Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=2)[CH3:14])[CH2:10][CH:9]1[C:23]([OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:40]1([C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=2[C:48]#[N:49])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CCN(CC)CC>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=2)[CH3:14])[CH2:10][CH:9]1[C:23]([N:43]1[CH2:42][CH2:41][N:40]([C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=2[C:48]#[N:49])[CH2:45][CH2:44]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1cccc(Br)c1)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(Cc1cccc(Br)c1)C1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 15.3 %

Procedure:
To a stirring mixture of 1-benzyl-4-[(3-bromo-benzyl)-methyl-amino]-pyrrolidine-2-carboxylic acid (0.2 mmol), EDC (0.3 mmol) and HOBT (0.3 mmol) in 3 mL of dry DMF were added 2-piperazin-1-yl-benzonitrile (0.24 mmol) and NEt3 (0.6 mmol), and the reaction mixture was stirred overnight and subsequently subjected to preparative HPLC purification on reversed phase eluting with a acetonitrile/water (0.05% NEt3) gradient. 17.5 mg of title product was obtained in 15.2% yield as brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.I[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CCI
Reactant: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSc1ccc(C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A mixture of 4-methylbenzenethiol (100 g, 0.8 mol) in acetone (1 L) was added iodoethane (190 g, 1.2 mol) and potassium carbonate (220 g, 1.6 mol). The mixture was stirred at 60° C. overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude ethyl(p-tolyl)sulfane (120 g, 99%) as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([OH:12])=[O:11].[CH2:13](O)[CH2:14][CH3:15].CCN=C=NCCCN(C)C.O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11]
Reactant: CCCO
Reactant: Cc1cc(O)c(C(=O)O)c(=O)o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOC(=O)c1c(O)cc(C)oc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.9 %

Procedure:
In 30 ml of toluene, 0.85 g of 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylic acid, 0.9 g of 1-propanol and 0.12 g of 4-dimethylaminopyridine were dissolved, and 0.96 g of WSC was added to the mixture, and the mixture was stirred at room temperature for 16 hours. Subsequently, water was poured into the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The resultant organic layer was washed with saturated a saturated solution of sodium chrolide, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to obtain 0.37 g of propyl 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylate (Compound No. 2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52]O>>[ClH:1].[CH3:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: COCCOCCOCCO
Product: COCCOCCOCCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-(2-(2-methoxyethoxy)ethoxy)ethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester, hydrochloride. MS (ES+) m/z calcd. for C38H43Cl2F2N3O7: [(M)+]762. found: 762.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:29][C:30]1[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36](Cl)=[O:37])=[CH:32][CH:31]=1.O>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][O:28][C:36](=[O:37])[CH2:35][O:34][C:33]2[CH:39]=[CH:40][C:30]([Cl:29])=[CH:31][CH:32]=2)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C1=C(C)NC(COC(=O)COc2ccc(Cl)cc2)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 94.9 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.95 g) in pyridine (25 ml) was dropwise added over 5 minutes a solution of p-chlorophenoxyacetyl chloride (3.07 g) in methylene chloride under stirring and ice-cooling. The resultant mixture was stirred overnight under cooling with water at 20° C. After removal of the pyridine, water was added to the residue. The precipitated oily substance was extracted with ethyl acetate. The extract was adjusted to pH 4 to 5 with dil. hydrochloric acid, washed each three times with water and then an aqueous solution of sodium bicarbonate and dried over magnesium sulfate. The solvent was distilled off and the residual oil (4.75 g) was subjected to column chromatography on silica-gel using an eluent (benzene:ethyl acetate=10:1) to give an oil (2.65 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-(4-chlorophenoxy)acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 86° to 88° C. (recrystallized from a mixture of diisopropylether and ethanol).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>ClCCl>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C(=O)c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dichloromethane is added triethylamine (0.24 ml). Subsequently, thereto is added benzoyl chloride (0.2 ml) under ice-cooling, and the temperature thereof is raised to room temperature, and the mixture is stirred overnight. Water is added to the reaction solution and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1), and recrystallized from ethanol to give 5-(N-methyl-N-benzoylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.64 g) as colorless needles, m.p. 248°-249° C.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][NH:26][C:27]2[N:28]=[N+:29]([O-:40])[C:30]3[CH:39]=[C:38]4[C:34]([CH2:35][CH2:36][CH2:37]4)=[CH:33][C:31]=3[N:32]=2)[CH2:19]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH3:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][NH:26][C:27]2[N:28]=[N+:29]([O-:40])[C:30]3[CH:39]=[C:38]4[C:34]([CH2:35][CH2:36][CH2:37]4)=[CH:33][C:31]=3[N+:32]=2[O-:4])[CH2:19]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC1CCCN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1CCCN(CCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 8.2 %

