Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([S:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:22](Cl)([Cl:24])=[S:23]>C(Cl)(Cl)Cl.O>[Cl:24][C:22]([O:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([S:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])=[O:7])=[CH:4][CH:3]=1)=[S:23]
Reactant: S=C(Cl)Cl
Reactant: O=C(Sc1cc(Cl)c(Cl)cc1Cl)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Sc1cc(Cl)c(Cl)cc1Cl)c1ccc(OC(=S)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
S-(2,4,5-Trichlorophenyl) 4-(hydroxy)thiobenzoate (5.4 g) in dry chloroform (70 ml) at -20° C. was treated sequentially with sodium hydroxide (0.78 g) in water (3 ml) and thiophosgene (1.85 ml). The solution was allowed to warm to room temperature and was stirred for a further 2 hours. The reaction mixture was then dried over calcium chloride and the filtered solution evaporated to give a crude solid. Purification by chromatography on silica gel using ethyl acetate/hexane mixtures as eluants afforded 3.4 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]([C:31](OC4C=CC=CC=4)=[O:32])C(=O)OC4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[N:40]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:31]([N:48]4[CH2:49][CH2:50][CH:45]([N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[CH2:46][CH2:47]4)=[O:32])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (12.1 g, 23.2 mmol) synthesized in Production example 5-2 was dissolved in dimethylformamide (150 ml); 4-(1-pyrrolidinyl)piperidine (14.4 g, 93.3 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and concentrated to about 100 ml. The residue was allowed to be kept cool at 5° C. for overnight to precipitate crystals. The crystals were filtered off, washed with ethyl acetate to yield the title compound (7.8 g, 16.9 mmol, 73%) as white crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=O)=[CH:5][CH:4]=1)[CH3:2].C1(C)C=CC=CC=1>O.Cl.[Zn]>[CH2:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)CCC(=O)O)cc1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(CCCC(=O)O)cc1

Procedure:
To a 500 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 41.2 grams (200 mmol) 3-(4-ethylbenzoyl)-propionic acid, activated zinc prepared from 82.4 grams (400 mmol) mossy zinc and 8.2 grams mercuric chloride in 125 mL water and 8 mL concentrated hydrochloric acid, 77 mL water, 177 mL concentrated hydrochloric acid, and 100 mL toluene. The mixture was refluxed 60 hours with addition of two 50 mL portions of concentrated hydrochloric acid, cooled, and the layers separated. The organic layer was extracted into 3N aqueous sodium hydroxide, which was then acidified and extracted into ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to afford 28.9 grams (75%), M.P. 70°-72° C.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([O:15][CH3:16])[C:13]([C:17]#[N:18])=[C:12]([C:19]#[N:20])[CH:11]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:11]1[C:12]([C:19]#[N:20])=[C:13]([C:17]#[N:18])[N:14]([O:15][CH3:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: COn1c(-c2ccc(Cl)cc2)cc(C#N)c1C#N
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COn1c(C#N)c(C#N)c(Br)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 62501.7 %

Procedure:
Bromine (0,341 g, 0.00213 mol) is added to a stirred mixture of 5-(p-chlorophenyl)-1-methoxypyrrole-2,3-dicarbonitrile (0.5 g, 0.00193 mol) and sodium acetate (0.318 g, 0.00388 mol) in acetic acid. The reaction mixture is heated at 95°-100° C. overnight, cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed sequentially with water, saturated sodium bicarbonate solution, aqueous sodium metabisulfite solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a solid that is crystallized from ethyl acetate/hexanes to give the title compound as a yellow solid (0,406 g, 62%), mp 166.5°-167° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:30]=[CH:29][C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33].CCN(CC)CC>ClCCl>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])=[CH:8][CH:7]=5)[C:14]([CH3:15])=[CH:13][CH:12]=4)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CCCS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.5 %

