Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([Br:28])[C:26]=1[OH:27])[CH2:5][C@H:6]([C:21]([OH:23])=O)[NH:7][C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:9].[CH3:29]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:70][C@H:71]([C:84]([O:86]C)=[O:85])[CH2:72][CH2:73][CH2:74][CH2:75][NH:76][C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78]>CN(C)C=O>[CH3:29][N:70]([C:21](=[O:23])[C@@H:6]([CH2:5][C:4]1[CH:24]=[C:25]([Br:28])[C:26]([OH:27])=[C:2]([Br:1])[CH:3]=1)[NH:7][C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:9])[C@H:71]([C:84]([OH:86])=[O:85])[CH2:72][CH2:73][CH2:74][CH2:75][NH:76][C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78]
Reactant: COc1cccc(CCNC(=O)N[C@H](Cc2cc(Br)c(O)c(Br)c2)C(=O)O)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cccc(CCNC(=O)N[C@H](Cc2cc(Br)c(O)c(Br)c2)C(=O)N(C)[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)c1

Procedure:
To a mixture of 10 g (19.4 mmol) of 3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine, 2.6 g (20 mmol) of DIEA, 6.4 g (20 mmol) of TBTU, 2.64 g (19.5 mmol) of HOBt and 200 ml of dimethylformamide was added dropwise, with stirring, a solution of 5.04 g (19.4 mmol) of H-Lys(Boc)-OMe in 50 ml of dimethylformamide and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo and the residue was taken up in 250 ml of ethyl acetate. The ethyl acetate phase was then washed twice with 100 ml of saturated aqueous sodium hydrogen carbonate solution, once with 100 ml of 20% aqueous citric acid solution and finally once with 100 ml of saturated aqueous saline solution. The organic phase was dried with sodium sulphate, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/petroleum ether=2/1 (v/v)). After removal of the solvent in vacuo the residue was triturated with ether, the amorphous solid obtained (9.5 g; 66% of theory) was suction filtered and dried.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)(=[O:3])[CH3:2].C(O)C.[C:22]1(=[O:28])[NH:26][C:25](=[O:27])[CH2:24][CH2:23]1>N1C=CC=CC=1.O>[C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][N:26]1[C:22](=[O:28])[CH2:23][CH2:24][C:25]1=[O:27])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCC1CO1
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCC(O)CN1C(=O)CCC1=O

Procedure:
0.072 mol (18.2 g) of 1-(2'-acetylamino-5'-nitrophenoxy)-2,3-epoxypropane is introduced into 60 ml of absolute ethanol to which 6 drops of pyridine have been added. 0.087 mol (8.6 g) of succinimide is added and the mixture is then heated under reflux for 5 hours. After cooling, 150 ml of water are added and the alcohol is driven off in vacuo. The expected product, which is obtained initially in the form of a water-insoluble oil, crystallises slowly. It is filtered off and recrystallised from 96° strength alcohol. After drying, it melts at 157° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])(C)C)=[N:7][C:8]=1[CH3:9])#[N:2].[CH2:19]1COC[CH2:20]1>CO.[Ni]>[NH2:2][CH2:1][C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10][C:11](=[O:17])[O:12][CH2:13][CH2:16][CH2:19][CH3:20])=[N:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1C#N
Reactant: C1CCOC1
Agent: [Ni]
Solvent: CO
Product: CCCCOC(=O)Nc1cc(C)c(CN)c(C)n1
Reaction time: 144 h

Procedure:
To a mixture of tert-butyl 5-cyano-4,6-dimethylpyridin-2-ylcarbamate (10.8 g, 43.7 mmol) in THF (100 ml) were added about 15 cm3 of a Raney-Ni suspension in MeOH under Ar. The flask was sealed, and the suspension was vigorously stirred at it for 6 d under an atmosphere of hydrogen. The reaction mixture was filtered over a plug of cellite and eluted with DCM (200 ml), DCM-MeOH (9:1, 200 ml) and NH3 in MeOH (7N, 100 ml). Removal of all volatiles in vacuo afforded the crude product which was recrystallized from MeOH-DCM to afford the title compound. LCMS RtM=1.13 min, [M+H]+=252.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:32])[C:16]([NH:18][C:19]([CH3:31])([CH3:30])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[Sn](Cl)Cl.O1CCOCC1>C(O)C.C(OCC)(=O)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:16](=[O:17])[C:15]([NH:14][C:5]2[CH:6]=[CH:7][C:8]([C:9]3[O:13][CH:12]=[N:11][CH:10]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:32])([CH3:30])[CH3:31])=[CH:22][CH:23]=1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccc([N+](=O)[O-])cc2)ccc1-c1cnco1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccc(N)cc2)ccc1-c1cnco1
Yield: 75.9 %

