Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: NC1CCCCC1
Product: N#Cc1c(NC2CCCCC2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and cyclohexylamine in !)ME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[N:15]O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C(NCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H].[O-]S([O-])(=O)=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:7][C@H:8]1[NH:15][C@H:9]1[C:10]2([CH3:14])[CH3:13]
Reactant: COc1ccc2c(c1)C(C)(C)C(=NO)CC2
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(C)[C@@H]1N[C@@H]1C2
Temperature: 0 °C
Yield: 71 %

Procedure:
To a solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-napthalen-2-one oxime (15.3 g, 70 mmol) in THF (240 mL) was added diethylamine (18 mL). The reaction mixture was cooled to 0° C. and a 2.0 M solution of lithium aluminum hydride in THF (100 mL, 200 mmol) was added slowly over 20 min to control the rate of hydrogen evolution. The reaction mixture was heated to 70° C. for 1 h, cooled to 0° C. and Na2SO4 10H2O (20 g), brine (60 mL), and EtOAc (300 mL) were added. The solid were washed with EtOAc (4×100 mL); the combined organic layers were washed with water (4×100 mL) and brine (100 mL), dried with Na2SO4, and concentrated to give crude title product (14.3 g). The crude product was dissolved in EtOAc (500 mL), extracted with 0.1 N HCl (100 mL), then with 0.3 N HCl (225 mL). Sodium carbonate (8 g, 75 mmol) was added to the aqueous layer which was extracted with EtOAc (4×200 mL). Organic layers were combined, dried with Na2SO4 and concentrated to give the title compound as an oil (10.1 g) which crystallized on standing to a tan solid. (m/z): [M+H]+ calcd for C13H17NO 204.14; found 204.2.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)=[CH:4][CH:3]=1.CC(O)=O>C(Cl)Cl.[Zn]>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ccccc1Nc1ccc(Cl)cc1

Procedure:
To a solution of 2-(4-chloroanilino)-nitrobenzene (57.0 g) in CH2Cl2 (40 mL) was added AcOH (90 mL), then Zn (105 g) was added in small portions. After Zn was added, the color of the mixture became light green, filtered by suction, washed with CH2Cl2. The filtrate was concentrated to dryness. Water was added, filtered, and washed with water to give a brown solid. This solid was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.CC(O)=O.S(=O)(=O)(O)O.C1C(=O)N([I:33])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([I:33])[C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cccc(F)c2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1I
Reaction time: 7 h
Yield: 85.1 %

Procedure:
A round-bottom flask was charged with 2-chloro-3′-fluoro-5-methoxy-1,1′-biphenyl (1.288 g, 5.44 mmol), DCM (8.00 ml), AcOH (8.00 ml), and sulfuric acid (0.160 ml, 2.99 mmol) to give a clear solution. n-Iodosuccinimide (1.224 g, 5.44 mmol) was added in one portion to give a maroon-colored solution. After 7 h, the mixture was diluted with DCM, washed with water, washed with saturated aq. sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel column, 0-5% EtOAc/Heptane) give 2-chloro-3′-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (1.68 g, 4.63 mmol, 85% yield) as a clear oil. m/z (ESI) 362.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[C:19]([C:25]([C:27]3[CH:28]=[N:29][C:30](F)=[CH:31][CH:32]=3)=[O:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[CH2:15][O:16][CH3:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C-:34]#[N:35].[K+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[C:19]([C:25]([C:27]3[CH:28]=[N:29][C:30]([C:34]#[N:35])=[CH:31][CH:32]=3)=[O:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[CH2:15][O:16][CH3:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccc(F)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C#N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-tert-Butyl-N-[5-chloro-2-(6-fluoro-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide (444 mg, 0.899 mmol) was dissolved in DMF (5 mL). KCN (300 mg, 4.6 mmol) was then added and the reaction mixture was heated to 60° C. for 2 hours. Additional KCN (110 mg, 1.7 mmol) was then added and the reaction was stirred for another 2 hours. The solvent was removed under reduced pressure and the resulting brown oil purified by column (1:4 EtOAc/hexanes) to give 172 mg (0.345 mmol, 38% yield). MS calc'd for C24H24ClN4O4S (MH+): 499.1, found 499.1.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8](=O)[NH:7][N:6]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:6][N:7]=1
Reactant: COc1ccc2c(CC3CC3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(CC3CC3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-cyclopropylmethyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11](O)[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.P(Br)(Br)[Br:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([Br:19])[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1
Reactant: OC1Cc2ccccc2Sc2cc(Br)ccc21
Reactant: BrP(Br)Br
Product: Brc1ccc2c(c1)Sc1ccccc1CC2Br

