Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C=O.Cl[CH:16]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[CH:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH3:18]>O>[C:1]1([S:7][CH:16]([N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(OC(C)C(Cl)n2cncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OC(C)C(Sc2ccccc2)n2cncn2)cc1

Procedure:
13 q (0.12 mol of thiophenol were added slowly at 25° C. to a solution of 4.0 g of sodium hydride (80% strength by weight suspension in mineral oil) and 100 ml of N,N-dimethylformamide, followed, after stirring for 30 minutes, by 19.8 g (0.08 mol) of 1-chloro-1-(1,2,4-triazol-1-yl)-2-(4-methylphenoxy)-propane. After a reaction time of 24 hours at 25° C., 100 ml of water were added. Extraction with methyl tert-butyl ether was carried out, after which the organic phase was washed and was worked up in a conventional manner.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].OO.[OH:28]S(O)(=O)=O>C(Cl)Cl.O>[CH:11]1[C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]([Cl:18])=[C:7]([N:6]2[N:5]=[C:4]([C:19]#[N:20])[C:3]([S+:21]([O-:28])[C:22]([F:25])([F:24])[F:23])=[C:2]2[NH2:1])[C:12]=1[Cl:13]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: OO
Solvent: O
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Temperature: 13.5 °C
Yield: 74.4 %

Procedure:
1.5 liter of methylene dichloride & 421.0 gms of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluromethylphenyl)-4-trifluromethylthio pyrazole was charged in a reactor flask with overhead stirring & condenser system. This mass was cooled to 12-15° C. and 68.0 gms of H2O2 (50.0% w/w) & 500.0 gms of H2SO4 (90.0% w/w) were simultaneously added to the mass over a period of 3.0-4.0 hours. The reaction temperature was then raised to 28-30° C. & maintained for about 2.0 hours. The reaction mass obtained thereafter was slowly added into 1700 ml of chilled water at a temperature of about 10-20° C. over a period of 2.0 hours. To this mass, 1500 ml of methylene dichloride was added and the mixture was heated to 60° C. to separate the aqueous and organic layers. The organic phase was washed with water & then with 5% NaHCO3 solution, followed by water wash, till a neutral pH was obtained. The crude yield obtained was 425.0 gms. The obtained crude fipronil was then crystallized from same solvent after partial evaporation to yield crystalline Fipronil (325 gms) with 94.0% purity.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:14][CH:15]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1ccc(O)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)c1ccc(OC(C)=O)cc1
Yield: 93.1 %

Procedure:
1.85 grams of ethyl 4-hydroxybenzoylacetate was added to 15 ml of anhydrous pyridine. 0.91 grams of acetic anhydride was added along with a few crystals of dimethylaminopyridine (Aldrich). After 1 hour at room temperature the pyridine was removed exvacuo. The oily residue was stirred with 25 ml of water and 25 ml of ether. The aqueous phase was separated and extracted twice with 50 ml of ether. The combined ether extracts were washed with 0.5N HCl (25 ml), then with saturated sodium bicarbonate solution (25 ml), and finally with 25 ml of brine. The extracts were then dried with magnesium sulfate, filtered and the ether removed exvacuo. To yield 2.07 grams of ethyl 4-acetoxybenzoylacetate.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])=[C:6]([OH:21])[CH:5]=1.[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C=O)C>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[O:9])=[C:6]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:5]=1
Reactant: COCCOCCl
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCOCCOC
Reaction time: 4 h
Yield: 95 %

