Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.CSC.[C:5]([CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12](O)=[O:13])(O)=[O:6]>C1COCC1>[Cl:18][C:17]1[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][C:9]=1[CH2:8][CH2:5][OH:6]
Reactant: O=C(O)Cc1cc(C(=O)O)ccc1Cl
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCc1cc(CO)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of borane-methyl sulfide complex (2M in THF, 12.0 mL) was added portionwise over 3 minutes to a suspension of 3-(carboxymethyl)-4-chlorobenzoic acid (example 75, step a) (2.06 g) in dry THF (30 mL) at room temperature. The resulting effervescing dense suspension was stirred at room temperature for 1 hour, then heated to reflux for 1 hour. The cooled mixture was quenched by the portionwise addition of methanol (10 mL) over 2 minutes. The solution was stirred at room temperature for 30 minutes and then concentrated onto silica and purified by flash chromatography on silica eluted with 5% methanol in dichloromethane to afford the subtitled compound as a white solid. Yield 0.983 g.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8](S(CCCCl)(=O)=O)[C:9]1[C:10]([F:22])=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[C:12]([O:14]C)=[O:13])(=[O:7])=[O:6].[OH-].[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[C:10]([F:22])=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(N(S(=O)(=O)CCCCl)S(=O)(=O)CCCCl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc([N+](=O)[O-])cc(NS(=O)(=O)CCCCl)c1F
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of crude methyl 3-{bis[(3-chloropropyl)sulfonyl]amino}-2-fluoro-5-nitrobenzoate (D141) (900 mg, 1.81 mmol, 1 equiv) in MeOH (25 ml) was added a 2N aqueous NaOH solution (15 ml, 30 mmol, excess) and the resulting mixture was stirred for 1 h. Most of MeOH was removed in vacuo and the residue partitioned between AcOEt and a 2N aqueous HCl solution. The two layers were separated and the aqueous phase was dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O/iso-hexane to give 3-{[(3-chloropropyl)sulfonyl]amino}-2-fluoro-5-nitrobenzoic acid (D143) (600 mg, 97%) as a light tan solid which was used in the next step without further purification. No molecular ion, RT=3.05 min.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][CH2:28][C:29]#[N:30]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:30][CH2:29][CH2:28][C:27]#[N:26])=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: N#CCCN
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCCC#N)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 3-aminopropionitrile and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>O1CCCC1.ClCCl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([CH:21]=[CH2:22])[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C=Cc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 85 °C
Yield: 78.5 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (1.005 g, 3.21 mmol) and Pd(PPh3)4 (369 mg, 0.32 mmol) in tetrahydrofuran (10 mL) was treated with vinyl tributyl tin (0.985 mL, 3.36 mmol). The reaction mixture was heated in a sealed tube at 85° C. for 18 hours. After cooling, the mixture was diluted with dichloromethane and water. The organic layer was dried by filtration through an EX-TUBE. Silica gel chromatography afforded 691 mg (78%) of 3-(pyrid-2-yl)-5-(3-cyano-5-vinylphenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): □□□□□□ (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.23 (d, 1H), 7.90 (m, 2H), 7.48 (m, 1H), 6.78 (dd, 1H), 5.98 (d, 1H), 5.55 (d, 1H).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1>Cl.O1CCOCC1>[F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CCCF)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FCCCc1ccc(N2CCNCC2)cc1
Temperature: 25 °C

