Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21]Br>C(O)C>[CH2:10]([O:9][C:7](=[O:8])[C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:21][C:20]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:18]([Cl:17])[CH:19]=1)[CH3:11]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(Cl)c(Cl)c1)(NC(C)=O)C(=O)OCC
Reaction time: 0.5 h

Procedure:
Sodium pellets were dissolved in ethanol (200 ml). Diethyl acetamidomalonate (6.53 g) was added and the solution stirred for 30 minutes. 3,4-Dichlorobenzyl bromide (10.0 g), was added and the solution refluxed for 3.5 hours. The solution was filtered whilst hot and allowed to cool before water (200 ml) was added. On standing at 4° C. for 12 hours the title compound precipitated as colourless crystals which were removed by filtration and dried under vacuum (9.27 g). 1H NMR (360 MHz, CDCl3) δ7.32 (1H, d, J=8 Hz), 7.10 (1H, d, J=2 Hz), 6.85 (1H, dd, J=8, 2 Hz), 6.55 (1H, s), 4.28 (2H, m), 3.62 (2H, s), 2.05 (3H, s), 1.3 (3H, t, J=7 Hz).
Reaction SMILES: S(=O)(=O)(O)O.C([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15](C(=O)C)=[CH:16][CH:17]=3)[CH:12]([CH3:25])[C:11]=2[CH:10]=1)(=O)C.C([O:29][C:30](=[O:32])[CH3:31])(=O)C.OO>O.ClCCl>[C:30]([O:32][C:16]1[CH:15]=[CH:14][C:13]2[C:12]3[C:11](=[CH:10][C:9]([O:29][C:30](=[O:32])[CH3:31])=[CH:21][CH:25]=3)[CH:19]([CH3:20])[C:18]=2[CH:17]=1)(=[O:29])[CH3:31]
Reactant: CC(=O)c1ccc2c(c1)C(C)c1cc(C(C)=O)ccc1-2
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)C(C)c1cc(OC(C)=O)ccc1-2
Temperature: 24 °C
Reaction time: 7 h
Yield: 36.9 %

Procedure:
36M-sulfuric acid (12 mL) was slowly dropwise added to a mixture of 2,7-diacetyl-9-methylfluorene (30 g), dichloromethane (30 mL), acetic anhydride (35 g) and a 34% hydrogen peroxide aqueous solution (34.6 g) while maintaining 3° C. or lower. The resulting mixture was stirred at 24° C. for 7 hours and then poured into water. The separated organic layer was sufficiently washed in order with saturated sodium hydrogencarbonate, 10% saturated sodium hydrogensulfite and water, and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the resulting residue was purified by means of column chromatography (silica gel, eluting solvent: heptane/toluene [6/4]) and recrystallization (ethanol) to obtain 2,7-diacetyloxy-9-methylfluorene (12.4 g) of colorless crystal. Melting point: 138.6-139.7° C.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1>ClC1C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])=[CH:18][CH:19]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: Cc1ccc(C)cc1
Solvent: Clc1ccccc1
Product: Cc1ccc(CON2C(C)(C)CC(O)CC2(C)C)cc1
Temperature: 140 °C
Yield: 12 %

Procedure:
A mixture of 8.60 g (0.1 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 53.09 g (0.5 mol) of p-xylene in 61 mL of chlorobenzene under a nitrogen atmosphere is heated at 140° C. for 56 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is washed with 10 w/v % ascorbic acid (3×30 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from heptane to give 3.33 g (48% yield) of the title compound as a white solid melting at 92.5-93° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>O.C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C@@H:11]2[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][C@H:10]2[OH:13])=[CH:18][CH:17]=1
Reactant: COc1ccc(O)cc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(O[C@@H]2CN(Cc3ccccc3)C[C@H]2O)cc1

Procedure:
A mixture of 17.5 g. (0.10 mole) of 1-benzyl-3,4-epoxypyrrolidine, 13.4 g. (0.11 mole) of p-methoxyphenol, and 3 drops of water was heated on a steam bath overnight. The dark residue was dissolved in methylene chloride and the solution was washed with two 50-ml. portions of 5% sodium hydroxide. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated to give 23.7 g. of viscous dark oil. This oil was chromatographed on 480 g. of silica gel 60 and the product was eluted with a 1:1 benzene:ether solution. The appropriate fractions were concentrated to give 10.0 g. of a yellow oil which crystallized upon scratching. The solid was recrystallized from cyclohexane to yield 7.2 g. (24%) tan solid, m.p. 84°-5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH2:15])[N:14]=[C:10]2[CH:9]=[C:8]([Br:16])[CH:7]=1)=[O:5])[CH3:2].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:20]([NH:19][CH2:17][CH3:18])=[O:21])[N:14]=[C:10]2[CH:9]=[C:8]([Br:16])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1cc(Br)cc2nc(N)nn12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Temperature: 100 °C

