Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5]
Reactant: ClCC1CO1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1

Procedure:
A solution of 3.5 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide and 1.9 g of potassium carbonate in 100 ml of acetone was refluxed for 30 hours under an inert atmosphere with 11 ml of epichlorohydrin and the insoluble material was filtered off. The filtrate was evaporated to dryness and the residue was purified by chromatography over silica (eluent:chloroform/acetone/TEA 6:3:1). Fractions having a Rf=0.45 were evaporated to dryness and the residue was empasted with ether, filtered and dried under reduced pressure at 60° C. to obtain 3.65 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)benzamide melting at 171° C.
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Na+].[Na+].[C:27]([O:31][C:32](=[O:47])[NH:33][CH2:34][CH2:35][CH2:36][C:37]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)=O)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1.C(OCC)(=O)C>[C:11]([O:10][C:8](=[O:9])[CH:7]=[C:37]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:36][CH2:35][CH2:34][NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:47])([CH3:12])([CH3:13])[CH3:14]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: COc1ccc(C(=O)CCCNC(=O)OC(C)(C)C)cn1
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=CC(=O)OC(C)(C)C)CCCNC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of t-butyl dimethylphosphonoacetate (6.86 g, 30.6 mmol) in tetrahydrofuran (150 mL) at −78° C. under argon was added a solution of sodium bis(trimethylsilylamide) (30.6 mL of a 1.0 M solution). After 15 min., a solution of 1-3 (3.0 g, 10.2 mmol) in tetrahydrofuran (30 mL) was added, and the reaction was warmed to ambient temperature, then heated to 40° C. for 1 h. The reaction mixture was then cooled to ambient temperature, diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, then saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give an oil that was purified by flash column chromatography (silica gel, 15 to 25% ethyl acetate/hexanes) to give 1-4 and its 2 isomer.
Reaction SMILES: [C:1]([C:9]1([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])[CH2:14]CCC[C:10]1=[O:15])(=O)[C:2]1C=CC=C[CH:3]=1.[OH:30]O>C(O)(C)(C)C.S(=O)(=O)(O)O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([CH2:17][CH2:16][C:9]2([C:10]([OH:30])=[O:15])[CH2:14][CH2:3][CH2:2][CH2:1]2)=[O:19])=[CH:23][CH:24]=1
Reactant: COc1ccc(COC(=O)CCC2(C(=O)c3ccccc3)CCCCC2=O)cc1
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: COc1ccc(COC(=O)CCC2(C(=O)O)CCCC2)cc1
Reaction time: 48 h
Yield: 44.5 %

Procedure:
To a solution of 2-benzoyl-2-[2-(4-methoxybenzyloxycarbonyl)-ethyl]cyclohexanone (see Preparation 9) (2.16 g, 5.47 mmol) in tert-butanol (4.3 ml) was added, dropwise, a 30% aqueous solution of hydrogen peroxide (0.74 ml, 6.56 mmol) and concentrated sulphuric acid (98% w/w, one drop) at room temperature. The mixture was stirred for 48 hours, partitioned between toluene (25 ml) and 5% aqueous sodium sulphite solution and the layers separated. The toluene layer was washed with dilute aqueous ammonia solution (25 ml of 0.880 ammonia in 200 ml of distilled water, 4×25 ml). The combined aqueous extracts were washed with toluene (25 ml), acidified to pH 2-3 with 5.ON aqueous hydrochloric acid solution and extracted with toluene (3×25 ml). The combined toluene extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as an oil, (0.746 g, 44.6%). RF. 0.16 silica, hexane/ethyl acetate 2:1). 1H-NMR (300 MHz, CDCl3) =1.45-1.59 (m, 2H), 1.65-1.78 (m, 4H), 1.98-2.06 (m, 2H), 2.12-2.22 (m, 2H), 2.34-2.46 (m, 2H), 3.84 (s, 3H), 5.06 (s, 2H), 6.91 (d, 2H), 7.31 (d, 2H) ppm. Analysis %: Found: C, 67.05; H, 7.18; C17 H2205 requires C, 66.65; H, 7.24.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].C(OCC)(=O)C>CCCCCC>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 103.4 %

