Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br.[CH3:12][N:13]([CH3:30])[CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21].[Cl-:31].[NH4+]>CCOCC>[ClH:31].[CH3:30][N:13]([CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH3:2])[CH:5]=1)[OH:21])[CH3:12]
Reactant: COc1cccc(CBr)c1
Reactant: [Cl-]
Reactant: COc1cccc(C(C2CCCCC2=O)N(C)C)c1
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cccc(CC2(O)CCCCC2C(c2cccc(OC)c2)N(C)C)c1
Product: Cl
Temperature: 25 °C
Yield: 48.4 %

Procedure:
0.32 g (13.0 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.61 g (13.0 mmole) of 3-methoxybenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (10.8 mmole) of the 2-[dimethyl-amino-(3-methoxyphenyl)methyl]cyclohexanone prepared according to Example 9 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 15 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.87 g of crude base (101% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times, each time with 15 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.34 g of crude base (61.2% of theory) were obtained, from which 2.04 g of 2-[dimethylamino-(3-methoxyphenyl)methyl]-1-(3-methoxybenzyl)cyclohexanol, hydrochloride (48.4% of theory) were obtained according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 75° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14]1>>[CH2:9]([O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:13]2[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18]2)[CH:7]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: C1=CCNCC1
Product: CC#CCOc1cc(N2CC=CCC2)ncn1
Reaction time: 2 h
Yield: 100.9 %

Procedure:
0.3 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 0.41 g of 1,2,3,6-tetrahydropyridine were mixed and left for 2 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.38 g of 1-(6-(2-butynyloxy)pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine (hereinafter, referred to as Compound (54)).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:32])[CH2:12][O:11][S:10](=[O:14])(=[O:13])[N:9]1[CH:15](C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C1(C)COS(=O)N1C)=O)(C)(C)C>>[C:1]([O:5][C:6]([C:8]1([CH3:32])[CH2:12][O:11][S:10](=[O:13])(=[O:14])[N:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2C(C)(C(=O)OC(C)(C)C)COS2(=O)=O)cc1
Agent: CN1S(=O)OCC1(C)C(=O)OC(C)(C)C
Product: CN1C(C)(C(=O)OC(C)(C)C)COS1(=O)=O
Yield: 94 %

Procedure:
The same reaction conditions used to obtain 14a were applied to 42 mg of 13b (0.18 mmol), providing 14b (42 mg, 94%) as a white solid: mp 54-55° C. (EtOAc/hexane); 1H NMR (CDCl3) δ1.50 (9H, s), 1.52 (3H, s), 2.93 (3H, s), 4.22 (1H, d, J=8.8), 4.88 (1H, d, J=8.8). Anal (C9H17NO5S)C,H,N.
Reaction SMILES: CS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10]2.[N-:17]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[NH:17][CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCCc2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 110.6 %

Procedure:
Methanesulfonic acid (100 mL) was added to a solution of 5-bromoindanone (25 g, 46 mmol) in CH2Cl2 (200 mL) at 0° C. Sodium azide 10.5 g, 162 mmol) was added slowly in portions to this mixture. After the sodium azide addition was complete, the mixture was stirred for an additional 30 min, and an aqueous mixture of NaOH (20 wt %) was added until the mixture was slightly basic. The mixture was extracted with methylene chloride, and the combined organic layers were evaporated under reduced pressure. Purification of the mixture by flash column chromatography on silica gel (0% to 50% EtOAc/Hexanes then 0% to 7% MeOH/CH2Cl2) provided 11.5 g of 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one. MS (ESI) 226.1 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.O[N:35]=[C:36]([C:38]1[CH:42]=[C:41]([CH3:43])[O:40][N:39]=1)[NH2:37]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:37]=[C:36]([C:38]3[CH:42]=[C:41]([CH3:43])[O:40][N:39]=3)[N:35]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: Cc1cc(C(N)=NO)no1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](c2nc(-c3cc(C)on3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and N′-hydroxy-5-methyl-3-isoxazole-carboximidamide, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=444.2.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]2=[N:4][C:3]=1[CH2:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(=O)NC(=O)C2=CC=CC=C12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:11][C:10]1[C:5]2[N:6]([C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:3]([CH2:12][NH2:13])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2c(Cl)cccn2c1Br
Agent: O=C1NC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1nc2c(Cl)cccn2c1-c1ccccc1

