Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]I.[Mg].[Cl-].[C:5]1([CH2:11][N+:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>CCOCC>[C:5]1([CH2:11][N:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]2[CH3:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CI
Reactant: Cc1cc[n+](Cc2ccccc2)cc1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1=C(C)C(C)N(Cc2ccccc2)C=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of methyl iodide (112 mL, 1.8 mole) in ether (225 mL) was added dropwise to a suspension of magnesium turnings (44 g, 1.8 mole) in ether (225 mL) under nitrogen over a period of 1 hour. The mixture was stirred at room temperature for 1 hour, transferred into a 1000 mL addition funnel and then was added to a suspension of N-(phenylmethyl)-3,4-dimethylpyridinium chloride (350.7 g, 1.5 mole) in ether (1500 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours and was then poured into a solution of saturated ammonium chloride (3 L). The organic layer was separated and the aqueous layer was extracted with ether (1000 mL). The combined ether layers were washed with water (500 mL), then brine (500 mL) and were dried over sodium sulfate and potassium carbonate. The solvent was removed in vacuo to afford 284.1 g (76%) of 1,2-dihydro-N-(phenylmethyl)-2,3,4-trimethylpyridine as an amber oil.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[S:23](Cl)(=[O:25])=[O:24])[CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[S:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)(=[O:25])=[O:24])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of ethyl 4-aminobenzoate (5 gm, 30.3 mmol) under nitrogen atmosphere was added pyridine (50 ml) at 0° C. and stirred for 10 min. Quinoline-8-sulfonyl chloride 89 (8.94 gm, 39.4 mmol) was then added to the reaction mixture at the same temperature. The resulting mixture was stirred for 16 hr at RT. After completion of the reaction, the solvent was removed under low pressure. The traces of pyridine were removed by co-distillation with toluene. Diethylether was added to the resulting residue, and the solid product was filtered out and air-dried. The resulting crude product (8.0 gm, 74%) was taken to the next step without further purification.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:35]1[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][C:43](=[NH:45])[NH2:44])=[CH:37][CH:36]=1)(=O)=O.CS(O)(=O)=O>N1C=CC=CC=1.C(OCC)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:35]2[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][C:43](=[NH:44])[NH2:45])=[CH:37][CH:36]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: N=C(N)C=Cc1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1

Procedure:
To a solution of 106 g of 4-guanidinobenzoic acid hydrochloride in 1.3 liters of pyridine, while being cooled in ice and stirred, was added 122 g of DCC. After 30 minutes of stirring, to the mixture was added slowly 127 g of 4-(β-amidinoethenyl)phenol methanesulfonate. The resulting clear solution was stirred overnight and the precipitated solid substance was collected by filtration. The solid substance was suspended in 2 liters of water, thoroughly stirred, and filtered. To the filtrate was added at room temperature about 2 liters of saturated aqueous sodium bicarbonate solution. The mixture was stirred and the precipitated crystals were collected by filtration, washed with water, and then with acetone. After air-drying for a short time, the orange-yellow crystals were suspended in 200 ml of methanol and admixed with about 100 g (2 equivalents) of methanesulfonic acid while stirring at room temperature. Ethyl ether was added to the reaction mixture to precipitate crystals which were collected by filtration. The crystals were suspended in methanol and converted again to the carbonate. The carbonate was suspended in 300 ml of ethanol at room temperature and admixed with methanesulfonic acid to turn the suspension into a clear solution. The solution was stirred for a while to precipitate crystals which were collected by filtration at room temperature and thoroughly washed with cold ethanol. The yield was 45 g (18%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[CH:7][CH:8]=[C:9]([C:15]([O:17]C)=[O:16])[C:10]=2[C:11]([O:13]C)=[O:12])[N:6]=1.[OH-].[Na+].Cl>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[CH:7][CH:8]=[C:9]([C:15]([OH:17])=[O:16])[C:10]=2[C:11]([OH:13])=[O:12])[N:6]=1
Reactant: COC(=O)c1ccc2nc(C)[nH]c2c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2ccc(C(=O)O)c(C(=O)O)c2[nH]1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of dimethyl 2-methyl-4,5-benzimidazoledicarboxylate and 8 equivalents of 10N sodium hydroxide is stirred 4 hours at 70° C., cooled and acidified with hydrochloric acid to afford the title product as cream-colored crystals, mp 270° C. (dec).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[C:10]([CH2:17][CH3:18])([CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:15][NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH2:17][CH3:18])[CH3:16]
Reactant: [H][H]
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1NC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1NC

