Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(OC(=O)[NH:21][C@@H:22]([CH3:25])[CH2:23]O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl>C(Cl)Cl.O.CCOC(C)=O>[NH2:21][C@@H:22]([CH3:25])[CH2:23][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (30 g, 145 mmol), (S)-tert-butyl-1-hydroxypropan-2-ylcarbamate (51.4 g, 291 mmol), triphenylphosphine (77 g, 291 mmol) and 210 ml of EtOAc were place in to the reaction vessel under nitrogen atmosphere and stirred for 15 min. DIAD (57.8 ml, 291 mmol) was added slowly in 1.5 h at RT keeping the temperature stable and the reaction was stirred overnight at RT. Concentrated HCl (134 ml, 1453 mmol) was added and the mixture was stirred at RT overnight. Water (165 ml) and DCM (240 ml) were added, the mixture was stirred for 30 min and layers were separated. Organic phase was washed with 2×270 ml of acidic water (pH˜1). Water phases were combined and washed with 2×120 ml of dichloromethane. Dichloromethane (150 ml) was added, pH set to 11.5 by 50% NaOH and the mixture was stirred for 75 min. The solution was filtered through the celite, layers were separated and organic phase was washed with 171 ml of water. DCM was distilled out at 33° C. under reduced pressure and 60 ml of heptanes was added. Precipitation was started, 60 ml of heptane added and the mixture was stirred overnight. Some DCM was evaporated, 60 ml heptanes was added and the mixture was cooled to 10° C. The precipitate was filtered, washed with 20 ml of IPA:heptane (10:90) and dried under vacuum to obtain 24.55 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 1.03 (d, 3H), 3.34-3.43 (d, 2H), 4.14 (d, 2H), 6.99 (d, 1H), 7.89 (d, 1H), 7.96 (dd, 1H), 7.99 (dd, 1H), 8.12-8.14 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C([O-])([O-])=O.[K+].[K+].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 120 °C

Procedure:
The mixture of 4-chloro-3-(trifluoromethyl)phenol (2 g, 10.18 mmol), K2CO3 (2.109 g, 15.26 mmol) and 4-fluorobenzonitrile (1.232 g, 10.18 mmol) in DMF (20 ml), was heated at 120° C. overnight. It was diluted with water and extracted with EtOAc. The organic phases were collected, washed with water and brine, dried over Na2SO4 and concentrated to afford the title compound as a brown oil. LCMS: rt=3.81 min, [M+H+]=298
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1C[CH2:10][CH2:9][CH2:8]1.[Cl:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20])=[O:16].CCOCC>O>[CH:9]([O:16][CH:15]([CH3:14])[CH3:17])([CH3:10])[CH3:8].[Cl:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[CH:15]([OH:16])[C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][OH:20]
Reactant: C1CCOC1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)OC(C)C
Product: OCc1ccccc1C(O)c1ccccc1Cl
Reaction time: 1 h

Procedure:
To a stirred suspension of 22.8 g. (0.60 mole) of lithium aluminum hydride in 700 ml. of dry tetrahydrofuran was added 104 g. (0.40 mole) of 2-(2-chlorobenzoyl)benzoic acid prepared as above in portions keeping the reaction mixture temperature between 15°-30° with ice cooling. After the addition was complete the reaction mixture was stirred for one hour. Ether (400 ml.) was added followed by the slow addition of 80 ml. of water, with ice cooling. The mixture was filtered through a large sintered glass funnel which contained a matting of Celite filter-aid. The filtered solids were washed with tetrahydrofuran and the combined filtrates were evaporated under vacuo to a yellow oil which crystallized upon scratching. The material was recrystallized from 150 ml. of isopropyl ether to give 2-chloro-2'-hydroxymethylbenzhydrol as a slightly pink solid, m.p. 85°-87°. A sample was recrystallized three times from isopropyl ether to give colorless prisms, m.p. 86°-87°.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[C:4]2[N:13]=[CH:12][N:11]([CH3:14])[C:5]2=[N:6][C:7]=1[C:8]([OH:10])=[O:9].[Si](C=[N+]=[N-])(C)(C)[CH3:17]>C1COCC1.CO>[CH3:17][O:9][C:8]([C:7]1[N:6]=[C:5]2[N:11]([CH3:14])[CH:12]=[N:13][C:4]2=[C:3]([F:15])[C:2]=1[Br:1])=[O:10]
Reactant: Cn1cnc2c(F)c(Br)c(C(=O)O)nc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1nc2c(ncn2C)c(F)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1.00 equivalent) in THF-MeOH at 0° C. is added TMSCHN2 (1.30 equivalents, 2 M solution in hexanes). The resulting mixture is warmed to room temperature and stirred for 2 hours. The reaction is quenched with AcOH. The reaction mixture is diluted with EtOAc. The organic layer is washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product that is used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(O)(=O)C.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH:16]=O.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:16][C:15]2[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[CH:4][CH:3]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: Nc1ccc(Br)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1cccc(F)c1CNc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.1 %

