Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[CH3:10])=[O:7]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2cccc(C)c2)cc1
Yield: 43.8 %

Procedure:
The title compound (D33) (30 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D14) (50 mg, 0.18 mmol) and 3-methylbenzyl bromide (0.05 ml, 0.36 mmol). (Na2CO3: 2.5 eq; reaction time: 5 hrs; 70° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]2.C(N(CC)C(C)C)(C)C.[Br:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:33](Cl)=[O:34])=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:33]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]3)=[O:34])=[CH:28][CH:27]=1
Reactant: COC(=O)C1Cc2cccc(N)c2C1
Reactant: O=C(Cl)C(c1ccc(CBr)cc1)C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CBr)cc3)C3CCCC3)c2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
235 mg (1.228 mmol) of methyl 4-amino-2,3-dihydro-1H-indene-2-carboxylate (racemic; Example 88A) were dissolved in 10 ml of THF, and 428 mg (4.911 mmol) of N,N-diisopropylethylamine and 388 mg (1.228 mmol) of [4-(bromomethyl)phenyl](cyclopentyl)acetyl chloride were added at 0° C. The mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium bicarbonate solution was then added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. This gave 577 mg of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[NH2:30][C:31]1[C:32]([C:49]([OH:51])=O)=[N:33][C:34]([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])=[CH:39][CH:38]=2)=[CH:35][N:36]=1.[NH2:52][NH:53][C:54]([NH2:56])=[S:55]>CN(C=O)C.O>[NH2:30][C:31]1[C:32]([C:49]([NH:52][NH:53][C:54](=[S:55])[NH2:56])=[O:51])=[N:33][C:34]([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH:46]([CH3:47])[CH3:48])(=[O:45])=[O:44])=[CH:39][CH:38]=2)=[CH:35][N:36]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Reactant: NNC(N)=S
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(N)=S)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TBTU (749.4 mg, 2.334 mmol) and Et3N (157.5 mg, 216.9 μL, 1.556 mmol) were added to a suspension of 3-amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carboxylic acid (500 mg, 1.556 mmol) and aminothiourea (141.8 mg, 1.556 mmol) in DMF (10 mL). The reaction was allowed to stir at ambient temperature for 1 h. The reaction mixture was added to rapidly stirring water and the resultant precipitate isolated by filtration to give the product as a khaki solid (587 mg, 96%) 1H NMR (400 MHz, DMSO) d 1.18 (d, 6H), 3.40-3.56 (m, 1H), 7.64 (s, 2H), 7.79 (s, 2H), 7.88 (d, 2H), 8.56 (d, 1H), 9.03 (s, 1H), 9.41 (s, 1H) and 10.75 (s, 1H) ppm; MS (ES+) 395.2
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:19]([CH3:20])=[CH:18][C:14]2[N:15]=[CH:16][S:17][C:13]=2[C:12]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:2]([CH3:4])([CH3:3])[CH3:1])[C:11]1[C:19]([CH3:20])=[CH:18][C:14]2[N:15]=[CH:16][S:17][C:13]=2[C:12]=1[C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@H](O)COC(=O)C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
A solution of (S)-2-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyethyl pivalate (5I) (0.016 g, 0.040 mmol) and perchloric acid, 70% (6 μl, 0.1 mmol) in tert-butyl acetate (1 mL) was stirred at room temperature for 2 h. Reaction mixture was quenched with solid sodium bicarbonate (0.05 g) for 1 h. Saturated sodium bicarbonate solution was added and extracted with ethyl acetate (3×). The combined organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes). LCMS-ESI+: calc'd for C25H30ClNO3S: 460.2 (M+H+). Found: 460.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[C:5]2=[N:6][C:7]=1[Cl:8].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[C:9]([CH3:13])=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:17][CH:14]1[CH2:16][CH2:15]1
Reactant: Cc1nccc2nc(Cl)c(Cl)nc12
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nccc2nc(NC3CC3)c(Cl)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
2,3-Dichloro-5-methylpyrido[3,4-b]pyrazine (1.700 g, 7.94 mmol) was added to dioxane (15.88 mL), then cyclopropanamine (0.864 mL, 12.71 mmol) and DIPEA (2.24 mL, 13.50 mmol) were added sequentially. The mixture was stirred for 12 h at room temperature then concentrated under reduced pressure. Column chromatography using a gradient of 10% to 75% EtOAc in hexanes provided 3-chloro-N-cyclopropyl-5-methylpyrido[3,4-b]pyrazin-2-amine (1.3 g) as a brown solid.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:13][C:14](=O)[O:15]CC)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])#[N:2].[NH:19]([C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:20].C(OCC)(=O)C.O>CN1C(=O)CCC1>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:4]1[N:13]=[C:14]([OH:15])[N:20]2[N:19]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:2]=[C:1]2[CH:3]=1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)NN
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1nc2cc(-c3ccc(Cl)cc3Cl)nc(O)n2n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
3.0 g (10.5 mmol) of ethyl [2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate (Example 128A) and 1.39 g (10.5 mmol) of ethyl hydrazino(oxo)acetate are dissolved in NMP (16 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 4 h. The reaction mixture is cooled to RT and ethyl acetate (150 ml) and water (100 ml) are added. The organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 1:1, then with dichloromethane/methanol 100:1). The crude product is concentrated, mixed with water and stirred for 1 h. The solid is filtered off with suction and dried; 1.31 g (35% of theory) of the product are obtained.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:12][CH2:11][C:10]([CH:17]([NH:20]S(C(C)(C)C)=O)[CH2:18][CH3:19])([C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:8]1)(C)(C)C.Cl.OP([O-])([O-])=O.[K+].[K+]>CC(O)C>[NH2:20][CH:17]([C:10]1([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]1)[CH2:18][CH3:19]
Reactant: CCC(NS(=O)C(C)(C)C)C1(C(F)(F)F)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC(C)O
Product: CCC(N)C1(C(F)(F)F)CCC(O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
3.22 g (7.26 mmol) of 2-Methyl-propane-2-sulfinic acid {1-[4-(tert-butyl-dimethyl-silanyloxy)-1-trifluoromethyl-cyclohexyl]-propyl}-amide (73) were dissolved using 200 ml of 2-propanol. 60 ml of a 10% aqueous solution of HCl was added and the mixture was stirred for 5 h at ambient temperature and the mixture allowed to stand at ambient temperature for 16 h. Afterwards, 300 ml of a saturated aqueous solution of K2HPO4 were added and the 2-propanol evaporated. The resulting mixture was extracted twice using 100 ml of ethyl acetate each. The organic layer was dried using MgSO4 and evaporated to yield 1.50 g of 74 as an oil, used without further purification. Rt=0.82 min (Method P).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14](=[O:24])[NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH:13]=1)[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].CO.O.[Li+].[OH-]>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14](=[O:24])[NH:15][C@@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)cc(C(=O)N[C@H](C)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1cc(C(=O)O)cc(C(=O)N[C@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of (R)-methyl 3-acetyl-5-((1-phenylethyl)-carbamoyl)benzoate (332 mg, 1.02 mmol) in a mixture of THF (1.4 mL), MeOH (2.8 mL) and H2O (7.0 mL), was added LiOH (73.4 mg, 3.06 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The aqueous layer was washed with ethyl acetate twice and acidified with 1N HCl solution to pH around 2˜3. The aqueous layer was extracted with ethyl acetate 3 times and the combined organic layers were dried over sodium sulfate and concentrated under vacuum to give the title compound which was ready for next step without further purification (300 mg, 95% yield): HPLC retention time: 1.662 min (method A). MS (ESI) (M+H)+ 311.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([S:12]([CH3:14])=[O:13])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[OH:19][C:20]1[N:21]([CH3:25])[N:22]=[CH:23][CH:24]=1.CC1C=NC=CC=1.S(Cl)(Cl)=O.CC1CCCCC1>C(OCC)(=O)C.O>[OH:19][C:20]1[N:21]([CH3:25])[N:22]=[CH:23][C:24]=1[C:5]([C:4]1[CH:8]=[CH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[C:11]([S:12]([CH3:14])=[O:13])[C:3]=1[O:2][CH3:1])=[O:7]
Reactant: COc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)=O
Reactant: Cn1nccc1O
Solvent: O=S(Cl)Cl
Solvent: Cc1cccnc1
Solvent: O
Product: COc1c(C(=O)c2cnn(C)c2O)ccc(C(F)(F)F)c1S(C)=O
Yield: 97.4 %