Procedure:
A mixture of 44 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(4-nitrophenyl)ethyl]oxalamide and 90 mg (0.5 mmol) of tin(II) chloride were stirred and heated at 85° C. in 2 ml of ethanol and 1 ml of 1,4-dioxane for 5 hours. The resulting solution was cooled, diluted with ethyl acetate and washed with 2M sodium hydroxide. The organic phase was dried over magnesium sulphate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/petrol (2:1) for the elution. After trituration with petrol there was obtained 31 mg of N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 409 M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P].[CH3:9][O:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([NH:17][NH:18][C:19](=O)[CH3:20])=O)=[CH:13][CH:12]=1>ClC1C=CC=CC=1Cl>[CH3:9][O:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]2[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:19]([CH3:20])=[N:18][N:17]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)NNC(C)=O)cc1
Reactant: Nc1ccccc1
Agent: [P]
Solvent: Clc1ccccc1Cl
Product: COc1ccc(-c2nnc(C)n2-c2ccccc2)cc1

Procedure:
Using the procedure of Step B in Example 1, 26.3 ml of aniline, 150 ml of o-dichlorobenzene, 4.65 ml of phosphorus trichlorode and 10 g of N-(4-methoxybenzoyl)-N'-acetyl-hydrazine [prepared by process of J. Org., Vol. 19 (1954), p. 194-201] were reacted to obtain 7.1 g of 3-(4-methoxyphenyl)-4-phenyl-5-methyl -4H-1,2,4-triazole melting at 140°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[C:4]([O:18][CH3:19])[CH:3]=1.[Cl-].[NH4+]>CO.O.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: COc1cc(F)ccc1Oc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Product: COc1cc(F)ccc1Oc1ccccc1N
Temperature: 25 °C
Yield: 100.5 %

Procedure:
To a solution of title compound 90 (9.32 g, 35.4 mmol) in MeOH (30 mL) and water (5 mL) was added ammonium chloride (3.79 g, 70.8 mmol) and zinc chloride (20.83 g, 319 mmol) and the reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and filtered and the solvent removed. The residue was diluted with ethyl acetate and water and the organic phase was washed well with water, dried over Na2SO4, filtered and concentrated to afford title compound 91 (8.3 g, 100%). LRMS (ESI): (calc) 233.09. (found) 234.1 (MH)+.
Reaction SMILES: C([Li])CCC.C(N)(C)C.[C:10]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].Cl[CH2:20][S:21][CH2:22]Cl>CCOCC>[C:10]([C:12]([CH3:18])([CH2:20][S:21][CH3:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CCOC(=O)C(C)C#N
Reactant: ClCSCCl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)N
Product: CCOC(=O)C(C)(C#N)CSC
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (24.2 mL, 60 mmol, 2.5 M solution in hexanes) was added to a solution of iso-propylamine (8.1 mL, 58 mmol) in dry ether (70 mL) under nitrogen at a rate needed to maintain temperature below −60° C. Upon completion, the reaction was allowed to warm to 10° C., re-cooled to −78° C. before addition of ethyl 2-cyanopropanoate (7 g, 55 mmol). After stirring at −78° C. for 90 minutes, chloromethylsulfide (4.61 mL, 55 mmol) was added and the mixture was warmed to room temperature over 14 hours, diluted with ether (350 mL), washed with water (100 mL), brine (100 mL), dried over MgSO4, concentrated under reduced pressure and distilled at 0.04 mm Hg. Yield of yellow liquid 3.95 g. (38%): by 145° C.; IR (KBr thin film) 1751 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.30 (q, J=7.1 Hz, 2H), 3.08 (d, J=13.9 Hz, 1H), 2.91 (d, J=13.9 Hz, 1H), 2.30 (s, 3H), 1.67 (s, 3H), 1.35 (t, J=7.4 Hz, 3H); EIMS m/z 187.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:5]([CH2:8][C:9]#[CH:10])[C:6]=1[Cl:7].[OH-].[Na+].[I:23]I>CO.O>[Cl:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:5]([CH2:8][C:9]#[C:10][I:23])[C:6]=1[Cl:7]
Reactant: C#CCn1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1c(Cl)c(Cl)n(CC#CI)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 12 h