Procedure:
N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), 1-propanesulfonyl chloride (11 μL, 0.10 mmol) and Et3N (28 μL, 0.20 mmol) were dissolved in dichloromethane (1.0 mL) and allowed to stir at 25° C. for 16 hours. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-(propylsulfonamidomethyl)biphenyl-3-yl)cyclopropanecarboxamide (5.3 mg, 10%). ESI-MS m/z calc. 506.6, found 507.3 (M+1)+; retention time 3.48 minutes.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(I)c4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 656.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[NH:14][C:13](=[O:23])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH:25]([CH2:30][CH3:31])[C:26]([O:28][CH3:29])=[O:27]>CC1CCCO1>[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:11][CH2:12][C:13](=[O:23])[N:14]([C@@H:25]([CH2:30][CH3:31])[C:26]([O:28][CH3:29])=[O:27])[C@@H:15]2[C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(Br)C(=O)OC
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC[C@@H](C(=O)OC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1.25 h

Procedure:
To a 50° C. solution of 33.8 g (60% in mineral oil, 845 mmol) of sodium hydride in 2-methyltetrahydrofuran (550 mL) was added a solution of 240 g (750 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in 2-methyltetrahydrofuran (550 mL) over a period of 45 min. After an additional 1.25 h at 50° C., 105 mL (912 mmol) of methyl 2-bromobutyrate was added over a 20 min period. The resulting slurry was stirred at 50° C. for 3.5 h, and then was cooled to room temperature and quenched with saturated aq. NH4Cl solution. Water was added to dissolve the precipitate and the resulting mixture was extracted with ethyl acetate (4×). The combined organic layers were washed with sat. aq. NaCl solution (1×), dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap™ column (Biotage, LLC, Charlotte, N.C.), 0 to 35% EtOAc/DCM, gradient elution) provided the title compound as a white oily solid.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([O:8][C:9]1[C:10]([F:21])=[C:11]2[C:17]([N+:18]([O-])=O)=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)[CH3:7].[OH-].[Na+]>Cl>[CH2:6]([O:8][C:9]1[C:10]([F:21])=[C:11]2[C:17]([NH2:18])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)[CH3:7]
Reactant: CCOc1cnc2[nH]cc([N+](=O)[O-])c2c1F
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: CCOc1cnc2[nH]cc(N)c2c1F
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Tin chloride (674 mg, 3.55 mmol) was added to 5-ethoxy-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (160 mg, 0.711 mmol) in 6N HCl (5 mL) at about 0 to about 5° C., and then the reaction was stirred at 0 to about 5° C. for 2 hours. The solution was neutralized by addition of 6N NaOH and then extracted with CHCl3/IPA (3:1). The combined organic phases were dried over MgSO4 and concentrated to leave 5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (120 mg, 86% yield) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19]Br>CC(=O)CC>[Br:17][CH2:18][CH2:19][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCCBr)cc1
Yield: 70.7 %

Procedure:
A mixture of p-nitro-phenol (6.0 g, 43.1 mmol), potassium carbonate (14.9 g, 108 mmol) and 1,2-dibromoethane (24.3 g, 129 mmol) in butanone (80 mL) was heated at reflux for 18 h. The mixture was cooled, the inorganic salts filtered and the filtrate concentrated under vacuum to give a brown viscous liquid, which was partitioned between dichloromethane and water. The organic phase was separated and concentrated in vacuo to obtain a residue which was purified by column chromatography using 4% ethyl acetate in petroleum ether as eluent to afford 1-(2-bromo-ethoxy)-4-nitro-benzene (7.5 g, 70%) as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH:15](=[O:18])[CH2:16][CH3:17].C(O)(=O)C>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:16]([CH3:17])[CH:15]=[O:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CCC=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
108.5 g of p-tert.butyl-benzaldehyde are added under nitrogen gasification to a solution of 1.4 g of potassium hydroxide in 100 ml of methanol and 39.2 g of propionaldehyde are subsequently added dropwise at 40° C. over a period of 6 hours. Subsequently, the mixture is further stirred at 40° C. for 1 hour, 1.5 ml of acetic acid are added and the mixture is concentrated on a rotary evaporator. The oily suspension is taken up in ether, washed neutral with water, dried and evaporated. By distillation there is obtained pure 3-(p-tert.butyl-phenyl)-2-methyl-acrolein of boiling point 165° C./11 Torr.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17]C3C4NC(=NC(=O)C(F)(F)F)SC=4C=C(OC(F)(F)F)C=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CS(OCC[N:46]1[C:50]2[CH:51]=[CH:52][C:53]([O:55][C:56]([F:59])([F:58])[F:57])=[CH:54][C:49]=2[S:48][C:47]1=[N:60][C:61](=[O:66])[C:62]([F:65])([F:64])[F:63])(=O)=O.Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1>C1(C)C=CC=CC=1>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:46]3[C:50]4[CH:51]=[CH:52][C:53]([O:55][C:56]([F:59])([F:57])[F:58])=[CH:54][C:49]=4[S:48][C:47]3=[N:60][C:61](=[O:66])[C:62]([F:63])([F:64])[F:65])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(N2CCN(CCc3cc(OC(F)(F)F)cc4sc(=NC(=O)C(F)(F)F)[nH]c34)CC2)cc1
Reactant: CS(=O)(=O)OCCn1c(=NC(=O)C(F)(F)F)sc2cc(OC(F)(F)F)ccc21
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCN(CCn3c(=NC(=O)C(F)(F)F)sc4cc(OC(F)(F)F)ccc43)CC2)cc1