Procedure:
To a well stirred suspension of sodium hydride (0.34 g of 60%, 0.014 mole) in 5 ml dry DMF was added a solution of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxy benzamide (3.57 g, 0.012 mole) in 15 ml dry DMF at room temperature over 18 minutes. The mixture was then stirred an additional hour giving essentially a clear solution. To this was added dropwise a solution of 2-methoxyethoxymethyl chloride (1.74 g, 0.014 mole) in 5 ml dry DMF. After an additional four hours at ambient temperature, the mixture was concentrated in vacuo, and the residue partitioned between water (200 ml) and methylene chloride (75 ml). The aqueous phase was extracted twice with 75 ml portions of methylene chloride. After combining, the organic phase was washed three times with 50 ml of 10% aqueous sodium hydroxide and three times with brine; dried over sodium sulfate, filtered, concentrated in vacuo, to give 4.26 grams of residue. Crystallization from ether gave 2.53 grams of the title compound, mp 79°-81° C. The NMR spectrum (90 MHz) in CDCl gave the following resonances: δ 8.18 (s, 2H); 6.61 (s, 1H); 5.40 (s, 2H); 4.40 (s, 2H); 3.84 (m, 2H); 3.50 (m, 4H); 3.44 (s, 3H); 2.56 (m, 6H); 1.04 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:21][S:22](O)(=[O:24])=[O:23]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:7][C:8]=1[S:22]([Cl:21])(=[O:24])=[O:23]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(S(=O)(=O)C(C)C)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(C)C)cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of crude 1-methoxy-4-(propane-2-sulfonyl)benzene (8 mmol) in dry dichloromethane (20 mL), chlorosulfonic acid (1 mL) was added dropwise at 0° C. The reaction mixture was warmed to room temperature followed by the addition of PCl5 (0.5 g). The resulting reaction mixture was refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into ice water (50 mL) with vigorous stirring. The aqueous layer was then extracted with EtOAc (2×75 mL). The combined organic extracts was washed with saturated sodium chloride aqueous solution (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (3:1) to give 1.25 g of 2-methoxy-5-(propane-2-sulfonyl)benzenesulfonyl chloride. 1H NMR (CDCl3, 400 MHz): δ 1.31 (d, 1H), 3.23 (m, 1H), 4.18 (s, 3H), 7.30 (d, 1H), 8.18 (dd, 1H). 8.46 (d, H) ppm.
Reaction SMILES: CN(CC[C:6]1[C:10]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:8][CH:7]=1)C.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:28]([N:32]([CH:37](O)[CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:32]([CH2:37][CH2:38][C:9]1[C:10]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:12])[CH3:13])[CH:6]=[CH:7][CH:8]=1)[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN(CCCC)C(C)O
Reactant: CC(C)C1(C(C)C)C=CC=C1CCN(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCCCN(CCCC)CCC1=CC=CC1(C(C)C)C(C)C
Yield: 53 %

Procedure:
The reaction was carried out in a manner analogous to that for (dimethylaminoethyl)di(2-propyl)cyclopentadiene, the tosylate of N,N-di-n-butylaminoethanol being prepared in situ. The conversion was 94%. The non-geminal di-n-butylaminoethyldi(2-propyl)-cyclopentadiene was obtained by distillation with a yield of 53%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C@@H:26]([OH:28])[CH3:27])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C@@H:26]([OH:28])[CH3:27])=[CH:23][CH:24]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Product: C[C@H](O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 26.4 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.089 g, 0.34 mmol) was reacted with (5)-1-(4-aminophenyl)propan-2-ol (0.061 g, 0.41 mmol) to afford the title compound (0.034 g, 26%) as a light yellow solid. MW=378.89. 1H NMR (DMSO-d6, 500 MHz) δ 8.06 (s, 1H), 7.91-7.88 (m, 1H), 7.76-7.72 (m, 1H), 7.46-7.38 (m, 2H), 7.23-7.14 (m, 5H), 4.53 (d, J=4.5 Hz, 1H), 3.86-3.78 (m, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.71-2.65 (m, 1H), 2.58-2.52 (m, 1H), 2.08 (quin, J=7.5 Hz, 2H), 1.05 (d, J=6.5 Hz, 3H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:21][CH:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25]1)[CH:22]([NH:21][C:16]([C:15]1[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=[CH:13][CH:14]=1)=[O:18])[CH2:23]2
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc2nc(-c3ccccc3)oc12
Yield: 57 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzoxazole-7-carboxamide was prepared from 2-phenylbenzoxazole-7-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 57% yield as a white solid: mp 179-180° C.; 1H NMR (300 MHz, CDCl3) δ 8.21 (dd, J=7.5, 2.1 Hz, 2H), 8.10 (dd, J=7.8, 1.2 Hz, 1H), 7.92 (dd, J=7.8, 1.2 Hz, 1H), 7.61-7.54 (m, 3H), 7.51-7.46 (m, 2H), 4.38-4.33 (m, 1H), 3.63-3.54 (m, 1H), 3.13-3.05 (m, 2H), 2.23 (q, J=3.0 Hz, 1H), 2.00-1.90 (m, 1H), 1.84-1.73 (m, 2H), 1.71-1.64 (m, 1H); MS (ESI) m/z 348[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]N1C(=O)CCC1=O>>[Cl:1][C:2]1[C:11]([CH2:12][Br:17])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl

Procedure:
80 g (0.3 mol) of methyl 2-chloro-3-methyl-4-methylsulfonylbenzoate, 54 g (0.31 mol) of N-bromosuccinimide and 1.5 g of azoisobutyronitrile are stirred at 76° C. for 6 h. The reaction mixture is filtered and freed form the solvent under reduced pressure. Yield: 104 g; m.p. 83-85° C.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[NH:8][C:7](=[O:12])[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:30](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[OH-].[Na+].C(O)(=O)C>CO>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[NH:8][C:7](=[O:12])[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.33 h