Procedure:
To a stirred mixture of 1.91 g (5.5 mmol) of 4,5-dichloro-2-(3,4-dichlorophenyl)-1-(2-propynyl)-pyrrole-3-carbonitrile in 500 mL of methanol is added 69 mL of 10% aqueous sodium hydroxide and then 0.70 g (2.7 mmol) of iodine. The mixture is stirred for 12 hours and then acidified and diluted with 200 mL of water. The precipitated solids are collected and recrystallized from methanol to afford 0.51 g while crystals, m.p. 115°-116° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:24]=3[CH:25]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][C:24]=3[CH:25]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(C(F)(F)F)ccc4o3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of methyl 3-[(2S)-2-methylpyrrolidin-1-yl]-2-[5-(trifluoromethyl)-1-benzofuran-2-yl]quinoxaline-6-carboxylate (150 mg, 0.33 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (53 mg, 1.33 mmol) with stirring overnight at room temperature. The resulting mixture was concentrated in vacuo and dissolved in water (15 mL), adjusted to pH 7 with HCl (3N). The product was collected by filtration to give 3-[(2S)-2-methylpyrrolidin-1-yl]-2-[5-(trifluoromethyl)-1-benzofuran-2-yl]quinoxaline-6-carboxylic acid as a yellow solid (72.8 mg, 50%).
Reaction SMILES: C(N(CC)CC)C.O=[C:9]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH2:10][C:11]#[N:12].Cl.[CH:20]([NH:23][NH2:24])([CH3:22])[CH3:21]>C(O)C>[CH3:21][CH:20]([N:23]1[C:11]([NH2:12])=[CH:10][C:9]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:24]1)[CH3:22]
Reactant: N#CCC(=O)C1CCOCC1
Reactant: CC(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)n1nc(C2CCOCC2)cc1N
Reaction time: 1 h
Yield: 81.6 %

Procedure:
0.43 ml of triethylamine is added to a solution of 640 mg of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile and 347 mg of isopropylhydrazine hydrochloride in 8 ml of ethanol under an argon atmosphere. The mixture is refluxed with magnetic stirring for 1 h and then concentrated to dryness under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and the organic phase is washed twice with 40 ml of a saturated sodium hydrogen carbonate solution. The combined aqueous phases are extracted twice with 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure, so as to obtain 536 mg of 1-(propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine.
Reaction SMILES: O[C:2]1C=CC(C=O)=C[C:3]=1OC.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>>[CH2:2]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])[CH3:3]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Product: CCOc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
This example was according to Example 1, except that 4-hydroxy-3-methoxybenzaldehyde was replaced by 68.5 g 4-hydroxy-3-nitro-benzaldehyde (0.41 mol) to obtain 68.7 g 4-ethoxy-3-nitrobenzaldehyde in a yield of 86%. 1H-NMR (ppm) δ: 9.96 (1H, s; —CHO); 7.73 (1H, m; 2-ArH); 7.58 (1H, m; 6-ArH); 7.33 (1H, m; 5-ArH); 4.15 (2H, q; —CH2); 3.82 (3H, s; —OCH3); 1.53 (3H, t; —CH3). MS (m/Z): 195 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][CH:29]([CH2:32][C:33]([OH:35])=O)[CH2:28][CH2:27]4)=[CH:22][C:21]=3[CH3:36])=[N:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:37]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:37]([N:44]1[CH2:49][CH2:48][N:47]([C:33](=[O:35])[CH2:32][CH:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][C:16]4[N:17]=[CH:18][C:13]([NH:12][S:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)(=[O:10])=[O:11])=[CH:14][CH:15]=4)=[C:21]([CH3:36])[CH:22]=3)[CH2:31][CH2:30]2)[CH2:46][CH2:45]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1cc(N2CCC(CC(=O)O)CC2)ccc1Oc1ccc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)cn1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(N2CCC(CC(=O)N3CCN(Cc4ccccc4)CC3)CC2)ccc1Oc1ccc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)cn1
Reaction time: 1 h

