Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:21])[CH2:5]1.[CH3:22][C:23]([CH3:32])([CH3:31])[CH2:24][CH2:25]CS([O-])(=O)=O>CN(C)C=O>[CH3:22][C:23]([CH3:32])([CH3:31])[CH2:24][CH2:25][N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6](=[O:21])[CH2:5][C:4]1=[O:3]
Reactant: CC(C)(C)CCCS(=O)(=O)[O-]
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)CCN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
Sodium hydride 80% dispersion in oil (0.10 g) was added portionwise to a solution of 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.7 g) in dry dimethylformamide (60 ml). The reaction mixture was stirred for 30 min, then a solution of 3,3-dimethylbutylmethanesulphonate (0.575 g) in dry dimethylformamide (3 ml) was added. The reaction mixture was stirred at 90° for 50 min at 23° for 15 h, at 90° for 2h and at 140° for 45 min, then concentrated in vacuo. The residue was diluted with water (30 ml) and brine (20 ml) and extracted with ethyl acetate (150 ml); the organic layer was washed with water (2×50 ml) and brine (50 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 1:1) to give the title compound as a white foam (0.4 g). T.l.c. CH-EA (1:1 ), Rf=0.39.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]([OH:21])=[O:20])[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]([OH:21])=[O:20])[CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C(O)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC[C@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Yield: 62.8 %

Procedure:
(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidine-3-carboxylic acid was prepared by reacting 4-fluoro-2-methoxy-1-nitro-benzene (342 mg, 2.0 mmol) with (S)-Piperidine-3-carboxylic acid (258 mg, 2.0 mmol) at 80° C. in DMF using K2CO3 (608 mg, 2.20 mmol) as a base scavenger. After 16 h the reaction was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous phase was acidified with 1N HCl to pH 4-5. The resulting yellow solid was filtered, rinsed with water, and air dried overnight to yield 352 mg (63%) of (S)-1-(3-Methoxy-4-nitro-phenyl)-piperidine-3-carboxylic acid as a yellow solid. LC/MS (E/I+) 281.08 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[C:24](=[O:43])[N:25]([CH:28]4[CH2:33][CH2:32][N:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[CH2:40][NH:41][CH3:42])[CH2:30][CH2:29]4)[CH2:26][CH2:27][C:22]=3[C:21]([C:44]([NH2:46])=[O:45])=[N:20]2)=[CH:15][CH:14]=1>C(Cl)Cl>[C:1]([N:41]([CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[N:31]1[CH2:32][CH2:33][CH:28]([N:25]2[CH2:26][CH2:27][C:22]3[C:21]([C:44]([NH2:46])=[O:45])=[N:20][N:19]([C:16]4[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=4)[C:23]=3[C:24]2=[O:43])[CH2:29][CH2:30]1)[CH3:42])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CNCc1ccccc1N1CCC(N2CCc3c(C(N)=O)nn(-c4ccc(OC)cc4)c3C2=O)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(C2CCN(c4ccccc4CN(C)C(C)=O)CC2)CC3)cc1
Yield: 10 %

Procedure:
A solution of the product from Part H (17 mg, 0.02 mmol), acetyl chloride (0.05 mL), and pyridine (0.05 mL) in anhydrous CH2Cl2 (1 mL) was stirred at room temperature for 2 h under N2. Two products (1:5) were detected by LC/MS (ESI+): 531.6 (M+H) and 513.6 (M+H) for the amide (I-1) and the nitrile (I-2), respectively. The mixture was then concentrated in vacuo, and the residue was purified by prep LC-MS (5-98% CH3CN/H2O in a 10-min run) to obtain the product I-1, 6-[1-(2-{[acetyl(methyl)amino]methyl}phenyl)-4-piperidinyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (1.6 mg, 10%). LC/MS (ESI+), 531.6 (M+H). And product I-2, N-(2-{4-[3-cyano-1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]-1-piperidinyl}benzyl)-N-methylacetamide (8 mg, 50%). LC/MS (ESI+), 513.6 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: O=C=NC1CCCCC1
Reactant: NCCCN1CCN(Cc2ccc(F)cc2)CC1
Solvent: ClCCl
Product: O=C(NCCCN1CCN(Cc2ccc(F)cc2)CC1)NC1CCCCC1
Yield: 85 %