Procedure:
Tert-butyl 4-(4-(3-fluoropropyl)phenyl)piperazine-1-carboxylate (78 mg, 0.24 mmol) was dissolved in a 4.0M solution of HCl in dioxane (3 mL) and stirred at room temperature. After 1 h 1-(4-(3-fluoropropyl)phenyl)piperazine hydrochloride was collected as a white solid via filtration (63 mg). 1H NMR (300 MHz, CDCl3): δ 9.58 (br s, 2H), 9.38 (br s, 1H), 7.15 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=8.6 Hz), 4.49 (t, 1H, J=6.0 Hz), 4.34 (t, 1H, J=6.0 Hz), 3.40 (dd, 4H, J=5.5, 4.7 Hz), 3.22 (br s, 4H), 2.59 (dd, 2H, J=8.1, 6.3 Hz), 1.98-1.80 (m, 2H); 19F NMR (282.4 MHz, CDCl3): δ−217.98 (m, 1F); 13C NMR (75.5 MHz, CDCl3): δ 147.3, 133.6, 128.9, 116.71, 83.6 (82.5), 46.2, 42.2, 31.5 (31.4), 29.7 (29.6); HRMS calcd for C13H19FN2:223.160503 found 223.16060.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O-].[Na+].[Na].[O:9]=[C:10]([CH:22]=[CH2:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CO>[O:9]=[C:10]([CH2:22][CH2:23][CH2:4][N+:1]([O-:3])=[O:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C=CC(=O)CCCCCCCC(=O)OC
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCCCCCC(=O)CCC[N+](=O)[O-]
Temperature: -20 °C

Procedure:
Nitromethane (12.8 g; 0.21 mole) is added dropwise to a solution of sodium methoxide, prepared from sodium (4.6 g; 0.2 mole) and methanol (200 ml), at 0°-5° C. The solution is cooled to -20° C. and 9-keto-10-undecanoic acid, methyl ester (III) (21.2 g; 0.1 mole) is added dropwise into the solution over 5 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9](=[O:16])[NH:8][C:7]=3[C:6]=2[CH:17]=1.[CH3:18][O:19][C:20]([C:22]1(OC)[CH2:26][CH2:25][CH:24](OC)O1)=[O:21]>>[CH3:18][O:19][C:20]([C:22]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]3[CH:14]=[CH:13][C:12]4[NH:11][C:10](=[O:15])[C:9](=[O:16])[NH:8][C:7]=4[C:6]=3[CH:17]=2)[CH:24]=[CH:25][CH:26]=1)=[O:21]
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: Nc1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1
Product: COC(=O)c1cccn1-c1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1

Procedure:
8.8 mmol of 9-aminobenzo[f]quinoxaline-2,3(1H,4H)-dione were reacted with 8.8 mmol of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].[OH:11]C1C=C(C=CC=1)C#N.P(S)(OCC)(OCC)=S>O>[OH:11][C:7]1[CH:2]=[C:3]([C:8](=[S:10])[NH2:9])[CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc(O)c1
Reactant: NC(=S)c1ccccc1O
Agent: CCOP(=S)(S)OCC
Solvent: O
Product: NC(=S)c1cccc(O)c1
Yield: 57 %

