Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.ClC(OCC(C)C)=O.[CH3:32][N:33]([CH:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)[CH3:34]>O1CCCC1>[CH3:32][N:33]([CH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH2:37][CH2:36]1)[CH3:34]
Reactant: Cn1nnnc1CCCC(O)=S
Reactant: CN(C)C1CCC(N)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C1CCC(NC(=S)CCCc2nnnn2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-(1-Methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml), and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise 4-(N,N-dimethylamino)cyclohexylamine (54 mmole), and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the resulting residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and then dried over anhydrous sodium sulfate. Chloroform is distilled off, and the resulting residue is subjected to silica gel column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-[4-(N,N-dimethylamino)cyclohexyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 47%).
Reaction SMILES: C[N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1.C(OCC)C>[C:21]([N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CN1CCN2c3ccccc3Cn3cccc3C2C1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
To the solution of 1.9 g of 2-methyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine in 50 ml of benzene, 2.14 g of ethyl chloroformate are added and the mixture is refluxed for 3 days. It is diluted with diethyl ether, washed with N hydrochloric acid and with both saturated aqueous sodium chloride and sodium bicarbonate, dried and evaporated, to yield the 2-carbethoxy-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine showing in the NMR-spectrum peaks at 8.55(t), 6.60(m), 5.65(q) and 3.90(d) ppm, and in the mass-spectrum a molecular ion of 311.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9][C@@H:8]1[C:22]([O:24][CH3:25])=[O:23].ClCCl>CO.O>[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9][C@@H:8]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)[C@H]1CN(CCCc2ccccc2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1CN(CCCc2ccccc2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 1.25 h
Yield: 87.1 %

Procedure:
0.15 g of sodium borohydride was added portionwise at a temperature in the region of 20° C. and under an inert atmosphere to a stirred solution of 1.59 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-3-carboxylate in 25 cm3 of methanol. The mixture was subsequently stirred for 75 minutes at a temperature in the region of 20° C. 15 cm3 of distilled water were then added while maintaining the same temperature. The mixture, with a milky appearance, was concentrated under reduced pressure (5 kPa) at a temperature in the region of 30° C. The residue obtained was taken up in 40 cm3 of distilled water to which have been added 80 cm3 of dichloromethane, stirred, and then separated by settling. The organic phase was withdrawn and then washed with one times 40 cm of water and dried over magnesium sulfate. After filtering through paper and then evaporating the solvent under reduced pressure (5 kPa) at a temperature in the region. of 40° C., 1.39 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-3-carboxylate were obtained in the form of a sticky solid with a foamy appearance and an orange color.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(CO)[CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH:37]2[CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCC4CCC4)c(C)c3C)c2cc1OC
Yield: 87.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclobutylmethanol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (59 mg, yield 83%).
Reaction SMILES: [O:1]([C@H:9]1[CH:13]=[CH:12][C@H:11]([OH:14])[CH2:10]1)[Si](C(C)(C)C)(C)C.CC[O:17][C:18]([CH3:20])=[O:19].[CH3:21][CH2:22]CCCC>>[OH:14][C@@H:11]1[CH:12]=[CH:13][C@@H:9]([O:1][CH:20]([CH2:21][CH3:22])[C:18]([OH:17])=[O:19])[CH2:10]1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@H](O)C1
Product: CCC(O[C@@H]1C=C[C@@H](O)C1)C(=O)O
Yield: 71 %

Procedure:
Compound 22 was subjected to general procedure D. Yield=71%. TLC: Rf=0.33 (10% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3): δ0.05 (s, 6H), 0.90 (s, 9H), 1.30 (t, 3H), 1.90 (m, 1H), 2.20 (m, 1H), 4.05 (s, 2H), 4.20 (q, 2H), 4.75 (m, 1H), 5.05 (m, 1H), 6.00 (m, 2H). Subsequent subjection of the product to general procedure K gave compound 23. Yield=91%. TLC: Rf=0.25 (50% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3): δ1.25 (t, 3H), 2.00 (m, 1H), 2.25 (m, 1H), 4.05 (s, 2H), 4.20 (q, 2H), 4.80 (m, 1H), 5.05 (m, 1H), 6.05 (m, 2H).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)CCN.C1(=O)CCCCC1>C(OC(=O)C)C>[CH:1]1([N:7]([CH2:21][CH2:22][CH:23]([CH3:28])[CH3:24])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CC(C)CCN
Solvent: CCOC(C)=O
Solvent: O=C1CCCCC1
Product: CC(C)CCN(C(=O)Nc1ncc(SCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 3-methyl-butylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]1[N:8]([CH2:9][CH2:10][NH+:11]([CH2:22][C:23]([O-:25])=[O:24])[CH2:12][CH2:13][N:14]2[CH2:21][C:19](=[O:20])[O:18][C:16](=[O:17])[CH2:15]2)[CH2:7][C:5](=[O:6])[O:4][C:2]1=[O:3].[NH2:26][CH2:27][CH2:28][NH2:29]>CS(C)=O.CS(C)=O.C1CN2C(=NCCC2)C1>[C:16]([CH2:15][N:14]1[CH2:21][C:19](=[O:20])[NH:29][CH2:28][CH2:27][NH:26][C:2](=[O:3])[CH2:1][N:8]([CH2:7][C:5]([OH:4])=[O:6])[CH2:9][CH2:10][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:12][CH2:13]1)([OH:18])=[O:17]
Reactant: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Reactant: NCCN
Agent: C1CN=C2CCCN2C1
Solvent: CS(C)=O
Product: O=C(O)CN1CCN(CC(=O)O)CC(=O)NCCNC(=O)CN(CC(=O)O)CC1
Reaction time: 48 h
Yield: 30.4 %

