Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:17]2[C:22]([C:23]=1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:17]2[C:22]([C:23]=1[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3NC(=O)OC(C)(C)C)n(CCC(=O)O)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)n(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-{2-[(tert-butoxycarbonyl)amino]phenyl}-3-cyclohexyl-6-(methoxycarbonyl)-1H-indol-1-yl]propanoic acid in DCM (0.05 M) a large excess (>100 eq) of TFA was added and the solution was stirred at RT for 1 h. The volatiles were removed in vacuo to afford the title compound (quant); MS (ES+) m/z 421 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34](=[O:36])[NH2:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:11][CH2:10]1)C)(C)(C)C>Cl.O1CCOCC1.CO>[F:22][C:20]1[CH:19]=[CH:18][C:17]([NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([NH2:35])=[O:36])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[C:16]([O:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH:7][CH3:6])[CH2:10][CH2:11]2)[CH:21]=1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](N(C)C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.684 g tert-butyl-trans-4-(−2-(6-carbamoyl-5-methylthieno[2,3-d]pyrimidin-4-ylamino)-5-fluorophenoxy)cyclohexyl(methyl)carbamate in 5 ml 4 M HCl/dioxane and 5 ml MeOH was stirred at rt for 1.5 h. The reaction mixture was concentrated in vacuo. The crude was purified by chromatography to give the desired product.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:15]([CH3:16])=[C:14]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:13]=[C:12]([CH3:27])[N:11]=1>CS(C)=O>[CH2:2]([CH:3]([O:6][C:10]1[C:15]([CH3:16])=[C:14]([O:17][C:18]2[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])[N:13]=[C:12]([CH3:27])[N:11]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: Cc1cc(C)c(Oc2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC)Oc1nc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-pentanol (0.3 ml) and sodium hydride (60% in oil, 32 mg, 0.81 mmol) in DMSO was stirred at room temperature for 5 minutes. 4-Chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine (150 mg, 0.54 mmol) was added and the resulting mixture was heated at 150° C. for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a beige solid. The solid was purified through silica gel column chromatography using 20% chloroform in hexane as eluent to give the title compound as white crystals, mp 93.5–95.5° C. 1H NMR (CDCl3) δ 6.85 (s, 2H), 5.11 (t, 1H), 2.27 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 2.03 (s, 6H), 1.68 (p, 4H), 0.92 (t, 6H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: CN=C=O
Reactant: NCCSCc1cccnn1
Product: CNC(=O)NCCSCc1cccnn1

Procedure:
By the procedure of Example 24, 3-[(2-aminoethyl)thiomethyl]pyridazine is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-])=O)[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][N:6]([CH2:19][CH3:20])[CH2:5][C:4]1=[O:21])[CH3:2].C(O)C.C(OCC)(=O)C>[Pd]>[NH2:16][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:8]2[CH2:7][N:6]([CH2:19][CH3:20])[CH2:5][C:4](=[O:21])[N:3]([CH2:1][CH3:2])[C:9]=2[CH:10]=1
Reactant: CCN1CC(=O)N(CC)c2cc([N+](=O)[O-])c(OC)cc2C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN1CC(=O)N(CC)c2cc(N)c(OC)cc2C1
Yield: 73.7 %

