Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2>C1COCC1>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[N:29]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][CH:34]=[CH:33]3)[C:14](=[O:16])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CN(Cc2ccccc2)CC(=O)N1c1ccc2[nH]ccc2c1

Procedure:
N-Benzyliminodiacetic acid was reacted with CDI and 5-aminoindole in THF to obtain 4-benzyl-1-(1H-indol-5-yl)piperazine-2,6-dione, which was then reacted with lithium aluminum hydride in THF. Conc. hydrochloric acid and palladium hydroxide were added to an ethanol solution of thus obtained compound and the whole was reacted under a hydrogen atmosphere of 3 atm for 65 hours to obtain an objective compound.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].C(N(CC)CC)C.[C:23](OC([O-])=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C)C=O>[C:26]([O:25][C:23]([N:12]1[CH2:13][CH2:14][C:6]2([C:5](=[O:15])[N:4]([O:3][CH3:2])[C:8](=[O:9])[CH2:7]2)[CH2:10][CH2:11]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON1C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (1.5 g) in dimethylformamide (100 ml) was added triethylamine (1 ml), followed by tert-butyl dicarbonate (2.05 ml), and this was followed by stirring at room temperature for 1 hour. The solvent was evaporated off under reduced pressure. To the residual oil dichloromethane (50 ml) was added, after which it was washed with a 10% aqueous solution of citric acid, then with water. After drying the organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residual solid was recrystallized with ethyl ether to obtain 1.4 g of a colorless crystal having a melting point of 117° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[O:33])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N=C=O
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: COc1ccccc1NC(=O)NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 2-methoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[C:32]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>ClCCl>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[N:6][CH:7]=2)=[O:41])=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Reaction time: 0.08 h

Procedure:
To a solution of compound of example 392 (100 mg, 0.295 mmol) in dichloromethane (3 mL), pyridine (70.53 mg, 0.885 mmol) was added and stirred for 5 min. To the reaction mixture, 4-tert-butylbenzoyl chloride (87.27 mg, 0.443 mmol) was added and stirred for about 16 h. After completion of the reaction, the solvent was evaporated and the crude material obtained was triturated with diethyl ether to obtain the title compound, which was filtered and dried.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6]1C(=O)C)C.Cl.O1CCOCC1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CC(O)=O.[OH-].[Na+]>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([N:6]2[CH2:7][CH2:8][C@@H:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:5]2[C:4]([OH:3])=[O:19])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1[C@H](c2ccccc2)CCN1C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2CC[C@@H](c3ccccc3)[C@H]2C(=O)O)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
N-Acetyl-cis-3-phenylproline ethyl ester (614 mg, 2.35 mmol) (prepared via the method of Chung, et al., J. Org. Chem.55: 270-275 (1990)) was dissolved in HOAc (4 mL) and 6N HCl (12 mL) and heated at reflux for 18 hr. The mixture was cooled to room temperature and the volatiles were evaporated in vacuo to give a white solid. The solid was dissolved in 1N NaOH (15 mL) and dioxane was added (10 mL), followed by 4-toluene-sulfonyl chloride (458 mg, 2.40 mmol). The mixture was stirred at room temp for 18 hr before addition of 6N HCl to bring the pH<4. The mixture was extracted with Et2O (3×40 mL) and the extracts were dried (MgSO4), filtered, and evaporated in vacuo to give N-(toluene-4-sulfonyl)-cis-3-phenylproline as a white solid (765 mg, 94%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([O:14][CH3:15])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:3]([CH3:16])=[C:4]([O:14][CH3:15])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=4[C:12]=3[CH3:13])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)(C)C2
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 49.2 %

Procedure:
By using 5-bromo-7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran (600 mg, 2.10 mmol) synthesized in Reference example 94 and 1-(4-fluorophenyl)piperazine (757 mg, 4.20 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 397 mg (yield 49%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Cl[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1
Reactant: ClCc1cscn1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2cscn2)c1Cl