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-fluorobenzyl)piperazine (2.0 g; 8 mmole) and cyclohexyl isocyanate (1.0 g; 8 mmole) in methylene chloride (20 ml) was stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was mixed with ether (20 ml). The ether solution was filtered, and the filtrate was applied to a silica gel column (300 g) and developed in the same solvent. Fractions containing the product were eluted with methylene chloride/methanol/ammonium hydroxide (45:5:1), and on evaporation provided 1-{3-[4-(4-fluorobenzyl)piperazin-1-yl]propyl}-3-cyclohexylurea as a pale yellow oil (2.6 g; 85% yield). The product was dissolved in ether, precipitated with ethereal hydrogen chloride and recrystallized from ethanol to yield the title compound as colorless crystals (2.96 g; 80% yield), m.p. 203°-206° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:16][CH3:17].[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH3:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:23])[F:22])[CH2:16][CH3:17]
Reactant: CI
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 20 mL cintillation vial was charged with (S)—N-(3-(1H-indol-2-yl)propyl)-2-(2,2,2-trifluoroacetamido)butanamide (60 mg, 0.169 mmol) and dimethylformamide (0.75 mL). Sodium hydride (6.0 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. Methyl iodide (0.012 mL, 0.193 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was then concentrated in-vacuo and purified via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-50:50 Heptane:EtOAc) to yield N-[3-(1-methyl-1H-indol-2-yl)-propyl]-2-(S)-(2,2,2-trifluoro-acetylamino)-butyramide. 1H NMR (300 MHz, CDCl3) δ7.52 (d, J=7.7 Hz, 1H), 7.25-7.28 (m, 1H), 7.14-7.19 (m, 1H), 7.04-7.10 (m, 1H), 6.26 (s, 1H), 4.31-4.36 (m, 1H), 3.64 (s, 3H), 3.33-3.46 (m, 2H), 2.75-2.82 (m, 2H), 1.80-2.09 (m, 3H), 1.59-1.71 (m, 1H), and 0.87-0.92 (m, 3H); MS (ES+) 370 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Cl)=[O:5])[CH3:2].[C:12]12([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:12]23[CH2:13][CH:14]4[CH2:20][CH:18]([CH2:17][CH:16]([CH2:15]4)[CH2:21]2)[CH2:19]3)=[CH:27][CH:26]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCCCl
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: CCOC(=O)CCCCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Analogously to the procedure described in Example 5, the use of 5-chloro-pentanecarboxylic acid ethyl ester and p-(1-adamantyl)-phenol as starting materials gives 5-[4-(1-adamantyl)-phenoxy]-pentanecarboxylic acid ethyl ester of boiling point 170°-180° C (0.05 mm).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].FC(F)(F)CCCC(O[C:18]([CH3:21])([CH3:20])[CH3:19])=O>>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([O:7][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:6]
Reactant: O=C(O)CCC(F)(F)F
Reactant: CC(C)(C)OC(=O)CCCC(F)(F)F
Product: CC(C)(C)OC(=O)CCC(F)(F)F

Procedure:
Preparation 4A was prepared from 4,4,4-trifluorobutanoic acid (4.99 g, 35.1 mmol) using the general procedure shown for Preparation 1A. Preparation 4A (5.58 g, 80%) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.47-2.52 (2H, m), 2.37-2.45 (2H, m), 1.46 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=S)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N=C=NC(C)C)(C)C.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[NH:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>O1CCCC1>[C:44]([O:43][C:41]([NH:40][CH2:39][CH2:38][CH2:37][N:36]1[C:27]2[CH:28]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=[CH:35][C:26]=2[N:25]=[C:14]1[NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:42])([CH3:46])([CH3:47])[CH3:45]
Reactant: COC(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Reactant: COc1cc(N=C=S)cc(OC)c1OC
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(Nc3cc(OC)c(OC)c(OC)c3)n(CCCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
3,4,5-trimethoxyphenyl isothiocyanate (6.6 g, 1.2 eq) and diisopropylcarbodiimide (9.1 g, 3 eq) are successively added to a solution of methyl 4-amino-3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)benzoate (7.75 g, 1 eq) in tetrahydrofuran (130 ml). The mixture is heated under reflux for 16 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Water (100 ml) and dichloromethane (200 ml) are added to the residue obtained. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 3:7) produces the expected compound in the form of a solid which is washed with ether (4.4 g; 36% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2ccc(C)c(C)c2)c1

Procedure:
11.0 g (50.1 mmol) of methyl 5-bromonicotinate and 7.7 g (50.1 mmol) of 3,4-dimethylphenylboronic acid were reacted according to the General Method 1A. Yield: 4.0 g (31% of theory)
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])=[C:25]([CH3:37])[NH:24][C:23]=1[CH:38]=O.N1CCCCC1>C(O)C>[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]2)=[O:29])=[C:25]([CH3:37])[NH:24][C:23]=1/[CH:38]=[C:14]1\[C:15](=[O:20])[NH:16][C:17]2[C:13]\1=[CH:12][C:11]([S:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[CH:19][CH:18]=2
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 3,5-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrrole-2-carbaldehyde (174 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with acetone to give the titled compound as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[NH:7][C:8](=[O:21])[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[N:7]([CH3:26])[C:8](=[O:21])[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c2c1C
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)n(C)c(=O)c2c1C
Yield: 58 %

