Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23](=[O:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]N1C(=O)CCC1=O.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([Br:26])=[CH:11][C:10]=1[C:23](=[O:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
51.2 g of 1-(2,4-Bis-benzyloxy-phenyl)-ethanone (0.154 mol, 1 eq) were dissolved in 250 ml DMF. 27.42 g N-bromosuccinimide (0.154 mol, 1 eq) in 100 ml DMF were added dropwise. The mixture was stirred at room temperature over night. The reaction mixture was poured onto 700 ml of water and the precipitate filtered off. The filter cake was rinsed with water and the colourless solid was recrystallised from 370 ml acetonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:22]
Reactant: COc1cccc(N=C=O)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: COc1cccc(NC(=O)Nc2ccc([N+](=O)[O-])cc2O)c1
Yield: 46.2 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 3-methoxy phenyl isocyanate (1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (140 mg, 46%). EI-MS m/z 302 (M-H)-
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=[CH:16][CH:15]=4)[C:6]=3[N:7]=[C:2]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3cccc4ccccc34)c2n1
Product: c1ccc2c(CSc3ncnc4c(N5CCOCC5)nc(N5CCNCC5)nc34)cccc2c1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-4-morpholino-8-(1-naphthylmethyl-thio)-pyrimido[5,4-d]-pyrimidine (m.p.: 206°-209° C.) and piperazine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(CO)cc1
Reactant: COC(=O)Cc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1OCc1ccc(/C=C/c2nc(-c3ccccc3)oc2C)cc1
Reaction time: 15 h
Yield: 66 %

Procedure:
To a mixture of [4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]phenyl]methanol (0.50 g), methyl 2-(2-hydroxyphenyl)acetate (0.27 g), triphenylphosphine (0.63 g) and tetrahydrofuran (30 mL) was dropwise added a solution (40%, 1.04 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. To the reaction mixture was added ethyl acetate, the mixture was washed successively with water, a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-[2-[4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]benzyloxy]phenyl]acetate as a pale-yellow oil (0.4-6 g, 66%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:21][CH3:22])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.3 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.3 g of 1-iodopropane were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.1 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-propylmalononitrile (hereinafter, referred to as the present compound (82)).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:26])O[C:14](=[O:25])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:3]1.[NH3:27].O>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:26])[NH:27][C:14](=[O:25])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:3]1
Reactant: N
Reactant: Cn1cc(C2=C(c3cccc([N+](=O)[O-])c3)C(=O)OC2=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cccc([N+](=O)[O-])c3)C(=O)NC2=O)c2ccccc21
Reaction time: 6 h
Yield: 75 %

