Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CO[C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[N:25]([CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[C:26]=[S:27]>ClCCl>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][CH:5]2[NH:6][C:26](=[S:27])[N:25]([CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:4]2=[O:17])=[CH:9]1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: S=C=NCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(Cc2c[nH]c3ccccc23)NC(=S)N1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
To a solution of L-tryptophan methyl ester hydrochloride (0.250 mg, 0.001 mol.) in dichloromethane (10 mL) was added triethyl amine (3.0 eq.) followed by 4-(2-isothiocyanato-ethyl)-morpholine (0.190 gm, 0.0011 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-17 (292 mg, 83%): mp 167-169° C., 1H NMR (500 MHz, CDCl3): 2.45-2.51 (m, 6H), 3.02-3.07 (dd, J=9.5 and 15.0 Hz, 1H), 3.46-3.50 (dd, J=4.0 and 15.0 Hz, 1H), 3.65 (m, 4H) 3.89 (d, J=7.0 Hz, 2H), 4.35-4.38 (m, 1H), 6.38 (s, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.16-7.19 (m, 1H), 7.23-7.25 (dd, J=1.5 and 8.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [O:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[NH:5][CH3:6])[CH3:2].[Al](CC)(CC)CC.CO[C:20](=[O:42])[C:21]1[CH:26]=[C:25]([C:27]2[CH:28]=[N:29][C:30]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:32]=2[C:33]#[N:34])[C:24]([Cl:39])=[CH:23][C:22]=1[O:40][CH3:41]>ClCCCl.N#N>[Cl:39][C:24]1[C:25]([C:27]2[CH:28]=[N:29][C:30]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:32]=2[C:33]#[N:34])=[CH:26][C:21]([C:20]([N:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:1][CH3:2])[CH3:6])=[O:42])=[C:22]([O:40][CH3:41])[CH:23]=1
Reactant: CNc1ccccc1OC
Reactant: COC(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OC
Agent: CC[Al](CC)CC
Agent: N#N
Solvent: ClCCCl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)N(C)c1ccccc1OC
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 7.4 %

Procedure:
To a mixture of 2-methoxyl-N-methylaniline (27.7 mg, 0.2 mmol) and Et3Al (196 μL, 1.9 M in toluene, 0.2 mmol) in 1,2-dichloroethane (1 mL) which was preheated at 50° C. for 10 min under N2 atmosphere, was added 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid methyl ester (50 mg, 0.14 mmol). The mixture was sealed in N2 atmosphere and heated at 80° C. for 16 hrs. Upon cooling to rt, the mixture was quenched with 2 N HCl (5 mL) and diluted with 1,2-dichloroethane. The organic layer was separated and concentrated. The residue was purified via reverse phase preparative LCMS to yield 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-(2-methoxy-phenyl)-N-methyl-benzamide 38-1 (4.9 mg). MS [M+H]+475.9; tR=5.91 min (method 3)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.[S:19](Cl)([Cl:22])(=[O:21])=[O:20]>CCOCC.C(OCC)(=O)C>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([S:19]([Cl:22])(=[O:21])=[O:20])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Temperature: -78 °C
Yield: 51.4 %