Procedure:
H2O2 (70%, 2.5 mL, ca. 51 mmol) was added dropwise to a stirred solution of TFAA (7.1 mL, 51 mmol) in DCM (70 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 40 (1.75 g, 5.1 mmol) and TFA (0.84 mL, 11 mmol) in CHCl3 (70 mL) at 0° C. The solution was stirred at 20° C. for 5 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCl3 (3×80 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (4-20%) of MeOH/DCM, to give 1,4-dioxide 41 (0.15 g, 8%) as a red gum: 1H NMR δ 8.91 (br s, 1H, NH), 8.05 (s, 2H, H-5, H-9), 4.09 (t, J=5.8 Hz, 2H, CH2N), 3.84 (td, J=12.8, 1.9 Hz, 1H, CHO), 3.57-3.66 (m, 4H, 2×CH2), 3.57 (s, 3H, OMe), 3.40 (td, J=13.3, 3.5 Hz, 1H, CH2), 3.01-3.12 (m, 5H, H-6, H-8, CH2), 2.19 (p, J=7.4 Hz, 2H, H-7), 2.16-2.23 (m, 1H, CH2), 2.02-2.08 (m, 1H, CH2), 1.62-1.72 (m, 1H, CH2), 1.37-1.48 (m, 1H, CH2); 13C NMR δ 155.6, 149.4, 146.1, 138.1, 129.7, 115.5, 111.7, 73.2, 69.7, 67.6, 61.4, 56.9, 36.5, 33.3, 32.4, 28.5, 25.6, 20.3; HRMS (FAB+) calcd for C18H26N5O3 (MH+) m/z 360.2036, found 360.2039.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][N:19]4[C:27]5[C:22](=[C:23]([O:28][C:29]6[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=6)[CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][N:19]4[C:27]5[C:22](=[C:23]([O:28][C:29]6[CH:37]=[CH:36][C:32]([CH2:33][OH:34])=[CH:31][N:30]=6)[CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1ccc(Oc2cccc3c2CCN3CC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)nc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CN1CCc2c(Oc3ccc(CO)cn3)cccc21)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
6-{1-[2-(4-Benzo[1,3]dioxol-5-ylmethylpiperazin-1-yl)-2-oxoethyl]-2,3-dihydro-1H-indol-4-yloxy}nicotinic acid (0.789 g, 1.53 mmol) was suspended in THF (15 mL). To the suspension were added triethylamine 0.234 mL, 1.68 mmol), then ethyl chloroformate (0.161 g, 1.68 mmol) under cooling in an ice-salt bath, and the resulting mixture was stirred for 30 minutes at the same temperature. The reaction mixture was filtered, and to the filtrate was added 80% solution of sodium borohydride (0.289 g, 7.64 mmol) in methanol (20 mL) under cooling with ice, and then the solution was stirred for 30 minutes at the same temperature. The reaction mixture was concentrated and the residue was extracted with ethyl acetate (50 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated to yield 0.671 g of the title compound as a pale brown amorphous powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@:32]12([CH2:42][S:43](O)(=[O:45])=[O:44])[C:39]([CH3:41])([CH3:40])[CH:36]([CH2:37][CH2:38]1)[CH2:35][C:33]2=[O:34]>CC(C)=O.CO>[C@@:32]12([CH2:42][S:43]([O:22][C@@:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([C@H:14]([C:11]3[S:12][CH:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:10]=3)[CH3:31])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)(=[O:45])=[O:44])[C:39]([CH3:41])([CH3:40])[CH:36]([CH2:37][CH2:38]1)[CH2:35][C:33]2=[O:34]
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CO
Solvent: CC(C)=O
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@@](Cn1cncn1)(OS(=O)(=O)C[C@@]12CCC(CC1=O)C2(C)C)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (43.7 g) in acetone (800 ml) a solution of (1R)-10-camphorsulfonic acid (23 g) in methanol (300 ml) was added and the mixture was heated under reflux until a clear solution was obtained. The solution was slowly cooled to rt, seeded with crystals of the title enantiomeric salt and let overnight. The solid was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This crude salt was then taken up in methylenechloride (100 ml) and water (ca. 100 ml) and the mixture was basified with aqueous sodium hydroxide solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride (50 ml) and combined. The organic phases were then washed twice with water (2×50 ml), dried with sodium sulfate, filtrated and the solvent removed under reduced pressure. The crude product was then mixed with isopropanol (ca. 150 ml), heated for 10 min, cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with isopropanol and dried under reduced pressure to provide the enantiomerically pure title compound (17.5 g, 41% yield, 99.1% ee); m.p. 164-166° C.; [α]=−30° (c=1, methanol, 25° C.); NMR (CDCl3): 1.23 (3H, d, J=8 Hz), 4.09 (1H, q, J=8 Hz), 4.26 (1H, d, J=14 Hz), 4.92 (1H, d, J=14 Hz), 5.75 (1H, s), 6.75-6.85 (2H, m), 7.45-7.54 (2H, m), 7.62 (1H, s), 7.69 (1H, s), 7.75 (1H, d, J=8 Hz), 7.86 (1H, s), 8.03 (1H, d, J=8 Hz). The analytical data were identical with published (U.S. Pat. No. 5,648,372 and Chem. Pharm. Bull. 1998, 46, 623-630).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[NH:12])SC)[CH:5]=[C:4]([Cl:13])[C:3]=1[CH3:14].[NH2:15][NH2:16].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH2:12])=[N:15][NH2:16])[CH:5]=[C:4]([Cl:13])[C:3]=1[CH3:14]
Reactant: CSC(=N)Nc1cc(Cl)c(C)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)cc(NC(N)=NN)cc1Cl

