Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[CH2:18][CH2:17][C:11]3[N:12]=[N:13][C:14](Cl)=[CH:15][C:10]=3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[CH2:18][CH2:17][C:11]3[N:12]=[N:13][C:14]([NH:22][NH2:23])=[CH:15][C:10]=3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccc(Br)cc1)C2

Procedure:
10.2 g of 6-(p-bromobenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 55 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 2 hours. The title compound has a M.P. of 192°-195° (decomp., from absolute ethanol/methanol 3:1).
Reaction SMILES: [O:1]=[CH:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:19]=[CH:18]3)([OH:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]1[C:31]#[N:32].[O-:33][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[C:31]([C:5]1[N:4]([CH2:3][C:2]([OH:33])=[O:1])[CH:8]=[C:7]([C:9]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:19]=[CH:18]3)([OH:14])[C:10]([F:12])([F:13])[F:11])[CH:6]=1)#[N:32]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: N#Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn1CC=O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn1CC(=O)O
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a solution of 1-(2-oxoethyl)-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyrrole-2-carbonitrile (208 mg, 0.47 mmol, 1 equiv.) in 12 mL of 3:1 acetone-water was added KMnO4 (78 mg, 0.49 mmol, 1.1 equiv.). After 18 hours, the mixture was filtered through CELITE® filter aid and the filter cake washed with acetone. The filtrate was evaporated and the aqueous was diluted with water and EtOAc. The mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 197 mg (91%) of (2-cyano-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrol-1-yl)acetic acid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4][N:5]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=2F)[C:6]=1[CH:7]1[CH2:9][CH2:8]1.C([O:26][C:27](=O)[CH2:28][C:29]([CH3:31])=[O:30])(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4][N:5]([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:27](=[O:26])[CH2:28][C:29](=[O:30])[CH3:31])=[CH:12][CH:11]=2)[C:6]=1[CH:7]1[CH2:9][CH2:8]1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Nc1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)c(F)c1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)cc1
Temperature: 145 °C
Yield: 72.5 %

Procedure:
Intermediate 34 (1.83 g, 5.72 mmol) and t-Butylacetoacetate (1.9 ml, 11.4 mmol) were dissolved in xylene (5 ml) and heated to 145° C. f°r 90 mins. Reaction mixture was cooled to rt to obtain a solid. Solid that formed was filtered, washed with petether and dried to obtain N-{4-[4-chloro-5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3-oxobutanamide (1.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36](Cl)(=[O:38])[CH3:37].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:36](=[O:38])[CH3:37])[C:15]1[C:16]([O:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[N:17][C:18]([C:21]2[CH:26]=[N:25][CH:24]=[N:23][CH:22]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2nc(-c3cncnc3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Oc2nc(-c3cncnc3)ncc2N(C[C@@H]2CCCN2C(=O)OC(C)(C)C)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Compound 8b (89 mg; 0.19 mmol) in CH2Cl2 (7 mL) was added acetyl chloride (0.1 mL) and pyridine (0.1 mL) at ambient temperature. The mixture was stirred at room temperature for 3 h. Diluted the resulted mixture with CH2Cl2. The organic phase was washed sequentially with H2O and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to afford Compound 9a. The crude product was used in the next reaction without further purification. MS: m/z 521.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:32]=[CH:31][C:17]([O:18][CH:19]([CH3:30])[C:20]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:29])[O:27][CH3:28])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:30])[C:20]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:29])[O:27][CH3:28])=[O:21])=[CH:31][CH:32]=1)[CH:11]=[N:10]2
Reactant: COC(=O)NCCOC(=O)C(C)Oc1ccc(O)cc1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.99 g of 2,6-dichloroquinoxaline, 2.83 g of methyl 2-[[2-(4-hydroxyphenoxy)propionyl]oxy]ethylcarbamate, 1.4 g of potassium carbonate and 20 ml of N,N-dimethylformamide is stirred at room temperature overnight. For the working-up, the mixture is poured on to ice-water and extracted with ethyl acetate. The extracts are washed with water and sodium chloride solution, dried over sodium sulphate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (2:1) there is obtained pure methyl 2-[[2-[p-[(6-chloro-2-quinoxalinyl)oxy]phenoxy]propionyl]oxy]ethylcarbamate; m.p. 103°-104.5° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:24]=[CH:23][C:13]([O:14][CH2:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH:18]=[CH2:19])=[CH:12][CH:11]=1>ClC(Cl)(Cl)Cl>[Br:1][CH:15]([O:14][C:13]1[CH:23]=[CH:24][C:10]([Cl:9])=[CH:11][CH:12]=1)[C:16](=[O:22])[C:17]([CH3:20])([CH3:21])[CH:18]=[CH2:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CC(C)(C)C(=O)COc1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 5 °C
Yield: 103.5 %