Procedure:
2-Bromobiphenyl (2.33 g, 10 mmol) was dissolved in ether (10 ml) and cooled to −78° C. n-Butyllithium (2.5 M solution in hexane, 4.8 ml, 12 mmol) was added dropwise under constant stirring and an argon atmosphere. The resultant reaction mixture was stirred at −70° C. to −60° C. for 1 h. The reaction mixture was cooled to −78° C. and sulfuryl chloride (0.88 ml, 11 mmol) was added dropwise. After addition, the reaction mixture was allowed to attain ambient temperature slowly and stirred for 1 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water and the organic layer dried over anhydrous MgSO4. Removal of the solvent under reduced pressure gave a crude product, which was purified by column chromatography, using hexane followed by 5% ethyl acetate in hexane as eluent, to give 2-biphenylsulfonyl chloride as a solid (1.3 g, 51% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:14])[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:14][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC#CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC#CCCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
7.47 g (65 mmol) of methanesulfonyl chloride are added dropwise within 30 minutes at 10° C. to a solution of 7.56 g (60 mmol) of 3-octyn-1-ol and 12.45 ml (90mmol) triethylamine in 225 ml of methylene chloride, and the mixture is stirred for one hour. The reaction solution is washed with water, saturated sodium bicarbonate solution and again with water, dried and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10]([CH3:14])[C:11]([NH2:13])=[S:12].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)=O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@H:10]([C:11]1[S:12][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:13]=1)[CH3:14]
Reactant: C[C@@H](C(N)=S)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A mixture of (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyramide (26.7 g, 85.4 mmol) and a-bromo-4′-cyano-acetophenone (24.0 g, 0.107 mol) in EtOH (500 ml) was refluxed for 1 hr. The reaction mixture was cooled down to r.t. And the solvent was removed under reduced pressure down to 150 ml. The residue was poured into in to cold (0° C.) saturated NaHCO3 aq. (400 ml). The resulting mixture was extracted with EtOAc (300 ml+150 ml×2). The combined organic layer was washed with brine (200 ml), dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (Wako-gel C-300, Hexane:EtOAc=1:2) to give 4-{2-[(1R,2R)-2-(2,5-Difluoro-phenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]-thiazol-4-yl }-benzonitrile (32.0 g, 86%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].S(Cl)([Cl:14])=O.[CH3:16]O>>[ClH:14].[CH3:16][NH:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: CO
Reactant: NCCCC[C@@H](N)C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CN[C@H](CCCCN)C(=O)O

Procedure:
In the first step, D-lysine monohydrochloride reacts with thionyl chloride in the presence of methanol to give methyl-D-lysinate hydrochloride.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:29])[CH3:28])[CH:22]=1)=[O:19]>>[CH3:29][N:27]([CH3:28])[C:23]1[CH:22]=[C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:15]([NH:14][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[O:12])[CH:16]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Reactant: O=C(Cl)c1ccc2ncccc2c1
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc2ncccc2c1

Procedure:
Using an analogous procedure to that described in Example 2, 6-quinolylcarbonyl chloride was reacted with 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide to give the title compound; NMR Spectrum: (DMSOd6) 2.35 (s, 3H), 2.91 (s, 6H), 6.58 (m, 1H), 7.2 (m, 2H), 7.43 (d, 1H), 7.65 (m, 1H), 7.82 (d, 1H), 8.01 (s, 1H), 8.17 (m, 2H), 8.32 (d, 1H), 8.59 (d, 1H), 8.7 (d, 1H), 9.02 (s, 1H), 10.05 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][N:27](S(C3C=CC(C)=CC=3)(=O)=O)[CH:26]=2)=[O:24])[CH:7]=[N:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH:11]=1.Cl>CO.O1CCCC1>[CH3:3][C:4]1[CH:5]=[C:6]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][NH:27][CH:26]=2)=[O:24])[CH:7]=[N:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)Nc3cnc(C4=CCC(N5CCOCC5)CC4)c(C)c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(NC(=O)c2cc[nH]c2)cnc1C1=CCC(N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.4 %