Procedure:
The procedure used for the preparation of 3a was repeated with 3-hydroxybenzonitrile (5.48 g, 46.1 mmol), (EtO)2P(S)SH (7.72 mL, 46.1 mmol) and water (9.2 mL) at 80° C. for 36 hr to give 3d (4.04 g, 57%) as a yellow solid after chromatographic purification on silica gel (gradient EtOAc/CH2Cl2 : 6-12%) and crystallization from EtOAc/hexane. mp 139.0°-140.0° C.; IR (KBr) 3340, 3280, 3165, 1629, 1590, 1462 cm-1 ; 1H NMR (DMSO-d6) δ6.83 (1H, br d, J=7.0 Hz, Ar), 7.10-7.25 (2H, m, Ar), 7.27 (1H, s, Ar), 9.33 (1H, br s, NH), 9.58 (1H, s, OH), 9.72 (1H, br s, NH); FDMS m/z 153 (M+); Anal. Calcd for C7H7NOS: C, 54.88; H, 4.60; N, 9.14. Found: C, 55.01; H, 4.53; N, 9.02.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.CN(C1C=CC=CN=1)C.[NH2:26][C:27]1[CH:42]=[C:41]([F:43])[C:30]2[N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:32]=[N:33][C:29]=2[C:28]=1[CH3:44]>C(Cl)Cl>[C:37]([O:36][C:34]([N:31]1[C:30]2[C:41]([F:43])=[CH:42][C:27]([N:26]=[C:8]=[S:9])=[C:28]([CH3:44])[C:29]=2[N:33]=[CH:32]1)=[O:35])([CH3:39])([CH3:40])[CH3:38]
Reactant: Cc1c(N)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1c(N=C=S)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (0.393 mg) and dimethylaminopyridine (0.01 g) in methylene chloride (100 mL) is added dropwise over 30 minutes a solution of 5-amino-1-tert-butoxycarbonyl-7-fluoro-4-methylbenzimidazole (0.409 g) in methylene chloride (70 mL). The mixture is stirred at room temperature for 3 hours then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1 -tert-butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: Br([O-])(=O)=O.[Na+].[CH3:6][C:7]1[CH:12]([OH:13])[CH2:11][CH2:10][C:9]([CH3:15])([CH3:14])[C:8]=1/[CH:16]=[CH:17]/[C:18](/[CH3:47])=[CH:19]/[CH:20]=[CH:21]/[C:22](/[CH3:46])=[CH:23]/[CH:24]=[CH:25]/[CH:26]=[C:27](\[CH3:45])/[CH:28]=[CH:29]/[CH:30]=[C:31](\[CH3:44])/[CH:32]=[CH:33]/[C:34]1[C:39]([CH3:41])([CH3:40])[CH2:38][CH2:37][CH:36]([OH:42])[C:35]=1[CH3:43]>O.ClCCCl.BrBr>[CH3:43][C:35]1[C:36](=[O:42])[CH2:37][CH2:38][C:39]([CH3:40])([CH3:41])[C:34]=1/[CH:33]=[CH:32]/[C:31](/[CH3:44])=[CH:30]/[CH:29]=[CH:28]/[C:27](/[CH3:45])=[CH:26]/[CH:25]=[CH:24]/[CH:23]=[C:22](\[CH3:46])/[CH:21]=[CH:20]/[CH:19]=[C:18](\[CH3:47])/[CH:17]=[CH:16]/[C:8]1[C:9]([CH3:15])([CH3:14])[CH2:10][CH2:11][C:12](=[O:13])[C:7]=1[CH3:6]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(O)CCC2(C)C)C(C)(C)CCC1O
Agent: BrBr
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: ClCCCl
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1=O
Yield: 91.3 %

Procedure:
1.5 g of sodium bromate dissolved in 20 ml of water is added to 1.5 g of isozeaxanthin dissolved in 250 ml of 1,2-dichloroethane. While stirring, 10 ml of 1,2-dichloroethane in which 30 mg of bromine is dissolved is dripped in over a period of 30 minutes. The pH of the aqueous phase is 5.6. After stirring for 1 hour at room temperature, the phases are separated, the 1,2-dichloroethane is washed with sodium bicarbonate solution and water and dried, and the solvent is distilled off under reduced pressure. 20 ml of methanol is added to the residue and the whole stirred for 10 minutes at 50° C. After cooling, filtration gives 1.36 g (92% of theory) of canthaxanthin.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:31])[N:12]=[C:13]3[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][O:24]C4CCCCO4)=[CH:17][N:14]3[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.Cl>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:31])[N:12]=[C:13]3[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][OH:24])=[CH:17][N:14]3[C:15]=2[OH:16])=[O:9])=[CH:32][CH:33]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1c(O)n2cc(C#CCOC3CCCCO3)ccc2nc1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1c(O)n2cc(C#CCO)ccc2nc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-oxo-7-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl)-2H-pyrido[1,2-a]pyrimidine-3-carboxamide (Preparation 7, 12 mg) is dissolved in CH2Cl2 and treated with 0.5 M HCl in methanol (0.5 mL). The reaction mixture is stirred for 16 h at room temperature. The mixture is concentrated, and the residue is crystallized from ether/hexanes and dried to afford 7 mg of the title compound as a brown solid. Physical characteristics: 1H NMR (CD3OD) δ9.2, 8.35, 7.75, 7.4-7.5, 4.80, 4.50; MS (ESI+) m/z 386 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[O:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1.[Cl-].[NH4+]>C(OCC)C>[CH2:5]([O:4][C:1]([CH2:2][C:16]1([OH:15])[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:20][CH2:21]1)=[O:3])[CH3:6]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)CC1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 5.00 g (56.75 mmol) of ethyl acetate in 140 mL of diethyl ether are added slowly, at −78° C. under argon, 28.38 mL (56.75 mmol) of a solution of lithium diisopropylamide (2N). After stirring for 30 minutes, 12.57 g (53.91 mmol) of benzyl 4-oxopiperidine-1-carboxylate dissolved in 140 mL of diethyl ether are added dropwise, at −78° C. under argon. The reaction medium is then stirred at room temperature for 2 hours. Ethyl acetate is added and the medium is cooled in a bath of ice/water, followed by addition of saturated ammonium chloride solution. The aqueous phase is separated out and extracted three times with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel, eluting with an 85/15 mixture of cyclohexane and ethyl acetate to give 13.00 g of pure product in the form of an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][C:15]3[N:14]4[CH2:18][CH2:19][C:20](=[CH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]4=[CH:12][C:11]=3[CH:10]=2)O1.[OH-:30].[Na+].OO.Cl>C1COCC1>[OH:30][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C:20](=[CH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3=[CH:12][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(O)ccc12
Yield: 78.1 %