Procedure:
To 7.18 g of 1-(2,6-dichloro-4-tolyl)-2-methylisothiourea.HJ (C), suspended in 26 ml of ethanol, 1.3 ml of hydrazine.hydrate is added after which the mixture is refluxed for 20 hours. The precipitate formed is filtered off and the filtrate evaporated to dryness. Yield: 6.35 g. Melting point HJ salt: 203°-205° C; melting point HCl salt: 149°-150° C.
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[C:5]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)[C:4](=[O:29])[CH:3]=1.[CH3:30][Si](C=[N+]=[N-])(C)C>CO>[CH3:30][O:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[N:6]=[C:5]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)[C:4](=[O:29])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=c1cc(O)n(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Solvent: CO
Product: COc1cc(=O)c(-c2ccnn2-c2ccccc2)nn1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.6 %

Procedure:
To a solution 6-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.23 g, 0.58 mmol) in MeOH (10 mL) was added dropwise trimethylsilyldiazomethane (2 M solution in diethylether, 8.0 mL, 16.0 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt/hexane (20/80-100/0) and recrystallized from AcOEt/hexane to give the title compound (0.023 g, 10% yield) as white crystals: mp 139-141° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.90 (3H, s), 6.14 (1H, s), 6.97-7.02 (1H, m), 7.13 (1H, s), 7.22 (1H, d, J=1.9 Hz), 7.31-7.44 (6H, m), 7.56-7.61 (1H, m), 7.76 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 413 [M+H]+. Anal. Calcd for C21H15F3N4O2: C, 61.17; H, 3.67; N, 13.59. Found: C, 61.19; H, 3.71; N, 13.69.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2(CO)CCC(=O)CC2)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C2(COC(C)=O)CCC(=O)CC2)cc1
Reaction time: 20 h
Yield: 68 %

Procedure:
The 4-hydroxymethyl-4-(4-methoxyphenyl)cyclohexanone is dissolved in 12 ml. of pyridine and 6 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution and brine, and evaporated to dryness. The solid residue is recrystallized from a mixture of ether and Skellysolve B to give 2.95 g. (68% yield) of 4-acetoxymethyl-4-(4-methoxyphenyl)cyclohexanone, having a melting point of 86.5° to 88°C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[S:8][C:9]2[CH2:10][NH:11][CH2:12][CH2:13][C:14]=2[N:15]=1)=[O:6])[CH3:3].C(N(CC)CC)C.[C:23]1([N:29]=[C:30]=[S:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.O>[NH:29]([C:30]([N:11]1[CH2:12][CH2:13][C:14]2[N:15]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[S:8][C:9]=2[CH2:10]1)=[S:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: S=C=Nc1ccccc1
Reactant: CCOC(=O)c1nc2c(s1)CNCC2
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2c(s1)CN(C(=S)Nc1ccccc1)CC2
Reaction time: 0.25 h