Procedure:
To a solution of 6-bromopyridin-3-amine (500 mg, 2.89 mmol), in MeOH (3 mL), acetic acid (0.165 mL, 2.89 mmol), 2,6-difluorobenzaldehyde (0.31 mL, 2.89 mmol) was added. After stirring the resulting mixture at RT for 12 h, sodium cyanoborohydride (363 mg, 5.78 mmol) was added at 0° C. and resulting mixture was stirred at RT for 6 h. Solvent was evaporated under vacuum. Residue was purified by column chromatography to afford 200 mg (23%) of the title compound as white solid. GC-MS-298, 300 [M+, Br79,81]
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:15])=[O:14])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39](=[O:41])[CH3:40])=[CH:18][C:17]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:14])=[O:15])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@H](NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1)C(N)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCc2ccccc2)c1
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of (S)-3-(4-amino-2-benzyloxy-benzenesulfonylamino)-succinamic acid tert-butyl ester (1.41 g, 3.10 mmol) in methylene chloride (100 mL) and Et3N (0.44 mL, 3.10 mmol) was added acetyl chloride (0.25 mL, 3.1 mmol). The reaction was stirred for 3 h. The solvent was removed and replaced with EtOAc (150 mL). The organic solution was washed twice with 5% citric acid, saturated NaHCO3, water, and brine. The solution was dried over MgSO4, filtered, and the solvent was removed. The resulting crude product was purified using silica gel flash chromatography (20% hexanes in EtOAc). (S)-3-(4-Acetylamino-2-benzyloxy-benzenesulfonylamino)-succinamic acid tert-butyl ester was obtained in 63% yield (0.96 g) as an off white foam. MS (APCI) m/z 490.2 (M−1).
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:31]1([CH2:37][CH2:38][NH2:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:31]1([CH2:37][CH2:38][NH:39][C:26]([C:23]2[CH:24]=[CH:25][C:19]3[O:18][C:17]([CH2:16][O:15][C:14]4[CH:13]=[CH:12][C:11]([C:1]56[CH2:10][CH:5]7[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]7)[CH2:8]5)[CH2:2]6)=[CH:30][CH:29]=4)=[N:21][C:20]=3[CH:22]=2)=[O:27])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCCN1CCCCC1
Reactant: O=C(O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCCCC1)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (70.2 mg, 0.17 mmol) and 2-piperidine-1-yl-ethylamine (0.049 ml, 0.35 mmol) in DMF 5.0 mL was added HBTU (132.7 mg, 0.35 mmol) and DIPEA (0.061 ml, 0.35 mmol). After stirring at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=20:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (2-piperidine-1-yl-ethyl)-amide as a white foam (18.9 mg, 22% yield).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]([S:24][CH2:25][CH:26]([NH2:34])[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[C@@H:16]([OH:23])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].CC1[N:44](C(C2C=CC(Cl)=CC=2)=O)[C:43]2C=CC(OC)=CC=2C=1CC(O)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]([S:24][CH2:25][CH:26]([NH2:34])[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[C@@H:16]([OH:23])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].[NH2:44][CH2:43][CH2:25][C:26]1[N:34]=[CH:30][NH:29][CH:27]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H](SCC(N)C(=O)NCC(=O)O)[C@@H](O)CCCC(=O)O
Product: NCCc1c[nH]cn1
Reaction time: 1 h