Procedure:
A solution of 3-(1-methylindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione (9 g, 26 mmol) in DMF (20 mL) was heated to about 140° C. Aqueous ammonia (20 mL) was added in portions and the heating was continued for 6 h. Water (20 mL) was added and the reaction mixture was allowed to stand at room temperature overnight. The orange colored solid was filtered off, washed with water and dried under vacuum to afford 3-(1-methylindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (6.7 g, 75%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:28]=[O:29])C.O>C1COCC1>[CH:28]([C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: Cc1cc(C)c2c(c1C)OCC2c1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(-c3cccc(C=O)c3)coc2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 203 (1.77 g, 5.57 mmol) in THF (20 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 4.18 mL, 6.68 mmol) under argon atmosphere at −78° C., and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise DMF (0.86 mL, 11.14 mmol) at the same temperature, and the mixture was stirred for 30 minutes, and then was warmed to room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate, was filtered, and then was concentrated under reduced pressure to give 1.48 g (yield is quantitative) of the title compound. Oily matter.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O.OS(O)(=O)=O.C1COCC1.C([O:24][C:25](=O)[CH2:26][C:27]1([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=2)[CH2:31][C:30](=O)[NH:29][CH2:28]1)C>C1COCC1.ClCCl.C1COCC1.O>[Cl:40][C:35]1[CH:34]=[C:33]([C:27]2([CH2:26][CH2:25][OH:24])[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:38]=[CH:37][C:36]=1[Cl:39]
Reactant: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of LiAlH4 (450 mL, 1M in THF, 450 mmol) was cooled in a ice/acetone bath (-10° C.). A solution of H2SO4 (99.999%) (12 mL, 225.3 mmol) in THF (35 mL) was added dropwise. (Use caution when adding the H2SO4 to the THF and also when adding the H2SO4 /THF solution to the LiA1H4) After the addition was complete, the slurry was stirred for 1 h in an ice bath. The slurry was allowed to warm to ambient temperature and stir for 2 h. A solution of [3-(3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethyl ester (23.2 g, 73.4 mmol) in THF (70 mL) was added dropwise. The slurry was heated to 45°-50° C. for 36 h. The slurry was cooled in an ice bath and a solution of THF:H2O (1:1, 70 mL) was added dropwise. The slurry was filtered and the solids were rinsed with THF and dichloromethane. The salts were stirred with THF:H2 0:15% NaOH (1 L :70 mL :20 mL) for 2 h. The slurry was filtered and the combined filtrates were concentrated in vacuo to obtain a residue. The residue was dissolved in dichloromethane and the solution was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was recrystallized from diethyl ether to give the title compound:
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C@@H:6]1[C@H:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[C:9]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[N+:26]([O-])=O)[CH2:8][C@@H:7]1[CH3:29])#[N:2]>CCO>[NH2:26][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:20]=1[C@@H:9]1[CH2:10][C@H:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[C@H:7]([CH3:29])[CH2:8]1
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OCCC#N
Solvent: CCO
Product: C[C@@H]1C[C@H](c2ccncc2N)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1OCCC#N
Yield: 31 %

Procedure:
Method 6 was followed using (+/−)-tert-butyl (1R,5S,6S)-6-(2-cyanoethoxy)-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate with SFC (15% EtOH, 100 mL/min, OJ column) to yield tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-2-(2-cyanoethoxy)-3-methylcyclohexyl)carbamate (31% yield, 99% ee) and tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-(2-cyanoethoxy)-3-methylcyclohexyl) carbamate (26% yield, 99% ee). LC/MS (m/z)=375.3 (MH+), Rt=0.65 min.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:11]([CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:13])=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].NN.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:11]([CH2:14][CH2:15][NH2:16])(=[O:12])=[O:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN2C(=O)c3ccccc3C2=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
2.48 g (6.53 mmol) crude 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide were dissolved in 100 ml ethanol. 65.3 ml (10 equiv.) of a 1M hydrazine-solution in THF and 124 mg (0.1 equiv.) p-toluenesulfonic acid were added. The resulting mixture was stirred at 60° C. for 72 h. The formed precipitate was filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was co-distilled three times with 200 ml DMF to remove the excess hydrazine. Crude 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide was obtained as a colorless oil. Yield: 2.00 g
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7](Cl)[C:6]=2[CH:17]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[C:6]=2[CH:17]=1
Reactant: ClC1c2ccccc2C=Cc2ccc(Br)cc21
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C2c3ccccc3C=Cc3ccc(Br)cc32)CC1
Yield: 47.2 %