Procedure:
3.0 g of 2-methoxy-3-methylsulfinyl-4-trifluoromethylbenzoic acid and 1.02 g of 3-hydroxy-2-methylpyrazole are suspended in 20 ml of ethyl acetate and 5.07 ml of 3-methylpyridine under an inert atmosphere and cooled to −25° C. with stirring. 1.24 g of thionyl chloride are then slowly added dropwise such that the temperature always remains below −20° C. Following the complete addition of the thionyl chloride, the mixture is stirred for a further 20 minutes. 40 μl of cold water and 20 ml of methylcyclohexane are then added. The mixture is then stirred for a further 20 minutes at −25° C. The suspension is filtered and washed once with 10 ml of methylcyclohexane and twice with 10 ml of water in each case. Drying gives 3.67 g of (5-hydroxy-1-methyl-1H-pyrazol-4-yl)[2-methoxy-3-(methylsulfinyl)-4-(trifluoromethyl)phenyl]methanone (86.5% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH:6]=[CH:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.Cl.[CH3:19][C:20]1[CH:29]=[C:28]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>O1CCOCC1.O>[CH3:19][C:20]1[CH:29]=[C:28]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([NH:1][C@@H:2]3[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH:5]=[CH:6][CH2:7]3)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: N[C@H]1CC=CC[C@H]1C(=O)O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CC=CC[C@H]3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a stirred solution of 423.5 mg (3 mmol) of cis-2-amino-4-cyclohexene-1-carboxylic acid in 8 mL of dioxane and 8 mL of water was added 2.1 mL of triethylamine, followed by 1.13 g (3 mmol) of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride in one portion as a solid. The solution was stirred at room temperature overnight. After removal of the volatile material, 10 mL of dichloromethane and 10 mL of water were added to the residue. The mixture was adjusted pH to 5 with 1N HCl solution. The solid was collected by filtration, washed with a small volume of water, followed by dichloromethane to provide 1.05 g of cis-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylic acid in 77% yield. MS: 453.1 (M+H)+
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[C:19]([NH2:20])=[CH:18][C:17]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])=[CH:16][C:15]=1[C:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[OH:29]>C1COCC1.O.C(OCC)(=O)C>[CH3:27][C:22]1[C:21]([C:17]2[CH:16]=[C:15]([C:28]([OH:29])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:14]3[NH:13][C:6](=[O:7])[NH:20][C:19]=3[CH:18]=2)=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1noc(C)c1-c1cc(N)c(N)c(C(O)(c2ccccn2)c2ccccn2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)c2ccccn2)c2[nH]c(=O)[nH]c2c1
Reaction time: 72 h