Procedure:
A 500 mL three-neck flash was charged with 150 mL of dry DMSO and the flask flushed with nitrogen. Two syringes were charged separately with solutions of diethylenetriaminepentaacetic acid dianhydride (2.00 g, 5.60 mmol) in 125 mL of DMSO, and 1,2-diaminoethane (0.336 g, 5,60 mmol) in DMSO/DBN (122 mL/3 mL). The solutions were added simultaneously to the flask at ambient temperature at a rate of 40 mL/hour. After the addition was complete, the reaction mixture was allowed to stir for 48 hours, concentrated under vacuum to 10 mL and 5 mL of water added. This solution, at pH 10.9, was applied to AG1-X8 (100-200 mesh, OAc-) resin, and the column eluted with 0.5N acetic acid to yield 0.71 g (30%) product as a white solid after acetic acid removal and lyophilization.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([OH:59])[CH2:40]2)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:58][C:45]1[CH:44]=[C:43]2[O:42][CH:41]([OH:59])[CH2:40][C@@:10]3([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:48]2=[CH:47][C:46]=1[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(O)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 88.7 %

Procedure:
To a solution of 41 (20 mg, 25 μmol) in a mixture of MeOH (1.5 mL) and THF (0.5 mL) was added Pd(OH)2 on carbon (15 mg). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory HPLC to give 44 (10 mg, 90%) as a mixture of two diastereomers. LCMS m/z 433 (M−OH).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1F
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccccc4F)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 7 h
Yield: 32.6 %

Procedure:
1,1-Dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D54) (0.1 g, 0.218 mmol) and 2-fluorophenol (0.025 g, 0.436 mmol) were dissolved in DMF (5 mL). Potassium carbonate (0.06 g, 0.436 mmol) was added and the mixture was heated to 80° C. overnight then at 130° C. for 7 h. The mixture was left to stand at room temperature overnight and the solvent removed under vacuum. The residue was partitioned between EtOAc and water. The organic layer was dried and concentrated to produce a brown oil. The crude product was purified by MDAP to yield the formic acid salt. The salt was taken up in DCM and washed with sat. NaHCO3. The DCM layer was dried and concentrated to yield the title compound as a colourless oil (0.038 g). δH (CDCl3, 400 MHz) 8.02 (1H, d), 7.68 (1H, dd), 7.23 (2H, d), 7.15 (4H, m), 6.98 (2H, d), 6.78 (1H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.48 (3H, s), 3.46 (1H, d), 3.33 (1H, d), 3.08 (1H, td), 2.69 (1H, d), 2.51 (1H, d), 2.10 (1H, dd), 1.98 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH+ 535.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[N:17]1([CH2:22][CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>Cl>[ClH:8].[N:17]1([CH2:22][CH:23]2[CH2:28][CH2:27][C:26]3([NH:1][C:2]4[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][C:3]=4[S:13](=[O:15])(=[O:14])[NH:16]3)[CH2:25][CH2:24]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: O=C1CCC(CN2CCCC2)CC1
Agent: Cl
Product: NS(=O)(=O)c1cc2c(cc1Cl)NC1(CCC(CN3CCCC3)CC1)NS2(=O)=O
Yield: 168.9 %