Procedure:
4-Chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile (26.8 g 96.5 mmol) and 3-chloro-4-fluoroaniline 14.05 g 96.5 mmol) in 900 ml of iso-propanaol were refluxed under N2 for 3.5 hrs. TLC (ethyl acetate: hexane=1:1) showed no starting material left. After standing at room temperature overnight, the hydrochloride salt was filtered off and washed with isopropanol and ether giving 4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-6-nitro-quinoline-3-carbonitrile 38.6 g (95%) as a yellow hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:17][F:18]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:17][F:18])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: FCCl
Reactant: Oc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: FCOc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a tared, sealed 350 mL round-bottomed pressure flask containing a suspension of 3,5-dibromophenol (10.0 g, 39.7 mmol; see step (ii) above) and Cs2CO3 (20.7 g, 63.5 mmol) in DMF (150 mL) at −78° C. was added chlorofluoromethane via bubbling for 5 min through the septum. The septum was replaced with a Teflon stopper and the flask was then sealed and allowed to warm to room temperature where the flask was weighed and determined to contain 9.0 g (131 mmol) of chlorofluoromethane. The solution was heated in an oil bath set at 70° C. overnight. The flask was cooled to room temperature, the pressure cautiously released and the contents diluted with water (100 mL). The aqueous layer was extracted with Et2O (3×200 mL) then, the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with hexanes afforded the sub-title compound (7.9 g, 71%) as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.CN.[CH:37]([OH:39])=[O:38].ClC1C=[C:43]([N:47]2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:37]([OH:39])=[O:38].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][NH:47][CH3:43])[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CN
Solvent: C1CCOC1
Solvent: O=CO
Product: CNCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and methylamine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 26 mg (26% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[O:31][CH2:30]1)[CH2:26][CH2:27][CH3:28].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:39][C:38]1[CH:37]=[CH:36][C:35]([C@H:32]2[O:31][CH2:30][C@H:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:34][O:33]2)=[CH:42][CH:41]=1
Reactant: CCCC[C@H]1CO[C@H](c2ccc(C=O)cc2)OC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCC[C@H]1CO[C@H](c2ccc(C=C(Br)Br)cc2)OC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 13.6 g of tetrabromomethane in 150 ml of methylene chloride was placed at 0° C. in a sulphonation flask under argon gasification and treated within 10 minutes with a solution of 21.51 g of triphenylphosphine in 40 ml of methylene chloride. After completion of the addition, the clear orange solution was stirred at 0° C. for a further 5 minutes and then a solution of 5.08 g of p-(trans-5-butyl-1,3-dioxan-2-yl)benzaldehyde in 30 ml of methylene chloride was added dropwise within 5 minutes. The mixture was subsequently stirred at 0° C. for a further 30 minutes, then the flask content was poured into 800 ml of hexane and the separated precipitate was filtered off (rinsing with hexane). The concentrated filtrate was digested with 400 ml of hexane, left to stand at 0° C. for 15 hours, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (8.2 g) on silica gel with hexane followed by petroleum ether/ethyl acetate/triethylamine (97:3:0.5) gave 3.23 g of trans-2-[p-(2,2-dibromovinyl)phenyl]-5-butyl-1,3-dioxane as colourless crystals (purity 95.1%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[N:7]([C:18]([C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1.[C:25](#N)C>>[I:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:19][C:18]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[N:7][N:8]=2)=[CH:11][CH:12]=1
Reactant: CC#N
Reactant: CN(NC(=O)c1ccc(I)cc1)C(=O)c1ccc[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cccc1-c1nnc(-c2ccc(I)cc2)o1
Temperature: 100 °C

