Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[C:29](Cl)(Cl)=[O:30].O>C1COCC1>[Cl:1][C:2]1[N:11]2[C:29](=[O:30])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1nc(NNc2ccccc2)c2ccccc2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=c1n(-c2ccccc2)nc2c3ccccc3nc(Cl)n12
Reaction time: 0.08 h

Procedure:
To a mixture of 2-chloro-4-phenylhydrazinoquinazoline (2 g, 7.4 mmol) and N,N-diisopropylethylamine (2 ml, 11.4 mmol) in THF was added phosgene (6 ml, 20% in Toluene) slowly, then stirred for additional 5 min. The reaction mixture was poured into water and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine and dried over Na2SO4 and evaporated under reduced pressure. The residue was triturated with ethanol and filtered to afford 5-chloro-2-phenyl-1,2,4-triazolo[4,3-c]quinazolin-3-one (1.8 g) as a yellow solid. m.p. 167°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(-c2ccccc2Cl)cc1
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(-c2ccccc2Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of 21.6 g. (0.1 mole) of 4-(2'-chlorophenyl)benzaldehyde is heated on a steam bath with 13.2 g. of malonic acid and 95 ml. of pyridine containing 5 drops of piperidine. The mixture is heated for four hours until the liberation of carbon dioxide ceases. The cooled mixture is poured into a mixture of 110 ml. concentrated hydrochloric acid and 500 ml. of ice water. The solid which separates is filtered, washed and 15 ml. portions of cold water and then resuspended in 200 ml. of cold water, filtered, washed with cold water and dried at 40°C. The residue is then recrystallized from ethanol to obtain 4-(2'-chlorophenyl)cinnamic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)c1ccc(CO)c(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(C=O)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
The alcohol compound (195 mg, 0.981 mmol) obtained in Step 1-3 was dissolved in chloroform (5 ml). Activated manganese dioxide (1.27 g) was added to the obtained solution, and they were violently stirred at 50° C. for 2 hours. After leaving to cool, manganese dioxide was filtered out, and the filtrate was concentrated under reduced pressure. After the purification by the silica gel column chromatography, 2-chloro-4-t-butylbenzaldehyde (yield: 152 mg, 79%) was obtained.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([OH:18])(=[O:17])[C:11]([CH2:13][C:14](O)=[O:15])=[CH2:12].N(CCO)(CCO)CCO>>[CH2:1]([N:9]1[C:14](=[O:15])[CH2:13][CH:11]([C:10]([OH:18])=[O:17])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CCCCCCCCN
Solvent: OCCN(CCO)CCO
Product: CCCCCCCCN1CC(C(=O)O)CC1=O
Yield: 162.3 %

Procedure:
129 g of octylamine, 130 g of itaconic acid and 149 g of triethanolamine were used to obtain 391 g of N-octyl-5-oxopyrrolidine-3-carboxylic acid triethanolammonium salt with
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1.ClCCl>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 95 %

Procedure:
To a solution in which 1,2-phenylenediamine (0.5 mmol) was dissolved in pyridine (1 mL) was added p-toluenesulfonyl chloride (1.1 mmol) at room temperature, and the mixture was reacted for 6 hours with stirring. After completion of the reaction, the reaction mixture was diluted with dichloromethane, and back extracted using 1N hydrochloric acid to remove pyridine. After the organic layer was dried with anhydrous sodium sulfate, and concentrated. The obtained solid was washed using diethyl ether on a Buchner funnel, and dried under reduced pressure to obtain an objective substance as a white solid in a yield of more than 95% yield.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([O-:15])=[O:14])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[NH2+]1CCCCC1.Cl>O.CO>[OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(C=CC(=O)Nc2ccccc2C(=O)[O-])ccc1O
Agent: C1CC[NH2+]CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc(C=CC(=O)Nc2ccccc2C(=O)O)ccc1O
Yield: 98.5 %