Procedure:
1N Aqueous solution of sodium hydroxide (20 ml) was added to a suspension of N-{5-methyl-6-[4-(morpholin-4-yl)cyclohex-1-en-1-yl]pyridin-3-yl}-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carboxamide (2.07 g) in methanol (20 ml) and tetrahydrofuran (30 ml), and stirred at room temperature for 2.5 hours. 1N Hydrochloric acid aqueous solution was added at 0° C. to the reaction solution and concentrated in vacuo. The precipitated solid was washed with ethanol to give N-{5-methyl-6-[4-(morpholin-4-yl)cyclohex-1-en-1-yl]pyridin-3-yl}-1H-pyrrole-3-carboxamide (1.2 g) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([C:12]2[CH:21]=[CH:20][C:15]3[NH:16][CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:22]([N:29]1[CH2:33][CH2:32][CH:31](OS(C)(=O)=O)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:3]1([S:9]([C:12]2[CH:21]=[CH:20][C:15]3[N:16]([CH:31]4[CH2:32][CH2:33][N:29]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:30]4)[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
To a suspension of sodium hydride (0.033 g. of a 60% dispersion in mineral oil, 0.834 mmol) in 3 mL dimethylformamide was added portionwise 7-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.200 g, 0.726 mmol), and the resulting suspension was stirred at room temperature for 10 minutes. Racemic methanesulfonic acid 1-benzyl-pyrrolidin-3-yl ester (0.259 g., 1.018 mmol) was added dropwise and the reaction mixture was heated to 65° C. for 21 hours. The reaction mixture was then poured into 100 mL water, and extracted three times with 50 mL ethyl acetate. The organic fraction was washed twice with 50 mL 10% aq. hydrogen chloride and once with 50 mL saturated sodium bicarbonate. The organic fraction was then dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (2%-5% methanol in dichlormethane) to give 0.127 g (0.292 mmol, 40%) of 7-benzenesulfonyl-4-(1-benzyl-pyrrolidin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine as a red oil. MS: 474 (M+ACN)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].O.C1COCC1.C(=O)(O)[O-].[Na+].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O>[CH2:29]([O:28][C:26]([N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)CCNCc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N(CCC(=O)OC)Cc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Compound 1040 (35.2 g, 176.6 mmol) in 1:1 water/THF (1. L) was added solid sodium bicarbonate (32.6 g, 388.6 mmol) and ethyl chloroformate (20.3 mL, 212.0 mmol). The reaction was stirred at room temperature overnight, at which point LCMS indicated complete disappearance of starting material. The reaction mixture was diluted with water, extracted with ethyl acetate, and the volatiles removed under reduced pressure to give methyl 3-(ethoxycarbonyl(thiophen-2-ylmethyl)amino)propanoate as a pale yellow oil (Compound 1041, 19.9 g, 41%); 1H NMR (300 MHz, CDCl3): δ 7.20-7.12 (m, 1H), 6.94-6.83 (m, 2H), 4.56 (s, 2H), 4.10 (td, J=14.5, 7.3 Hz, 2H), 3.52 (s, 3H), 3.46 (t, J=6.6 Hz, 2H), 2.47-2.39 (m, 2H), 1.97 (s, H) and 1.24-1.15 (m, 3H) ppm. The aqueous layer contained some 3-(ethoxycarbonyl(thiophen-2-ylmethyl)amino)propanoic acid (Compound 1042) resulting from hydrolysis of the methyl ester. Compound 1042 could be isolated by adjusting the pH of the aqueous layer to 2 with 6M HCl followed by extraction with 10% n-BuOH in chloroform, which after concentration gave the carboxylic acid as a pale yellow oil (17.33 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccc(F)c(C#N)c1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(F)c(C#N)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of compound methyl (3-cyano-4-fluorophenyl)acetate (200 mg, 1.03 mmol) in 15 mL of anhydrous THF was cooled to −78° C. NaHMDS (1.11 mmol) was added to the reaction dropwise at −78° C. After the addition, the mixture was stirred at −78° C. for 1 h and then CH3I (160 mg, 1.33 mmol) was added to the reaction dropwise at −78° C. The reaction was warmed to room temperature slowly and stirred at ambient temperature over night. The reaction was quenched with NH4Cl solution, extracted with EtOAc. The orgianic layer was washed with saturated chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified via preparative TLC to afford methyl 2-(3-cyano-4-fluorophenyl)propanoate.
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[C:36]([C:38]1[S:42][C:41](S(N)(=O)=O)=[CH:40][CH:39]=1)#[N:37]>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:7][C:5]([NH:4][S:1]([C:41]3[S:42][C:38]([C:36]#[N:37])=[CH:39][CH:40]=3)(=[O:3])=[O:2])=[O:6])=[CH:32][CH:33]=1)[CH:20]=[CH:19]2
Reactant: NC(=O)N=S(=O)=O
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Reactant: N#Cc1ccc(S(N)(=O)=O)s1
Product: N#Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(-n3ccc4cc(N)c(F)cc4c3=O)cc2)s1