Procedure:
2-((3-Bromo-8-chloroimidazo[1,2-a]pyridin-2-yl)methyl)isoindoline-1,3-dione was coupled with phenyl boronic acid according to Step C3b in General Procedure C. Partial hydrolysis of the phthalimide was observed under the reaction conditions. The crude intermediate was treated with DCM and TFA for a week. The reaction mixture was concentrated under reduced pressure and purified by reverse phase semi-prep HPLC. The fractions containing the desired product were lyophilized. The lyophilate was partitioned with satd. aq. NaHCO3 solution and EtOAc. The aq. layer was extracted three times with EtOAc. The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure to give (8-chloro-3-phenylimidazo[1,2-a]pyridin-2-yl)methanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([CH:24]([CH3:26])[CH3:25])=[C:15]([C@@H:16]([C:21]([O-:23])=[O:22])[CH2:17][C:18]([O-:20])=[O:19])[C:9]=3[C:8]([N:27]3[CH2:32][CH2:31][NH:30][CH:29]([CH2:33][CH2:34][O:35][CH3:36])[CH2:28]3)=[N:7][C:6]=2[CH:37]=1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.[Cl-].[Na+]>[C:21]([OH:23])(=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([CH:24]([CH3:26])[CH3:25])=[CH:15][C:9]=3[C:8]([N:27]3[CH2:32][CH2:31][N:30]([CH3:38])[C@@H:29]([CH2:33][CH2:34][O:35][CH3:36])[CH2:28]3)=[N:7][C:6]=2[CH:37]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCCC1CN(C2=Nc3cc(Cl)ccc3Nc3ccc(C(C)C)c([C@H](CC(=O)[O-])C(=O)[O-])c32)CCN1
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3ccc(C(C)C)cc32)CCN1C
Product: O=C(O)CCC(=O)O
Yield: 27.3 %

Procedure:
Dissolve (S)-8-chloro-2-isopropyl-11-[3-(2-methoxy-ethyl) piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine succinate (0.089 g, 0.22 mmol) in dichloromethane (12 ml). Add sodium triacetoxyborohydride (0.137 g, 0.65 mmol) and formaldehyde (0.013 g, 0.43 mmol, 0.035 g of a 37% aqueous solution) and stir the mixture for two hours at ambient temperature. Dilute the mixture with 50 mL of saturated aqueous sodium chloride and extract three times with dichloromethane. Combine the organic layers, dryover sodium sulfate and remove the solvent under reduced pressure. Purification via flash chromatography, eluting with a mixture of 75% hexanes and 25% chloroform with 1% total volume isopropylamine, gives the free base of the title compound (0.027 g, 0.06 mmol, 29% yield) as a yellow amorphous solid. Convert to the succinate salt as described previously: Mass Spectrum (m/e): 427(M+1); Exact Mass Spec: Calc. 427.2265; Found 427.2279.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[C:27]([CH3:37])=[N:28][N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[C:27]([CH3:37])=[N:28][N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:30]=1)[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1cn(-c2ccccn2)nc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2cn(-c3ccccn3)nc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 67.5 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.28 g), tetraethyl methylenediphosphonate (0.18 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.030 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.24 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (5:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 103-104° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]=[C:7]([CH3:14])[CH:6]=[CH:5]2.[Se](=O)=[O:16]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]=[C:7]([CH:14]=[O:16])[CH:6]=[CH:5]2
Reactant: O=[Se]=O
Reactant: COc1cc(F)cc2ccc(C)nc12
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(F)cc2ccc(C=O)nc12
Yield: 78.7 %