Procedure:
A mixture of 4-amino-6-chloro-1,3-benzenedisulfonamide (5.72 g., 0.02 mole) and 4-(1-pyrrolidinylmethyl) cyclohexanone (5.0 g., 0.027 mole) in 2 N ethanolic HCl (100 ml.) is refluxed one and one half hours and cooled to give 8.2 g of 4'-(1-pyrrolidinylmethyl)-6-chlorospiro[2H-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-7-sulfonamide-1,1-dioxide hydrochloride which melts at 268°-70° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN.C(O)C>C(Cl)Cl>[NH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
A mixture of 2.62 g (6.35 mmole) of N-[[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl]phthalimide, 1.21 ml (1.25 g, 25 mmole) of 100% hydrazine hydrate, and 35 ml of absolute ethanol was stirred at room temperature for 7.5 hours. During this time all of the solid gradually dissolved, followed by precipitation. Glacial acetic acid (3.7 ml) was added, and stirring was continued overnight. The white solid was then removed by filtration, and the filtrate was concentrated at room temperature. The residual oil was taken up in 100 ml of ether and washed with 2×50 ml of saturated aqueous Na2CO3 solution. Next, the product was extracted by shaking the ethereal solution with 50 ml of 0.5 N HCl. The aqueous layer was separated and basified by addition of excess saturated Na2CO3. The product, which oiled out, was extracted with 100 ml of ether. The ether phase was dried (Na2SO4), filtered, and concentrated at 30° C. to give 1.58 g (88%) of a very pale yellow, viscous oil, homogeneous by TLC in 95:5:0.5 CH2Cl2 --MeOH-concd NH40H.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH:25]C(OC(C)(C)C)=O)[C:20](=[O:24])[N:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(Cl)[Cl:35]>>[ClH:35].[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH2:25])[C:20](=[O:24])[N:21]([CH3:22])[CH3:23])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCc1ccc(-c2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Reactant: ClCCl
Product: COC(=O)CCc1ccc(-c2ccc(CC(N)C(=O)N(C)C)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Amide compound 45 (2.7 g) was dissolved in CH2Cl2 (50 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 2 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual sticky solid was dried under vacuum without further purification to yield the crude hydrochloride salt 53 (2.2 g, 94.8%). 1H NMR (DMSO-d6): 10.55 (b, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.31 (overlapped d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 4.57 (m, 1H), 3.58 (s, 3H), 2.99-3.20 (m, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.80 (s, 3H), 2.69 (s, 3H), 2.66 (t, J=7.6 Hz, 2H).
Reaction SMILES: [CH:1]1([N:6]([C@H:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29]C=2)C=C)[C:7](=[O:23])[CH:8]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]1([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH:1]1([N:6]2[C@H:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:33]=3)[CH:11]=[CH:10][CH2:9][C@@H:8]([N:12]3[C:20](=[O:21])[C:15]4[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13]3=[O:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:1]1([N:6]2[C@H:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:11]=[CH:10][CH2:9][C@H:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1
Reactant: C=CCC(C(=O)N(C1CCCC1)[C@@H](C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Temperature: 80 °C
Reaction time: 0.58 h
Yield: 90 %

Procedure:
To a solution of N-cyclopentyl-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[(1S)-1-phenylprop-2-en-1-yl]pent-4-enamide (330 mg) dissolved in Toluene (30 mL) at 80° C. under N2 was added Grubbs catalyst (2nd generation) (33 mg) and the reaction mixture was stirred at 80° C. for 35 minutes, cooled to RT and concentrated in vacuo. The crude product was directly purified via flash chromatography (gradient—10%, 15% EtOAc/hexanes) to give the title compounds, 2-[(3R,7S)-1-cyclopentyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-1H-isoindole-1,3(2H)-dione (8d) (182 mg) and 2-[(3S,7S)-1-cyclopentyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-1H-isoindole-1,3(2H)-dione (8c) (95 mg, combined yield of 90%). (8d) 1H NMR (300 MHz, CDCl3) δ 1.44-1.70 (m, 6H), 1.85-2.04 (m, 3H), 2.36-2.43 (m, 1H), 3.69-3.81 (m, 1H), 5.02-5.15 (m, 2H), 5.18-5.30 (m, 1H), 5.98-6.05 (m, 1H), 6.35-6.42 (m, 1H), 7.19-7.52 (m, 5H), 7.64-7.87 (m, 4H). MS APCI, m/z=401 (M+1), LC/MS, 2.73 min. (8c) 1H NMR (300 MHz, CDCl3) δ 1.14-1.88 (m, 9H), 2.25-2.32 (m, 1H), 3.37-3.48 (m, 1H), 4.01-4.11 (m, 1H), 5.30 (dd, 1H, J=13 Hz, J=4 Hz), 5.52 (d, 1H, J=7 Hz), 6.04-6.11 (m, 1H), 6.43-6.50 (m, 1H), 7.29-7.55 (m, 5H), 7.69-7.90 (m, 4H). MS APCI, m/z=401 (M+1), LC/MS, 2.80.
Reaction SMILES: [Mg].[O:2]([CH2:10][CH2:11][C:12]1[CH:13]=[C:14](Br)[CH:15]=[CH:16][CH:17]=1)[Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:23]=[CH:22][C:21]=1[C:32]([O:34]C1C=CC=CN=1)=S>O1CCCC1>[NH2:19][C:20]1[N:24]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[N:23]=[CH:22][C:21]=1[C:32](=[O:34])[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][CH2:10][O:2][Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4])[CH:13]=1
Reactant: Nc1c(C(=S)Oc2ccccn2)cnn1-c1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.9 %