Procedure:
CDI (1.1 g, 6 mmol) was added to a solution of (2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanol (1.43 g, 3.7 mmol) in THF (10 mL) and the reaction mixture was stirred for 3 days. The reaction mixture was diluted with 100 mL water and 100 mL ethyl acetate and sonicated and filtered to yield the desired product.
Reaction SMILES: [F:1][C:2]12[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:8]=3[C@@:7]1([CH3:20])[N:6]=[C:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]([CH3:30])([CH3:29])[S:3]2(=[O:32])=[O:31]>CCOC(C)=O.CO.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][CH2:12][C:2]3([F:1])[S:3](=[O:32])(=[O:31])[C:4]([CH3:30])([CH3:29])[C:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[N:6][C@:7]3([CH3:20])[C:8]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCCC2(F)S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCCC2(F)S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.3 %

Procedure:
A round bottom flask was charged with Pd/C (0.020 g, 0.019 mmol) and put under a nitrogen atmosphere. A solution of tert-butyl ((11bR)-4a-fluoro-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.090 g, 0.191 mmol) in EtOAc (477 μl) and MeOH (477 μl) was added via syringe and the flask was evacuated and filled with hydrogen. The mixture was stirred at RT under hydrogen atmosphere for 17 hours. The mixture was filtered through Celite and washed with EtOAc and the filtrate was concentrated to yield tert-butyl ((11bR)-10-amino-4a-fluoro-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.071 mg, 0.161 mmol, 84% yield) as a light yellow solid. LC/MS (ESI+) m/z=442.3.
Reaction SMILES: [Na].[Cl-].[CH3:3][O:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH:35]=O>C(O)C>[CH3:3][O:4][CH:5]=[CH:35][C:26]1[CH:27]=[CH:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: COC=Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To the solution produced by reacting sodium (0.92 g) in dry ethanol (60 ml) was added methoxymethyltriphenylphosphonium chloride (15.2 g). After stirring at room temperature for 0.5 hours, 2-naphthaldehyde (5.5 g) was added and the mixture heated at reflux for 5 hours. The mixture was evaporated to dryness and extracted with boiling ether, cooled to precipitate triphenylphosphine oxide, filtered and evaporated. The residue in dichloromethane (5 ml) was passed through a column of alumina and eluted with hexane to give 2-(2-methoxyvinyl) naphthalene (3.6 g), nD20 1.6505, which was hydrolysed in dioxan (50 ml) containing 2N sulphuric acid (5 ml) at 70° for 5 hours. After adding water, the mixture was extracted with ether, and the extract washed, (saturated sodium chloride), dried, (sodium sulphate) and evaporated to give 2-naphthylacetaldehyde (3.25 g) nD20 1.6232.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([OH:27])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:30][N:29]=[N:28][N:24]=3)=[CH:15][CH:16]=2)[N:8]=[C:7]([C:25]([OH:27])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 82.7 %