Procedure:
A mixture of 100 mg of ethyl 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, 40 mg of potassium carbonate, 10 mL of acetonitrile and 40 mg of methyl iodide was heated under reflux for 1.5 hours. After condensing the reaction mixture under reduced pressure, the residue was purified on silica gel column chromatography (ethyl acetate:hexane=1:1) to provide 60 mg (58%) of the title compound.
Reaction SMILES: [CH2:1]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[CH2:1]([CH:7]1[CH:11]([CH2:16][N+:13]([O-:15])=[O:14])[CH2:10][CH2:9][C:8]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[N+](=O)[O-]
Reactant: CCCCCCC1=CCCC1=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCC1C(=O)CCC1C[N+](=O)[O-]

Procedure:
In a 2-L flask fitted with a reflux condenser, is placed 332 g of 2-n-hexyl-2-cyclopentenone, 183 g of nitromethane, 30 ml of 40% methanolic solution of benzyltrimethylammonium hydroxide (Triton B) and 200 ml of dry dioxane. The reaction mixture is refluxed for 23 hours. The solvent is distilled off under a reduced pressure and the residue is dissolved in 1 L of ether. The ether solution is washed successively with dilute hydrochloric acid, water and sodium bicarbonate solution and dried over anhydrous sodium sulphate. The solvent is removed at atmospheric pressure and the residue is distilled through a short Vigreux column. After a lower boiling fraction (35 g, 65°C/0.2 mm) consisting of 2-n-hexyl-2-cyclopentenone, the product is collected at 135°C/0.3 mm, yield 365 g (80%), nD20 1.4733.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:24][S:25][CH2:26][CH2:27][CH2:28][NH2:29]>C(O)C>[CH3:24][S:25][CH2:26][CH2:27][CH2:28][NH:29][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: CSCCCN
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCCCSC)ncc2c(=O)[nH]1
Yield: 56.1 %

Procedure:
In a similar manner to Example 38 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.79 g) and methylthiopropylamine (0.50 g) in ethanol (15 ml) for 40 hours yielded a crude product which was purified by elution from silica with 40-60° petroleum ether:chloroform (gradient elution) to yield the title compound 0.52 g, m.p. 173-4° C. (recrystallized from methanol).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].[Br:18]Br.C1(C)C=CC=CC=1>CC(O)=O>[Br:18][C:15]1[C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]([OH:17])=[C:2]([Br:1])[CH:16]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2c(Br)cc(Br)c(O)c2s1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea (50 mg, 0.158 mmol) in AcOH (2 mL) at about 20° C. was added Br2 (9 μl, 0.174 mmol). The reaction mixture was stirred at about 20° C. for about 15 minutes. Toluene (10 mL) was added and the solvents evaporated. The crude material was purified by preparative LC/MS to give 19 mg (30%) pure 18. 1H NMR (DMSO) δ 1.09 (t, 3H, J=6 Hz CH3), 3.19 (m, 2H, CH2), 6.55 (br s, 1H, NH), 7.68 (s, 1H, ArH), 10.51 (br s, 1H, NH or OH), 11.20 (br s, 1H, NH or OH). HPLC retention timer 2.90 minutes.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1CC#N.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:19][C:18]([OH:21])=[O:20]
Reactant: CC(=O)O
Reactant: N#CCc1ccc(F)cc1OCC(F)(F)F
Agent: Cl
Product: O=C(O)Cc1ccc(F)cc1OCC(F)(F)F

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetonitrile (0.60 g, 2.7 mmol) from Step 4 above in acetic acid (10 mL) was added 12 N aqueous HCl (5 mL). The mixture was refluxed for 4 h. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and water (2×50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetic acid as an amorphous solid (HPLC retention time=7.5 min (method A)).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[NH:13][C:12]4=[N:24][NH:25][CH:26]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12.C(N(C(C)C)CC)(C)C.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1>CO>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:19][CH2:20][N:21]([C:42](=[NH:37])[NH2:43])[CH2:22][CH2:23]4)[NH:13][C:12]4=[N:24][NH:25][CH:26]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1cccc2nonc12
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#CC1=C(C2CCN(C(=N)N)CC2)Nc2n[nH]cc2C1c1cccc2nonc12
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (1.5 g) in MeOH (30 mL) was added diisopropylethylamine (4.2 g), and 1H-pyrazole-1-carboxamidine hydrochloride (0.96 g) at room temperature and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound (1.0 g) as yellow crystals.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:3]([C:5]2[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=4)=[N:14][O:15][C:16]=3[CH2:17][OH:18])[CH:9]=2)=[O:4])[CH2:29][CH2:30]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Reactant: NC1CCOCC1
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NC1CCOCC1
Yield: 42 %