Procedure:
The title compound may be prepared by dissolving 6-butyl-2-methyl-5-[(2'-(N-triphenylmethyl-tetrazol-5-yl)biphen-4-yl)methyl]pyrimidin-4(3H)-one in methanol and adding excess concentrated HC1 and stirring for 10-30 minutes. An indicator quantity of phenolphthalein is added followed by 10% NaOH solution until pink. Excess acetic acid is added and the mixture is extracted three times with ether. The combined organic material is dried over MgSO4, stripped of solvent in vacuo, and MPLC'd to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC.O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[N:11]([CH3:16])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(-c2c[nH]c(C3CC3)n2)cc1
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(Br)cc2)nc1C1CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 4-(4-bromophenyl)-2-cyclopropyl-1H-imidazole (2.43 g, 9.23 mmol) and cesium carbonate (6.02 g, 18.47 mmol) in THF (30 mL) was added iodomethane (1.27 mL, 20.31 mmol). The reaction was stirred at rt for 19 hours. Water was added and the mixture was extracted with ethyl acetate. The organics were dried (MgSO4) and concentrated to afford the title compound which was used without further purification. LCMS: [M+1]+=277.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH:10]=[CH:14][N:15]([CH3:17])[CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Product: CN(C)C=CC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Yield: 77 %

Procedure:
10 g (0.053 mol) of 3', 5'-dichloroacetophenone are dissolved, at room temperature and with stirring, in 50 ml of N,N-dimethylformamide dimethyl acetal. Stirring is maintained and the reaction mixture is heated for 2 h at 90° C. The mixture is concentrated to dryness under reduced pressure. The residue is taken up in 150 ml of heptane. The orange residue is filtered to give 10.0 g (yield 77%, melting point: 100° C.) of 1-(3,5-dichlorophenyl)-3-dimethylamino-2-propen-1-one.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.C1CCCCC1>O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCCCC1
Solvent: O
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 1113.8 %

Procedure:
Crystalline form 1 of maraviroc phosphate (5 gm) was dissolved in water (40 ml) and pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (4 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate and treated with carbon. The ethyl acetate was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added cyclohexane (400 ml) and stirred for 15 minutes at room temperature, filtered. The solid obtained was dried under vacuum at 85° C. for 12 hours to obtain 47 gm of maraviroc amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]2[NH:10][N:11]=[CH:12][C:4]=12.C([O-])(=O)C.[Na+].[I:18]Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.C(OCC)(=O)C.CO>[I:18][C:12]1[C:4]2[C:5](=[N:6][C:7]([NH2:9])=[N:8][C:3]=2[O:2][CH3:1])[NH:10][N:11]=1
Reactant: COc1nc(N)nc2[nH]ncc12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(N)nc2[nH]nc(I)c12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
4-Methoxy-pyrazolo[3,4-d]pyrimidin-6-ylamine (6.75 g, 40.87 mmol) was suspended in an aqueous solution containing sodium acetate (6.0 g, 44.09 mmol) and iodine monochloride (9.12 g, 56.17 mmol) and stirred at 100° C. in a sealed reaction vessel for 24 h. The resulting mixture was cooled to room temperature and treated with a solution of sodium metabisulfite (3.6 g, 18.94 mmol) in 24 mL of water. The solid that formed was filtered, rinsed with water and dried: 6.93 g (58%) yield; TLC (10% methanol in ethyl acetate), Rf=0.57; 1H NMR (DMSO-d6) δ 13.08 (1H, br s, N−1 proton), 10.58 (1H, s, N−5 proton), 6.60 (2H, br s, 6-amino).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=[C:12]([C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)[C:13](=O)[CH2:14][O:15][CH3:16])[C:6]#[N:7].[NH2:24]/[C:25](/[CH3:29])=[CH:26]\[C:27]#[N:28]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([CH:11]2[C:12]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)=[C:13]([CH2:14][O:15][CH3:16])[NH:24][C:25]([CH3:29])=[C:26]2[C:27]#[N:28])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:7]
Reactant: C/C(N)=C/C#N
Reactant: COCC(=O)C(=Cc1ccc(C#N)cc1OC)c1nc(C)cs1
Solvent: CC(C)O
Product: COCC1=C(c2nc(C)cs2)C(c2ccc(C#N)cc2OC)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.305 mmol) of the compound from example 14A and 25 mg (0.305 mmol) of 3-amino-crotononitrile are dissolved in 3 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 59 mg (49% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: Nc1ccc(Br)cc1NC(=O)N1CCCC1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2cccnc2)cc1NC(=O)N1CCCC1
Temperature: 90 °C
Yield: 68.9 %