Procedure:
To a solution of tert-butyl 2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (330 mg, 0.835 mmol) in THF (10 mL) was added a 2.0 M aqueous solution of sodium hydroxide (4.17 mL, 8.35 mmol). Then was added dropwise hydrogen peroxide (30 wt % aqueous solution, 0.853 mL, 8.35 mmol). The mixture was stirred at 23° C. for 25 min before 0.5 M HCl (50 mL) was added. The resulting mixture was extracted with dichloromethane (2×35 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography to provide the title compound as a pale yellow solid (186 mg). LCMS m/z=286.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)[CH:11]([F:13])[F:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)[CH:11]([F:12])[F:13]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Reaction time: 6 h
Yield: 77.5 %

Procedure:
EX-371A) To a solution of 3-aminophenol (4.91 g, 45.0 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g. 45.0 mmol) dissolved in 100 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (14.28 g 67.5 mmol) and glacial acetic acid (2.7 mL, 47.3 mmol). The reaction mixture was stirred for 6 h, water was added, and the mixture was extracted with dichloromethane. The organics were washed with saturated aqueous sodium bicarbonate then dried over MgSO4. The dried organic layer was evaporated to give 11.00 g (78%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol product as a dark orange oil. 1H NMR (CDCl3) δ4.32 (s, 2H), 5.88 (tt, 1H), 6.08 (t, 1H), 6.17-6.22 (m, 2H), 7.00 (t, 1H), 7.11 (dd, 1H), 7.24-7.27 (m, 2H), 7.33 (t, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]([CH:6]=O)[C:4]#[N:5].[OH:8][CH2:9][CH2:10][NH:11][NH2:12]>CO>[OH:8][CH2:9][CH2:10][NH:11][N:12]=[CH:6][C:3](=[N:2][OH:1])[C:4]#[N:5]
Reactant: NNCCO
Reactant: N#CC(C=O)=NO
Solvent: CO
Product: N#CC(C=NNCCO)=NO
Temperature: 5 °C
Yield: 99 %

