccc(O)cc12)C1CC1
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(NCCc1c[nH]c2ccc(OC3C=CCCC3)cc12)C1CC1

Procedure:
1.98×10-2 mol of potassium carbonate, 1.33×10-2 mol of N-[2-(5-hydroxyindol-3-yl)ethyl]cyclopropylcarboxamide dissolved in 20 cm3 of anhydrous acetone, and 2.1×10-2 mol of 3-bromocyclohexene are introduced into a 50 cm3 flask with a ground neck. The mixture is heated under reflux for 22 hours. The reaction medium is filtered and the filtrate is evaporated under reduced pressure. Recrystallisation of the evaporation residue in ethyl acetate yields purified N-{2-[5-(cyclohexen-3-yloxy)indol-3-yl]ethyl}-cyclopropylcarboxamide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:27]=[CH:26][C:7]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:20][CH2:19][N:18]([CH2:21][C:22](=[NH:24])[NH2:23])[C:17]3=[O:25])[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1.O=[C:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34](OC)=[O:35].[O-]CC.[Na+]>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[NH:23][C:34](=[O:35])[C:30]5[CH2:31][CH2:32][CH2:33][C:29]=5[N:24]=4)[C:17]3=[O:25])[CH2:12][CH2:11]2)=[O:9])=[CH:26][CH:27]=1
Reactant: COC(=O)C1CCCC1=O
Reactant: COc1ccc(C(=O)C2CCN(C3CCN(CC(=N)N)C3=O)CC2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=O)C2CCN(C3CCN(Cc4nc5c(c(=O)[nH]4)CCC5)C3=O)CC2)cc1
Temperature: 100 °C
Yield: 19.8 %

Procedure:
To a solution of 2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetimidamide hydrochloride (140 mg, 0.37 mmol) and methyl 2-oxocyclopentanecarboxylate (0.060 mL, 0.47 mmol) in ethanol (4 mL) was added sodium ethoxide (0.160 mL, 0.44 mmol, 21%). The mixture was heated at 100° C. for 24 h. The resulting mixture was purified via flash column chromatography (methanol: dichloromethane, 1:99 to 10:90) and then crystalized out from methanol to provide slightly yellow solid (33 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 10.85 (s, 1H), 7.95 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 4.32-4.47 (m, 2H), 3.89 (s, 3H), 3.60-3.73 (m, 1H), 3.40-3.56 (m, 2H), 3.23-3.37 (br. s, 1H), 3.00-3.20 (br. s, 3H), 2.84 (ddd, 4H, J=14.7, 7.5, 7.4 Hz), 2.46-2.62 (br. s, 1H), 2.38 (d, 1H, J=7.0 Hz), 2.15-2.25 (br. s, 1H), 2.10 (dq, 2H, J=7.8, 7.6 Hz), 1.82-2.01 (br. s, 4H) HRMS calculated for C25H30N4O4 451.2345. found (ESI, [M+H]+), 451.2362.
Reaction SMILES: [O:1]=[C:2]1[CH:10]=[C:9]2[C:5]([C:11]([O:13][CH3:14])=[O:12])([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH2:3]1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>CCO>[O:1]=[C:2]1[CH2:10][C@@H:9]2[C@:5]([C:11]([O:13][CH3:14])=[O:12])([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH2:3]1.[O:1]=[C:2]1[CH2:10][C@H:9]2[C@:5]([C:11]([O:13][CH3:14])=[O:12])([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH2:3]1
Reactant: COC(=O)C12CCCC1=CC(=O)CC2
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Product: COC(=O)[C@]12CCC[C@@H]1CC(=O)CC2
Product: COC(=O)[C@]12CCC[C@H]1CC(=O)CC2
Yield: 29.5 %
Yield: 20.84 %

Procedure:
To a stirred solution of methyl 6-oxo-2,3,3a,4,5,6-hexahydro-1H-indene-3a-carboxylate (1.32 g, 6.80 mmol) in EtOH (30 mL) was added palladium, 10 wt. %(dry basis) on activated carbon, wet, degussa type e101 ne/w (0.120 ml, 6.80 mmol) and the resulting mixture underwent hydrogenation using the hydrogenation kit for 3 h. The mixture was filtered through celite, concentrated and chromatographed on silica gel using 0-25% heptane/hexane to afford (3aS,7aR)-methyl 6-oxooctahydro-1H-indene-3a-carboxylate (0.278 g, 1.417 mmol, 20.84% yield) and (3aS,7aS)-methyl 6-oxooctahydro-1H-indene-3a-carboxylate (0.394 g, 2.008 mmol, 29.5% yield) as colorless oil. MS m/z=181.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([NH:33][CH3:34])[CH3:32]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27](=[O:26])[N:33]([CH2:31][CH3:32])[CH3:34])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CCN(C)C(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 24 μl of N-ethyl-N-methylamine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a mixture of petroleum ether and ethyl acetate (gradient 40/60 to 0/100 by volume) followed by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 12 mg of 3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)-1-ethyl-1-methylurea, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]([NH:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Product: Cl