Procedure:
A 10 g quantity of piperidinium N-(4-hydroxy-3-methoxycinnamoyl)anthranilate is dissolved in a mixture of 80 ml of water and 60 ml of methyl alcohol with heating, and the resultant solution is added dropwise to 85 ml of diluted hydrochloric acid (5 ml of conc. hydrochloric acid and 80 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at 90°-100° C. under reduced pressure for 3 hours to yield N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid (98.5% yield), m.p. 230°-233° C. The compound structure is confirmed by elemental analysis, and by IR and NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][C@@H:25]([CH3:29])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[C@@H:25]([CH3:29])[CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 4-boc-2-(S)-methyl-piperazine following procedure B. LC-MS showed the product had the expected M+H+ of 403. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (d, 1H) 8.0 (m, 2H) 7.6 (d, 1H) 7.5 (m, 2H) 4.8 (d, 1H) 4.1 (m, 1H) 3.6 (m, 2H) 3.3 (m, 1H) 3.0 (m, 2H) 2.5 (m, 2H) 1.4 (s, 9H) 1.1 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37].C[O-].[Na+:41].CO>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O-:38])=[O:37].[Na+:41]
Reactant: COc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)O)CCO5)cc3)n2)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)[O-])CCO5)cc3)n2)cn1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 6-chloro-7-(4-(6′-methoxy-2,3′-bipyridin-6-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.080 g, 0.150 mmol) in 1:1 THF/methanol (2 ml) was added a 0.5 M solution of sodium methoxide in methanol (0.301 ml, 0.150 mmol), and the reaction was stirred for 2 hours, then concentrated to yield the desired compound (0.080 g, 0.144 mmol, 96.0% yield). MS (apci) m/z=532.2 (M-Na+2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.I[CH2:31][CH:32]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:31][CH:32]2[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:33]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(CI)C1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)ccc34)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Cn2nc(-c3cnc4c(n3)c(C=O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)C1
Yield: 63.6 %

Procedure:
2-(6-Fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (225 mg, 547 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (162 mg, 547 μmol) and cesium carbonate (534 mg, 1.64 mmol) in dimethylformamide (4 mL) were heated in a microwave at 150° C. for 30 min. The mixture was partitioned between ethyl acetate and water. Then the organic phase was washed with water 3 times, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((6-fluoro-3-(7-formyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (202 mg, 64%).
Reaction SMILES: CC([O-])(C)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>COCCOC.CCOCC.CCCCCCCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:17][CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)(C)c1ccc(N2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of Pd2(dba)3 [92 mg, 0.1 mmol (4.6 mg, 0.005 mmol, 2 mol % Pd per reaction)], ligand 1 (see FIG. 1) [168 mg, 0.4 mmol (8.4 mg, 0.02 mmol, 4 mol % per reaction)] and NaOt-Bu [40 mg, 0.4 mmol (2 mg, 0.02 mmol, 4 mol % per reaction)] were stirred in 10 mL DME (anhy). After 10 minutes, 0.5 mL of the solution was added via syringe to a test tube containing (under an Argon atmosphere) K3PO4 (148 mg, 0.7 mmol), 1-bromo-4-tert-butylbenzene (86 μL, 0.5 mmol), and morpholine (52 μL, 0.6 mmol). The test tube was capped (with a proper cap-no rubber septa) and heated at 100° C. for 18 hours. The reaction mixture was allowed to cool to r.t., diluted with ether and dodecane was added as an internal standard. The GC yield was calculated to be 12%.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][C:8]1[C:14]([CH3:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[CH3:16])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:30]>ClCCl>[CH:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][C:8]1[C:9]([CH3:16])=[CH:10][C:11]([NH:12][C:29](=[O:30])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:13][C:14]=1[CH3:15])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1ccc(Cc2c(C)cc(N)cc2C)cc1C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cc(C)c(Cc2ccc(OC)c(C(C)C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
246 mg (0.86 mmol) of 4-(3-isopropyl-4-methoxybenzyl)-3,5-dimethylaniline (Example VII) are dissolved with 97 mg (0.96 mmol) of triethylamine in 10 ml of dichloromethane, and 160 mg (1.17 mmol) of ethoxalyl chloride are added dropwise. The mixture is stirred at room temperature for 4 hours, washed with sodium bicarbonate solution and water and dried over sodium sulphate, and the solvent is removed in vacuo. Purification by chromatography affords 128 mg (38%) of ethyl 2-[4-(3-isopropyl-4-methoxybenzyl)-3,5-dimethylanilino]-2-oxoacetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.[OH-].[K+]>CS(C)=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:17]1[CH:18]=[C:14]([CH3:13])[N:15]=[CH:16]1
Reactant: Cc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 45.4 %

