Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[O-:10][CH2:11][CH3:12].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:11]([O:10][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: OCc1ccc(Cl)nc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1ccc(CO)cn1
Temperature: 95 °C
Reaction time: 36 h

Procedure:
A mixture of (6-chloropyridin-3-yl)methanol (1.4 g, 0.010 mol, Aldrich, Cat. 536016) and sodium ethoxide (3.0 g, 0.044 mol) in ethanol (30 mL) was stirred at 95° C. for 36 hours. The reaction mixture was cooled to r.t., diluted with ethyl acetate, washed with water and brine successively, dried with MgSO4, and concentrated to afford the desired compound. The crude product was directly used in the next step without further purification. LCMS (M+H)+: m/z=154.3.
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH2:5]1)#[C:2][CH3:3].Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([OH:31])([CH3:30])[C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:29][C:26]([F:27])([F:28])[C:25]([C:22]1[CH:23]=[N:24][C:19]([N:9]2[CH2:8][CH2:7][N:6]([S:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)(=[O:12])=[O:11])[CH2:5][CH:4]2[C:1]#[C:2][CH3:3])=[N:20][CH:21]=1)([OH:31])[CH3:30]
Reactant: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Reactant: CC#CC1CN(S(=O)(=O)c2cccs2)CCN1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC#CC1CN(S(=O)(=O)c2cccs2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
A mixture of 3-(1-propyn-1-yl)-1-(2-thiophenylsulfonyl)piperazine (55 mg, 0.203 mmol), 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (100 mg, 0.441 mmol, Intermediate E), Hünig's base (100 μL, 0.573 mmol), and dioxane (2 mL) was heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 1 h and then at 160° C. for 3 h. The resulting red mixture was purified via silica gel chromatography (10-50% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(2-(2-(1-propyn-1-yl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (18 mg) as a mixture of 4 isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:3]=1.C([O-])=O.[NH4+].O>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1C=Cc1ccccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Oc1ccc(Cl)cc1CCc1ccccn1
Temperature: 60 °C
Yield: 90.7 %

Procedure:
To a solution of 24.0 g (74.57 mmol) 4-chloro-2-[2-(pyridin-2-yl)vinyl]-phenol in 400 ml ethanol is added 1.0 g palladium on charcoal 10% followed by 23.5 g (373 mmol) ammonium formate. The reaction mixture is then heated in an oil bath at 60° C. for 6 hours under a nitrogen atmosphere. The reaction mixture is filtered through celite, and the filtrate evaporated in vacuo to leave a colorless solid. Distilled water is added to the residue, which is extracted with 500 ml and then 300 ml DCM. The organic extracts were dried using MgSO4 and concentrated in vacuo to give the title compound as a colourless solid (15.81 g, 91%), m.p. 135-137° C. δH (250 MHz, CDCl3) 8.52-8.49 (dd, J=5.8,1.7 Hz, 1H), 7.65 (dt, J=7.8,1.7 Hz, 1H), 7.26-7.17 (m, 2H) 7.11 (d, J=2.6 Hz, 1H), 7.04 (dd, J=8.6, 2.6 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.31-3.26 (m, 2H), 3.10-3.05 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[OH:24][C:25]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33].O>C1COCC1>[OH:24][C:25]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCCCCC(O)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(C=Cc1cccnc1)NCCCCCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.4 g (23.0 mmol) 3-(3-pyridyl)-acrylic acid and 3.7 g (23.0 mmol) CDI are heated under reflux in 50 ml THF under moisture exclusion. After one hour this is cooled to RT and 6.5 g (21.9 μmmol) 8-hydroxy-8,8-diphenyloctylamine, dissolved in 20 ml THF, is added dropwise. After complete addition, stirring is carried out for a further three hours at RT and this is left to stand overnight. 50 ml water is added to the mixture and extracted three times with acetic acid ethyl ester by shaking. The combined organic phases are washed with saturated NaCl solution, dried over sodium sulfate, and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5) and subsequently, crystallized twice from 200-ml and 140 ml acetic acid ethyl ester: Colorless crystals with MP. 139-140° C. in a yield of 3.7 g (39%). C28H32N2O2 (428.6)
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]2[N:22]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[CH:23]=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=[C:16]([Cl:40])[CH:15]=3)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:40][C:16]1[CH:15]=[C:14]2[C:19]([C:20]([C:21]3[N:22]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[CH:23]=[N:24][C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:12]([CH2:10][NH:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[NH:13]2)=[CH:18][CH:17]=1
Reactant: O=C(NCCN1CCOCC1)c1[nH]c2cc(Cl)ccc2c1-c1c(-c2ccccc2)ncn1Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Clc1ccc(Cn2cnc(-c3ccccc3)c2-c2c(CNCCN3CCOCC3)[nH]c3cc(Cl)ccc23)cc1