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.7 g) and 1-benzyl-4methylamino-3-ethyl-3-methyl piperidine (6 g, 24.39 mmol) in methanol (60 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-methylamino-3-ethyl-3-methylpiperidine. Yield 2.5 g (66%), C9H20N2, m/z 157 (M+1).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].C1(C)C=CC=CC=1.[Cl:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][CH2:18][CH:19]([OH:37])[C:20]([NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]#[CH:34])=[C:27]([O:35][CH3:36])[CH:26]=2)=[O:21])=[CH:15][CH:14]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH:19]([O:37][CH2:3][C:2]#[CH:1])[C:20]([NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]#[CH:34])=[C:27]([O:35][CH3:36])[CH:26]=2)=[O:21])=[CH:38][CH:39]=1
Reactant: C#CCBr
Reactant: C#CCOc1ccc(CCNC(=O)C(O)COc2ccc(Cl)cc2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C#CCOc1ccc(CCNC(=O)C(COc2ccc(Cl)cc2)OCC#C)cc1OC
Reaction time: 16 h

Procedure:
A 80% solution of propargyl bromide in toluene (1.6 g, 11 mmol) is added slowly at room temperature to a mixture of 3-(4-chloro-phenoxy)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-propionamide (3.5 g, 8.7 mmol), 30% sodium hydroxide solution (4.5 ml, 44 mmol) and catalytic amounts of tetrabutylammonium bromide (50 mg) in 30 ml of dichloromethane. The reaction is stirred for 16 hours at +40° C. Subsequently the mixture is evaporated and the residue is diluted with water and dichloromethane. The phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated. The remaining oil is purified by chromatography on silica gel (ethyl acetate/hexane 1:1) to yield 3-(4-chloro-phenoxy)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-prop-2-ynyloxy-propionamide (Compound E1.24).
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[S:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[S:31])[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=S)Cc3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=S)Cc3ccccc3)[C@H]2S1
Yield: 98.7 %

Procedure:
Acetic acid (4.5 ml) and zinc powder (3.6 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate (2.79 g) in anhydrous dimethylformamide (15 ml), and the mixture was stirred for 2 hours at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5% hydrochloric acid (75 ml) and ethyl acetate (50 ml), and extracted. The extract was washed with water and dried. After the solvent was distilled off, the residue was crystalized by adding ether to give colorless crystals of 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid (2.0 g), mp 168° to 171° C. (dec.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][OH:23].C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl>[F:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:22]=[O:23]
Reactant: CC(C)(C)OC(=O)NC1(CO)CCc2c(F)cc(F)cc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C=O)CCc2c(F)cc(F)cc21
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of oxalyl chloride (0.91 mL, 10.4 mmol) in CH2Cl2 (40 mL) at −78° C. was added DMSO (1.48 mL, 20.9 mmol), dropwise, over 5 min. The reaction mixture was stirred for 30 min, during which time it warmed to −60° C., then a solution of tert-butyl [4,6-difluoro-1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]carbamate from Step E (2.08 g, 6.95 mmol) in CH2Cl2 (22 mL) was added, dropwise, over 30 min. During the addition, the reaction temperature rose to −45° C. and it was stirred at this temperature for an additional 15 min. To the resulting mixture was added N,N-diisopropylethylamine (7.28 mL, 41.7 mmol), dropwise, over 2 min. The mixture was allowed to warm to 0° C., stirred for 15 min then poured into ice (60 mL) and 1 N aqueous HCl (30 mL). The resulting mixture was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with H2O (30 mL), then brine (50 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=224 (M−OC4H9).
Reaction SMILES: [F:1][C:2]1[N:3]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.C([Li])CCC.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[N:3]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=[C:5]([C:38](=[O:39])[NH:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: O=C(Nc1ccccc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Reaction of 2-fluoro-1-triphenylmethylimidazole with n-butyl lithium at -75° followed by treatment with phenylisocyanate gave 2-fluoro-4-phenylcarbamoyl-1-triphenylmethylimidazole, n.m.r. in CDCl3 : 7.0-7.5 (m, 19H); 7.6 (d, 2H); 8.6 (s, 1H). Reaction of this product with toluene-p-sulphonic acid in DMF at 85° for 15 minutes gave 2-fluoro-4-phenylcarbamoylimidazole, n.m.r. in CDCl3 : 6.9-8.0 (m, 6H); 9.6 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([S:23][CH3:24])=[C:9]([C:21]#[N:22])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:9]([C:21]#[N:22])=[C:8]([S:23][CH3:24])[O:7][C:6]=2[C:4]([OH:5])=[O:3])=[CH:16][CH:15]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1oc(SC)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CSc1oc(C(=O)O)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Yield: 29.7 %