Procedure:
1,4-Diethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0017 mol) was hydrogenated in a solution of Ethanol (40 mL, 0.7 mol), Ethyl acetate (40 mL, 0.4 mol) and 10% Pd/C (10:90, Palladium:carbon black, 0.05 g) for 12 hrs. The reaction was filtered and the filtrate evaporated to give an oil. This was chromatographed on Alumina (12 g) and eluded with DCM/EtOH (20-1) to give 8-Amino-1,4-diethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as an oil (0.33 g, 74%). LCMS (m/e) 264 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.76 (s, 1H), 6.61 (s, 1H), 5.75 (s, 1H), 4.86 (s, 2H), 3.77 (s, 3H), 3.72-70 (q, 2H, J=6.06 Hz), 3.38 (s, 2H), 2.89 (s, 2H), 1.05-01 (t, 3H, J=7.07 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=2)[CH:5]=[CH:4][C:3]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1.C1C=CN=CC=1.F.[Si](OC)(C)(C)C>CC#N>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][NH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)c1
Agent: CO[Si](C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C1CN(c2ccc(-c3cc[nH]c3)cc2O)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[2-hydroxy-4-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one in MeCN (10 mL) is added HF-Pyridine (0.2 mL, 2.23 mmol) and the reaction mixture is stirred at RT for 2 h. TMSOMe (5 mL) is added to consume unreacted HF, and the crude reaction mixture is concentrated in vacuo. The residue is purified by reverse phase MPLC using 1-40% MeCN/H2O as eluent to give the title compound: (M−1)−=292.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:25](O)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Reactant: CCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(OC(=O)CCCCC)cc3)s2)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
In a 200 ml-round-bottomed flask, 2.00 g (5.93 mM) of 2-(4-hexylphenyl)-5-(4-hydroxyphenyl)thiazole, 0.76 g (6.54 mM) of hexanoic acid and 40 ml of dichloromethane were placed and mixed. To the solution, 1.24 g (6.01 mM) of N,N'-dicyclohexylcarbodiimide and 0.10 g of 4-pyrrolidinopyridine were successively added under stirring at room temperature, followed by further stirring for 7 hours at room temperature to precipitate N,N'-dicyclohexylurea. The resultant N,N'-dicyclohexylurea was filtered off and the solvent of the filtrate was distilled-off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized from a mixture solvent of toluene-methanol to obtain 1.81 g of 2-(4-hexylphenyl)-5-(4-hexanoyloxyphenyl)thiazole (Yield: 70.1%). ##STR198##
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])=[N:3]1.[Li+].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.C1COCC1.IC.O>C1COCC1>[CH3:14][CH:9]1[CH2:10][CH2:11][N:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:8]1=[O:12]
Reactant: Cn1ccc(N2CCCC2=O)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC1CCN(c2ccn(C)n2)C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (1.5 g) in THF (60 mL) was added 1.3 M LHMDS THF solution (7.3 mL) at −78° C., and the mixture was stirred at −78° C. for 1 hr. Iodomethane (0.60 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (927 mg).
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.[C:37]1([CH2:43]CO)[CH:42]=[CH:41][CH:40]=[CH:39][CH: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][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCCc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCc4ccccc4)c(C)c3C)c2cc1OC
Yield: 82.4 %

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, 2-phenyl-1-ethanol (28 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 (60 mg, yield 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26]Cl)[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.[CH3:37]OC([Si](C)(C)C)C.[NH:45]1[CH2:50][CH2:49][S:48](=[O:52])(=[O:51])[CH2:47][CH2:46]1>FC(F)(F)C(O)=O>[CH3:25][CH2:24][N:12]([CH:11]([CH3:10])[CH3:28])[CH:13]([CH3:14])[CH3:37].[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26][N:45]4[CH2:50][CH2:49][S:48](=[O:52])(=[O:51])[CH2:47][CH2:46]4)[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(C)[Si](C)(C)C
Reactant: O=S1(=O)CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1N(CCCN2CCS(=O)(=O)CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 72.1 %

Procedure:
In a manner similar to the method described in example 60b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(3-chloro-propyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 60a (0.21 mg, 0.31 mmol) was reacted with thiomorpholin 1,1-dioxide (0.47 g, 3.48 mmol), trifluoroacetic acid (10 mL) and then N,N′-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[3-(1,1-dioxo-thiomorpholin-4-yl)-propyl]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (72 mg, 36.2%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([N:12]3[C:16](N)=[CH:15][C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13]3)[CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[OH-:22].[Na+].Cl[C:25]([O:27][C:28]([CH3:30])=[CH2:29])=[O:26]>CCOC(C)=O>[C:18]([C:14]1[CH:15]=[C:16]([C:25]([O:27][C:28]([CH3:30])=[CH2:29])=[O:26])[N:12]([C:8]2[CH:7]=[C:6]([C:4]3[CH:3]=[N:2][N:1]([C:25]([O:27][C:28]([CH3:30])=[CH2:29])=[O:22])[CH:5]=3)[CH:11]=[CH:10][CH:9]=2)[N:13]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C=C(C)OC(=O)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(-c3cn[nH]c3)c2)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)c1cc(C(C)(C)C)nn1-c1cccc(-c2cnn(C(=O)OC(=C)C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.1 %