Procedure:
A mixture of Example 2 (101 mg, 0.18 mmol), AlCl3 (117 mg, 0.88 mmol) and LAH (33 mg, 0.88 mmol) in THF (2 mL) is refluxed. After completion the reaction mixture is quenched by sodium-potassium tartarate and neutralized by saturated aqueous NaHCO3. EtOA is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless powder; ES-MS: M+H=561.8: AtRet=3.74 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:7]=[N:8][CH:9]=1.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24]>>[CH2:22]([NH:26][C:17](=[O:19])[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:6]2[CH:7]=[N:8][CH:9]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=2)=[CH:15][CH:14]=1)([CH3:21])[CH3:20])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CN
Reactant: COCc1cncc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Product: COCc1cncc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 73 %

Procedure:
Prepared in a similar manner to example 3 from 2-(4-(5-(methoxymethyl)pyridine-3-yl)phenyl)-2-methylpropanoic acid (example 32a) and isobutylamine. Yield 73%. 1H NMR (400 MHz, DMSO): δ 0.72-0.74 (d, 6H), 1.46 (s, 6H), 1.68 (m, 1H), 2.83 (t, 2H), 3.32 (s, 3H), 4.5 (s, 2H), 7.36 (t, 1H), 7.39-7.42 (d, 2H), 7.66-7.68 (d, 2H), 7.95 (t, 1H), 8.48-8.49 (d,1H), 8.78-8.79 (d, 1H). MS (M+H, 341).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=O)[CH3:2].[H][H]>[Pd].C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1ccc2c(c1)CC(=O)N2