Procedure:
10.5 G. 3-bromo-10,11-dihydro-11-hydroxydibenzo[b,f]thiepin and 25 cc. phosphorous tribromide are stirred for 2 hours, poured onto ice and extracted with ether. The ether is dried and evaporated to yield 10.65 g. of a brown oil which solifies on standing. The material is used as such for the next step.
Reaction SMILES: [CH2:1]([N:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 4 h

Procedure:
A suspension of 3.82 g (10 mmol) of tert-butyl trans-benzyl[4-(4-hydroxyphenyl)-cyclohexyl]carbamate (cf. preparation 1.2) and of 0.48 g of 60% sodium hydride (12 mmol) in dimethylformamide (38 ml) is stirred for 25 minutes and then 1.44 ml of ethyl bromoacetate (13 mmol) are added. The reaction is left stirring for 4 h. The reaction medium is neutralized by the addition of a saturated aqueous ammonium chloride solution. The solvents are evaporated under reduced pressure and water and dichloromethane are added. The organic phase is washed 5 times with water and then dried over magnesium sulfate. Ethyl trans-(4-{4-[benzyl(tert-butoxycarbonyl)amino]cyclohexyl}phenoxy)acetate is obtained in the form of a white solid (4.68 g, 100%) after evaporation of the solvents under reduced pressure.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1COCC1>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@@H:9]([C:20]([OH:22])=[O:21])[NH2:8])=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reaction time: 2 h

Procedure:
N-tert-Butoxycarbonyl-O-ethyl-L-tyrosine (III, EXAMPLE 2, 195 g, 632 mmol) is suspended in THF (1200 mL), p-toluenesulfonic acid monohydrate (240 g, 1.26 mol) is added at 20-25°. The resulting mixture is heated at reflux for 2 hr. The mixture is neutralized with sodium hydroxide (2N, about 700 mL) to pH between 5 and 6 at 20-25°. The resulting mixture is stirred at 5° for 2 hr before it is filtered. The cake is washed with THF/water (4/1, 50 mL×3). The precipitate is dried to give the title compound. The filtrate is removed of all volatile, adjusted pH again to give more precipitate. The precipitate is dried to give additional title compound, NMR (D2O/NaOH) δ7.14, 6.88, 4.02, 3.40, 2.88, 2.73 and 1.30; CMR (D2O/NaOH) δ182.8, 157.0, 131.4, 131.0, 64.8, 57.8, 40.3 and 14.3.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].C1COCC1.[CH2:17]([N:24]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[CH2:17]([N:24]1[CH2:28][CH2:27][C@H:26]([O:29][C:8](=[O:10])[CH3:9])[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)Cl
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CCN(Cc2ccccc2)C1
Yield: 90 %