Procedure:
2-Amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (7) (760 mg, 2.66 mmol) was dissolved in THF/toluene (1:1, 40 mL), then ethyl isocyanate (1.89 g, 26.6 mmol) and a catalytic quantity of dibutyltindiacetate (10 drops) were added to the mixture. The reaction was then heated in a sealed tube at 100° C. for 15 h. This mixture was allowed to cool, then the solvents removed under reduced pressure to afford a solid which was purified by flash chromatography on silica 2% MeOH/CH2Cl2 as eluant) to give 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (8) LCMS (APCI+) 356, 358.
Reaction SMILES: C1(=O)N(CCCO[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:12][C:11]=2[Cl:23])C(=O)C2=CC=CC=C12.O.NN>C(O)(C)C>[NH2:20][CH2:19][CH2:18][CH2:17][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][C:11]=1[Cl:23]
Reactant: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)c(Cl)c2)=NN1
Agent: NN
Solvent: CC(C)O
Solvent: O
Product: NCCCc1ccc(C2=NNC(=O)CC2)cc1Cl
Yield: 122.4 %

Procedure:
A mixture of 5.4 g (13.1 mmol) of the phthalimide prepared above and 700 microliters (14.4 mmol) of hydrazine monohydrate in 150 ml of isopropanol is heated at reflux overnight. The solvent is removed under vacuum, the residue is taken up in 15 ml of 70:30 (CH3OH:NH4OH) and flash chromatographed on silica gel (90:10:2 CHCl3 :CH3OH:NH4OH) to give 2.13 g of 6-[4-(3-aminopropyl)-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone as a pale yellow solid. Yield, 58%.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([NH2:21])=O)=[CH:15][N:16]=1)=[CH:8]2.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:19]([CH2:18][CH2:17][C:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:16][CH:15]=1)#[N:21]
Reactant: CN(c1cccc2cc(-c3ncc(CCC(N)=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CN(c1cccc2cc(-c3ncc(CCC#N)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanamide (1.32 g) and pyridine (15 mL) was added trifluoroacetic anhydride (0.90 mL) at 0° C. over 15 min. The reaction mixture was stirred at room temperature for 2 hr and concentrated. 10% Aqueous citric acid solution was added to the residue. The resulting crystals were collected by filtration, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.20 g, yield 95%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). melting point 207-208° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:7]=[CH:6][NH:5][N:4]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:17][C:16]1[C:11]([N:5]2[CH:6]=[N:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1nc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ncn(-c2ncccc2Cl)n1
Temperature: 120 °C
Reaction time: 27 h
Yield: 11.3 %

Procedure:
A mixture of 3.5 g of 3-trifluoromethyl-1H-1,2,4-triazole, 3.8 g of 2,3-dichloropyridine, 6.0 g of potassium carbonate and 30 ml of N,N-dimethylformamide was stirred at 120° C. for 27 hours. After the reaction mixture was allowed to cool to room temperature, water was poured and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.72 g of 3-chloro-2-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)pyridine of the formula:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:25]4[S:26][CH:27]=[CH:28][C:24]=4[CH3:23])[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccsc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3sccc3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 3-methylthiophene-2-boronic acid pinacol ester (125 mg, 0.557 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(3-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.52-7.71 (m, 2H), 7.42 (s, 1H), 7.4 (m, 2H), 7.35 (s, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.82 (m, 1H), 3.58 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H), 2.42 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: B.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][C:12](=O)[N:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]2)=[CH:5][C:4]=1[C:19]#[N:20].CO.[ClH:23]>O1CCCC1>[ClH:23].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][CH2:12][N:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]2)=[CH:5][C:4]=1[C:19]#[N:20]
Reactant: CC(C)N1CC(c2ccc(N)c(C#N)c2)OCC1=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N1CCOC(c2ccc(N)c(C#N)c2)C1
Reaction time: 3 h