Procedure:
Into an oven dried flask containing magnesium turnings (0.386 g, 15.9 mmol) and tetrahydrofuran (10 ml) was added 3-(2-tert-butyldimethylsiloxyethyl)bromobenzene (5.0 g, 15.9 mmol) and the reaction mixture was heated at reflux. After 3 h, the reaction mixture was cooled to room temperature and 5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (2.37 g, 7.6 mmol) was added and the stirring was continued for 16 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous ammonium chloride and brine and dried over sodium sulfate. The organics were removed in vacuo and the residue was purified by flash chromatography (elution gradient: 10-30% ethyl acetate/hexane) to give 5-amino-1-(4-fluorophenyl)-4-[3-(2-tert-butyldimethylsiloxyethyl)benzoyl]pyrazole (1.20 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](C(Cl)(Cl)Cl)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:13]Cl>>[Cl:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1
Reactant: Clc1cnc(C(Cl)(Cl)Cl)c(Cl)c1
Reactant: ClCl
Product: Clc1cnc(Cl)c(Cl)c1

Procedure:
The batch chlorinator R1 was charged with 50 grams of starting material containing 90.4% 3,5-dichloro-2-trichloromethyl pyridine by weight, and chlorine was sparged through the reactor by means of sparger 14 for 15 hours at a reaction temperature of 170° C. Samples were taken at the time which corresponded to about 14% conversion of the 3,5-dichloro-2-trichloromethly pyridine. The yield of 2,3,5-trichloropyridine at this temperature, was about 14%, i.e., about half the yield of like runs at 200° C. (Table ONE). The chlorination was then continued under the same reaction conditions except at a temperature of 160° C. and yielded no appreciable quantity of 2,3,5-trichloropyridine in 8 hours. Analytical data with respect to this Example are presented in the following Table TWO:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=O)[CH3:4].[C:8](O)(=O)C.[CH:12]([NH2:14])=[NH:13]>C(O)CCC>[C:2]([C:3]1[CH:4]=[CH:8][N:14]=[CH:12][N:13]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: N=CN
Reactant: CC(=O)O
Reactant: CC(=O)C(C)(C)C
Solvent: CCCCO
Product: CC(C)(C)c1ccncn1
Temperature: 130 °C
Reaction time: 24 h
Yield: 36.7 %

Procedure:
A 100 mL reaction flask is charged with 3,3-dimethyl-butan-2-one (10 g, 0.1 mol), formamidine acetate (57 g, 0.5 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 4-tert-butyl-pyrimidine (˜5 g) is obtained.
Reaction SMILES: [O:1]1CCCC1.[Cl:6][C:7]1[C:8]([C:20]([NH2:22])=O)=[N:9][CH:10]=[C:11]([Cl:19])[C:12]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16].[C:23]([N:30]1C=CN=C1)(N1C=CN=C1)=[O:24].N12CCCN=C1CCCCC2>O>[Cl:6][C:7]1[C:8]([C:20]2[NH:22][O:1][C:23](=[O:24])[N:30]=2)=[N:9][CH:10]=[C:11]([Cl:19])[C:12]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Reactant: NC(=O)c1ncc(Cl)c(OCC(F)(F)F)c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=c1nc(-c2ncc(Cl)c(OCC(F)(F)F)c2Cl)[nH]o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4 ml of tetrahydrofuran were added 0.55 g of 3,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide=oxime and 0.38 g of 1,1′-carbonyldiimidazole, and the mixture was stirred at room temperature for 2 hours. Thereafter, 0.36 g of 1,8-diazabicyclo[5,4,0]undec-7-ene was added at 10° C., and the mixture was stirred for 8 hours. To the reaction solution were added water and a 10% aqueous HCl solution, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.56 g of 3-[3,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-one (present compound (47)).