Procedure:
Antagonism for LTD4 was determined in isolated male guinea-pig (300-400 g) trachea prepared as spiral strip. Tracheal preparations were suspended under 1 g tension in 10 ml organ baths containing 5 μM of indomethacin and they were incubated for 1 hour prior to used. Contractile responses to LTD4 (2×108 g/ml) were obtained after the maximal response to histamine (104M). Test compounds dissolved in 100% dimethyl sulfoxide were added to the organ baths (final concentration of 106 g/ml) 30 min prior to LTD4 addition, and then contractile responses to LTD4 were compared with those of control which was obtained from a paired trachea in the absence of test compounds. LTD-induced contractions were expressed as a percentage of the maximal response to histamine. The antagonism was determined as follows:
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:6]1)(=O)C.[H-].[Na+].C(O)(=O)C>C(O)C=C.C(OCC)(=O)C>[CH2:29]([O:28][C:26]([CH2:25][O:24][CH2:23][C@@H:7]1[CH2:6][C@H:5]([SH:4])[CH2:9][N:8]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])=[O:27])[CH:30]=[CH2:31]
Reactant: C=CCOC(=O)COC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C=CCO
Product: C=CCOC(=O)COC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a solution of (2S,4S)-4-acetylthio- 2-(allyloxycarbonylmethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.25 g) in allyl alcohol (40 ml) was added sodium hydride (62.8% in oil suspension) (0.5 g) at -5°~0° C. in a nitrogen stream. After stirring for 1 hour, acetic acid (1 ml) was added to the mixture. The mixture was concentrated under reduced pressure to give a syrup. The syrup was dissolved in ethyl acetate (50 ml), washed in turn with water (50 ml) and brine (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (30 g) and eluted with chloroform to give (2S,4S)-2-(allyloxycarbonylmethyloxymethyl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.29 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[CH:23]([O:26][C:2]([C:4]1([OH:3])[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)([CH3:11])[CH3:1])([CH3:25])[CH3:24]
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1=CCC(O)(C(C)(C)OC(C)C)CC1

Procedure:
By procedures similar to those described in Embodiments 24 and 25, 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene was treated with isopropyl alcohol in the presence of p-toluenesulfonic acid to obtain 1-(1-isopropoxy-1-methylethyl)-4-methyl-3-cyclohexen-1-ol. This alcohol was treated with vanadium(IV) bis(2,4-pentandionate) oxide and tert-butyl hydroperoxide followed by p-toluenesulfonic acid to obtain (±)-2-exo-hydroxy-4-(1-isopropoxy-1-methylethyl)-1-methyl-7-oxabicyclo[2.2.1]heptane. This intermediate was treated with benzyl chloride to yield the desired product, b.p. 120°-130° C. (0.2 mm).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:26][C:27]([OH:29])=O)[C:13]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH:53]12[CH2:61][CH2:60][CH:57]([CH2:58][CH2:59]1)[CH2:56][NH:55][CH2:54]2.Cl>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:53]12[CH2:61][CH2:60][CH:57]([CH2:58][CH2:59]1)[CH2:56][N:55]([C:27]([CH2:26][N:14]1[C:15]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([CH2:19][CH3:20])=[N:18][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C:13]1=[O:30])=[O:29])[CH2:54]2
Reactant: C1CC2CCC1CNC2
Reactant: CCC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)O)c2c(C)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-1-carboxymethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.22 g), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (642 mg), 1-hydroxybenzotriazole (453 mg), 3-azabicyclo[3.2.2]nonane (419 mg) and triethylamine (1.55 ml) in N,N-dimethylformamide (30 ml) was stirred at room temperature overnight. Ethyl acetate and 0.1N aqueous hydrochloric acid were added to the reaction mixture, which was stirred for several minutes. The separated organic layer was washed with 1N aqueous hydrochloric acid, water twice, a saturated aqueous solution of sodium bicarbonate and brine, successively, and then dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was triturated in diisopropyl ether and collected by filtration to afford (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.23 g, 79.9%) as a crystalline powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1.I[CH2:28][CH:29]1[CH2:38][CH2:37][C:32]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)[CH2:28][CH:29]1[CH2:38][CH2:37][C:32]2([O:33][CH2:34][CH2:35][O:36]2)[CH2:31][CH2:30]1
Reactant: COC(=O)Cc1ccc(SC)c(Cl)c1
Reactant: ICC1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCC2(CC1)OCCO2)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
A solution of diisopropylamine (0.23 mL, 1.63 mmol) in dry tetrahydrofuran (5.0 mL) cooled to −78° C. under nitrogen was treated with a 2.5M solution of n-butyllithium in hexanes (0.65 mL, 1.63 mmol). The reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 340 mg, 1.48 mmol) in dry tetrahydrofuran (3.0 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.0 mL). The reaction mixture turned dark in color and was allowed to stir at −78° C. for 1 h, at which time, a solution of 8-iodomethyl-1,4-dioxa-spiro[4.5]decane (500 mg, 1.78 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C., where it was stirred for 24 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified using a 10% aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S Silica 8/2 hexanes/ethyl acetate) afforded the 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(1,4-dioxa-spiro[4.5]dec-8-yl)-propionic acid methyl ester (315 mg, 55%) as a yellow viscous oil: EI-HRMS m/e calcd for C19H25ClO4S (M+) 384.1162, found 384.1169.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[N:5][N:6]=1.[NH2:7][CH2:8][CH2:9][CH2:10][NH2:11]>>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:2]1[S:3][CH:4]=[N:5][N:6]=1
Reactant: Brc1nncs1
Reactant: NCCCN
Product: NCCCNc1nncs1