Procedure:
A solution of 2-chloro-5-nitroanisole (187 mg, 1 mmol), of 4-methyl-1H-imidazole (335 mg, 4 mmol) and of potassium hydroxide (99 mg, 1.5 mmol) in DMSO (0.86 mL) was stirred for 5 h at 80° C. under an atmosphere of nitrogen. After cooling to 20° C. the reaction was poured onto ice-water. A precipitation was formed and the suspension was stirred for 15 min. The solid was filtered off, washed with water, dissolved in dichloromethane, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield a yellow solid. The crude product was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (106 mg, 45%) as a pale-yellow solid. Alternatively the product can be also crystallized from the crude material from diethyl ether.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:33])=[C:16]([NH:21][C:22](=O)[CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:35])[CH3:34])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:33])=[C:16]([NH:21][CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:35])[CH3:34])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CC(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Solvent: CCCCCC
Product: COc1ccc(CCNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 66 %

Procedure:
By using N-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-4-methoxyphenylacetamide, the title compound was synthesized according to Example 2b. Yield: 66%. Melting point: 63-65° C. (Hexane).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:21]=[C:20]([OH:22])[C:19]3C[C:18]=3[C:17]=2O)[C:11]([O:13]CC)=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2].[CH3:30][OH:31]>>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:17]=[CH:18][C:19]3[O:31][CH2:30][O:22][C:20]=3[CH:21]=2)[C:11]([OH:13])=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CO
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1cc(O)c2c(c1O)C2
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A 1 L 3 necked 24/40 round bottom flask equipped with a mechanical stirrer, a dropping funnel, and a nitrogen inlet was charged with a solution of 76.3 g 0.185 mol) of the semi-purified product of Step A dissolved in 500 mL of methanol. The flask was purged with nitrogen, the stirrer was started, and 37 mL of a 5.0N aqueous solution of sodium hydroxide was added over a 30 minute period via an addition funnel. The reaction mixture was stirred at room temperature for an additional 30 minutes at which point TLC analysis (CH2Cl2 -MeOH-NH4OH 90:10:1) indicated that the starting material had been consumed. The reaction mixture was adjusted to pH=4 with 6N HCl, and the bulk of the organic solvent was removed in vacuo. The precipitated organic product and the aqueous layer were next partitioned between CH2Cl2 (1 L) and water (1 L) which produced a copious emulsion. The reaction mixture was then aged overnight in a refrigerator which resulted in crystallization of the organic product. The crystalline solid was separated from the two phase mixture by filtration and washed with CH2Cl2. The solid was slurried again in diethylether, filtered, washed with hexane, and then dried in a vacuum to afford 65 g (94%) of the title compound as a white crystalline solid.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([S:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: C[n+]1ncc(N)cc1Cl
Reactant: SCc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[n+]1ncc(N)cc1SCc1ccccc1

Procedure:
24.4 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 200 parts of acetonitrile is stirred with 12.4 parts of benzylmercaptan and 20 parts of triethylamine for 3 hours at 80°C. The solvent is then distilled off at subatmospheric pressure, the residue is treated with about 300 parts of water and the sparingly soluble reaction product is suction filtered. 29.5 parts (89.2% of theory) of 1-methyl-4-amino-6-benzylmercaptopyridazinium perchlorate is obtained; C12H14O4N3SCl, melting point 139° to 141°C.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH:24]=[CH:25][CH:26]=[C:27]([OH:28])[C:20]5=[N:19][C:18]=4[CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1>[Pt].[Pd].C(O)(=O)C>[CH3:29][C:18]1[N:19]=[C:20]2[N:21]([CH2:24][CH2:25][CH2:26][CH:27]2[OH:28])[C:22](=[O:23])[C:17]=1[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [Pd]
Agent: [Pt]
Solvent: CC(=O)O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O