Procedure:
Dissolve 3-(4-tert-butyl-phenyl)-4-cyano-5-methylsulfanyl-furan-2-carboxylic acid ethyl ester (110 mg, 0.32 mmol) in a solution of THF: MeOH: H2O (3:2:1, 5 ml). Add lithium hydroxide (80 mg, 3.3 mmol) to the mixture and stir the reaction at 60° C. for 30 minutes. Add 6N HCl until pH approx. 1 to obtain the desired white solid of the titled compound (30 mg, 30%): Mass spectrum (M−1)=314. EA, Calculated: C; 61.91, H; 5.68, N; 4.25. Found: C; 61.75, H; 5.42, N; 3.91.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].Cl.[CH3:22][N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH3:22][N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][C:27]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])[CH:12]=2)[CH2:17]1)=[O:28]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: CN(C)CCCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)CCCC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Reaction time: 8 h

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 67 mg 4-dimethylaminobutyric acid hydrochloride, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight. The reaction mixture is quenched with 3 ml water and 5 ml dichloromethane. The organic phase is separated, the water phase extracted twice with dichloromethane. The combined organic phases are dried and evaporated. 280 ml of a yellow oil is obtained, which is further purified by preparative HPLC-methods.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:21])[CH3:20])[CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCC(C2CNc3ccccc32)CC1
Product: CC(=O)N1CCC(C2CN(C(C)=O)c3ccccc32)CC1

Procedure:
A mixture of 3-(1-acetyl-4-piperidyl)indoline (41.1 g) and acetic anhydride (300 ml) was refluxed for 3 hours. The excess acetic anhydride was distilled off under reduced pressure and the residue was dissolved in ethyl acetate (500 ml). The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml), water (100 ml) and a saturated aqueous solution of sodium chloride successively and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel, elution being carried out with a mixture of chloroform and methanol (40:1 V/V) to give 3-(1-acetyl-4-piperidyl)-1-acetylindoline (32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:8][C:6]1[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1C
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)c1ccc(Cl)cc1CBr