Procedure:
3-{2-[4-(4-Methoxyphenyl)-1-piperazinyl]ethyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride may be prepared in the following manner: a mixture of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulphonate (4.52 g), toluene (120 cc) and the base liberated from 4-(p-methoxyphenyl)piperazine dihydrochloride (10.56 g) is heated to reflux for 1 hour, cooled to +4° C. and then drained. The toluene filtrate is evaporated under reduced pressure and then treated with 1.2N aqueous hydrochloric acid solution (45 cc). The hydrochloride separates in amorphous form and then crystallizes on grinding with ethanol (50 cc). After draining, washing with ethanol (15 cc) and drying at 50° C. at 20 mmHg, 3-{2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (1.7 g) is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:12]([N:14]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(CC)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 137.2 %

Procedure:
To a solution of 2.11 g (14 mmol) of 4-nitrobenzaldehyde in 50 mL dichloroethane was added diethylamine (1.13 g, 15.4 mmol) followed by sodium triacetoxyborohydride (4.45 g, 21 mmol). The mixture was stirred at room temperature overnight. A solution of saturated aqueous sodium bicarbonate (25 mL) was added to the reaction mixture and the resulting solution was extracted with ethyl acetate (1×150 mL, 2×50 mL). The combined organic extract was dried (sodium sulfate), filtered, and solvent removed under reduced pressure to provide crude N-ethyl-N-(4-nitrobenzyl)ethanamine as an oil (4.0 g). The material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([Sn](CCC)(CCC)C=C)[CH2:12]C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N+:8]([C:7]1[C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C=C[Sn](CCC)(CCC)CCC
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ncccc1[N+](=O)[O-]
Yield: 54 %