Procedure:
5-tert-butyl 2-ethyl 6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate obtained in step V of example 1 was deprotected to get the hydrochloride salt of 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester. To a solution of a HCl salt of 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester (1 eq) in dichloromethane, triethyl amine (1.2 eq) was added at 0° C. and the reaction mixture was stirred for 15 min. To this, a solution of phenyl isothiocyanate (1 eq) in dichloromethane was added and the reaction was continued at room temperature for 3 h. Water was added and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded—ethyl 5-(anilinocarbonothioyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[ClH:1].[C:21]1([NH:20][C:2]2[N:11]=[C:10]([N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(c1ccccc1)c1nc(Cl)nc2ccccc12
Reactant: Nc1ccccc1
Solvent: CCO
Product: CN(c1ccccc1)c1nc(Nc2ccccc2)nc2ccccc12
Product: Cl

Procedure:
2-Chloro-4-(N-methylphenylamino)quinazoline (2.0 g, 0.007 mol) was dissolved in ethanol (20 ml) with aniline (1.37 g, 0.15 mol) and heated in a sealed vessel at 150° for 5 hours. After cooling and removal of excess solvent in vacuo pressure the solid was treated with ethanolic hydrogen chloride to form the hydrochloride which was recrystallised from ethanol to give 2-phenylamino-4-(N-methylphenylamino)quinazoline hydrochloride (1.99 g, 74%), m.p. 265°-267°.
Reaction SMILES: C[Si]([NH:5][OH:6])(C)C.[OH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][C:10](=[O:21])[C:9]=1[C:22](OCC)=[O:23]>O1CCOCC1>[OH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][C:10](=[O:21])[C:9]=1[C:22]([NH:5][OH:6])=[O:23]
Reactant: C[Si](C)(C)NO
Reactant: CCOC(=O)c1c(O)c2ccc([N+](=O)[O-])cc2[nH]c1=O
Solvent: C1COCCO1
Product: O=C(NO)c1c(O)c2ccc([N+](=O)[O-])cc2[nH]c1=O
Temperature: 100 °C
Reaction time: 20 h
Yield: 55.8 %

Procedure:
4 ml of trimethylsilylhydroxylamine (30 mmol) were sprayed at room temperature into a suspension of 1.38 g of ethyl 4-hydroxy-7-nitro-2-oxo-1,2-dihydro-quinoline-3 -carboxylate (5 mmol) in 40 ml of dioxan. After heating to 100° C. all passed slowly into solution. The reaction mixture was left to stir at 90° C. for 20 hrs., cooled to room temperature and the separated voluminous precipitate was filtered off. This was washed with water and dried in a high vacuum. 740 mg of 4,N-dihydroxy-7-nitro-2-oxo-1,2-dihydro-quinoline-3-carboxamide (65%) were obtained as pale beige crystals.
Reaction SMILES: Br.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:6]=2[N:7]=1.O[CH2:14][CH:15]=[CH:16][S:17]([O-:20])(=[O:19])=[O:18].[K+:21].[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(O)(=O)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:5]2[S:4][C:3](=[CH:2][C:22](=[O:24])[CH3:23])[N:7]([CH2:14][CH:15]=[CH:16][S:17]([O-:20])(=[O:19])=[O:18])[C:6]=2[CH:8]=1.[K+:21]
Reactant: O=S(=O)([O-])C=CCO
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2sc(C)nc2c1
Agent: Br
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)C=C1Sc2ccc(C)cc2N1CC=CS(=O)(=O)[O-]
Temperature: 100 °C
Reaction time: 1 h

Procedure:
52 g of 2,5-dimethyl-benzothiazole hydrobromide and 48 g of potassium 3-hydroxy-1-propensulphonate were heated to 140° C. for 1 hour. 90 ml of acetic anhydride and 32 ml of triethylamine were added to the resulting melt of the quaternary salt and the mixture was stirred at 100° C. for 1 hour. The acetic acid formed in the reaction was then distilled off and the residue was taken up with water. Hydrochloric acid was added, whereupon the intermediate product crystallized.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH3:11][O:12][CH:13](OC)OC>>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[C:6](=[CH:11][O:12][CH3:13])[C:4](=[O:5])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(OC)OC
Product: COC=C1C(=O)OC(C)(C)OC1=O
Temperature: 90 °C

Procedure:
10g of meldrum acid were dissolved in 39 ml of trimethylorthoformate and the mixture refluxed at 90° C. under nitrogen atmosphere for 3 hours. After cooling at room temperature, pale yellow solid was collected by filtration. washed with a small amount of trimethylorthoformate, petroleum ether, then dried to yield 7.8 g product.