Procedure:
The 5-acetyloxindole (54 g, 308 mmol), acetic acid (400 ml) and palladium on carbon (10%, 5 g) are combined and treated with hydrogen for 14 hours at 55 psi. The catalyst is removed by filtering through a bed of Celite, the filtrate is concentrated under reduced pressure and the residue is treated with ether to give 5-ethyloxindole
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.Cl.O.[OH-].[Na+]>C(O)(=O)C>[NH2:4][C:5]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1cc(N(C)C)c([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)c1cc(N)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 2-acetylamino-4-dimethylamino-5-nitrobenzoic acid (6.5 g), concentrated hydrochloric acid (20 ml), and water (80 ml) is stirred at 100° C. for 30 minutes. After cooling, solid sodium hydroxide (5 g) and then 10% aqueous sodium hydroxide solution are added until the mixture becomes a clear solution. The resulting solution is adjusted to the pH of about 4 with acetic acid. The precipitate is collected and recrystallized from methanol to give the title compound (4.8 g), mp 240°-250° C.
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=O)=CC=1)([O-])=O.[CH3:19][NH:20][CH2:21][CH2:22][N:23]([CH2:29][C:30]1[CH:31]=[C:32]([CH:66]=[CH:67][CH:68]=1)[C:33]([NH:35][C:36]1[S:37][C:38]2[CH2:65][CH2:64][CH2:63][CH2:62][C:39]=2[C:40]=1[C:41]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][C:52]2[CH:61]=[CH:60][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:53]=2)=[CH:46][CH:45]=1)=[O:42])=[O:34])[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26].C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:19][N:20]([CH2:21][CH2:22][N:23]([CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:29][C:30]1[CH:31]=[C:32]([CH:66]=[CH:67][CH:68]=1)[C:33]([NH:35][C:36]1[S:37][C:38]2[CH2:65][CH2:64][CH2:63][CH2:62][C:39]=2[C:40]=1[C:41]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:60][CH:61]=2)=[CH:46][CH:45]=1)=[O:42])=[O:34])[C:9](=[O:8])[O:11][CH2:12][C:13](=[O:14])[O:15][CH3:16]
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: COC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)N(CCN(C)C(=O)OCC(=O)OC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
A mixture of 100 mg of methyl {[(4-nitrophenoxy)carbonyl]oxy}acetate and 5.0 mL of THF was added to a mixture of 180 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 0.15 mL of N-ethyl-N-isopropylpropan-2-amine, and 5.0 mL of THF under ice cooling, followed by stirring for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, followed by extraction with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane:chloroform=4:6), thereby obtaining 204 mg of methyl 4-{2-[4-({[2-({3-[7-methyl-3,6-dioxo-10-(pentan-3-yl)-2,5-dioxa-7,10-diazaundecan-11-yl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[CH:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2.O.C(OCC)(=O)C>C1(C)C=CC=CC=1.[Ti]>[F:14][C:13]([F:15])([F:16])[C:10]([CH:11]=[N:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2)([OH:17])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F
Temperature: 105 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
2.40 g (7.39 mmol) of rac-4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is dissolved with 1.30 g (7.34 mmol) of 5-amino-8-fluoro-2-methylquinazoline in 30 ml of toluene, and 3.10 ml (14.7 mmol) of titanium tetraethylate is added at room temperature. The mixture is stirred for 3 hours at 105° C. After cooling, the mixture is added to water, stirred for several minutes, suctioned off on diatomaceous earth, rewashed with ethyl acetate and water, and the phases are separated. The aqueous phase is extracted several times with ethyl acetate, and the combined organic phases are washed with saturated NaCl solution and dried with sodium sulfate. The solvent is removed in a rotary evaporator, and the crude product is chromatographed on silica gel (eluant hexane/ethyl acetate 4:1). 3.20 g (90%) of the desired compound is isolated.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1>N1C=CC=CC=1>[CH2:8]1[C:7]2[CH:12]([CH2:13][CH:14]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[CH:2][CH2:1]3)[CH2:11][CH2:10][CH2:9]1
Reactant: c1ccc2cc3ccccc3cc2c1
Solvent: c1ccncc1
Product: C1=CCC2CC3CCCCC3=CC2=C1

Procedure:
1000 g raw anthracene were dissolved under heating in 3.8 liters technical pyridine (base mixture) for purification. The crystals precipitating upon cooling of the solution were centrifuged, washed with little solvent and water and were dried. The yield of anthracene was 880 g with a purity of more than 99 percent (Melting point 216°-217° C.). The residue from evaporation of the mother liquor (about 118 g) was returned to the hydrogenation stage.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH:13][C:14]1[C:15](=[O:25])[C:16]2[C:21]([C:22](=[O:24])[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2>C1C=CC=CC=1.[Ag]>[O:25]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([O:24][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:23][C:14]1=[O:13]
Reactant: CC(C)(C)OC(=O)CCCCBr
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CCCCOC1=CC(=O)C(=O)c2ccccc21
Yield: 30.3 %

Procedure:
A mixture of tert-butyl 5-bromovalerate (1 g, 4.2 mmol) and the silver salt of 2-hydroxy-1,4-naphthoquinone (0.8 g, 3.84 mmol) in benzene (10 mL), was stirred for 24 h at 50° C. The reaction mixture was filtered through celite and the solvent was removed in vacuo. The residue was purified by flash chromatography (5% methanol in chloroform) to give a yellow solid (384 mg, 30%). 1H NMR (CDCl3) 8.12 (d, J=7.7 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.70 (t, J=6.1 Hz, 1H), 7.59 (t, J=6.4 Hz, 1H), 5.95 (s, 1H), 4.17 (t, J=5.9 Hz, 2H), 2.35 (t, J=7.2 Hz, 2H), 1.90-2.05 (m, 2H), 1.78-1.90 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[S:9])[NH:2]1.[CH2:12](O)C.[OH-].[Na+].IC>O>[CH3:12][S:9][C:3]1[C:4]2=[CH:8][S:7][CH:6]=[C:5]2[S:1](=[O:10])(=[O:11])[N:2]=1
Reactant: CCO
Reactant: O=S1(=O)NC(=S)c2cscc21
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSC1=NS(=O)(=O)c2cscc21