Procedure:
To 6-fluoro-8-methoxy-2-methylquinoline (500 mg, 2.62 mmol) in dioxane/water (5 mL/0.5 mL) at ambient temperature was added selenium dioxide (348 mg, 3.14 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro-8-methoxyquinoline-2-carbaldehyde (423 mg, 78.8% yield) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][C@H:22]([CH2:26][OH:27])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].C(OC([N:35]1[CH2:39][CH2:38][CH2:37][C@@H:36]1[C:40](O)=[O:41])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:40]([C@H:36]4[CH2:37][CH2:38][CH2:39][NH:35]4)=[O:41])[C@H:22]([CH2:26][OH:27])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN[C@H](CO)C3)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4)[C@H](CO)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a stirred solution of the ((S)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)piperazin-2-yl)methanol (0.072 g, 0.18 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.078 g, 0.36 mmol) in dichloromethane (2.0 mL) was added HATU (0.14 g, 0.36 mmol) and iPr2NEt (0.10 mL, 0.57 mmol). The reaction mixture was stirred at room temperature for 30 min, and was then diluted with dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 30-100% ethyl acetate in hexanes) to afford the desired product (0.072 g, 0.12 mmol, 30% for 2 steps).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[O:16][CH3:17])(O)=[O:2].Cl.CN.Cl.[CH2:22]([N:24]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:17][O:16][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:4]=1[C:1](=[O:2])[NH:24][CH3:22])[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)C=Cc1ccc(C(=O)O)c(OC)c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)OC)cc1OC
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution of methyl 4-carboxy-3-methoxycinnamate (400 mg) in N,N-dimethylformamide were added methylamine hydrochloride (126 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (390 mg) and 1-hydroxybenzotriazole (320 mg) at ambient temperature, and the mixture was stirred for 18 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform methanol=40:1, v/v) to give methyl 3-methoxy-4-(methylcarbamoyl)cinnamate (319 mg).
Reaction SMILES: [O:1]=[O+][O-].C([C:6](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:7]([C@@H:9]([NH:14][C:15](=[O:28])[O:16][C:17]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])#N.[CH3:48][C@H:49]([NH2:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>ClCCl>[O:1]=[C:6]([NH:56][C@@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH3:48])[C:7]([C@@H:9]([NH:14][C:15](=[O:28])[O:16][C:17]1([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:19][CH2:20]1)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:8]
Reactant: C[C@H](N)c1ccccc1
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCC1)C(=O)C(=O)N[C@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 10 %