Procedure:
By the procedure of Example 188, 2-bromo-1,3,4-thiadiazole is reacted with 1,3-diaminopropane to give 2-(3-aminopropylamino)-1,3,4-thiadiazole and this intermediate is reacted with methyl isothiocyanate to give N-methyl-N'-[3-(2-(1,3,4-thiadiazolyl)amino)propyl]thiourea.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][NH:17][C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[BH4-].[Na+]>CC#N.CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]2[C:12]([CH2:15][CH2:16][NH:17][CH:18]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=CNC(=O)Cc2ccc(Cl)c(Cl)c2)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: COc1cc2c(cc1OCc1ccccc1)C(Cc1ccc(Cl)c(Cl)c1)NCC2
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a suspension of N-[2-(4-benzyloxy-3-methoxy-phenyl)-vinyl]-2-(3,4-dichloro-phenyl)-acetamide (13.3 g, 30 mmol) in CH3CN (100 mL) at rt is added dropwise phosphoroxychloride (8.1 mL, 13.5 g, 88 mmol). The resulting white suspension is heated to reflux, and the resulting yellow solution is heated at reflux for 3 h. The dark yellow solution is allowed to cool and is evaporated to a yellow oil. The oil is taken up in MeOH (100 mL) and evaporated to yield an orange solid. The material is redissolved in MeOH (100 mL) and the solution is cooled to 0° C. NaBH4 (3.61 g, 95 mmol) is added in portions with gas evolution and a strong exotherm. The resulting white suspension is stirred at rt for 16 h. The reaction mixture is partitioned between EtOAc (200 mL) and water (200 mL), and the aqueous phase is extracted with EtOAc (3×200 mL). The combined organic phase is washed with water and brine, and evaporated to provide the title compound as a faint yellow oil which is used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17].Cl>O.CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:10][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(O)cc1
Reactant: O=C(O)C(=O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1csc(-c2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Hydroxybenzenecarbothioamide (1.53 g, 10 mmol) and potassium hydroxide (1.50 g, 26.8 mmol) were dissolved in a mixture of 60 ml of water and 15 ml of methanol. A solution of bromopyruvic acid (1.67 g, 10 mmol) in 10 ml of methanol was added dropwise at room temperature. The resulting mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into 100 ml of water and adjusted with 0.2N HCl solution to pH2. The mixture was placed in a refrigerator for 15 h. The title compound was obtained by filtration as a brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].C(=O)([O-])[O-].[K+].[K+].F[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17]>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: Sc1cccs1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Sc1cccs1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of thiophene-2-thiol (1.5 mL), potassium carbonate (8.0 g) and N,N-dimethylformamide was treated dropwise with 2-fluorobenzaldehyde (1.7 mL), and the resulting mixture was stirred at room temperature for 42 hours. The mixture was treated with ice/water, extracted with ethyl acetate and the combined organic extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 9:1 by volume), followed by distillation at 50° C./11 mbar to afford the title compound as a red oil (1.9 g).
Reaction SMILES: [N:1]([C:3]1C=CC=CC=1)=O.[C]=[O:10].[C:11]1(C)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Rh](Cl)(Cl)Cl.[Co](I)I>[C:11]1([N:1]=[C:3]=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [C]=O
Reactant: Cc1ccccc1
Reactant: O=Nc1ccccc1
Agent: Cl[Rh](Cl)Cl
Agent: I[Co]I
Product: O=C=Nc1ccccc1
Temperature: 200 °C
Yield: 29 %

Procedure:
The autoclave was charged with 10.0 grams of nitroso benzene, 63 grams (73 ml.) of toluene, 0.5 grams of rhodium trichloride, and 0.5 grams of anhydrous cobalt iodide. The autoclave was closed and then charged with sufficient carbon monoxide to increase the pressure to 1400 psig. The autoclave was heated to a temperature of 200°C. for 2 hours. After cooling the autoclave was vented, the contents filtered and the filtrate was analyzed by vapor phase chromotography. The product contained 3.2 grams of phenyl isocyanate, which corresponded to a corrected yield of 29 percent phenyl isocyanate.