Procedure:
To a mixture of 0.9 g. (0.0044 mole) of thieno[3,4-d]isothiazole-3(2H)-thione 1,1-dioxide in 4 ml. of ethanol is added a solution of 0.35 g. (0.0044 mole) of 50% sodium hydroxide in 3 ml. of water. To this thick mixture is added 0.62 g. (0.0044 mole) of iodomethane. The mixture is heated under reflux for 5 minutes, and then filtered to give 0.35 g. of product. On cooling, a second crop of 0.1 g. of material is obtained. A small amount of the first crop is recrystallized from ethanol to afford an analytical sample, m.p. 184°-6° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([NH:10][N:11]=[C:12]([CH3:16])[C:13](O)=[O:14])(=[S:9])[NH2:8].Cl>O>[CH3:16][C:12]1[C:13](=[O:14])[NH:8][C:7](=[S:9])[NH:10][N:11]=1
Reactant: CC(=NNC(N)=S)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1n[nH]c(=S)[nH]c1=O
Temperature: 25 °C

Procedure:
To a solution of Na2CO3 (4.84 g, 45.6 mmol) in water (300 mL) was added 2-(2-carbamothioylhydrazono)propanoic acid (3, 7.35 g, 45.6 mmol). The mixture was heated at refluxing temperature for 3.5 h. After cooling to room temperature, the clear solution was acidified with 2 N HCl to pH˜5. The mixture was extracted with EtOAc (60 mL×4) and CH2Cl2 (60 mL×4). The combined extracts were dried over Na2SO4 and concentrated to give 6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (4) as a white solid. MS: m/z, 144 (100%, M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32]C5C=C(C=CC=5)C(OC)=O)[C:28](=O)[CH2:27]4)=[N:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:3]1.N1(C2N=CC(NC(C3OC(N4CCCC(C)C4)=NC=3C(F)(F)F)=O)=CC=2)CCCNCC1.[C:76]1([CH2:82][S:83](Cl)(=[O:85])=[O:84])[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1>>[CH2:82]([S:83]([N:29]1[CH2:32][CH2:30][CH2:31][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:17]([C:10]3[O:9][C:8]([N:4]4[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]4)=[N:12][C:11]=3[C:13]([F:15])([F:14])[F:16])=[O:18])=[CH:21][CH:22]=2)[CH2:27][CH2:28]1)(=[O:85])=[O:84])[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)c1cccc(CN2CCN(c3ccc(NC(=O)c4oc(N5CCCC(C)C5)nc4C(F)(F)F)cn3)CC2=O)c1
Agent: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc(N4CCCNCC4)nc3)o2)C1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc(N4CCCN(S(=O)(=O)Cc5ccccc5)CC4)nc3)o2)C1

Procedure:
Compound 41 was prepared by the general procedure for compound 8, by using compound 39 and α-toluenesulfonyl chloride as starting materials. 1H NMR (500 MHz, CDCl3) δ 8.10 (d, 1H, J=2.5 Hz), 7.85 (dd, 1H, J=2.5, 9 Hz), 7.50 (s, 1H), 7.40 (m, 3H), 7.35 (m, 2H), 6.50 (d, 1H, J=9 Hz), 4.25 (s, 2H), 4.10 (m, 2H), 3.75 (m, 4H), 3.20 (m, 2H), 3.05 (t, 1H, J=9.5 Hz), 2.95 (t, 1H, J=6 Hz), 2.75 (t, 1H, J=11 Hz), 1.60-2.00 (m, 6H), 1.20 (q, 1H, J=11 Hz), 1.00 (d, 3H, J=7 Hz). MS (M+1): 607.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)c(I)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: Clc1ccc(Cl)c(-c2ccccn2)n1
Yield: 75.6 %