Procedure:
To a solution of (1-{4-[5-(3,4-dichlorobenzenesulfonylamino)pyridin-2-yloxy]-3-methylphenyl}piperidine-4-yl)acetic acid (1.70 g, 3.1 mmol) and 1-benzylpiperazine (0.71 g, 4.0 mmol) in DMF (40 mL) were added triethylamine (1.08 mL, 7.8 mmol) and diethyl cyanophosphonate (0.76 g, 4.3 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling. To this reaction solution was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1), after which the resulting product was recrystallized from ethanol, to thereby yield 1.61 g of the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:21])([CH3:20])[C:4]([O:7][P:8](Cl)(=[O:18])[O:9][C:10]([Br:17])([Br:16])[C:11]([CH3:15])([CH3:14])[CH2:12][Br:13])([Br:6])[Br:5].[OH2:22]>C1C=CC=CC=1>[P:8]([OH:22])([O:9][C:10]([Br:17])([Br:16])[C:11]([CH3:15])([CH3:14])[CH2:12][Br:13])([O:7][C:4]([Br:6])([Br:5])[C:3]([CH3:21])([CH3:20])[CH2:2][Br:1])=[O:18]
Reactant: O
Reactant: CC(C)(CBr)C(Br)(Br)OP(=O)(Cl)OC(Br)(Br)C(C)(C)CBr
Solvent: c1ccccc1
Product: CC(C)(CBr)C(Br)(Br)OP(=O)(O)OC(Br)(Br)C(C)(C)CBr

Procedure:
A solution of bis(tribromoneopentyl)phosphorochloridate in benzene was stirred with water. Crystalline solids slowly came out, and were removed by filtration. The product was a colorless crystalline solid, m.p. 130° C. Titration with standard 0.1-N NaOH in aqueous acetone medium or KOH in methanol showed it to have an equivalent weight of 710 corresponding to [(CHBr)3CCH2O]2P(O)(OH), bis(tribromoneopentyl) hydrogen phosphate. The aqueous acetone sodium salt solution or the alcoholic potassium salt solution was applied to cotton polyester fabric to obtain a dry add-on of 20% of the alkali metal salt of bis(tribromoneopentyl) acid phosphate. Fixation of the finish was achieved by applying a solution of magnesium chloride, which gives in situ formation of the water-insoluble magnesium salt of bis(tribromoneopentyl) hydrogen phosphate. The resultant finish imparts flame retardant properties and is wash-durable.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([CH2:15][C:16](=[O:18])[CH3:17])(=[O:14])[CH3:13]>>[CH3:7][O:6][C:5]1[C:8]([OH:9])=[CH:10][CH:11]=[C:3](/[CH:2]=[CH:13]/[C:12]([CH2:15][C:16](/[CH:17]=[CH:2]/[C:3]2[CH:4]=[C:5]([O:6][CH3:7])[C:8]([OH:9])=[CH:10][CH:11]=2)=[O:18])=[O:14])[CH:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)CC(C)=O
Product: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Yield: 80 %