Procedure:
1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-amine (160 mg, 0.57 mmol) in EtOAc (3 mL) was cooled to 0° C. and treated with 1M NaOH (0.85 mL, 0.85 mmol) and isopropenyl chloroformate (0.080 mL, 0.74 mmol). The reaction was allowed to warm to RT overnight. The organic layer was washed with saturated NaHCO3, brine, dried (Na2SO4) and was concentrated to a film, which was dissolved in Et2O (5 mL) and the solution was lowed to stand overnight. The resultant crystals were collected, washed with Et2O and dried in vacuo to provide prop-1-en-2-yl 4-(3-(3-t-butyl-5-((prop-1-en-2-yloxy)carbonyl)-1H-pyrazol-1-yl)phenyl)-1H-pyrazole-1-carboxylate (193 mg, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.73 (brs, 1H), 8.96 (d, J=−0.7 Hz, 1H), 8.46 (d, J=0.7 Hz, 1H), 7.87 (t, J=1.7 Hz, 1H), 7.81 (dt, J=8.2, 1.3 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.41 (brd, J=7.9 Hz, 1H), 6.34 (s, 1H), 5.02 (s, 2H), 4.66 (brs, 1H), 4.57 (brs, 1H), 2.06 (s, 3H), 1.76 (brs, 3H), 1.30 (s, 9H). MS (ESI) m/z: 450.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][CH2:6][C:5]2[CH:8]=[C:9](Br)[CH:10]=[CH:11][C:4]=2[O:3]1.BrCCBr.[CH2:18]([O:25][C:26]([N:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:29][CH:30]=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1([CH3:13])[O:7][CH2:6][C:5]2[CH:8]=[C:9]([CH:30]([OH:31])[CH2:29][N:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: O=CCN(CCCCCCOCCCCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC1(C)OCc2cc(Br)ccc2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC1(C)OCc2cc(C(O)CN(CCCCCCOCCCCc3ccccc3)C(=O)OCc3ccccc3)ccc2O1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To 0.166 g (6.83 mmol) Mg in 1 ml THF is added dropwise a few drops of a solution comprising 1.51 g (6.21 mmol) 2,2-dimethyl-6-bromobenzo-1,3-dioxane in 20 ml THF and a catalytic amount of 1,2-dibromoethane. Once the reaction has started, the remaining 2,2-dimethyl-6-bromobenzo-1,3-dioxane solution was added while maintaining the temperature at 40° C. Upon completion of the addition (15 min), the reaction is allowed to stand a further 30 min at 40° C. The mixture is then cooled to −7° C. and a solution of 2.64 g (6.21 mmol) N-benzyloxycarbonyl-N-2-oxoethyl-6-(4-phenylbutoxy)hexylamine in 5 ml THF is added thereto. After allowing the reaction to stand at 0° C. for 1 hr, the temperature of the reaction mixture is allowed to increase to room temperature, 30 ml of a saturated NH4Cl solution is added and the mixture stirred for 15 min. Finally, 30 ml AcOEt is added, the EtOAc phase is separated, washed with 30 ml H2O, dried on anhydrous Na2SO4 concentrated to dryness and the residue purified by column chromatography on silica gel (gradient CH2Cl2 to CH2Cl2/EtOAc 4:1), to give 1.50 g (40.9%) N-[2-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-2-hydroxyethyl]-N-benzyloxycarbonyl-6-(4-phenylbutoxy)hexylamine.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:24]3[C:16](=[CH:17][N:18]=[C:19]4[C:23]=3[CH:22]=[CH:21][NH:20]4)[N:15]=[N:14]2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.O>C(Cl)Cl>[N:13]1([C@H:10]2[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]2)[C:24]2[C:16](=[CH:17][N:18]=[C:19]3[C:23]=2[CH:22]=[CH:21][NH:20]3)[N:15]=[N:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A mixture of racemic trans [3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester (900 mg, 2.63 mmol), trifluoroacetic acid (5 mL), water (50.0 μL) and DCM (10 mL) was stirred at ambient temperature for 5 hours. The solvents were removed in vacuo and the resulting residue purified by column chromatography (SCX-2, gradient: methanol to 2M NH3 in methanol) to give 586 mg (92%) of racemic trans 3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine as a white foam solid. LCMS (Method B, ESI): RT=0.36 & 1.05 min, m+H=243.3; 1H NMR (400 MHz, DMSO) δ: 12.35 (br s, 1H), 8.98 (s, 1H), 7.59 (d, 1H), 6.98 (d, 1H), 5.67 (m, 1H), 3.67 (m, 1H), 2.52 (m, 1H, partially obscured by DMSO), 2.40 (m, 1H), 2.25-2.03 (m, 3H), 1.54 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: COC(=O)c1ccc(C2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2 g, 8.99 mmol), methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 2.168 g, 9.89 mmol) and DIPEA (3.91 mL, 22.47 mmol) were dissolved in DMA (10 mL) and sealed into a microwave tube. The mixture was heated to 110° C. for 5 minutes in the microwave reactor and cooled to room temperature. The reaction mixture was added dropwise to stirred water (30 mL), stirred for 10 minutes then the precipitate was collected by filtration, washed with ether (2×2 mL) and dried to give methyl 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoate (3.32 g, 91%) as a solid.