Procedure:
Synthesized as described in Example 39 from 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile and 4-(chloromethyl)-1,3-thiazole: MS (ESI) m/z 324 (M+1)
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5](=[C:7]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[C:8]1=O)[O-])C.[K+].[O:16]=[S:17]1(=[O:24])[CH2:21][CH2:20][CH:19]([NH:22][NH2:23])[CH2:18]1>>[O:16]=[S:17]1(=[O:24])[CH2:21][CH2:20][CH:19]([N:22]2[C:8]3[C@@H:9]4[CH2:10][C@@H:11]4[CH2:12][C:7]=3[C:5]([C:4]([OH:3])=[O:14])=[N:23]2)[CH2:18]1
Reactant: NNC1CCS(=O)(=O)C1
Reactant: CCOC(=O)C([O-])=C1C[C@H]2C[C@H]2C1=O
Agent: [K+]
Product: O=C(O)c1nn(C2CCS(=O)(=O)C2)c2c1C[C@H]1C[C@@H]21

Procedure:
(1aR,5aR)-2-(1,1-Dioxo-tetrahydrothiophen-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid was prepared in a manner similar to that described in Method C and D using potassium 2-ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate and (1,1-dioxo-tetrahydrothiophen-3-yl)hydrazine.
Reaction SMILES: N12CCCN=C1CCC[CH2:3][CH2:2]2.C(I)C.[C:15]([NH:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:21]([OH:23])=[O:22])(=[O:17])[CH3:16].C(NC(NC(OCC1C=CC=CC=1)=O)(C)C(OCC)=O)(=O)C>C(#N)C>[C:15]([NH:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:21]([O:23][CH2:2][CH3:3])=[O:22])(=[O:17])[CH3:16]
Reactant: CC(=O)NC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCC2=NCCCN2CC1
Agent: CCOC(=O)C(C)(NC(C)=O)NC(=O)OCc1ccccc1
Solvent: CCI
Solvent: CC#N
Product: CCOC(=O)[C@@H](CNC(C)=O)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.45 ml., 3.0 mmole) and ethyl iodide (0.3 ml., 3.75 mmole) are added to a solution of (R)-3-(acetylamino)-2-[[(benzyloxy)carbonyl]amino]propanoic acid (0.7 g., 2.5 mmole) in acetonitrile (15 ml.). The reaction is allowed to stir overnight then concentrated in vacuo. The residue is dissolved in methylene chloride, washed with 2N hydrochloric acid (2×50 ml.), sodium bicarbonate (2×50 ml.), and brine, and then dried over sodium sulfate. The solvent is removed in vacuo and the resulting oil is chromatographed on silica gel eluting with ethyl acetate to yield 0.6 g. of (R)-3-(acetylamino-2-[[(benzyloxy)carbonyl]amino]propanoic acid, ethyl ester as a clear oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:20][N:21]([CH3:24])[CH:22]=[O:23].C(N(CC)CC)C.CN(C)C(Cl)=O>O>[CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH:17][C:22]([N:21]([CH3:24])[CH3:20])=[O:23])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CC1Cc2cc(COc3ccc(N)cc3)ccc2O1
Reactant: CN(C)C=O
Agent: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1Cc2cc(COc3ccc(NC(=O)N(C)C)cc3)ccc2O1
Temperature: 25 °C

Procedure:
6.5 g of 4-(2,3-dihydro-2-methyl-5-benzofuranylmethyloxy)aniline was dissolved into 70 ml of N,N-dimethylformamide, and 2.8 g of triethylamine was added thereto. 3.8 g of N,N-dimethylcarbamoyl chloride was slowly added dropwise thereto. After the mixture was stirred at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (2/1) as a developer to obtain 5.8 g of Compound No. 41 shown in Table 2.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([O:26]C)=[O:25])=[CH:14][CH:13]=1>>[CH2:1]([C:5]1[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[N:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncn[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1ncnn1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 20.5 %