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-cyanothiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-5-cyanothiophene-2-sulfonamide. ES-MS (M+H)+=498.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[N+:8]([O-])[CH:9]=[CH:10][CH:11]=1.C[Si]([C:20]#[N:21])(C)C.C(N(CC)CC)C>C(#N)C>[C:20]([C:7]1[C:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)#[N:21]
Reactant: [O-][n+]1cccc(Oc2cccc(F)c2)c1
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ncccc1Oc1cccc(F)c1

Procedure:
A mixture of 33.44 g of 3-(3-fluorophenoxy)pyridine N-oxide, 64.6 ml of trimethylsilyl cyanide and 45.9 ml of triethylamine in 180 ml of acetonitrile was refluxed for 4 hours. After the reaction mixture was concentrated, 200 ml of methylene chloride and 100 ml of 2M aqueous potassium carbonate was added to the residue and the mixture was stirred for a few minutes. The organic layer separated was washed with 50 ml of water, dried over anhydrous sodium sulfate, and concentrated. The solid obtained was washed with isopropyl ether to yield 28.30 g of pale brown crystals, which were recrystallized from ethyl acetate to give slightly brown crystals, mp 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][NH:8]1.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:6][C:7]2([CH3:12])[CH2:11][CH2:10][CH2:9][N:8]2[C:18]1=[O:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1(CNCc2ccccc2Cl)CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC12CCCN1C(=O)N(Cc1ccccc1Cl)C2
Reaction time: 4 h
Yield: 22 %

Procedure:
To a cold (0° C.) solution of (2-chloro-benzyl)-((rac)-2-methyl-pyrrolidin-2-ylmethyl)-amine (0.5 g, 1 eq) in DCM (15 mL) was added a solution of triphosgene (0.5 eqv) in DCM (5 mL) over a period of 5 minutes followed by the addition of triethylamine (3 eq). The reaction mixture was allowed to stir for 4 h. After the completion of the reaction on TLC, the reaction mixture was quenched with 1M HCl (10 mL) and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated using rotary evaporator to give sticky crude, which was then purified with column chromatography (1-2% Methanol:DCM, Mesh Size-100-200 silica, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to afford the desired product (rac)-2-(2-chloro-benzyl)-7a-methyl-hexahydro-pyrrolo[1,2-c]imidazol-3-one as white solid (22-70%). MS (ES+): 265.5 (MH+))
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCCCCCCCC=Cc1ccco1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: O=C(O)CCCCCCCCCCc1ccco1
Yield: 89.6 %