Procedure:
1.00 gram (3.27 millimoles) of 3-bromo-5-chloro-5H-dibenzo[a,d]cycloheptene, 0.7 gram (about 7 millimoles) of N-methylpiperazine and 3 milliliters of dimethylformamide were stirred together at room temperature under an atmosphere of nitrogen for 60 hours. At the end of this period, water and aqueous sodium carbonate solution was added, and the resulting aqueous solution extracted with ether. The ether solution was washed five times with water, then with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed from the dried solution in vacuo to obtain a residue. The residue was triturated with acetonitrile and crystallized from acetonitrile. It was then purified by passing through a Still column using 3 percent methanol in chloroform as eluant, crystallized from acetonitrile, and the crystals dried over phosphorus pentoxide at 78° C./0.2 mm Hg for 17 hours to obtain 0.57 gram of 1-(3-bromo-5H-dibenzo[a,d]cyclohepten-5-yl)-4-methylpiperazine product, m.p. 128°-130° C. Elemental analyses were as follows:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[C:46](=O)[CH2:47][CH2:48][OH:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:51][S:52](Cl)(=[O:54])=[O:53]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49][S:52]([CH3:51])(=[O:54])=[O:53])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(C(=O)CCO)CCC3)cc1
Reactant: CS(=O)(=O)Cl
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)cc1

Procedure:
In analogy to the procedure described in example 8(b), the (3R,4R)-3-[1-(3-hydroxy-propoyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 4(a)] was treated with methanesulfonyl chloride to yield the (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester, which was directly used in the next step without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[C:32]1([C:38]2[S:39][CH:40]=[C:41]([C:43](Cl)=[O:44])[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:43]([C:41]2[N:42]=[C:38]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[S:39][CH:40]=2)=[O:44])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1csc(-c2ccccc2)n1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Oc3ccc(NC(=O)c4csc(-c5ccccc5)n4)cc3F)ccnc2cc1OCCCN1CCOCC1

Procedure:
Q1 was prepared from 3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]aniline and 2-phenyl-1,3-thiazole-4-carbonyl chloride following the general procedure reported in Preparative Example 1 Step 3. 1H NMR (400 MHz, d4-MeOD, 300K) δ 2.17 (m, 2H), 2.73 (m, 4H), 2.81 (t, J=7.4 Hz, 2H), 3.77 (t, J=4.7 Hz, 4H), 3.98 (s, 3H), 4.24 (t, J=6.0 Hz, 2H), 6.50 (d, J=5.4 Hz, 1H), 7.33 (s, 1H), 7.35 (t, J=8.8 Hz, 1H), 7.50 (m, 4H), 7.62 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 8.01 (dd, J=12.6 Hz, J=2.5 Hz, 1H), 8.07 (m, 2H), 8.32 (s, 1H), 8.39 (d, J=5.4 Hz, 1H). MS (ES) C33H31FN4O5S requires: 614. Found: 615 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:15][C:14]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:13]=3[CH2:12]2)=[N:8][CH:7]=1)=[O:5])C.O.[OH-].[Li+].O>C1COCC1>[C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:15][C:14]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:13]=3[CH2:12]2)=[N:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc(N2CC3=C(CN(C(=O)OC(C)(C)C)C3)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2=C(C1)CN(c1ncc(C(=O)O)s1)C2
Reaction time: 8 h