Procedure:
Following General Procedure A, 5.0 g (39.9 mmol) of 5-butyl-1H-1,2,4-triazole was coupled with 12.2 g (39.9 mmol) of the alkylating reagent prepared in step 1 of Example 1 to give 3.1 g (22%) of a faster moving isomer: NMR (CDCl3) δ 0.90 (t, J=8 Hz, 3H), 1.29–1.45 (m, 2H), 1.63–1.76 (m, 2H), 2.71 (t, J=8 Hz, 2H), 3.62 (s, 3H), 5.34 (s, 2H), 7.14–7.20 (m, 2H), 7.24–7.33 (m, 3H), 7.40 (dt, J=8 and 2 Hz, 1H), 7.50 (dt, J=8 and 2 Hz, 1H), 7.82 (dd, J=8 and 2 Hz, 1H), 7.85 (s, 1H) and 3.7 g (26%) of a slower moving isomer: NMR (CDCl3) δ 0.92 (t, J=8 Hz, 3H), 1.31–1.46 (m, 2H), 1.66–1.79 (m, 2H), 2.73 (t, J=8 Hz, 2H), 3.62 (s, 3H), 5.28 (s, 2H), 7.21–7.34 (m, 5H), 7.39 (dt, J=8 and 2 Hz, 1H), 7.50 (dt, J=8 and 2 Hz, 1H), 7.83 (dd, J=8 and 2 Hz, 1H), 7.94 (s, 1H). The faster moving isomer was hydrolyzed to give 2.75 g (92%) of 4′-[(5-butyl-1H-1,2,4-triazol-1-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ 0.85 (t, J=8 Hz, 3H), 1.23–1.38 (m, 2H), 1.52–1.65 (m, 2H), 2.76 (t, J=7 Hz, 2H), 5.41 (s, 2H), 7.16–7.24 (m, 2H), 7.27–7.37 (m, 3H), 7.44 (dt, J=8 and 2 Hz, 1H), 7.56 (dt, J=8 and 2 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H), 7.86 (s, 1H); MS (FAB) m/e (rel intensity) 336 (100), 307 (7), 289 (7), 224 (8), 211 (100), 193 (9).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[CH:22](OCC)=[O:23]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH:15][CH:22]=[O:23])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: CCOC=O
Product: O=CN[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Yield: 100 %

Procedure:
trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) was dissolved in 1 mL of ethyl formate. The resulting mixture was heated to reflux for 18 h. The cooled mixture was evaporated to give trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)formamide (12.0 mg, 100%). Data: (m/z)=329 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:21])C=1>C(OCC)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:12])[N+:11]=1[O-:21])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOc1cccc(C)n1
Solvent: CCOCC
Product: CCCCOc1cccc(C)[n+]1[O-]
Yield: 51.5 %

Procedure:
To a solution of 19.0 g (0.12 mol) of 6-butoxy-α-picoline dissolved in 250 ml of diethyl ether was portionwise added 23.8 g (0.14 mol) of m-chloroperbenzoic acid under ice-cooling. After standing under ice-cooling for one hour, the mixture was further left to stand at room temperature for several days. The reaction mixture was extracted with water and then adjusted to pH=11 with an addition of sodium carbonate. After extraction with chloroform, the extract was concentrated under a reduced pressure to give 11.2 g of the desired product.
Reaction SMILES: C(O)CC.Cl.[CH2:6]([O:8][NH2:9])[CH3:7].[CH3:10][N:11]1[C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[CH3:33])=O)=[CH:14][CH:13]=[N:12]1>O>[CH2:6]([O:8][N:9]=[C:16]([C:15]1[N:11]([CH3:10])[N:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[CH3:33])[CH3:7]
Reactant: CCON
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccnn2C)c1
Agent: Cl
Solvent: O
Solvent: CCCO
Product: CCON=C(c1ccccc1COc1cc(C)ccc1C)c1ccnn1C
Yield: 45.9 %