Procedure:
Reaction of ethyl 5-chloro-o-toluate with N-bromosuccinimide as described in Example 1a provides ethyl α-bromo-5-chloro-o-toluate.
Reaction SMILES: C(S(C1C=C(C2C=CC(O)=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C.[CH2:27]([S:29]([C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:44]([O:47][C@H:48]([CH3:51])[CH2:49][OH:50])=[C:43]3[C:39]=2[C:40]2[CH:55]=[C:54]([CH3:56])[CH:53]=[N:52][C:41]=2[NH:42]3)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28]>>[CH2:27]([S:29]([C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:44]([O:47][C@@H:48]([CH3:51])[CH2:49][OH:50])=[C:43]3[C:39]=2[C:40]2[CH:55]=[C:54]([CH3:56])[CH:53]=[N:52][C:41]=2[NH:42]3)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O[C@H](C)CO)c3[nH]c4ncc(C)cc4c23)c1
Agent: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(O[C@@H](C)CO)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 using an analogous procedure to that outlined in the preparation of Compound 211. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.45 Hz, 3H) 1.36 (d, J=6.06 Hz, 3H) 2.26 (s, 3H) 3.40 (q, J=7.41 Hz, 2H) 3.63-3.72 (m, 2H) 4.63 (m, 1H) 4.90 (t, J=6.19 Hz, 1H) 7.07 (d, J=8.08 Hz, 1H) 7.15-7.19 (m, 1H) 7.56 (s, 1H) 7.85 (t, J=7.71 Hz, 1H) 7.97-7.99 (m, 2H) 8.07-8.10 (m, 1H) 8.27 (d, J=2.02 Hz, 1H) 11.82 (s, 1H); [M+H] calc'd for C23H25N2O4S, 425.2; found, 425.3.
Reaction SMILES: [C:1]([C:5]([OH:7])=[O:6])([F:4])([F:3])[F:2].C([O:12][C:13](=[O:35])[C@H:14]([CH3:34])[NH:15][S:16]([C:19]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:33])=[CH:24][N:25]=[C:26]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:21][CH:20]=1)(=[O:18])=[O:17])(C)(C)C>C(Cl)Cl>[F:2][C:1]([F:4])([F:3])[C:5]([OH:7])=[O:6].[Cl:33][C:23]1[C:22]2[C:27](=[CH:28][C:19]([S:16]([NH:15][C@H:14]([C:13]([OH:35])=[O:12])[CH3:34])(=[O:17])=[O:18])=[CH:20][CH:21]=2)[C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[N:25][CH:24]=1
Reactant: C[C@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
CF3CO2H (1.0 mL) was added to a stirred solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-alanine t-butyl ester (ca. 150 mg, 0.35 mmol) in CH2Cl2 (3.0 mL) and the mixture stirred at room temperature for 2 h. The mixture was evaporated in vacuo, azeotroping with PhMe and CH2Cl2, and then triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-alanine trifluoroacetate (62 mg, 0.126 mmol) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[N:13][N:7]3[C:6]=2[CH:26]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:37]1(C)[CH:42]=CC=C[CH:38]=1.C(Br)C=C>C1COCC1>[CH2:42]([C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:8]2[CH2:9][O:10][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][C:6]=3[N:7]2[N:13]=[C:12]1[C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[CH:37]=[CH2:38]
Reactant: CON(C)C(=O)C1=NN2c3cc(Cl)ccc3OCC2C1c1ccccc1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1(c2ccccc2)C(C(=O)N(C)OC)=NN2c3cc(Cl)ccc3OCC21
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
8-Chloro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-1; a racemic mixture, 0.43 g, 1.1 mmol) was dissolved in anhydrous THF (10 mL) and cooled to −78° C. in an acetone/dry ice bath under an N2 atmosphere. The resulting solution was treated with LHMDS (1.39 mL of a 1M toluene solution, 1.39 mmol) and stirred 2 minutes to produce a deep red color. Allyl bromide (0.20 mL, 2.2 mmol) was added neat and the solution was allowed to stir 10 minutes at −78° C. and then removed from the ice bath. Upon reaching ambient temperature, the reaction was judged complete by TLC and quenched by at addition of sat. aqueous NH4Cl (10 mL). The mixture was extracted with Et2O (3×10 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified using flash column chromatography (ISCO Redisep 40 g SiO2 column, 0-40% EtOAc/hexanes gradient) to provide pure 3-allyl-8-chloro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-2; a racemic mixture): 1H NMR (300 MHz, CDCl3) δ 7.42-7.15 (m, 6H), 6.77 (m, 2H), 5.83 (m, 1H), 5.27 (dd, J=16.9, 1.1 Hz, 1H), 5.21 (d, J=10.0 Hz, 1H), 4.10 (dd, J=10.3, 3.7 Hz, 1H), 3.90 (s, 3H), 3.63 (dd, J=11.0, 3.6 Hz, 1H), 3.35 (dd, J=13.4, 6.0 Hz, 1H), 3.32 (s, 3H), 2.96 (m, 2H); MS (M+H+, C22H22ClN3O3) 412.3 found 412.9 required.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[N+](C1C=C([N+]([O-])=O)C=CC=1C(NCC(OCC1C=CC=CC=1)=O)=O)([O-])=O.[Cl:46][C:47]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][C:48]=1[C:49](Cl)=[O:50]>>[Cl:46][C:47]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][C:48]=1[C:49]([NH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:50]
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cc([N+](=O)[O-])ccc1Cl)OCc1ccccc1
Yield: 82 %

Procedure:
The reaction of 2-chloro-5-nitrobenzoyl chloride (prepared from 2-chloro-5-nitrobenzoic acid, 1.0 g and SOCl2, 10 mL) with benzyl glycinate.PTS salt (1.9 g, 5.9 mmol) in the presence of triethylamine (2.0 mL, 14.88 mmol) as described in intermediate 1 gave the title compound as a colorless solid (1.42 g, 82%), mp 116-118° C. 1H NMR (400 MHz, CDCl3): δ 8.54 (1H, d, J=2.8 Hz), 8.23 (1H, dd, J=8.6, 2.6 Hz), 7.61 (1H, d, J=8.8 Hz), 7.38 (5H, br s), 6.88 (1H, br s), 5.24 (2H, s), 4.32 (2H, d, J=4.8 Hz); LC-MS (positive ion mode): m/z 349, 351 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccncc1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccncc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and isonicotinic acid (pyridine-4-carboxylic acid)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:17])([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[C:21](Cl)(Cl)=[O:22].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:16][N:15]1[CH2:14][C:11]2([CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[O:17][C:21]1=[O:22]
Reactant: O=C(Cl)Cl
Reactant: CNCC1(O)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1CC2(CCN(Cc3ccccc3)CC2)OC1=O

Procedure:
A solution of 23 g 1-benzyl-4-hydroxy-4-methylaminomethylpiperidine and 250 ml dichloromethane is mixed with 100 ml of a 15% solution of phosgene in toluene. Evaporation of solvent gives a residue which is treated with 300 ml dichloromethane and 300 ml aqueous sodium bicarbonate. Separation of the dichloromethane layer followed by evaporation gives 20 g 3-methyl-8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 137°-138°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)c2ccncc2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)c2ccncc2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+): m/z=387.1, tR (minutes, Method F)=1.56