Procedure:
12.5 g (0.07 mol) of N-bromosuccinimide were added to a solution of 16.7 g (0.07 mol) of 5-(4-chlorophenoxy)-3,3-dimethylpent-1-en-4-one and a pinch of azoisobutyronitrile in 200 ml of tetrachloromethane. The mixture was then heated at the boil for 8 hours, under UV irradiation. The mixture was then cooled to 5° C. and filtered off from the precipitated succinimide. The filtrate was concentrated in vacuo. 23 g of crude 5-bromo-5-(4-chlorophenoxy)-3,3-dimethylpent-1-en-4-one were obtained as an oil, which was directly reacted further. ##STR29##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:19][N:20]([CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25]>>[CH3:19][N:20]([CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:28][C:27]=1[CH3:34])=[O:25]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(C(=O)NCCN(C)C)c2C)c1
Yield: 13.8 %

Procedure:
6-(3-Methoxyphenyl)-1,3-dihydroindol-2-one (30 mg, 0.13 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (30 mg) to give 8 mg (14%) of the title compound as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][N:20]([CH2:30][CH2:31][OH:32])[C:21]1[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:20]([CH2:30][CH2:31][OH:32])[CH2:19][CH2:18][OH:17])=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:20]([CH2:19][CH2:18][OH:17])[CH2:30][CH2:31][OH:32])=[CH:22][CH:23]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc(N(CCO)CCO)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N(CCO)CCO)cc3)cc2)cc1)c1ccc(N(CCO)CCO)cc1

Procedure:
Compound 327 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-bis(2-hydroxylethyl)aminobenzoate. [M+H]+ calcd for C35H38N4O7: 627.28; found: 627.06.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:9]=2[NH:10][C:11]=1O)=[O:5])[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][C:11]1[S:7][C:8]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:9]=2[N:10]=1)[CH3:2]
Reactant: CCOC(=O)C1=C(O)Nc2ccc(Br)cc2S1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2ccc(Br)cc2s1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
7-Bromo-3-hydroxy-4H-benzo[1,4]thiazine-2-carboxylic acid ethyl ester (2.47 g, 7.8 mmol) was dissolved in 50 mL of acetic acid and heated to 110° C. under nitrogen. Zinc powder (7.5 g, 114.7 mmol) was added in portions at room temperature over 80 minutes. The mixture was stirred at 110° C. for additional 2 hours and cooled to room temperature. Zinc was filtered off and rinsed with 20 mL EtOAc. The combined filtrate was concentrated to yellow crystals and purified by column chromatography (silica gel, 20:90 EtOAc:hexane) to give (6-bromo-benzothiazol-2-yl)-acetic acid ethyl ester.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[C:6]=1[NH2:14])=O.CN.[C:17]([Cu])#[N:18]>>[CH3:17][NH:18][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[C:6]=1[NH2:14])=[O:2]
Reactant: COC(=O)c1ccc2c(c1N)OCO2
Reactant: N#C[Cu]
Agent: CN
Product: CNC(=O)c1ccc2c(c1N)OCO2

Procedure:
4-Amino-benzo[1,3]dioxole-5-carboxylic acid methylamide was prepared by heating a mixture of 4-amino-benzo[1,3]dioxole-5-carboxylic acid methyl ester (198 mg, 1.01 mmol, Dallacker, Franz, et al. Justus Liebigs Ann Chem 1966, 694 117-22) with 2.0 M methanolic MeNH2 (7 mL, 14 mmol) and CuCN (1.42 g, 28.6 mmol) to 50° C. for 72 h. Excess catalyst was removed by filtration; filtrate was extracted into CH2Cl2, washed with water and dried by passing through a plug of Na2SO4. Evaporation of solvent afforded a white powder (187 mg, 95%) that was used in subsequent steps without further purification.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]2[CH:36]=[CH:35]C(N)=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:14]([N:12]3[C:3](=[O:4])[C:5]4[S:6][C:7]([C:15]([CH:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)=[O:16])=[CH:8][C:9]=4[N:10]=[CH:11]3)=[CH:33][CH:32]=2)[CH2:26][CH2:25]1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Reactant: COC(=O)c1sc(C(=O)C2CCOCC2)cc1N=CN(C)C
Product: CN1CCCN(c2ccc(-n3cnc4cc(C(=O)C5CCOCC5)sc4c3=O)cc2)CC1

Procedure:
3-(Dimethylaminomethyleneamino)-5-(tetrahydropyran-4-carbonyl)thiophene-2-carboxylic acid methyl ester and 4-(4-methyl[1,4]diazepan-1-yl)phenylamine were reacted by method A1. The product with the molecular weight of 452.58 (C24H28N4O3S) was obtained in this way; MS (EST): 453 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C:7](=[O:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Li]CCCC.[CH2:18]([O:25][CH2:26][C:27]([O:29]CC)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1COCC1>[CH2:18]([O:25][CH2:26][C:27](=[O:29])[CH:8]([CH3:9])[C:7](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCC(=O)C(C)C(=O)OC
Reactant: CCOC(=O)COCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)C(=O)C(C)C(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl 2-methyl-3-oxopentanoate (13.05 g) in THF (100 ml) was added to a suspension of NaH (3.80 g) in THF (100 ml) at 0° C., and after stirring at 0° C. for 15 minutes, 1.63 M n-BuLi (58 ml) was added and the mixture was stirred at 0° C. for 20 minutes to prepare a light yellow dienolate. The reaction solution was cooled to −78° C., a solution of ethyl 2-(benzyloxy)acetate (17.56 g) in THF (30 ml) was added, and the mixture was stirred at −78° C. for 5 minutes and then at 0° C. for one hour. Diluted hydrochloric acid was poured into the reaction solution for quenching, and extraction was performed with AcOEt at near neutral. The organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→3/1) to obtain methyl 6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:23][C:22]4[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]=4[C:14]=3[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].CO.[ClH:38]>>[ClH:38].[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:23][C:22]4[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=4[C:14]=3[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2oc3ccc(S(=O)(=O)c4ccccc4)cc3c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccc2oc3c(c2c1)CNCCC3
Reaction time: 4 h