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28° C. to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The cis to trans ratio is 87 to 89/9 to 13. The amount of dehalogenated by product is <0.1%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:11]([C:9]1[CH:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)c1cc2ccc(Br)cn2n1
Product: CC(C)(C)c1cc2ccc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, a white solid, MS: m/e=275.4 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine (example 41, step 3) and phenylacetylene.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:22]([O-])([OH:24])=[O:23].O>C(O)(=O)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][C:16]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: CCOC(=O)c1ccc(OCCOC)c(OCCOC)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of ethyl 3,4-bis(2-methoxyethoxy)benzoate (23.23 g, 77.87 mmol) in acetic acid (80 mL) was added dropwise to concentrated nitric acid (21 mL) cooled with an ice bath at such a rate as to keep the internal temperature below 5° C. After 30 min, the solution was allowed to warm to room temperature and stirred for 48 h. The solution was poured onto iced water (400 mL) and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed cautiously with saturated aqueous sodium bicarbonate (3×200 mL) and brine (2×100 mL). The organic phase was dried (Na2SO4) and concentrated to give the title compound as a solid (24.82 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:43][C:44]1[CH:66]=[CH:65][C:47]2[CH2:48][CH2:49][C:50]3[C:51]([C:62]([NH2:64])=[O:63])=[N:52][N:53]([C:55]4[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=4)[C:54]=3[C:46]=2[CH:45]=1.CC1C(C(O)=O)=CN=C(Cl)C=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([NH:43][C:44]1[CH:66]=[CH:65][C:47]2[CH2:48][CH2:49][C:50]3[C:51]([C:62]([NH2:64])=[O:63])=[N:52][N:53]([C:55]4[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=4)[C:54]=3[C:46]=2[CH:45]=1)=[O:7]
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Reactant: O=C(O)c1cc(Cl)ncc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1cc(Cl)ncc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
2,5-Dichloroisonicotinic acid (1.65 g, 0.0086 mol), HATU (3.27 g, 0.0086 mol), and Et3N (2.32 mL, 0.0166 mol) were added to a solution of the title compound of Example 244 (1.85 g, 0.00574 mol) in 29 mL of DMF. The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was confirmed by monitoring the disappearance of the title compound of Example 246 step 2 in LC/MS. The crude reaction mixture was concentrated to about 10 mL of DMF. Upon addition of water to this DMF residue, a white solid was formed. This white solid was triturated in water for 20 min and filtered. The solid was collected, dissolved in THF, and dried with MgSO4. Removal of the solvent afforded a brown solid that was crystallized from CH3CN to give 2.1 g of the title compound as white needles (yield 73%). 1H NMR (300 MHz, d6-DMSO): 2.86–2.91 (m, 4H), 7.18 (d, 1H, J=1.2 Hz), 7.25 (s, 1H), 7.32–7.36 (m, 4H), 7.52–7.56 (m, 3H), 7.75 (s, 1H), 8.57 (s, 1H), 10.49 (s, 1H). M+1=497.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)N>O>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([OH:10])=[O:9])[CH:2]=1
Reactant: O=C(O)c1cccnc1Cl
Solvent: Nc1cccc(Cl)c1
Solvent: O
Product: O=C(O)c1cccnc1
Reaction time: 1 h
Yield: 188.5 %

Procedure:
A mixture of 2-chloro-3-pyridinecarboxylic acid (78.75 g, 0.500 mol), 3-chloroaniline (127.6 g, 1.00 mol), paratoluenesulfonic acid. H2O (8.5 g, 45 mmol), and H2O (500 mL) was refluxed 4 hrs. The solids dissolved, and after 1 hr, the solution gave a precipitate. The cooled mixture was filtered, and the collected yellow solid was washed with cold H2O and was dried (60°) to give 2-[3-chlorophenyl)amino]-3-pyridinecarboxylic acid (116.0 g, 93.3%), mp 197°-199° C.