Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH2:42][CH2:43][C:44]([OH:46])=[O:45])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:39]3[CH2:38][CH2:37][N:36]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])[CH2:41][CH2:40]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(O)CCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC(=O)O)CC1
Product: Cl

Procedure:
3-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-propionic acid hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 3-piperazin-1-yl-propionic acid in an analogous manner as described in example 25. LR-MS: 651.4 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28](O)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:29]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1cc(Cl)cc(Cl)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3,5-dichloro-benzoic acid to yield (3aR,4S,7aR)-methyl 4-(3,5-dichlorobenzoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=8.825 min; LC-MS Method II
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=O)[O:8][CH:7]2[CH3:12].COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:22]2)=CC=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[S:22])[O:8][CH:7]2[CH3:12]
Reactant: CC1OC(=O)c2c(O)cccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CC1OC(=S)c2c(O)cccc21

Procedure:
1.67 g of 7-hydroxy-3-methyl-phthalide (see Example 101) and 2.17 g of 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetan (Lawesson reagent) are heated in 8 ml of xylene at 138° C. for 3 hours. When it has cooled, the reaction material is filtered directly over a column of silica gel [eluant: ethyl acetate/n-hexane (1:4)] in order to isolate the 7-hydroxy-3-methyl-isobenzofuran-1(3H)-thione; m.p. 38°-40° C.; IR spectrum: 1624, 1604, 1368, 1330, 1304, 1165 cm-1 ; mass spectrum: 180 (M+ =100), 165 (58), 137 (24).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[O-:11][CH2:12][CH3:13].[Na+]>C(O)C.ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccnc(Br)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOc1ccnc(Br)c1

Procedure:
To a suspension of 2-bromo-4-nitropyridine (1.0 g) in ethanol (5 ml) was added a solution of sodium ethoxide in ethanol (20%, 2 ml), and the resultant mixture was stirred at 85° C. for 1.5 hours. After cooling, the mixture was diluted with dichloromethane and washed with water and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 2-bromo-4-ethoxypyridine (927 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18]2)=[O:16])[CH:12]=[CH:11][N:10]=1.[CH:31](=O)/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.C(O)C>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:19]3([CH2:20][CH2:21][N:22]([CH2:31]/[CH:32]=[CH:33]/[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:23][CH2:24]3)[CH2:18]2)=[O:16])[CH:12]=[CH:11][N:10]=1
Reactant: O=C(c1ccnc(Cl)c1)N1CC2(CCNCC2)c2ccccc21
Reactant: O=C/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(c1ccnc(Cl)c1)N1CC2(CCN(C/C=C/c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
1-(2-Chloropyridin-4-yl)carbonylspiro[indoline-3,4′-piperidine]trifluoroacetic acid salt (0.44 g) and trans-cinnamaldehyde (0.29 g) were suspended in tetrahydrofuran (8 ml) and ethanol (6 ml). Borane-pyridine complex (0.26 ml) was added and the reaction stirred vigorously overnight at room temperature. The mixture was evaporated and partitioned between dichloromethane and water. The organics were dried over anhydrous magnesium sulfate and evaporated in vacuo. Flash chromatography [SiO2; ethyl acetate-hexane-triethylamine (25:75:1), increasing polarity to (50:50:1)] yielded 0.42 g (94%) of the desired product.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[H-].[Na+].Br[CH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23]C)=[O:21])=[CH:18][CH:17]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[C:4]2[N:11]([CH2:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH3:1][S:2][C:3]1[C:4]2[C:5](=[CH:9][N:10]([CH2:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[N:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnc2cn[nH]c12
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cc3ncnc(SC)c3n2)cc1
Product: COC(=O)c1ccc(Cn2ncc3ncnc(SC)c32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (400 mg) in N,N-dimethylformamide (8 mL) was added 60% sodium hydride (98 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Then, ethyl 4-(bromomethyl)benzoate (606 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) to give methyl 4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate (251 mg) and methyl 4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate (450 mg) both as pale-yellow solids.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([NH:17][C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1Nc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a solution of 4-bromo-benzoyl chloride (11 g, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was added N-phenylbenzene-1,2-diamine (10.2 g, 55 mmol), then triethylamine (TEA) (17 ml, 122 mmol) slowly. The whole was stirred at room temperature (RT) overnight. Filtration gave a white solid 1 (6.5 g). The filtrate was worked up with water (300 ml), then extracted with DCM (300 ml) three times. The organic phase was collected and dried over MgSO4, concentrated and recrystallized in DCM/hexanes to give another portion of white solid 1 (10.6 g). Total amount of product 1 is 17.1 g, in 93% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:4]=1[CH:21]=[N:22][OH:23].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[C:25]#[CH:26].[O-]Cl.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:4]=1[C:21]1[CH:26]=[C:25]([C:24]([O:28][CH2:29][CH3:30])=[O:27])[O:23][N:22]=1
Reactant: C#CC(=O)OCC
Reactant: COc1cc(OC)c(C=NO)c(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2Oc2ccc([N+](=O)[O-])cc2)no1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirred solution of 1-[2,4-dimethoxy-6-(4-nitrophenoxy)phenyl]-N-hydroxymethanimine (2.06 g, 6.7 mmol) and ethyl propiolate (3.28 mL, 32.4 mmol, 5 eq.) in DCM was slowly added drop wise 15% NaOCl solution (65 mL) at 0° C. After stirring overnight, the organic phase was separated and the aqueous was extracted twice with DCM. The organic phases were pooled and washed with 1 M Na2SO3 solution, then with brine and dried over Na2SO4. The solvent was removed and the residue was carefully chromatographed on silica gel eluting with hexane/ethyl acetate 8/2 to provide the title compound (1.6 g, 57% yield)
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:16])(=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[CH2:6][CH2:5][CH2:4]1.[CH3:17][O:18][C:19](=O)[O:20]C>O1CCCC1>[O:14]=[C:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:3](=[O:15])(=[O:16])[CH2:4][CH2:5][CH:6]1[C:19]([O:18][CH3:17])=[O:20]
Reactant: O=C1CCCS(=O)(=O)c2ccccc21
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCS(=O)(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 134.2 %