Procedure:
n-Propanol (2 ml) and ethoxyamine hydrochloride (0.18 g, 1.8 mmol) were added to 2-(2,5-dimethylphenoxy-methyl)phenyl 1-methylpyrazol-5-yl ketone (0.20 g, 0.6 mmol), and the mixture was stirred under reflux for 3 days. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.11 g, 50.4%, as colorless crystals) and isomer B (0.10 g, 45.9%, as colorless crystals) of 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone O-ethyloxime.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=1[F:25])[CH:13]=[CH2:14].C(NC1C=CC(S([N:40]=[N+:41]=[N-])(=O)=O)=CC=1)(=O)C>C1COCC1>[CH2:12]([O:15][C:16](=[O:26])[C:17]([C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=1[F:25])=[N+:40]=[N-:41])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)Cc1cc(Br)ccc1F
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOC(=O)C(=[N+]=[N-])c1cc(Br)ccc1F
Temperature: 23 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.2 ml, 28 mmol) in THF (24 ml) at 23° C. was added a solution of (5-bromo-2-fluoro-phenyl)-acetic acid allyl ester (intermediate B3A) (7.29 g, 27 mmol) and commercially available p-acetamidobenzenesulfonyl azide ([CAS No. 2158-14-7], 6.94 g, 28 mmol) in THF (48 ml) over 1 h. The mixture was stirred for 5 h at 23° C. Then it was quenched with sat. aqueous ammonium chloride solution, diluted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. Removal of the solvent in vacuum left a yellow oil, which was purified by silica gel column chromatography with hexane/ethyl acetate to give the title compound as a yellow solid (7.344 g, 92%). MS (ISP): m/z=316.1 [(M+NH4)+] and 318.0 [(M+2+NH4)+].
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH:26]=O)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[N:28]1([C:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[S:36](=[O:44])(=[O:43])[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:44]=[S:36]1(=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:34]([N:28]2[CH2:33][CH2:32][N:31]([CH2:26][CH2:25][CH2:24][N:11]3[C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]=4[C:13]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:12]3)[CH2:30][CH2:29]2)=[N:35]1
Reactant: O=S1(=O)N=C(N2CCNCC2)c2ccccc21
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(C3=NS(=O)(=O)c4ccccc43)CC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a stirred solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (0.040 g, 0.13 mmol) and 3-piperazin-1-yl-benzo[d]isothiazole 1,1-dioxide (0.050 g, 0.21 mmol) in CH2Cl2 (0.5 mL), glacial AcOH (12 μL, 0.21 mmol) was added and stirred for 15 min at room temperature. NaBH(OAc)3 (0.058 g, 0.27 mmol) was added and stirred under nitrogen overnight. Saturated NaHCO3 (0.5 mL) was then added and stirred for 15 min. The layers separated and the aqueous layer was extracted with CH2Cl2 (0.5 mL). MPLC (silica, 2-15% MeOH/CH2Cl2) afforded the desired product as a white solid (0.048 g, 76%). TLC (silica, 12% MeOH/CH2Cl2): Rf=0.50. MS (electrospray): exact mass calculated for C28H31F3N6O4S2, 636.18; m/z found, 637.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.94 (dd, J=0.8, 7.6 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.73-7.63 (m, 2H), 7.68 (d, J=8.3 Hz, 2H), 4.57 (s, 2H), 4.17 (t, J=6.9 Hz, 2H), 4.04 (br s, 4H), 3.69 (t, J=5.7 Hz, 2H), 2.94 (s, 3H), 2.92 (t, J=6.2 Hz, 2H), 2.62 (t, J=5.0 Hz, 4H), 2.44 (t, J=6.6 Hz, 2H), 2.13 (q, J=6.6 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[NH:23]1[CH2:26][CH:25]([CH2:27][N:28]2[CH:32]=[CH:31][CH:30]=[N:29]2)[CH2:24]1>>[N:28]1([CH2:27][CH:25]2[CH2:26][N:23]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:24]2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: c1cnn(CC2CNC2)c1
Product: c1cnn(CC2CN(c3c4c(nc5ccnn35)CCNCC4)C2)c1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 1-azetidin-3-ylmethyl-1H-pyrazole was used as the amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@@H:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[NH:33][C:32](=[O:34])[N:31]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:30]=2[CH:41]=1>CCO.C(Cl)Cl>[C:17]([N:14]1[CH2:15][CH2:16][C:11]2[N:10]([CH2:20][C@@H:21]([OH:22])[CH2:23][N:38]3[CH2:37][CH2:36][CH:35]([N:31]4[C:30]5[CH:41]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=5[NH:33][C:32]4=[O:34])[CH2:40][CH2:39]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=3)[C:12]=2[CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2C[C@@H]2CO2)C1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCNCC1
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2C[C@@H](O)CN2CCC(n3c(=O)[nH]c4ccc(Cl)cc43)CC2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 11.7 %