Procedure:
Borane in tetrahydrofuran (1.0M solution; 7.5 ml) was added dropwise, at ambient temperature, to a stirred solution of 2-[4-amino-3-cyanophenyl]-4-[1-methylethyl]-5-oxomorpholine (0.83 g) in dry tetrahydrofuran (60 ml) under nitrogen. The mixture was then heated under reflux with stirring, under nitrogen, for three hours, cooled and methanol (4 ml) in tetrahydrofuran (10 ml) added carefully. The mixture was heated under reflux for one hour, cooled, hydrogen chloride gas passed and the mixture heated under reflux for one hour. After cooling and evaporation to dryness, the residue was dissolved in dilute hydrochloric acid, washed with diethyl ether, the aqueous phase made alkaline by addition of dilute aqueous sodium hydroxide and extracted with dichloromethane. The dichloromethane extracts were washed with brine, dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated to dryness. The residual oil was purified by chromatography on silica gel using 2-3% methanol in dichloromethane as eluant. Conversion to its hydrochloride salt by addition of ethereal hydrogen chloride and recrystallisation from acetone-diethyl ether gave the title compound, m.p. 200°-2° C., as a white solid.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[CH3:18])C=CC=CC=1.[CH3:20][C:21]([CH3:37])([CH3:36])[CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:24]([CH2:23][CH2:22][C:21]([CH3:20])([CH3:37])[CH3:36])[C:8]([NH:9][C:10]2[C:11]([CH3:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[CH3:16])=[O:19])=[CH:31][CH:30]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1ccc(CNCCC(C)(C)C)cc1
Reactant: Cc1cc(Cl)cc(C)c1NC(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CN(CCC(C)(C)C)C(=O)Nc2c(C)cc(Cl)cc2C)cc1

Procedure:
A solution of 825 mg of phenyl-N-(4-chloro2,6-dimethylphenyl)carbamate and 740 mg of N-[3,3-dimethylbutyl]-4-n-butylbenzenemethanamine in 40 ml of toluene was refluxed for 1 hour, cooled, and the solution was washed with 1N sodium hydroxide, brine, dried, and evaporated to dryness to yield a solid. The solid was recrystallized from hexane to yield 1-[(4-butylphenyl)methyl]-1-[3,3-dimethylbutyl]-3-[4-chloro-2,6-dimethylphenyl]urea as a white solid, mp 138°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[CH2:9]([OH:15])[CH2:10][CH2:11][CH2:12][C:13]#[CH:14]>C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:13][CH2:12][CH2:11][C:10]#[C:9][OH:15])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCCCO
Reactant: Clc1cccc(I)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OC#CCCCCc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 3-chloroiodobenzene (14.3 g, 60 mmol), tetrakis(triphenylphosphine) palladium (2.1 g, 1.8 mmol) and 5-hexyn-1-ol (5.9 g, 60 mmol) in triethylamine (120 ml) was stirred at 25° C. for 3H and partitioned between water and ether. The
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:19])[CH:17]=2)[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:19])[CH:17]=2)[N:12]=[C:11]([N:24]2[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:21][CH2:22][CH2:23]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(OCc2ccccc2)c2cc(Br)ccc2n1
Reactant: c1ccc2c(c1)CNCCS2
Product: Brc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of 4-(benzyloxy)-6-bromo-2-chloroquinazoline (700 mg, 2.0 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine (990 mg, 6.0 mmol) was heated at 80° C. for 10 minutes. The resulting reaction mixture was cooled to room temperature and purified by silica gel column chromatography (eluting with dichloromethane) to afford 600 mg of the desired product as a white solid (yield was 62.7%).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1>C(C(C)=O)C>[I:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1
Reactant: [I-]
Reactant: CCOC(=O)C(C)c1ccc(CCl)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)c1ccc(CI)cc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
After a solution of 15 g of sodium iodide in 140 ml of methyl ethyl ketone was refluxed for 1 hour, 12.5 g of ethyl 2-(4-chloromethylphenyl)propionate was added and refluxing was continued for further 8 hours. After the reaction was completed, methyl ethyl ketone was removed by distillation from the reaction mixture under reduced pressure, the residue was poured into ice-water and extracted with ether. The extract was washed with water and an aqueous sodium thiosulfate solution, successively, dried, and the solvent was evaporated to give 16.3 g of the desired compound as an oily and slightly yellow substance.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.P(Cl)(Cl)Cl>O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=C(NCc1ccc(Cl)cc1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 21.3 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.250 g) of Preparation 1 and 4-chlorobenzylamine (0.187 g) in 25 mL xylenes is heated to reflux. To this is added dropwise PCl3 (0.073 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected and recrystallized from EtOAc/hexanes to yield 0.088 g of the title product as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CC1O[N:29]=[C:28]([C:31]2C=CC=CC=2)[C:27]=1COC1C=CC(C(O)=O)=CN=1.C(N)(C)C>>[Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:29][CH:28]([CH3:31])[CH3:27])=[O:8]
Reactant: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)O)cc1Br
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Solvent: CC(C)N
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC(C)C)cc1Br
Yield: 86 %