Procedure:
In a similar apparatus used in Example 1 were charged 0.98 g (10 mmol) of 2-hydroxyimino-3-oxopropionitrile synthesized by the same method as in Example 1 and 6 ml of methanol, and the mixture was cooled to 5° C. while stirring. Then, 0.80 g (10 mmol) of 95% by weight 2-hydroxyethylhydrazine was added to the mixture at the same temperature, and reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, hexane was added to the concentrate, the resulting mixture was filtered and dried under reduced pressure to give 1.55 g (isolation yield: 99%) of 3-(2-hydroxyethyl)hydrazono-2-hydroxyiminopropionitrile as dark brownish solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:20])=[O:19])[C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([N:17]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:19])=[O:20])[C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc2c(NS(=O)(=O)c3cccc(F)c3)cccc2n1CC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(N(Cc3ccccc3)S(=O)(=O)c3cccc(F)c3)cccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
The product from step d.) (45 mg, 0.103 mmol) was dissolved in DMF (1 mL), treated with K2CO3 (20 mg, 0.145 mmol), benzyl bromide (25 μL, 0.206 mmol), and stirred at 80° C. for 3.5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed several times with water and concentrated under reduced pressure to give the sub-title compound that was used in crude form without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[CH3:17][Si:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:19])[CH3:18]
Reactant: C[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromophenol (17.3 g, 0.100 mol) and 9 ml of pyridine together with 100 ml of toluene were placed in a 3-necked 250 ml round-bottomed flask equipped with a reflux condensor, an addition funnel and thermometer/adaptor. Chlorotrimethylsilane (12.8 g, 15 ml, 0.12 mol) was added dropwise to the vigorously stirred solution. The resultant white reaction mixture was subsequently refluxed for 4 hrs and then stirred at room temperature overnight. The white precipitate was removed by filtration and the colorless filtrate was subjected to rotary evaporation to remove the solvent. The residual liquid was purified by simple distillation. The pure product was collected at 232°-233° C. Yield: 23.0 g (93%). Calc. for C9H13BrOSi: 44.08% C; 5.34% H; 32.59% Br. Found: 43.98% C; 5.36% H; 32.35% Br. Mass Spectroscopy: 244,246 (77%, 78%, M+) Proton NMR (δ in ppm, CHCl3); 0.27 (singlet, Me3Si--); 6.66-7.32 (complex, aromatic protons).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][OH:9].C(C1C=CC(N2C(C=O)=CN=C2)=CC=1)C>>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=[O:9]
Reactant: Cn1ncc(CO)c1Br
Agent: CCc1ccc(-n2cncc2C=O)cc1
Product: Cn1ncc(C=O)c1Br

Procedure:
(5-Bromo-1-methyl-1H-pyrazol-4-yl)methanol (C23) was converted to the product using a procedure analogous to that described for the synthesis of 1-(4-ethylphenyl)-1H-imidazole-5-carbaldehyde (C19) in Example 5, step 3. In this case, no chromatography was carried out. Yield: 1.46 g, 7.72 mmol, 92%. LCMS m/z 191.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 3.93 (s, 3H), 7.96 (s, 1H), 9.76 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]([CH2:26][CH3:27])[C:14]([CH3:28])=[N:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]([CH2:26][CH3:27])[CH:14]([CH3:28])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC1c2cc(OC)c(OC)cc2C(c2ccc(OC)c(OC)c2)=NNC1C

Procedure:
To a solution of 3.82 g (0.01 mole) of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine in 38 ml of glacial acetic acid a solution of 3 g of sodium borohydride in 10 ml of water is dropped within 2 hours at 3° to 8° C., under stirring. Then the reaction mixture is stirred further for 5 hours at 20° to 25° C. and evaporated in vacuo. The residue (18 g) is dissolved in 30 ml of water, and 10 ml of a 40% sodium hydroxide solution are added. The product separated in soft form crystallizes after cooling. Yield: 3.1 g. The product shrinks from 75° C. The pure compound can be obtained by proceeding as described in Example 2. Yield: 2.29 g. M.p.: 120° to 122° C. Molecular formula: C22H28N2O4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:16]1C=CC(S(O)=O)=CC=1C(O)=O.C(I)C>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:16])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Solvent: CCI
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 27 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and ethyl iodide in 20 ml ethanol/20 ml water and obtained in 27% yield. MS (m/e): 247.1 (MH−, 100%).