Procedure:
To a slurry of 0.3 mol of sodium hydride in 200 ml of tetrahydrofuran was added a solution of 21 g (0.1 mol) of 3,4-dihydro-1-benzothiepin-5(2H)-one 1,1-dioxide in 800 ml of tetrahydrofuran. The mixture was stirred at room temperature for 2 hours and a solution of 27 g (0.3 mol) of dimethylcarbonate in 50 ml of tetrahydrofuran was added. It was refluxed under a nitrogen atmosphere for 20 hours, part of the tetrahydrofuran was removed by distillation, the residue was carefully poured into ice water containing excess hydrochloric acid, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and evaporated to give 36 g of semi-solid which gave a positive ferric chloride test and an infrared band at 175° cm-1. It was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:6][C:5]=2[NH:4][N:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl.O>C(O)C>[ClH:18].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH2:6][C:5]2[NH:4][N:3]=[C:2]([CH3:1])[C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 174.5 %

Procedure:
A mixture of 3-methyl-6-(2-chlorophenyl)-4,5,6,7-tetrahydroindazol-4-one (0.22 g), aminoguanidine hydrochloride (0.098 g), concentrated hydrochloric acid (0.084 ml), water (0.084 ml) and ethanol (40 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was washed with diethylether and concentrated under reduced pressure, and the resulting crystals were recrystallized from water-ethanol to give 4-guanidinoimino-6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 21) (0.26 g) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[N:9]=[CH:8]1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: c1ccc(-n2cnc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncn2-c2ccccn2)C1
Yield: 21.6 %

Procedure:
A solution of 1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (0.050 g, 0.25 mmol), 2-chloro-3-trifluoromethyl benzoic acid (0.056 g, 0.25 mmol), HATU (0.10 g, 0.26 mmol, and DIPEA (0.09 mL, 0.50 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3×10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (22 mg, 22%). 1H NMR (400 MHz, CDCl3) δ 8.52 (dd, J=4.9, 1.8 Hz, 1H), 8.02 (d, J=18.1 Hz, 1H), 7.92-7.71 (m, 2H), 7.58-7.40 (m, 2H), 7.37-7.28 (m, 2H), 5.12-4.78 (m, 1H), 4.51-4.19 (m, 2H), 3.97 (ddd, J=13.4, 12.7, 9.9 Hz, 1H), 3.61-3.45 (m, 1H), 3.27-2.82 (m, 2H). MS (ESI): mass calculated for C19H14ClF3N4O, 406.1. m/z found 407.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][C:13]=2[N+:24]([O-])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[NH2:24][C:13]1[CH:14]=[C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH:16]=[CH:17][C:12]=1[NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: O=[N+]([O-])c1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 80.6 %