Procedure:
Triethylamine (1.3 mL, 9.30 mmols) and acetyl chloride (0.6 mL, 8.46) were added to THF (20 mL) solution of (3S)-1-benzyl-3-hydroxypyrrolidine (1.5 g, 8.46 mmols) by the order stated, under cooling with ice, and stirred at the same temperature for an hour. Ethyl acetate was added to the reaction liquid which then was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Concentrating the reaction liquid under reduced pressure, the residue was purified on silica gel column chromatography (KP—NH, ethyl acetate:hexane=1:20) to provide the title compound (1.68 g, 90%).
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:25][O:26]CC)[N:18]([CH2:19][C:20]3([OH:24])[CH2:23][CH2:22][CH2:21]3)[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.Cl.[OH-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CO>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:25][OH:26])[N:18]([CH2:19][C:20]3([OH:24])[CH2:23][CH2:22][CH2:21]3)[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCC1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: Nc1nc2cccnc2c2c1nc(CO)n2CC1(O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere boron tribromide (6.15 mL of 1M in dichloromethane) was added dropwise over a period of 10 minutes to a chilled (0° C.) solution of 1-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanol (0.67 g, 2.0 mmol) in dichloromethane (20 mL). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was cooled to 0° C. and then more boron tribromide (1.0 mL) was added. The reaction mixture was stirred at ambient temperature for 4 hours. Methanol (10 mL) and hydrochloric acid (10 mL of 6N) were added and the reaction mixture was heated at reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature and was then made basic with 6N sodium hydroxide. A portion of the solvent was removed under vacuum, water (10 mL) was added, and the mixture was sonicated. A solid was isolated by filtration and rinsed with water. The aqueous filtrate was extracted with chloroform (3×80 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was combined with the isolated solid and then purified by HPFC eluting with a gradient of 0-30% CMA in chloroform, triturated with acetonitrile, and dried. The resulting material was suspended in water (70 mL) and heated to 90° C. Concentrated hydrochloric acid (about 0.8 mL) was added until a solution was obtained. The hot solution was made basic with solid sodium bicarbonate and then allowed to cool. A precipitate was isolated by filtration, washed well with water, and then dried to provide 1-[(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanol as a white powder, mp 244.0-246.0° C. Anal. Calcd for C15H17N5O2 C, 60.19; H, 5.72; N, 23.40. Found: C, 59.97; H, 5.81; N, 23.31.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[CH:14]([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CI>O1CCCC1.CCCCCC.O.C(OCC)(=O)C>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: CC(C)[N-]C(C)C
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C(=O)O)c1ccccc1N(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(2-dimethylaminophenyl)acetic acid (1.8 g) in dry tetrahydrofuran (10 cc) is added at 10° C. to a solution of lithium diisopropylamide (prepared by the action of a 1.6M solution (2.6 cc) of butyllithium in hexane on a solution of diisopropylamine (2.8 g) in dry tetrahydrofuran (30 cc) at 10° C.). The reaction mixture is stirred for 30 minutes at 20° C. and then for 30 minutes at 35° C. After cooling to 20° C., methyl iodide (0.63 cc) is added and the mixture is heated to 35° C. for 1 hour. It is cooled and diluted with water (20 cc) and ethyl acetate (100 cc). The aqueous phase is washed with ethyl acetate (100 cc), acidified to pH 5 with hydrochloric acid and extracted with ethyl acetate (2×100 cc). The organic phases are washed with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) to give (RS)-2-(2-dimethylaminophenyl)propionic acid (1 g) in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[C:5](=[N:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].N.C([O-])(=O)C.[NH4+]>C(O)C.C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH:5]([NH2:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: COc1ccc(C(=NO)c2ccccc2OC)c(OC)c1
Agent: CC(=O)[O-]
Agent: N
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(N)c2ccccc2OC)c(OC)c1
Temperature: 25 °C