Procedure:
As described for example 8b, 5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (240 mg, 0.6 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, was converted, using isopropylamine instead of methylamine, to the title compound (229 mg, 86%) which was obtained as an off white foam. MS: m/e=430.3/432.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2].Br[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[C:1]([CH:3]([P:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])=[O:11])[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(C#N)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 100 °C

Procedure:
Diethyl cyanomethylphosphonate (0.35 ml, 2.164 mmol), tert-butyl 4-bromobenzoate (0.5096 g, 1.982 mmol), bis(tri-t-butylphosphine)palladium (0.051 g, 0.099 mmol), potassium phosphate, tribasic (1.2381 g, 5.83 mmol) and toluene (6 ml) were combined in a flask. Nitrogen was bubbled through the reaction for approximately two minutes to deoxygenate the reaction. The reaction was allowed to heat at 100° C. until complete (3-24 h). The reaction was filtered over celite. The resulting material was partially purified by column chromatography on silica gel. The partially purified material was further purified by HPLC. 1H NMR (CDCl3, 600 MHz) δ 8.01 (d, J=6 Hz, 2H), 7.52 (d, J=6.9 Hz, 2H), 4.30 (d, JP-H=26.4 Hz, 1H), 4.19-4.01 (m, 4H), 1.59 (s, 9H), 1.32 (m, 3H), 1.26 (m, 3H). MS: cal'd 354 (MH+), exp 354 (MH+).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]([F:13])([F:12])/[C:7](=[N:10]/[OH:11])/[S:8][CH3:9]>>[F:5][C:6]([F:13])([F:12])/[C:7](=[N:10]/[O:11][C:3](=[O:4])[NH:2][CH3:1])/[S:8][CH3:9]
Reactant: CS/C(=N\O)C(F)(F)F
Reactant: CN=C=O
Product: CNC(=O)O/N=C(\SC)C(F)(F)F
Yield: 95.6 %

Procedure:
A mixture of 17.12 g (0.3 mol) of methyl isocyanate and 47.74 g (0.3 mol) of S-methyl (Z)-2,2,2-trifluoro-N-(hydroxy)thioacetimidate was sealed in a glass tube and heated at 100° in a steam bath for 17 hours. The contents of the tube were distilled at reduced pressure to give 62.02 g (96%) of S-methyl (Z)-2,2,2-trifluoro-N-(methylcarbamoyloxy)thioacetimidate as a colorless, viscous liquid: bp 96° (0.6 mm); nD25 1.4638; ir (neat) 5.73μ (C=O); 19F NMR (CFCl3) δ -64.6 ppm (q, J=1.2 Hz); 1H NMR (CFCl3) δ 2.63 ppm (q, J=1.2 Hz, 3), 2.88 ppm (d, J=4.5 Hz, 3H) and 6.47 ppm (NH).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:13]1=[O:32])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:13]1=[O:32]
Reactant: [H][H]
Reactant: O=C1N(CCCOCc2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: [Pd]
Solvent: CO
Product: O=C1N(CCCO)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 98 %

Procedure:
A suspension of 1′-[3-(benzyloxy)propyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (6.27 g, 14.5 mmol) and 10% Pd/C (0.5 g) in MeOH (150 mL) was hydrogenated under the normal pressure of hydrogen overnight and filtered through a pad of celite. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from ether to yield the title compound (4.82 g) as a white solid in 98% yield: 1H NMR (300 MHz, CDCl3) δ 7.38-6.93 (m, 4H), 6.49 (s, 1H), 6.10 (s, 1H), 4.87 (m, 1H), 4.63 (m, 1H), 4.01-3.81 (m, 2H), 3.62 (t, 2H), 2.89 (br, 1H), 1.99-1.91(m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.8, 156.0, 148.9, 142.4, 142.1, 132.3, 129.0, 128.9, 124.1, 123.9, 119.0, 108.6, 103.0, 101.5, 93.6, 80.4, 58.3, 37.8, 29.8; MS (ES+) m/z 340.2 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10].P(Br)(Br)[Br:12]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10]
Reactant: BrP(Br)Br
Reactant: Cc1cccc(CO)c1C
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(CBr)c1C

Procedure:
A mixture of 1-hydroxymethyl-2,3-dimethylbenzene (ref) (5 g) and phosphorous tribromide (1.16 ml) in benzene (50 ml) was heated at reflux for 3 hours. The mixture was diluted with toluene, washed with water, dried (MgSO4) and evaporated. Yield 7 g.