Procedure:
Phosphorousoxychloride (2 ml) was added to 1H-pyrrole-2-carboxylic acid, 1-methyl-2-(4-iodobenzoyl)hydrazide (Intermediate 39) (150 mg) in acetonitrile (1 ml) and the reaction heated at 100° C. for 18 hours. The cooled reaction was poured onto ice/water (60 ml) and extracted with ethyl acetate (3×40 ml). The combined extracts were reduced to dryness under vacuum and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvent, 2-(4-iodophenyl)-5-(1-methyl-1H-pyrrol-2-yl)-1,3,4-oxadiazole.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:9]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[N:10][N:11]=1.[C:30]([O:49][CH2:50][CH:51]([CH2:53]O)[OH:52])(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>N1C=CC=CC=1>[C:30]([O:49][CH2:50][CH:51]([OH:52])[CH2:53][O:15][C:14](=[O:16])[CH2:13][S:12][C:9]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:7]([Br:6])=[N:11][N:10]=1)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (2.4 mmol) is added dropwise over 5 mins to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (810 mg, 2.0 mmol) in pyridine (20 mL) at 0° C. The mixture is stirred at 0° C. for a further 1 hour and then glyceryl monooleate (715 mg, 2.0 mmol) dissolved in pyridine (5 mL) is added dropwise over 5 mins. The mixture is stirred at 0° C. for a further 3 hours and 1 hour at 20° C. and then quenched by addition of water (1 mL). Volatile solvents are removed in vacuo and DCM (200 mL) added. The organic phase is washed with water (1×50 mL), saturated sodium carbonate solution (1×50 mL) and brine (1×50 mL), dried over Na2SO4, concentrated to dryness and purified by column chromatography (acetone/DCM eluent) to provide 3-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetoxy)-2-hydroxypropyl oleate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:12][CH2:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=O.[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])([CH3:15])[CH3:14].C1(C)C(C)=CC=CC=1>O>[C:24]([C:21]1[CH:20]=[C:19]([CH2:28][CH2:29][C:30]([NH:32][N:33]2[C:9](=[O:10])[CH:4]3[CH2:3][CH:2]([CH3:1])[CH2:12][CH2:11][CH:5]3[C:6]2=[O:8])=[O:31])[CH:18]=[C:17]([C:13]([CH3:14])([CH3:15])[CH3:16])[C:22]=1[OH:23])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CC1CCC2C(=O)OC(=O)C2C1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1CCC2C(=O)N(NC(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C(=O)C2C1
Yield: 100.5 %

Procedure:
A mixture of 4-methylhexahydrophthalic anhydride (32.8 g, 200 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (58.4 g, 200 mmol) and 650 ml of xylene was refluxed for 90 minutes under a nitrogen atmosphere with the azeotropic removal of water. The solvent was removed on a rotary evaporator to afford approximately 89 g of a white solid having a melting range of 87°-92° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][NH:10][C:5]2=[C:4](O)[CH:3]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:16])=O>>[CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][NH:10][C:5]2=[C:4]([Cl:16])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2[nH]ncc2n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)c2[nH]ncc2n1
Temperature: 25 °C
Yield: 87 %

Procedure:
The cyclized compound (12) (4.58 g, 30.7 mmol) in phosphorus oxychloride (30 mL) was heated at 110° C. for 30 minutes. The end of the reaction was checked by LC/MS (disappearance of 150, appearance of 168). After cooling down at room temperature, the reaction mixture was poured on ice and pH was adjusted with a 6N NaOH solution to pH=5. The solid was collected with filtration and the mother aqueous layer was extracted with ethyl acetate (3×250 ml). The above solid was dissolved in the combined organic phases, washed with a brine solution (1×250 ml) and dried with sodium sulfate, filtered and concentrated. The crude product was purified by running through a short silica gel chromatography column to give the desired product (13) as a pale yellow solid (4.50 g, 26.8 mmol, 87%). GC/MS: m/z=167 (100%);. LC/MS: [M+H]′=168.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1.CC(C)(O)[C:17]#[N:18].C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]1[C:17]#[N:18]
Reactant: O=C1CCC=C1CCCCCCCO
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC1CCC(=O)C1CCCCCCCO
Yield: 68.8 %

Procedure:
A mixture of 2-(7-hydroxyheptyl)cyclopent-2-en-1-one (17 g.), acetone cyanohydrin (8.5 g.), 6% aqueous sodium carbonate (8 ml.) and methanol (50 ml.) was stirred and heated under reflux for 4 hours. Methanol was removed in vacuo, water (100 ml.) was added and the mixture was extracted with diethyl ether and dried over magnesium sulphate. The solvent was removed by evaporation, and the residue was distilled under reduced pressure to give 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (13.3 g.), b.p. 144°-182° C./0.15 mm.Hg, nD25 1.4795.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])[O:7][C:6]1=[O:13])C.[CH:14]([NH2:17])([CH3:16])[CH3:15].CC(C)([O-])C.[Na+]>C(O)C>[CH:14]([N:17]1[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:6]([OH:13])=[O:7])=[CH:4]1)([CH3:16])[CH3:15]
Reactant: CC(C)N
Reactant: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(=O)c(C(=O)O)cn1C(C)C