Procedure:
2,2′,4-Trimethoxybenzophenone oxime (6 g, 20.9 mmol) is dissolved in ethanol (30 ml) and concentrated aqueous ammonia (150 ml). Ammonium acetate (0.81 g, 10.45 mmol) is added, followed by zinc powder (6.79 g, 104 mmol). The reaction is heated to reflux for 4 hours, cooled to ambient temperature, diluted with ethyl acetate and filtered through a Celite™ filter. Evaporation affords the title compound. δH 3.78 (s 3H), 3.80 (s 3H), 3.82 (s 3H), 5.62 (s 3H), 6.40-6.50 (m 2H), 6.85-9.95 (m 2H), 7.10 (d J 8), 7.20-7.30 (m 2H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:7])=[O:6].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.C(N(CC)CC)C.[N-]=C=O>ClCCl.CCOC(C)=O>[Br:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:18]([NH2:20])=[O:19])=[C:8]2[S:5]([NH:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[O:31])(=[O:6])=[O:7]
Reactant: NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Reactant: COc1ccc(N=C=O)cc1
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)NCCNS(=O)(=O)c2c(C(N)=O)[nH]c3ccc(Br)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Example 63 (50 mg) was combined with 4-methoxyphenyl isocyanate (21 mg) and triethylamine (58 μL) in 2 mL of dichloromethane and stirred at room temperature for 3 hours. An additional 18 μL of the isocyanate were added and the reaction stirred for 3 hours more, then diluted with EtOAc and washed with saturated NaHCO3 and brine. The solution was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative reversed-phase HPLC followed by triteration with Et2O/hexane to give the titled product. ESI+ MS: 510 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].O.[NH2:30][NH2:31]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[CH:24]=[C:25]([CH3:26])[NH:31][N:30]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: NN
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)[nH]n1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with hydrazine monohydrate (CAS Reg. No. 7803-57-8) to give the title compound as yellow solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[N:10]=1>CN(C=O)C.C1COCC1.O>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[N:10]=1
Reactant: Fc1cccc(F)n1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(-n2cccn2)n1
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Sodium hydride / 60 percent oil dispersion (0.80 g, 20 mmol) was added over 5 minutes to a solution of pyrazole (1.4 g, 20 mmol) in DMF (20 mL) and THF (6 mL). After 10 minutes, 2,6-difluoropyridine (1.9 mL, 21 mmol) was added in one portion. After stirring for 20 h, the reaction was diluted with water (250 mL) and extracted with ether (5×50 mL). The organics were combined, washed with water (3×50 mL), brine (50 mL) and dried (Na2SO4). Filtration and removal of solvent left a gold oil that was purified by reverse phase liquid chromatography, affording product as a colorless oil, 2.0 g, 12.3 mmol, 61 percent yield.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11].C[O:13][C:14](=[O:17])[CH:15]=[CH2:16]>CO.C(OCC)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:16][CH2:15][C:14]([OH:17])=[O:13]
Reactant: COc1ccccc1S
Reactant: C=CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccccc1SCCC(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
1.5 ml of a solution of 1N sodium hydroxide in methanol are added to a solution of 20.2 g of 2-methoxybenzenethiol in 20 ml of methanol and 20 ml of diethyl ether followed by cooling to 0° C. 13.9 ml of methylacrylate was then dropwise added to this solution. After completion of dropping, the reaction mixture was warmed to room temperature and stirred overnight. After concentrating the reaction mixture by a rotary evaporator, 8.7 g of sodium hydroxide, 100 ml of water and 35 ml of methanol was added followed by stirring vigorously overnight. The reaction mixture was acidified with concentrated hydrochloric acid while cooling and the resulting solution was extracted with chloroform. The chloroform layer was dried with magnesium sulfate, the solvent was distilled off and the resulting crystal was recrystallized from chloroform-hexane to obtain 25.4 g of the target 2-(2-methoxyphenylthio) ethanecarboxylic acid (yield: 83%, m.p.: 91°-91.5° C.).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].Br[CH2:26][C:27]#[N:28].O>O1CCCC1>[C:27]([CH2:26][CH:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:16])#[N:28]
Reactant: O=C1CC(c2ccccc2)(c2ccccc2)c2ccccc21
Reactant: N#CCBr
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC1C(=O)c2ccccc2C1(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Spiro[3,3-diphenyl-2,3-dihydro(1H)indene-1,3′-2′-cyanooxirane] (Compound 5) and 2-cyanomethyl-3,3-diphenylindanone (Compound 9) were synthesized as follows: 3,3-diphenylindanone (Compound 2), 5.0 g (0.0176 mole) and 2.62 g (0.0229 mole) of potassium hydride were stirred at room temperature in 40 mL of tetrahydrofuran. After the gas evolution subsided (approx. 45 min), 1.5 mL (0.0215 mole) of bromoacetonitrile was added. The dark red mixture was stirred for 1 hour and then 50 mL of water was added. The mixture was extracted three times with 75 mL of ethyl acetate. The combined organic extracts were concentrated in vacuo, loaded onto a silica gel column and eluted with 10% ethyl acetate in hexane. Three fractions were collected. After evaporation of the solvent, the first fraction yielded unreacted starting material (3.5 g). The second fraction yielded 0.49 g (9% yield) of spiro[3,3-diphenyl-2,3-dihydro(1H)indene-1,3′-2′-cyanooxirane] (Compound 5) as a white solid. The third fraction yielded 1.05 g (18% yield) of 2-cyanomethyl-3,3-diphenylindanone (Compound 9) as a yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>ClCCl>[Br:34][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.1 %

Procedure:
To an ice-cold solution of tert-butyl 4-hydroxybutylcarbamate (5 g, 26.41 mmol) in dichloromethane (200 mL) was added triphenylphosphine (10.38 g, 39.61 mmol) followed by carbon tetrabromide (13.15 g, 39.61 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica gel) using 10% ethyl acetate in pet-ether to give tert-butyl 4-bromobutylcarbamate (4.2 g, 63.3%) as a light green liquid. 1H NMR (400 MHz, CDCl3) δ ppm 4.53 (1H, s), 3.45-3.41 (2H, m), 3.18-3.13 (2H, m), 1.93-1.83 (2H, m), 1.68-1.61 (2H, m), 1.47 (9H, s).