Procedure:
To a solution of 4-chloro-N-(2-nitro-4-pyridin-4-ylphenyl)benzene sulfonamide (0.2 mmol) in ethyl acetate (10 mL), palladium on activated carbon (10%, wet, 10 mg) was added. The reaction mixture was deaerated under vacuum for 5 min and stirred under hydrogen atmosphere (1 atm) for 30 min. The reaction mixture was filtered through a short pad of Celite, washing the pad with methanol (10 mL) and ethyl acetate (15 mL). The combined organic phase was concentrated under vacuum to give 58 mg of N-(2-amino-4-pyridin-4-ylphenyl)-4-chlorobenzene sulfonamide.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)=[O:3].[Br:14]Br.Br>C(O)(=O)C>[Br:14][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-tert-butylacetophenone (5 g, 28.4 mmol) in acetic acid (2 mL) was carefully (the reaction was exothermic) treated with Br2 (1.46 mL, 28.5 mmol), followed by 48% aq. HBr (0.015 mL, 0.132 mmol). The reaction was stirred at room temperature for 4 hours, then was poured onto ice and was extracted with diethyl ether. The organic phase was concentrated and was then chromatographed on silica gel, eluting with 5% ethyl acetate-hexane, followed by 10% ethyl acetate-hexane, to afford the title compound as a pale brown oil, 1.305 g (18%). 1H NMR (DMSO-d6) δ 7.94 (d, 2H, J=8.5 Hz), 7.58 (d, 2H, J=8.5 Hz), 4.90 (s, 2H), 1.31 (s, 9H); MS (ESI+) m/z 255 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[NH:12]1[CH:17]=[CH:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:12]1[CH:13]=[CH:14][C:15](=[O:18])[CH2:16][CH2:17]1)=[O:5]
Reactant: O=C1C=CNCC1
Reactant: O=C(Cl)c1c(Cl)cccc1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=CN(C(=O)c2c(Cl)cccc2Br)CC1
Reaction time: 0.5 h
Yield: 399.9 %

Procedure:
A solution of 2-bromo-6-chlorobenzoic acid chloride (0.5 mmol) in dichloromethane (5 ml) was added dropwise to a solution of 2,3-dihydro-4-pyridinone (5.1 mmol, 495 mg) and triethylamine (1.2 ml) in dichloromethane (20 ml). After stirring for 30 minutes, the solution was diluted with water, separated, the aqueous extract further extracted with dichloromethane, the combined organic extracts combined and washed with brine, dried over sodium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 30% ethyl acetate in hexane to yield the title compound as a pale yellow oil (629 mg). MS (+CI) m /z 316 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25].[CH2:30]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:31]>>[CH2:30]([C:32]1[CH:38]=[CH:37][C:35]([N:36]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[C:17]([F:29])([F:28])[F:16])(=[O:26])=[O:25])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:34][CH:33]=1)[CH3:31]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4C(F)(F)F)CC3)C2=O)cc1

Procedure:
Off white solid. MS (ESI): 467.16 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethyl-benzenesulfonyl chloride and 4-ethyl-aniline.
Reaction SMILES: C([O:5][C:6]([C:8]([CH3:26])=[CH:9][C:10]1[C:11](=[O:25])[C:12]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:13]=2[NH:14][C:15](=[O:19])[C:16]=1[O:17][CH3:18])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:12]2[C:11](=[O:25])[C:10](/[CH:9]=[C:8](\[CH3:26])/[C:6]([OH:7])=[O:5])=[C:16]([O:17][CH3:18])[C:15](=[O:19])[NH:14][C:13]=2[CH:20]=1
Reactant: COc1c(C=C(C)C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(/C=C(\C)C(=O)O)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 25.1 %