Reaction SMILES: [CH:1]([N:4]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:16])=O)=[CH:10]2)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCCC1>[CH:1]([N:4]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14](=[S:34])[NH2:16])=[CH:10]2)([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)N(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Product: CC(C)N(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A mixture of 7-[isopropyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (320 mg), Lawesson's reagent (213 mg) and tetrahydrofuran (5 mL) was stirred at 70° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a methylene chloride.toluene mixture and washed with hexane to give the title compound (148 mg, yield 44%) as crystals. melting point 204-205° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13][C:12]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)(C)(C)C.[ClH:31]>CO.O1CCOCC1>[ClH:31].[NH2:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13][C:12]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1
Reactant: COc1cccc(-c2[nH]c(=O)c3ccccc3c2OCCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccc(-c2[nH]c(=O)c3ccccc3c2OCCN)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 3.2 g (7.8 mmol) of {2-[3-(3-Methoxy-phenyl)-1-oxo-1,2-dihydro-isoquinolin-4-yloxy]-ethyl}-carbamic acid tert-butyl ester in methanol (10 mL), 4M hydrochloric acid in dioxane (10 mL) was added and the mixture was stirred for 4 hours at room temperature under argon atmosphere. Solvent was evaporated to dryness and the solid residue was treated with methanol and then diethyl ether until precipitation of the hydrochloride salt occurred. The product was collected by filtration, washed with diethyl ether, affording 2.62 g of the title compound (97%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C@H:4]1[CH2:6][O:5]1.[CH2:15](I)[CH:16]=[CH2:17]>C1(C)C=CC=CC=1.[Ag-]=O>[CH2:17]([O:1][CH2:2][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C@H:4]1[CH2:6][O:5]1)[CH:16]=[CH2:15]
Reactant: C=CCI
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)[C@H]1CO1
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)[C@H]1CO1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl (S)-2-hydroxy-1-((S)-oxiran-2-yl)ethylcarbamate (0.125 g, 0.6 mmol; see: Kurokawa, N.; Ohfune, Y. Tetrahedron 1993, 49, 6195) in toluene (6 mL), was added allyliodide 0.3 mL, 3 mmol) followed by silver(I) oxide (0.7 g, 3 mmol). The solution was stirred at 65° C. in a darkened hood for a period of 15 h. The mixture was then cooled to ambient temperature, filtered through Celite, washed with CH2Cl2, and conc. in vacuo. Purification on SiO2 (10-20% EtoAc/Hexanes) gave the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:8][NH:9][CH2:10][CH2:11]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:15]>>[Cl-:15].[CH:1]1([CH2:8][NH2+:9][CH2:10][CH2:11][Cl:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCNCC1CCCCCC1
Reactant: O=S(Cl)Cl
Product: ClCC[NH2+]CC1CCCCCC1
Product: [Cl-]

Procedure:
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl -N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-(cycloheptylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]=[C:13]([C:25]#[N:26])[C:14](C#N)=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5]1)([CH3:3])[CH3:2].N.[CH3:28][OH:29]>>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]=[C:13]([C:25]#[N:26])[C:14]([O:29][CH3:28])=[N:15][C:16]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Reactant: CO
Agent: N
Product: COc1nc(-c2ccccc2)c(-c2ccc(=O)n(C(C)C)n2)nc1C#N
Temperature: 30 °C
Reaction time: 30 h

Procedure:
A suspension of 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile (100 mg) in a 2M solution of ammonia in MeOH (3 ml) was stirred at 25-35° C. for 30 hours in a sealed tube. The mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-methoxy-5-phenyl-2-pyrazinecarbonitrile as a solid (32 mg).