Procedure:
As described for example 100f, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (50 mg, 42%) which was obtained as a white solid. MS: m/e=447.3 [M+H]+.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[CH2:14][CH:13]=[C:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH:27]=[CH:26]1.C(OC(=O)C)(=O)C.C1(C=CC(O)=CC=1)O>C(O)(=O)C>[ClH:1].[CH2:2]([N:9]1[CH2:10][CH2:11][C:12]2[CH:13]([CH:26]3[C:25](=[O:31])[O:30][C:28](=[O:29])[CH:27]3[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:15]=2)[CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C=CC2=CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: Oc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C2C=C3CCN(Cc4ccccc4)CC3C3C(=O)OC(=O)C23)cc1

Procedure:
A solution of 21 g (0.06 moles) 1-benzyl-1,2,3,6-tetrahydro-4-(p-methoxystyryl)-pyridine, hydrochloride, from example 6, 37.8 g ground maleic anhydride, 135 ml. glacial acetic acid, 135 ml. acetic anhydride and 20 mg hydroquinone is refluxed under nitrogen for 1/2 hour. The solution is allowed to cool and evaporate to an oil. The crude Diels-Alder adduct (quantitative yield of 2-benzyl-1,2,3,4,6,7,8,8a-octahydro-6-(p-methoxyphenyl)-7,8-isoquinoline-dicarboxylic acid anhydride hydrochloride) is dissolved in 500 ml. methanol and 20 ml. hydrochloric acid in isopropanol and refluxed for 18 hours. The solution is allowed to cool and evaporated. The residue is triturated in ether and solid filtered to afford a quantitative yield of 2-benzyl-1,2,3,4,6,7,8,8a-octahydro-6-(p-methoxyphenyl)-7,8-isoquinoline-dicarboxylic acid, dimethyl ester, hydrochloride. After recrystallization from acetone-ether the mp is 200° to 209°C with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([NH:16][CH3:17])[S:15][C:11]=3[C:10]=2[N+:20]([O-])=O)[C:5]([O:23][CH3:24])=[CH:4][C:3]=1[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(OCC)(=O)C.CO.[Pd]>[NH2:20][C:10]1[C:11]2[S:15][C:14]([NH:16][CH3:17])=[N:13][C:12]=2[CH:18]=[CH:19][C:9]=1[O:8][C:6]1[C:5]([O:23][CH3:24])=[CH:4][C:3]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:2]([Cl:1])[CH:7]=1
Reactant: CNc1nc2ccc(Oc3cc(Cl)c(CC(=O)OC)cc3OC)c([N+](=O)[O-])c2s1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1nc2ccc(Oc3cc(Cl)c(CC(=O)OC)cc3OC)c(N)c2s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 19.3 (230 mg, 0.53 mmol) was dissolved in mixture of ethyl acetate (3 mL) and methanol (1 mL). 10% Pd/C (56 mg, 0.053 mmol) was added and the reaction mixture was stirred for 1.5 h under H2 at room temperature. The reaction mixture was filtered, the residue concentrated under reduced pressure to afford 19.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH3:14])[CH2:7][CH2:6]2.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([OH:13])[CH:8]([CH3:14])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCC(C)C2O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of 6-methoxy-2-methyl-3,4-dihydro-2H-naphthalen-1-one (7.0 g, 36.8 mmol) in MeOH (120 mL) is added NaBH4 (2.78 g, 73.6 mmol) portion wise and the mixture is stirred at RT for 20 min. Then the reaction is poured to 120 mL of water and extracted with ether. The organic phase is dried with MgSO4, concentrated to give the title compound as a light yellow oil and it is used in the next step without purification.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])=O.[H-].[Na+].ClC1[N:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([O:25][CH3:26])[N:18]=1.[OH-].[Na+]>O1CCCC1>[CH3:26][O:25][C:19]1[N:20]=[C:21]([O:23][CH3:24])[N:22]=[C:1]([NH:3][C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=2[N+:11]([O-:13])=[O:12])[N:18]=1
Reactant: Cc1ccc(NC=O)c([N+](=O)[O-])c1
Reactant: COc1nc(Cl)nc(OC)n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1nc(Nc2ccc(C)cc2[N+](=O)[O-])nc(OC)n1
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
N-formyl-4-methyl-2-nitroaniline (7.2 g) was dissolved in tetrahydrofuran (50 ml), and sodium hydride (60% purity, oily) (2.0 g) was added thereto at room temperature. After stirring for 10 minutes, 2-chloro-4,6-dimethoxy-[1,3,5]triazine (7.0 g) was added at room temperature, followed by stirring for 3 hours. A 10% aqueous sodium hydroxide solution was added thereto, and the crystals were collected by filtration, washed with water and dried to obtain 10.0 g of the desired product as a yellow powder (m.p. 189-191° C.).