Procedure:
A mixture of 0.92 g (5.80 mmol) of 2-chloro-3-nitro-pyridine, 1.60 g (5.80 mmol) tripropyl-vinyl-stannane, 0.335 g (0.290 mmol) Pd(PPh3)4 and 10 mL of toluene were combined and refluxed under an inert atmosphere overnight. After routine aqueous workup the crude product was purified by chromatography on silica gel to give 0.470 g (54% yield) of 3-nitro-2-vinyl-pyridine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Reaction time: 8 h
Yield: 8.7 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.188 g, 0.383 mmol) in methylene chloride (6 mL) was added with trifluoroacetic acid (6 mL) at room temperature, and the mixture was stirred overnight. The solvent was evaporated, then the residue was dissolved in methanol (8 mL), the solution was added with a 5% solution of hydrochloric acid in methanol (2 mL), and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, and added to saturated aqueous sodium hydrogencarbonate, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0130 g, 8%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([F:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].O>O1CCCC1>[Cl:19][C:15]1[CH:16]=[C:17]([F:18])[C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)c1cnn(-c2ncc(Cl)cc2F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1ncc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a solution of 1-(5-chloro-3-fluoropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1 g) in tetrahydrofuran (5 ml) were added 4 N aqueous solution of sodium hydroxide (5 ml) and water (5 ml), and stirred at room temperature overnight. After completion of the reaction, the organic solvent was evaporated in vacuo, then water and diethyl ether were added thereto, and the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, the precipitated solid was collected by filtration, and dried at 60° C. under air blow to give the titled compound (710 mg) as a white solid. MS (ESI) m/z: 256 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][S:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[Na].[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>CO>[C:2]([C:3]1[S:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=12)(=[O:1])[CH3:10]
Reactant: COC(=O)CSCC(C)=O
Reactant: O=C1CCCCC1=O
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sc(C(C)=O)c2c1CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
Add methyl 2-(2-oxopropylthio)acetate (35.4 g, 183.2 mmol) to a freshly prepared solution of solid sodium (8.78 g, 381.5 mmol) in dry MeOH (300 mL) at 0° C., followed by addition of a solution of cyclohexane-1,2-dione (20 g, 152.6 mmol) in MeOH (30 mL). Stir the mixture at 0° C. for 30 min and then at 50-60° C. for additional 1.5 hour. Remove the solvent under vacuum and dilute the residue with water (100 mL). Extract the aqueous mixture with ethyl acetate (100 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum. Purify the residue by a flash column on silica gel eluting with PE:EtOAc (50:1 to 30:1) to afford methyl 3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate as a white solid (10 g, 27.6%). MS (m/z): 239 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13]OCC)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]=[CH:13][N:21]([C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[O:18][CH3:17])[CH3:22])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC=Nc1ccc(C(=O)OCC)cc1
Reactant: CNc1ccccc1OC
Solvent: CCO
Product: CCOC(=O)c1ccc(N=CN(C)c2ccccc2OC)cc1

Procedure:
A mixture of ethyl N-(4-ethoxycarbonylphenyl)formimidate (Example Ia) (4.9 g, 0.022 mol) and 2-methoxy-N-methylaniline (3.2 g, 0.022 mol) were heated at 180° until 1.3 ml of ethanol had been collected by distillation. The resulting yellow oil was flash distilled to yield the desired product, bp≈200° C. (0.05 mm). ##STR14##
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].COCCOC.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[CH:7]=[O:8])=[CH:18][CH:17]=1
Reactant: O=Cc1sccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1sccc1-c1ccc(Cl)cc1

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromothiophene-2-carbaldehyde (10 g, 52.34 mmol, 1.00 equiv), ethylene glycol dimethyl ether (120 mL), (4-chlorophenyl)boronic acid (9 g, 57.55 mmol, 1.10 equiv), Pd(PPh3)4 (3 g, 2.60 mmol, 0.05 equiv), sodium carbonate (16.4 g, 154.73 mmol, 2.96 equiv), water (40 mL). The resulting solution was heated to reflux for 4 h. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (30/1). This resulted in 12 g (93%) of 3-(4-chlorophenyl)thiophene-2-carbaldehyde as a light yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:32]5[CH:37]=[CH:36][N:35]=[N:34][CH:33]=5)=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[N:24]=4)[N:21]=3)[CH2:15][CH:10]2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([N:14]4[CH2:13][CH:11]5[CH:10]([CH2:9][NH:8][CH2:12]5)[CH2:15]4)=[N:21][N:20]3[C:22]=2[C:32]2[CH:37]=[CH:36][N:35]=[N:34][CH:33]=2)=[CH:30][CH:29]=1
Reactant: Fc1ccc(-c2nc3ccc(N4CC5CN(Cc6ccccc6)CC5C4)nn3c2-c2ccnnc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Fc1ccc(-c2nc3ccc(N4CC5CNCC5C4)nn3c2-c2ccnnc2)cc1

Procedure:
The mixture of 1.2 g (2.4 mmol) of 6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-(1H)-yl)-2-(4-fluorophenyl)-3-(pyridazin-4-yl)-imidazo[1,2-b]pyridazine and 2.3 g (36 mmol) of ammonium formate in 40 ml of methanol is refluxed for 2 hours in the presence of palladium-on-charcoal (10%) containing 50% moisture.