Procedure:
tert-Butyl 5-(5-ethoxycarbonylthiazol-2-yl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carboxylate (1.34 g, 3.66 mmol) and lithium hydroxide hydrate (385 mg, 9.17 mmol) were stirred in 150 ml of THF and 50 ml of water at 50° C. for 2 h and at 80° C. for 8 h. THF was concentrated under reduced pressure and the water phase was extracted with ethyl acetate. The water phase was acidified and extracted again with ethyl acetate. The organic phase was concentrated. Yield: 662 mg (53%), M+H+: 338.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Mg].[O:11]=[C:12]([CH3:18])[CH2:13][CH2:14][CH2:15][C:16]#[N:17].Cl>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH:11][C:12]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)([CH3:18])[CH2:13][CH2:14][CH2:15][C:16]#[N:17]
Reactant: CC(=O)CCCC#N
Agent: Cl
Agent: Clc1cc(Cl)cc(I)c1
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CC(O)(CCCC#N)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
The Grignard reagent of 3,5-dichlorophenyl iodide was prepared by the reaction of 20.0 grams (0.073 mole) of 3,5-dichlorophenyl iodide and 1.8 grams (0.073 mole) of magnesium turnings in 350 mL of diethyl ether. The reaction mixture was heated at reflux for about three hours and then allowed to cool to ambient temperature. To the Grignard reagent, with stirring, was added dropwise during a 15 minute period a solution of 8.4 mL (0.073 mole) of 5-oxohexanenitrile in 25 mL of diethyl ether. The exothermic reaction caused the reaction mixture temperature to rise to about 30 ° C. Upon completion of addition, the reaction mixture was stirred for one hour and then was poured into 400 mL of water. The mixture was made acidic with about 80 mL of aqueous 2N hydrochloric acid and extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chroma-tography on silica gel, using 5% diethyl ether in methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.4 grams of 5-hydroxy-5-(3,5-dichlorophenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[CH3:17])N)=[CH:5][CH:4]=1.[CH3:21][CH2:22][O:23][C:24]([CH2:26][CH:27]1[C:32](=O)[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:28]3[CH:27]([CH2:26][C:24]([O:23][CH2:22][CH3:21])=[O:25])[CH2:32][CH2:31][CH2:30][C:29]=3[C:15]3[C:10]2=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: CC(C)c1ccccc1N(N)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(C(C)C)cccc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2-isopropylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared as a mixture of ethyl and isopropyl esters.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:9][CH2:10][OH:11].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][OH:11]
Reactant: OCCBr
Reactant: C[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 24020.5 %

Procedure:
A mixture of (R)-2-methylpyrrolidine hydrochloride (4 g, 0.03 mol), 2-bromoethanol (3.7 g, 0.029 mmol) and K2CO3 (8.28 g, 0.0618 mol) in acetonitrile (50 mL) was stirred at room temperature overnight. The mixture was filtered, and the filter cake was washed with ethyl acetate (100 mL). The combined filtrate was concentrated and the residue was purified on a silica gel column (MeOH/DCM=1/50) to give (R)-2-(2-methylpyrrolidin-1-yl)ethanol (0.9 g) as a colorless oil. 1H NMR (CDCl3): δ 3.63 (m, 2H), 3.14 (m, 1H), 2.95 (m, 1H), 2.44 (m, 1H), 2.24 (dt, 1H), 2.14 (m, 1H), 1.95 (m, 1H), 1.68 (m, 2H), 1.38 (m, 1H), 1.07 (d, 3H); LCMS: 130 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22]([CH2:24][S:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].[N-:38]=[N+:39]=[N-:40].[Na+]>>[NH:38]1[C:19]([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:21]=[C:22]([CH2:24][S:25][C:26]5[CH:35]=[CH:34][C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=5)[N:23]=[C:8]4[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)=[N:20][N:40]=[N:39]1
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CSc4ccc5ccccc5n4)cn23)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: c1ccc2nc(SCc3cn4c(-c5ccc(-c6nnn[nH]6)nc5)cnc(N5CCOCC5)c4n3)ccc2c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Compound 75c (54.9 mg, 0.114 mmol) NH4Cl (9.20 mg, 0.172 mmol), and NaN3 (11.2 mg, 0.172 mmol) were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with Argon gas. Dry DMF (1 mL) was added via syringe and then the mixture was stirred at 120° C. for 2 h. The reaction was cooled to rt, diluted with water (5 mL), and adjusted to pH 2 with 2M HCl. The precipitate was collected by filtration and then the solid was washed with water (2×5 mL). The solid was dissolved in a mixture of DCM (20 mL) and MeOH (10 mL), dried over Na2SO4, and filtered. The solvent was removed under reduced pressure. The residue was triturated with MeOH (5 mL) and the solid was collected by filtration. The residual solvent was removed under reduced pressure to afford the title compound 70. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.98 (s, 1H), 8.30 (s, 2H), 8.17 (d, J=8.6 Hz, 1H), 8.07 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 4.68 (s, 2H), 4.15-4.27 (m, 4H), 3.69-3.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H22N10OS: 523.2 (M+H). found: 523.3.