Procedure:
British patent No. 914 047 (publ. 28.12.62) describes the condensation of vanillin with acetylacetone in the presence of 2 mole equivalents of trialkyl borates and 0.35 molequivalents boric oxide to give curcumin with yields from 16-80% of the theory. Best results (80% yield) at room temperature were obtained in ethyl acetate as solvent with 2 molequivalents tri-isopropyl borate in the presence of 0.35 molequivalent of boric anhydride and 0.1 molequivalent butylamine (Pabon, H. J. J., Recueil 83, 379-386 [1964]). However, the purity of the curcumin is not mentioned.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: NCc1ccc(F)cc1
Solvent: C1CCOC1
Product: Fc1ccc(CNCc2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To 4-flourobenzylamine (1.17 g, 9.4 mmol) dissolved in 5 mL of THF was added 4-fluorobenzyl-bromide (0.88 g, 4.7 mmol) dropwise. The reaction was stirred overnight resulting in the formation of a white solid. After filtering off the solid solvent was removed to yield 1.08 g crude di-(4-fluorobenzyl) amine. To this was added 19 mL of CH2Cl2 and 19 mL of saturated (aq.) NaHCO3. Acetyl chloride (0.67 mL, 9.4 mmol) was added to the rapidly stirring mixture and the reaction allowed to proceed overnight. The mixture was diluted with CH2Cl2, transferred to a separatory funnel. The organic layer was separated, washed with satd (aq.) NaCl, dried over Na2SO4 and the solvent removed to yield 1.01 g oil. The product was purified by column chromatography (4×7 cm SiO2, 20-40% EtOAc/Hexanes) to yield 603 mg (55% yield) oil. LC/MS (M+H) calcd for C14H14NF2: 276.12, found: 276.13. HRMS (M+H) calcd for C14H14NF2: 276.1200, found: 276.1192. Anal calcd for C16H15F2NO: C, 69.80; H, 5.49; N, 5.08; found: C, 59.53; H, 5.41; N, 5.06. 1H NMR (500 MHz, DMSO) δ: 2.10 (s, 3), 4.45 (s, 2), 4.49 (s, 2), 7.18-7.27 (m, 8). 13C NMR (125 MHz, DMSO) δ; 21.34, 47.04, 50.04, 114.90, 115.07, 115.27, 115.45, 128.51, 128.58, 129.57, 129.64, 133.32, 133.34, 133.86, 133.89, 160.25, 160.33, 162.17, 162.27, 170.22.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:25][S:26]([C:29]1[C:30]([Cl:47])=[CH:31][C:32]([NH:40][CH2:41][C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[C:33]([CH:39]=1)[C:34]([O:36][CH2:37]Cl)=[O:35])(=[O:28])=[O:27]>C(#N)C>[NH2:25][S:26]([C:29]1[C:30]([Cl:47])=[CH:31][C:32]([NH:40][CH2:41][C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[C:33]([CH:39]=1)[C:34]([O:36][CH2:37][N:11]1[C@H:12]([CH3:15])[CH2:13][O:14][C@:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)([OH:17])[C@@H:10]1[CH3:16])=[O:35])(=[O:27])=[O:28]
Reactant: NS(=O)(=O)c1cc(C(=O)OCCl)c(NCc2ccco2)cc1Cl
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
A solution of free base of (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (20a) (0.023 mole) (U.S. Pat. No. 5,104,870), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (15) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (2S,3S,5R)-4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (520). See eg., U.S. Pat. No. 5,104,870) and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]([NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)c1cc2ccccc2o1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1cc2ccccc2o1
Yield: 82 %

Procedure:
2-Benzofuransulfonamide (7.6 mmol), prepared as described in Example 1, was reacted with 3,4-dichlorophenylisocyanate (7.6 mmol) as described in Method A to obtain 2.4 g of the title product as a solid. 1H NMR (CD3SOCD3): δ9.43 (s, 1 H), 7.88 (d, J =8 Hz, 1 H), 7.85 (s, 1 H), 7.80 (m, 1 H), 7.76 (m, 1 H), 7.59 (dd, J =6, 8 Hz, 1 H), 7.52 (d, J =8 Hz, 1 H), 7.45 (dd, J =6, 8 Hz, 1 H), 7.35 (dd, J =3, 6 Hz, 1 H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH3:8])=[CH:5][CH:6]=1.C([Li])CCC.[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[OH:15][CH:14]([C:2]1[S:3][C:4]([S:7][CH3:8])=[CH:5][CH:6]=1)[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CSc1ccc(Br)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
1.2 g of 2-bromo-5-(methylsulfanyl)thiophen (compound in Production Example 45) was dissolved in 20 mL anhydrous tetrahydrofuran, and 3.72 mL solution of 1.59 M n-butyl lithium in hexane was added dropwise there to at −70° C. After the mixture was stirred for 1 hour, 6 ml solution of 1.2 g t-butyl 4-formyl-piperidine-1-carboxylate in anhydrous tetrahydrofuran was added dropwise thereto and stirred at −70° C. for 2 hours. The temperature of the reaction solution was gradually increased to 0° C., water and an ammonium chloride solution were added thereto, and the reaction solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate and purified by silica gel column chromatography (ethyl acetate/hexane), to give 1.41 g of the title compound as pale pink crystals.