Procedure:
(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (31 mg, 0.10 mmol) and 6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (36 mg, 0.17 mmol) were combined in EtOH (0.3 mL) and heated to 70° C. After 18 h the mixture was allowed to cool, diluted with CH2Cl2 and purified by preparative TLC (silica, 8% MeOH/CH2Cl2) to give 7 mg (12%) of the title compound. HPLC (reverse phase conditions), tR=3.49 min. MS (electrospray): m/z calculated for C30H3535Cl2N6O3 [M++H] 597.22. found 597.20. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 9.16 (br d, J=10.1 Hz, 1H), 7.55 (br m, 1H), 7.40-7.28 (m, 2H), 7.18 (br s, 1H), 7.03 and 6.98 (A and B of ABX (with fine splittings), Jab=8.4 Hz, 2H), 4.85 and 4.74 (A and B of ABX (with fine splittings), Jab=15.7 Hz, 1H), 4.62 (s, 1H), 4.29-4.18 (m, 4H), 4.09-4.00 (m, 2H), 3.91-3.71 (m, 2H), 3.16-2.78 (m, 4H), 2.55-2.50 (m, 4H), 2.43 (s, 1.5H), 2.41 (s, 1.5H), 2.23 (m, 1H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 1.84 (br s, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:14].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][C:8]=1[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(NS(C)(=O)=O)ccc1Br
Reaction time: 2 h

Procedure:
Methanesulphonyl chloride (0.88 ml) was added dropwise to a stirred solution of 4-bromo-3-methylbenzenamine (1.02 g) in pyridine (9 ml) under nitrogen at -10° to -14° C. After 2 h, aqueous (8%) sodium bicarbonate (35.6 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined, dried organic extracts were evaporated and the residue crystallized from ethyl acetate to give the title compound as a white powder (100 mg). The mother liquors were evaporated onto silica gel (Merck 7734, 3 ml) and the residue applied as a plug to a flash column of silica gel (Merck 9385). Elution with hexane:ethyl acetate (85:15) afforded a further sample of the title compound as a white solid (250 mg).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:13])[CH:5]=[CH:4][N:3]=1.[CH2:14]([Zn]CC)[CH3:15].O.Cl>O1CCOCC1>[Cl:13][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:14][CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1c(Cl)ccnc1Br
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(Cl)ccnc1CC
Temperature: 40 °C
Yield: 63 %

Procedure:
Ethyl 2-bromo-4-chloropyridine-3-carboxylate (1.5 g, 5.7 mmol) was dissolved in anhydrous dioxane (45 mL). A solution of diethyl zinc (4.6 mL, 5.1 mmol, 1.1 M in toluene) was added dropwise, and then was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (62 mg, 85 mol). The mixture was heated at 40° C. overnight, and then water plus 1 N HCl were added. The reaction mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-15% hexane/ethyl acetate to afford ethyl 4-chloro-2-ethylpyridine-3-carboxylate (687 mg, 57% yield).