Procedure:
4-[2-(Tert-butoxycarbonyl)propenyl]-8-chloro-3-methyoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.35 g) in methylene chloride (7 mL) was treated with trifluoroacetic acid. The solution was stirred under argon at room temperature for 40 minutes and then it was concentrated to a white solid. The solid was dissolved in hot methanol (30 mL). The solution was filtered and concentrated to 7 mL volume as a solid formed. The solid was filtered off, washed with cold methanol, and air-dried to give a white solid (0.0748 g); mp=277.4°-278.6° C. (dec); 1H NMR (d6 -DMSO) 7.17 (s,1) for olefin proton; MS: m/z=304, 322 (base peak)(M+1). Analysis for C15H12ClNO5 : Calculated: C, 56.00; H, 3.76; N, 4.35; Found: C, 55.86; H, 3.82; N, 4.32.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:8].[CH:20]1([C:23]2[C:27]([CH:28]=O)=[CH:26][N:25]([CH3:30])[N:24]=2)[CH2:22][CH2:21]1.CO>COCCOC>[CH:20]1([C:23]2[C:27]([CH2:28][C:8]#[N:7])=[CH:26][N:25]([CH3:30])[N:24]=2)[CH2:22][CH2:21]1
Reactant: Cn1cc(C=O)c(C2CC2)n1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cn1cc(CC#N)c(C2CC2)n1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a suspension of potassium tert-butoxide (8.95 g, 79.9 mmol) in DME (250 mL)-78° C. under nitrogen was added a solution of 1-(isocyanomethyl sulfonyl)-4-methyl benzene (9.36 g, 47.94 mmol) in DME (50 ml). After stirring for 10 minutes, a solution of 3-cyclopropyl-1-methyl-1H-pyrazole-4-carbaldehyde (6 g, 39.95 mmol) in DME (100 mL) was added. The resulting mixture was allowed to stir at −78° C. for 1 hour and then at room temperature for 1 hour. Methanol (50 mL) was added and the resulting mixture refluxed for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (2×50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with hexane:EtOAc 90:10 to afford the title compound an off-white solid in 67% yield, 4.3 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH2:11][CH3:12])[N+:3]=1[O-]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH2:11][CH3:12])[N:3]=1
Reactant: CCc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CCc1cc(N)cc(Br)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-6-ethyl-4-nitro-pyridine 1-oxide (example 5b) (15.9 g, 69 mmol) in acetic acid (310 ml) was treated with powdered iron (25.8 g, 462 mmol). The mixture was slowly heated to 100° C. and kept for 1 hr at this temperature. Then the reaction mixture was cooled to rt and filtered. After evaporation of the solvent the residue was crystallized to yield the title compound as a beige material (88%). Mp. 75-77° C. (pentane), MS: m/e=200 (M+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15](OC)=[O:16])[CH3:8]>C1COCC1>[CH2:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH2:15][OH:16])[CH3:8]
Reactant: CCc1cnccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cnccc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (956 mg, 5.8 mmol) was stirred in anhydrous THF (40 mL). A solution of methyl 3-ethylpyridine-4-carboxylate (904 mg, 3.97 mmol) in anhydrous THF (10 mL) was added at 0° C., and then stirred at room temperature for 1 hour. The reaction was quenched with an aqueous solution of sodium hydroxide and extracted 5 times with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (3-ethylpyridin-4-yl)methanol was obtained as a yellow oil (770 mg, 97% yield) and used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].CNNC.[CH3:29][N:30](C=O)[CH3:31]>O>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:30]([CH3:31])[CH3:29])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Agent: CNNC
Solvent: O
Product: CN(C)c1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1
Yield: 25 %

Procedure:
A solution of 3-cyano-1-[4-fluoro-benzoyl]-pyrrolo[1,2-a]quinoline (56 mg, 0.18 mmol) and dimethylhydrazine (118 mg, 1.96 mmol) in DMF (5 mL) was refluxed for 24 h. It was diluted with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried, concentrated and the residue was purified by column chromatography (EtOAc/Hexane 6:1) to give 15 mg (25%) of the title compound. 1H NMR (CDCl3): 8.11–8.05–7.95 (m, 3H), 7.82–7.78 (m, 2H), 7.63–7.42 (m, 4H), 7.31 (s, 1H), 6.75 (d, J=9.30 Hz, 2H), 3.14 (s, 6H). MS, 340 (M+1).