Procedure:
To a solution of N-(2-amino-5-bromophenyl)pyrrolidine-1-carboxamide (0.26 g, 0.72 mmol) in THF (10 mL) and water (5 mL) were added pyridin-3-ylboronic acid (0.13 g, 1.07 mmol, 1.5 equiv.), sodium bicarbonate (0.11 g, 1.07 mmol, 1.5 equiv.) and palladium(0) (0.08 g, 0.07 mmol, 0.1 equiv.). The reaction mass was stirred at 90° C. for sixteen hours. The reaction crude was filtered on a celite bed and diluted in ethyl acetate. The organic layers were washed with water and brine then dried over Na2SO4 and concentrated. The residue was purified by column chromatography on eluting ethyl acetate and hexane to allow N-(2-amino-5-(pyridin-3-yl)phenyl)pyrrolidine-1-carboxamide (0.14 g, 63% yield).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][N:8]=[N:9][C:10]=2NN)[CH:6]=1.Cl.C1C=CC2C(=CN=NC=2O)C=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NNc1nncc2ccccc12
Agent: Cl
Agent: Oc1nncc2ccccc12
Product: Clc1nncc2ccccc12

Procedure:
In another major embodiment of this invention, a process of preparing pure hydralazine hydrochloride is disclosed, comprising the steps of: a) reacting phthalazinone with phosphorous oxychloride at a specific temperature to produce 1-chlorophthalazine salt; b) concentrating the reaction mixture by distillation; c) isolating the 1-chlorophthalazine salt concentrated in step (b) by precipitating 1-chlorophthalazine salt through the addition of a mineral add in the presence of a solvent, filtering the resulting solid precipitated 1-chtorophthalazine salt, and drying; d) reacting the isolated and dried 1-chlorophthalazine salt with hydrazine hydrate without any substantial amount of organic solvent present and precipitating the resulting hydralazine base by adding a solvent; e) purifying the hydralazine base in a non-aqueous medium; f) converting the purified hydralazine base to hydralazine hydrochloride in a non-aqueous medium, and isolating the same; and g) purifying the isolated hydralazine hydrochloride by dissolving hydralazine hydrochloride in hot water to make a solution, treating the solution with a color adsorbent and a chelating agent, filtering off the adsorbent and chelating agent, adjusting the pH of the solution using a base or acid, and precipitating hydralazine hydrochloride by adding a water miscible solvent at a lower temperature.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].C([O-])(=[O:46])C.C([OH:50])C.[ClH:51]>C(OCC)(=O)C>[CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:36][CH2:37]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].[OH2:46].[OH2:50].[OH2:20].[ClH:51]
Reactant: CC(=O)[O-]
Reactant: CCO
Agent: CCc1c2c(nc3ccc(OC(=O)N4CCC(N5CCCCC5)CC4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Agent: Cl
Solvent: CCOC(C)=O
Product: O
Reaction time: 1 h

Procedure:
To a suitable vessel were charged amorphous irinotecan acetate (14.5 g) and ethanol (101 mL). The resulting mixture was heated to reflux and remained as a suspension. 2N HCl (10 mL) was added to the reaction mixture to adjust the pH to less than 4. Ethyl Acetate (145 mL) was added to the resulting mixture. The mixture was then cooled to 0˜10° C. and stirred at this temperature for 1 hour, filtrated, and washed with ethyl acetate (100 mL). The solid was then dried in vacuum. Due to a lower than expected water content, the solid was put under atmosphere overnight to give irinotecan hydrochloride trihydrate Form II (13.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[F:13][CH2:14][C:15]([CH2:19][F:20])([OH:18])[C:16]#[CH:17].C(N(CC)CC)C.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:17]#[C:16][C:15]([CH2:19][F:20])([OH:18])[CH2:14][F:13]
Reactant: C#CC(O)(CF)CF
Reactant: FC(F)(F)c1ccc(Cl)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: OC(C#Cc1cc(C(F)(F)F)ccc1Cl)(CF)CF
Temperature: 80 °C
Yield: 72.1 %

Procedure:
A mixture of 4-chloro-3-iodobenzotrifluoride (63.3 g), 1-fluoro-2-fluoromethyl-3-butyn-2-ol (28.8 g), triethylamine (26.2 g), cuprous iodide (0.38 g), bis(triphenylphosphine)palladium chloride (1.40 g) and N,N-dimethylformamide (100 ml) was stirred under a nitrogen atmosphere under heating at 80° C. for 1.5 hours. To the reaction mixture, 2 N HCl and a hexane/ethyl acetate mixed solvent (3/1) were added and the insoluble matter was filtered off with Celite; following extraction with a hexane/ethyl acetate mixed solvent (3/1), the resulting organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was purified by distillation to give 4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-butyn-2-ol (44.5 g) having a boiling point of 105-107° C./1 mmHg.