Procedure:
A solution of 3-dimethylaminomethylene-6-methyl-pyran-2,4-dione (preparation 1a, 10.00 g, 38.6 mmol based on 70% purity), isopropylamine (5.00 mL, 58.4 mmol) and sodium tert-butoxide (5.50 g, 57.2 mmol) in ethanol (20 mL) is heated for 18 h at 90° C. The reaction mixture is evaporated under reduced pressure, treated with water and extracted with dichloromethane. The aqueous layer is acidified with 4 N aqueous HCl and extracted with dichloromethane. The combined organic layer is washed with water, dried over Na2SO4 and evaporated under reduced pressure. Yield: 7.16 g; ESI mass spectrum: [M+H]+=196; r.t. HPLC: 0.71 min (Z002_006).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[Cl:24])[C:6]=2[CH:11]=1
Reactant: Cc1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Reactant: Clc1cccc(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of Example 1 (1.17 g) (prepared as described previously described), 1-(bromomethyl)-2,3-dichlorobenzene (1.19 g) and K2CO3 (1.27 g) in DMF (80 mL) was stirred at 80° C. for 3 h. When TLC showed no starting material, the mixture was cooled to room temperature and filtered. The filtrate was then poured into water. It was then filtered to afford a solid and the solid was washed with water and then dried in-vacuo to afford the desired product (1.59 g, 83%)1H NMR (300 MHz, CDCl3) δ ppm 2.67 (s, 3H), 5.45 (m, 2H), 6.24 (t, 1H, J=7.8 Hz), 7.10 (t, 1H, J=7.8 Hz), 7.47 (t, 1H, J=7.8 Hz), 7.59 (d, 1H, J=1.8 Hz), 8.24 (d, 1H, J=1.8 Hz); LC-MS: m/e=416 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 57.6 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 36 (43 mg, yield 57.6%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccccc2F)sc1C(=O)NCc1ccccc1
Yield: 99 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-fluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 99% yield; 1H NMR (CDCl3, 300 MHz) δ 8.63 (t, J=5.8 Hz, 1H), 7.62-7.17 (m, 9H), 6.01 (s, br, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 369.7 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH3:14])[C:7]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:6]=3[C:5]=2[CH:4]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].[OH-].[Na+]>>[CH3:1][N:2]([C:3]1[CH:11]=[CH:10][C:9]2[N:8](/[CH:12]=[C:13](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:14])[C:7]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:6]=3[C:5]=2[CH:4]=1)[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc2c(c1)c1c(n2C=C(C)c2ccncc2)CCN(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(C)c1ccc2c(c1)c1c(n2/C=C(\C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,3,4,5-Tetrahydro-N,2-dimethyl-5-(2-(pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indol-8-amine (23 mg) was charged in round bottom flask and acetic anhydride (0.7 mL) was added. The contents were stirred at RT for 30 min. The reaction mixture was basified with 1N NaOH and compound extracted with EtOAc (2×25 mL). The organic layer was concentrated under vacuum and recrystallized in DCM:Hexane (1:3) to yield 2.38 mg of desired compound. 1H NMR (CDCl3, free base) δ (ppm): 8.62 (d, 2H), 7.42 (d, 2H), 7.25 (s, 1H), 7.10 (dd, 2H), 6.98 (d, 1H), 3.70 (s, 2H), 3.30 (s, 3H), 2.82 (m, 4H), 3.60 (s, 3H), 2.04 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH3:3].C(O)C.[OH-].[K+].Cl>CCOCC>[ClH:1].[ClH:1].[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH:5]([NH:4][CH2:2][CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCNC(Cc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCNC(Cc1ccccc1N)c1ccccc1
Reaction time: 3 h

Procedure:
3.00 g of N-Ethyl-2-nitro-α-phenylphenethylamine hydrochloride is treated with 100 ml of hot 95% ethanol containing 1.10 g of potassium hydroxide for 15 minutes, after which the mixture is filtered and placed in a Paar flask. 0.15 g of 10% palladium on charcoal is added and the mixture is hydrogenated at room temperature and 50 psia for 3 hours, after which the catalyst is removed. The ethanol is evaporated from the filtrate and the resulting yellow oil is poured onto 100 ml of water. The biphasic aqueous mixture is extracted with methylene chloride (2×100 ml). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride evaporated to afford a colorless oil. The oil is dissolved in 50 ml of ether. Ethereal hydrogen chloride (100 ml) is added precipitating the hydrochloride acid salt as an oil. The ethanol is evaporated and the oil is dissolved in 20 ml of i-propanol with heating. Upon cooling, white crystals, mp>248° C. dec, fell from solution providing 2-amino-N-ethylα-phenylphenethylamine dihydrochloride.