Procedure:
Ozone was bubbled through a solution of 402.0 mg (667.0 μmol) of 1-benzylcyclobutyl (1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate in 13 mL of dichloromethane at −78° C. for 15 min. The solution was purged with nitrogen for 5 min, then 86.0 μL (667.0 μmol) of (S)-α-methylbenzylamine was added and the solution was stirred at −78° C. for 15 min. The solution was concentrated and 5 mL of a 1 M solution of silver nitrate in tetrahydrofuran:water (4:1) was added and the mixture was stirred for 16 h at room temperature. The solution was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an acetone:hexanes solution (1:3) to give 30.2 mg (10%) of 1-benzylcyclobutyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate. Rf=0.24 (1:4 acetone:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.20 (d, J=8 Hz, 1H), 7.46 (d, J=7 Hz, 1H), 7.34-7.09 (m, 10H), 4.98 (p, J=8 Hz, 1H), 4.80-4.72 (m, 1H), 3.15 (s, 2H), 2.22-2.02 (m, 4H), 1.80-1.54 (m, 3H), 1.42 (d, J=7 Hz, 3H), 1.42-1.14 (m, 5H), 0.81 (t, J=7 Hz, 3H); HRMS C27H34N2O4+Na m/z 473.2416 (M+Na)Cal; 473.2423 (M+Na)Obs.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([O:13][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:11][CH3:12])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)Cc1cccc(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(Cc1cccc(OC)c1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
1-[3-(Methyloxy)phenyl]-2-butanol (51) (3.50 g, 19.4 mmol) was dissolved in CH2Cl2 (90 mL). To this solution was added Et3N (5.4 mL, 38.8 mmol) followed by catalytic amount of N,N-dimethylaminopyridine (DMAP). The mixture was cooled in an ice bath, methanesulfonyl chloride (2.3 mL, 29.1 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. Water was added to the mixture, CH2Cl2 layer was separated. The aqueous layer was further extracted with CH2Cl2 (50 mL). The extracts were combined and washed with brine, (Na2SO4), filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (4:1) to give 4.66 g (94%) of the title compound (52) as a yellow oil, which solidified upon freezing. 1H NMR (400 MHz, CDCl3): δ 1.03 (t, J=7.5 Hz, 3H), 1.70-1.85 (m, 2H), 2.53 (s, 3H), 2.94 (d, J=6.7 Hz, 2H), 3.80 (s, 3H), 4.70-4.80 (m, 1H), 6.75-6.85 (m, 3H), 7.20-7.25 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2].C(O)C.[BH4-].[Na+].C(O)(=O)C>O>[CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN(CC(=O)O)c1ccc(C=O)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCN(CC(=O)O)c1ccc(CO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
(a-2) To a stirred solution of 47.8 parts of ethyl N-(4-formyl-2-nitrophenyl)glycine in 280 parts of ethanol were added in small portions 3.8 parts of sodium tetrahydroborate. The whole was stirred for 30 minutes at room temperature. The reaction mixture was decomposed by a solution of 12 parts of acetic acid in 50 parts of water. The mixture was concentrated. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 34.1 parts (70.6%) of ethyl N-[4-(hydroxymethyl)-2-nitrophenyl]glycine (int. 30).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.[CH3:20][S@:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[NH:23])=[O:22]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:23]=[S@@:21]([CH3:20])(=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: C[S@](=N)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of 5-bromonicotinic acid (1.21 g, 6.0 mmol), N,N-diisopropylethylamine (2.1 mL, 12.0 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (931 mg, 6.0 mmol) in DMF (11.0 mL) cooled to 0° C. was treated with 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) (3.43 g, 6.6 mmol). The reaction mixture was stirred 10 minutes, the ice bath removed, and the reaction continued at room temperature for 2 hours. The mixture was taken up in EtOAc and washed with H2O, Na2CO3 solution, brine, AcOH solution, H2O, Na2CO3 solution, brine, dried with anhydrous Na2SO4 and concentrated. The residual brown oil was purified by chromatography (silica gel, hexane/EtOAc). The product containing eluent was concentrated and then triturated with hexane to give the title compound as an off-white solid (1.88 g, 92%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([N:15]=[C:16]=[S:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.O>[C:18]1([N:24]2[C:25](=[S:26])[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:7])[NH:15][C:16]2=[S:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC(N=C=S)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2ccccc2)NC(=S)N(c2ccccc2)C1=S
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
15.1 g (122 mmol) of potassium tert-butoxide are dissolved in 200 ml of tetrahydrofuran in a 500 ml, three-necked, round-bottomed flask under a dry argon atmosphere. The solution is cooled to -70° C. A solution containing 20 g (122 mmol) of alpha-methylbenzyl isothiocyanate, 16.55 g (122 mmol) of phenyl isothiocyanate and 50 ml of tetrahydrofuran is run in dropwise while keeping the temperature of the mixture below -60° C. On completion of addition, the mixture is held for 0.5 hour at -70° C. and then is left to return to more temperature. The mixture is poured into 500 ml of water. The mixture is acidified to pH=1 by addition of N hydrochloric acid. The product is extracted with ethyl acetate (2 extractions, each with 150 ml of solvent). The solution is dried over magnesium sulfate. The solution is concentrated under reduced pressure. The product is crystallized from 50 ml of ether. The precipitate is filtered. 21 g (yield: 58%) of 3,5-diphenyl-5-methyldithiohydantoin are thus obtained as a yellow powder melting at 157° C.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl.[Cl:12][CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:22]Cl)[C:17]=1[CH3:24].[OH-].[Na+]>>[Cl:12][CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:17]=1[CH3:24]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCCCl)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(SCCCl)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
According to the procedure indicated in Example A1, reaction of 2-mercapto-1H-benzimidazole with 4-(2-chloroethylthio)-2-chloromethyl-3-methylpyridine hydrochloride and NaOH gives, after crystallization from ethyl acetate, the title compound (62% of theory) as a colorless solid of m.p. 178-180° C.