Procedure:
This compound was synthesized from 11-(2-furyl)-10-undecenoic acid (1.25 g, 5 mmol) by a hydrogenation reaction using Pd/BaSO4 (125 mg). Crystallization (petroleum ether) afforded the product (1.13 g, 90%) as white crystals (mp 40-41° C.); IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.30 (m, 12 H), 1.65 (m, 4 H), 2.34 (t, 2 H), 2.60 (t, 2 H), 5.95 (d, 1 H), 6.28 (d, 1 H), 7.30 (s, 1 H), 10.10 (bs, 1 H). Anal. Calcd. for C15H24O3 : C, 71.39, H, 9.58%; Found: C, 71.21, H, 9.63%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>N1C=CC=CC=1>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N)cc2F)C1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(N2CC[C@@H](NC(=O)OC(C)(C)C)C2)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Amino-2-((3R)-3-(t-butoxycarbonyl)aminopyrrolidin-1-yl)fluorobenzene (27.33 g, 0.093 M) was dissolved in dry pyridine (150 ml) and cooled under nitrogen with stirring to 0°. Ethyl chloroformate (11.01, 0.102 M) was added dropwise, and the mixture stirred 30 minutes at the same temperature. Ice-water (250 ml) was added, and stirring continued for 1 hour. The resulting precipitate was collected, washed thoroughly with water, and dried, to give the desired product of sufficient quality for use without purification (33.6 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:11])/[C:7](=[N:12]\[OH:13])/[C:8](=[O:9])[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
592.1 g of acetoacetic acid tert.butyl ester are dissolved in 560 ml of glacial acetic acid. To this solution is added dropwise at 5°-10° C. during 21/2 hours a solution of 290.6 g of sodium nitrite in 655 ml of water. The resulting yellow suspension is stirred for 30 minutes at 20° C., treated with 940 ml of water and stirred for a further 2 hours. The mixture is treated with 900 ml of water and 900 g of ice and extracted in the stirring vessel three times with 1 l of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 l of water each time, then treated with 5 l of water and the pH-value is adjusted to 6.8 with sodium hydrogen carbonate. After separating the aqueous phase, the organic phase is washed once with water. Thereafter, the ethyl acetate solution is dried over sodium sulphate and evaporated in vacuo at 40° C. There is obtained (Z)-2-hydroxyimino-3-oxo-butyric acid tert-butyl ester as a yellow oil which is dried for a further 9 hours in a high vacuum at 40° C.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=O.[CH3:8][NH:9][C:10]([NH2:12])=[O:11].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:8][N:9]1[C:1](=[O:7])[CH2:2][C:3](=[O:5])[NH:12][C:10]1=[O:11]
Reactant: CNC(N)=O
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(=O)NC1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
To a solution of malonic acid (80 g, 0.79 mol) and methylurea (50 g, 0.68 mol) in 180 ml of acetic acid at 70° C., acetic anhydride (130 ml, 1.37 mol) is added slowly. After the completion of the addition, the reaction mixture is stirred at 90° C. for 3 hours, and then cooled to room temperature. The solvent is removed under reduced pressure, and the residue is treated with 350 mL of ethanol to precipitate out yellowish solid. The solid is recrystallized from ethanol to give 63.1 g product as crystalline solids (Yield: 65.8%). m.p.=131.2-133.1° C. [Lit.1: m.p.=130-131.5° C.].
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:33][CH:34]([CH3:39])[CH2:35][C:36]([OH:38])=[O:37].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>CN(C=O)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([NH:33][CH:34]([CH3:39])[CH2:35][C:36]([OH:38])=[O:37])=[O:16])=[CH:8][CH:9]=1
Reactant: CC(N)CC(=O)O
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CC(=O)O)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.08 h
Yield: 27.5 %

Procedure:
An aliquot of 4-[[4-(aminoiminomethyl)phenyl]-amino]-4-oxobutanoic acid prepared in Example 1, Step 1 (2 g) was added to dry DMF (65 ml) followed by N-methylmorpholine (0.75 g, 1 eq.) and isobutyl chloroformate (1 g) at 25° C. The mixture was stirred for 5 min. 3-Aminobutyric acid (1.1 g, 1.1 eq.) was added followed by triethylamine (1.5 g, 1.3 eq.) and dimethylaminopyridine. After 1 h, the solvent was removed under reduced pressure and the product was purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to give 750 mg of white solid: 1H NMR (d6 -DMSO) δ 1.06 (d, 3H, J=7 Hz), 2.2-2.6 (m, 6H), 4.05 (m, 1H), 7.8 (m, 4H), 7.85 (d, 1H, J=8 Hz), 9.05 (bs, 2H), 9.15 (bs, 2H), 10.4 (s, 1H); MS (FAB) m/z 321.1 (MH+), 236.