Procedure:
5-Butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]pyrazole-3-carboxylic acid (17.6 g), sodium azide (19.5 g), and ammonium chloride (13.4 g) were stirred in dimethylformamide (DMF) (140 ml) at 110°-120° C. for 5 days. The reaction mixture was poured into water (1.2 1), to which conc. HCl (35 ml) and ethyl acetate (700 ml) were added. The organic layer was washed with 0.1 N-HCl and water, dried, and concentrated under reduced pressure. To the residue was added ether, and the resultant crude crystals were recrystallized from ethyl acetate-ether to give colorless crystals (16.3 g, 83%).
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2C=CC=CC=2)[C:9]2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CC(C1C=CC([Cl:36])=CC=1)=O>O1CCCC1.CCCCCC>[Cl:36][C:5]1[CH:6]=[CH:7][C:2]([C:8]([CH3:15])=[CH2:9])=[CH:3][CH:4]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C)c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a slurry of triphenylmethylphosphonium bromide (71.4 grams (g), 200 millimole (mmole)) in 500 milliliters (ml) dry tetrahydrofuran (THF) (distilled from sodium/benzophenone), were slowly added dropwise 129 ml (200 mmole) 1.55 molar (M) n-butyllithium in hexane. The reaction mixture was stirred for 30 minutes at -10° C. whereafter a solution of 30.92 g (200 mmol) 4-chloroacetophenone in 100 ml dry THF was slowly added dropwise. The reaction mixture was then stirred for one hour at -10° C., slowly warmed to ambient temperature (about 23° C.) and stirring continued overnight. The mixture was thereafter filtered and the solvent removed by distillation at atmospheric pressure. Distillation, using a water aspirator, yielded 16.5 g (54.2% yield) of p-chloro-α-methylstyrene, boiling point (bp) 82°-86° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1NC(OCC)=CC([O-])=O.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[C:21]([Cl:29])[C:20]=1[NH:30]N.[Na]>>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[C:21]([Cl:29])[C:20]=1[NH2:30]
Reactant: COC(=O)c1cc(Cl)c(NN)c(Cl)c1
Agent: CCOC(=CC(=O)[O-])Nc1ccc(Cl)cc1Cl
Agent: [Na]
Product: COC(=O)c1cc(Cl)c(N)c(Cl)c1

Procedure:
2,6 -Dichloro-4-methoxycarbonylaniline (melting point: 72°-74°C) was prepared by introducing two chlorine atoms into the anilino nucleus using the method of Cohen; J. CHEM. SOC.; Vol. 81, Page 1336 (1902). The aniline was converted to 2,6 -dichloro-4-methoxycarbonylphenylhydrazine in a sodium nitritestannous chloride system using the method of D. S. Tarbell et al; JOURNAL OF THE AMERICAN CHEMICAL SOCIETY; Vol. 70, Page 1384 (1948). The melting point of the product was 130°-135°C.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]([F:28])([F:27])[CH2:12][O:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=1[O:25][CH3:26]>ClCCl.C(O)(=O)C.O>[CH3:26][O:25][C:15]1[CH:16]=[C:17]([C:23]([N+:6]([O-:9])=[O:7])=[CH:24][C:14]=1[O:13][CH2:12][C:11]([F:10])([F:28])[F:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1ccc(OCC(F)(F)F)c(OC)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(OC)c(OCC(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 52.9 %

Procedure:
Concentrated sulphuric acid (64 ml) and concentrated nitric acid (10.0 ml, 0.152 mol) were added cautiously, over 1 hour, to a two-phase system containing a stirred solution of ethyl 4-(2,2,2-trifluoroethoxy)-3-methoxybenzoate (35.3 g, 0.127 mol) in dichloromethane (340 ml), acetic acid (173 ml) and water (40 ml) at 5° C. The reaction was allowed to warm to ambient temperature over 60 hours (with vigorous mechanical stirring), the aqueous phase was separated, and the organic phase washed with water (6×250 ml). The organic phase was concentrated to a total volume of ˜200 ml, isohexane (150 ml) was added and the solid which precipitated out was collected by suction filtration. Drying of the solid in vacuo yielded ethyl 3-methoxy-4-(2,2,2-trifluoroethoxy)-6-nitrobenzoate (21.7 g, 52% yield) as a yellow solid. The mother liquors contained a mixture of product (28%) and starting material (72%) which was recycled in a latter reaction:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH2:22]([S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:30]4[CH:29]=[CH:28][C:27]([S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])=[CH:32][CH:31]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Product: CCS(=O)(=O)c1ccc(-c2ccc3oc(-c4ccc(OC)c([N+](=O)[O-])c4)nc3c2)cc1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.15 mmol) and 4-(ethylsulfonyl)phenylboronic acid (214 mg, 1.75 mmol) the subtitle compound was obtained (88 mg, 12%). MS 439 m/z (M+H)+.