Procedure:
In the step-b, the pyridine ring of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, compound of formula-11, is reduced by a suitable reducing agent as defined earlier. Good yields were obtained on hydrogenation using palladium or platinum catalyst in acidic conditions. In the preferred embodiment the reaction was performed by hydrogenation using palladium catalyst in presence of acetic acid to provide pure paliperidone.
Reaction SMILES: [OH-].[Na+].[CH:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4]1.Cl[C:12]1[C:13]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[O:18][C:14]=2[N:15]=[CH:16][N:17]=1.Cl>C1(C)C=CC=CC=1.COCCOC.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:12]([O:9][CH:5]4[CH2:6][CH2:7][CH2:8][CH:3]([OH:10])[CH2:4]4)=[N:17][CH:16]=[N:15][C:14]=3[O:18][C:19]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:26][CH:25]=1)[CH3:28]
Reactant: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(Cl)c23)cc1
Reactant: OC1CCCC(O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(OC4CCCC(O)C4)c23)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
Add 4.5 ml of 12.5N sodium hydroxide solution at 70° C. to a mixture of 1.65 g (14.17 mmol) of cyclohexane-1,3-diol in 45 ml of toluene, 15 ml of 1,2-dimethoxyethane and 15 ml of water. After adding 0.19 g (0.57 mmol) of tetra-n-butylammonium hydrogen sulfate and 2.0 g (5.67 mmol) of 4-chloro-5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidine, stir the reaction mixture at 70° C. for 17 hours. After cooling to room temperature, adjust to pH 7 with conc. hydrochloric acid. Extract with dichloromethane. Wash the organic phase with satd. sodium chloride solution, dry over sodium sulphate, filter and concentrate under reduced pressure. Chromatograph the residue on silica gel (eluent: cyclohexane/ethyl acetate 2:1). 0.60 g (24% of theory) of the desired product are obtained as a racemic diastereomer mixture.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH:14]=O>C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]=[N:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
To a solution of t-butyl carbazate (4.99 g, 37.76 mmol) in ethyl acetate (10 mL) was added with vigorous stirring a solution of 3,4-dichlorobenzaldehyde (6.77 g, 38.6 mmol) in ethyl acetate (10 mL) followed by hexanes (40 mL). Crystallization occurred and the resulting slurry was stirred at rt for 15 min, then cooled to 0° C. and held at that temperature for 45 min. The solids were filtered, rinsed with cold hexanes and dried in vacuo at 60° C. to afford the title compound as a solid (10.10 g, 92.4%): mp 173.8-174.4° C. (dec); 1H NMR (DMSO-d6) δ 11.16 (br s, 1 H), 7.79 (s, 1 H), 7.62 (d, 1 H, J=1.8 Hz), 7.57 (d, 1 H, J=8.5 Hz), 7.55 (m, 1 H), 1.44 (s, 9 H); 13C NMR (DMSO-d6) δ 152.9, 141.1, 136.1, 132.3, 132.1, 131.6, 128.6, 127.0, 80.4, 28.7; IR (KBr mull) 3358, 3010, 2983, 1736, 1508, 1475 cm−1. A portion was recrystallized (ethyl acetate) for analysis. Anal. Calcd. for C12H14Cl2N2O2: C, 49.84; H, 4.88; Cl, 24.52; N, 9.69. Found: C, 49.59; H, 4.71; Cl, 24.43; N, 9.57.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][N:9]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C#N)ccn2)CC1
Yield: 7 %

Procedure:
A solution of 2-chloro-isonicotinonitrile (2.00 g, 14.43 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.18 g, 15.88 mmol, 1.1 equiv; commercially available) in DMAc (10 mL) was heated by microwave irradiation to 150° C. for 30 min. The solvent was evaporated under reduced pressure and the crude material purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1) to yield 0.30 g (7%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.25-1.42 (m, 2H), 1.43 (s, 9H), 1.93-1.97 (m, 2H), 2.83-2.93 (m, 2H), 3.71-3.81 (m, 1H), 3.97-4.02 (m, 2H), 4.77 (d, J=8.1 Hz, 1H), 6.51 (s, 1H), 6.66 (d, J=5.2 Hz, 1H), 8.11 (d, J=5.2 Hz, 1H). MS (ISP): 303.0 [M+H]+.