Procedure:
The mixture of 3,6-dichloro-2-iodopyridine (21 g, 77% purity, 58.8 mmol), 2-(tributylstannyl)pyridine (37 g, 80% purity, 80 mmol) in toluene (300 mL) was degassed, then Pd(PPh3)4 (730 mg) was added, the mixture was degassed again and stirred at reflux under N2 overnight. The mixture was concentrated and the residue was purified via silica gel column (petroleum ether:EtOAc=10:1˜5:1) to give title compound (10 g, 76%) as a gray solid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Li+].C(=O)=O.CN>[Pt]>[CH2:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[C:7]=2[CH2:15][CH:14]=[CH:13]1
Reactant: c1ccc2c(c1)CCc1ccccc1C2CCN1CCCC1
Agent: [Pt]
Agent: CN
Agent: O=C=O
Product: C1=CCC2=C(C1)CCc1ccccc1C2CCN1CCCC1
Reaction time: 0.33 h

Procedure:
2.0 g of 1-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine and 2.5 g of lithium chloride are placed in a 100 ml glass vessel having a removable cover with 5 ground openings and fitted with a dry-ice condenser, thermometer, platinum sheet anode and cathode (each 2.5×2.5 cm, distance 2 cm). Subsequently, nitrogen is conducted through the apparatus for 20 minutes, the receiver is placed in a dry-ice/alcohol bath, the dry-ice condenser is charged with dry-ice and 70 g of methylamine are distilled directly into the apparatus from a pressure flask while stirring with a magnetic stirrer. Subsequently, a current of 2 amperes is applied, whereupon a voltage of 44 volts occurs and the cathode immediately becomes deep blue in color. The temperature is held at -10°. After a throughput of an amount of current of 3000 amperes (corresponding to 230% of the theoretical amount of current required for the complete conversion), the current is turned off and the solution is evaporated at 50° and under a slight vacuum. The residue is digested in hexane for a few minutes in an ultrasound bath. After filtration and evaporation, there is obtained crude 1-[2-(4,5,10,11-tetrahydro-1H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine which is purified in analogy to the details in Examples 1(j) to 1(l).
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17]CC)=[O:16])[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[NH:3]1.[OH-].[K+]>C(O)C>[CH3:1][C:2]1([C:15]([OH:17])=[O:16])[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)C1(C)C=CN(c2ccc(OC)cc2)N1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(N2C=CC(C)(C(=O)O)N2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
A mixture of ethyl 3-methyl-1-(4-methoxyphenyl)-1 H-pyrazolecarboxylate (0.01997 mol, 5.197 g) and potassium hydroxide (3.362 g, 3.0 eq.) in ethanol (70 mL) was stirred at ambient temperature for 5 h. The solvent was removed in vacuo and the residue was taken up in water. This was extracted with methylene chloride (3×) to remove unreacted starting material. The aqueous was made acidic (pH 3) by the dropwise addition of conc. HCl at 0° C. to give white precipitation of acid. The solid acid was obtained by filtration and pumped on for several hours to dry. This procedure gave 4.23 g of pure product (91%); mp: 161.8° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[NH:6][N:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[CH:9]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:24]O>>[O:17]1[C:13]2[CH:12]=[CH:11][C:10]([C:8]3[CH:9]=[C:4]([C:1]([O:3][CH3:24])=[O:2])[C:5](=[O:19])[NH:6][N:7]=3)=[CH:18][C:14]=2[CH2:15][CH2:16]1
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Carboxy-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one (5.9 g, 22.8 mmol) was suspended in methanol (100 mL), and thionyl chloride (3 g, 25.1 mmol) was added dropwise to the suspension under cooling with ice, followed by stirring for three hours at 80° C. The temperature of the reaction mixture was reduced to room temperature, and the solvent was removed under reduced pressure. Water was added to the residue under cooling on ice, and the formed precipitates were collected through filtration and washed with water, followed by drying, to thereby yield 4.90 g of the title compound as pale yellow micro-needles (78.8%).