Procedure:
The product of step F (22 mg, 0.05 mmol) in 2N HCl diethyl ether solution (5 mL) was stirred at 0-5° C. for 2 h and then at ambient temperature for 4 h. After concentration in vacuo, the solid obtained was treated with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude material which was purified by flash column chromatography (SiO2, 80:18:2 dichloromethane/methanol/ammonium hydroxide) followed by semi-preparative HPLC. After concentration in vacuo, the solid obtained was treated with 1.25M HCl methanol solution (0.5 mL) and lyophilized to yield 9-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzofuro[3,2-c]azepine hydrochloride (2.8 mg, 15%, AUC HPLC 98.8%) as a white solid: mp 211-216° C.; 1H NMR (CD3OD, 300 MHz) δ 8.12 (s, 1H), 7.96 (dt, J=6.6, 1.8 Hz, 2H), 7.81 (dd, J=8.7, 1.8 Hz, 1H), 7.76-7.51 (m, 4H), 4.02 (s, 2H), 3.19 (br s, 2H), 3.05 (t, J=6.0 Hz, 2H), 1.95 (br s, 2H); ESI MS m/z 328 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: COc1cccc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 47.6 %

Procedure:
6-(3-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (106 mg, 47%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.8 mmol) and 3-methoxyphenyl boronic acid (0.137 g, 0.90 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:5]2[CH2:4][CH2:3][NH:2]1.[Br:15]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:15][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[N:5]2[CH2:4][CH2:3][NH:2][C:1](=[O:14])[C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1NCCn2c1cc1c2CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCn2c3c(c(Br)c21)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-1-one 104j (9.5 g, 49.94 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL), followed by the addition of N-bromosuccinimide (9.8 g, 55.06 mmol, 1.10 equiv) in several batches at 0° C. The resulting solution was stirred at room temperature for 2 h and diluted with 500 mL of water. The precipitate was filtered and dried in a vacuum oven to afford 9.5 g (71%) of 119a as a light brown solid.
Reaction SMILES: [CH2:1]([Si:3]([CH2:29][CH3:30])([CH2:27][CH3:28])[O:4][C@H:5]([C:9]([CH3:26])=[CH:10][C:11]1[N:12]=[C:13]([CH2:16][O:17][C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[S:14][CH:15]=1)[CH2:6][CH:7]=C)[CH3:2].C[N+]1([O-])CC[O:35]CC1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.C1C=CC=CC=1.[Os](=O)(=O)(=O)=O.O>[CH2:27]([Si:3]([CH2:1][CH3:2])([CH2:29][CH3:30])[O:4][C@H:5]([C:9]([CH3:26])=[CH:10][C:11]1[N:12]=[C:13]([CH2:16][O:17][C:18]([O:20][CH2:21][C:22]([Cl:24])([Cl:23])[Cl:25])=[O:19])[S:14][CH:15]=1)[CH2:6][CH:7]=[O:35])[CH3:28]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H](O[Si](CC)(CC)CC)C(C)=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Agent: O=[Os](=O)(=O)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: CC[Si](CC)(CC)O[C@@H](CC=O)C(C)=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 12 h
Yield: 67.7 %

Procedure:
Osmium tetraoxide (1 wt % in THF, 20.3 mL) is added to a mixture of (4S)-4-(triethylsilyloxy)-5-methyl-6-(2-(2,2,2-trichloroethoxycarbonyloxymethyl)-thiazol-4-yl)-1,5-hexadiene (20.6 g), H2O (21 mL), and N-methylmorpholine N-oxide (50% in THF, 10 mL, 0.048 mol) in tert-butanol (155 mL) at 0° C. After the resulting mixture is stirred for 12 hours, Na2SO3 (10 g) and water (5 mL) are added. The resulting solution is stirred at 25° C. for 30 minutes and then extracted with ether. The combined extracts are washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography on SiO2 provides a 1:1 diastereomeric mixture of the diol as a colorless, viscous oil (18.8 g, 85%). Lead tetraacetate (19.1 g) is added portionwise over 5 minutes to a suspension of the diol (18.0 g) and Na2CO3 (8.67 g) in 500 mL of benzene at 0° C. After stirring for 15 minutes, the mixture is filtered through a SiO2 pad to afford the aldehyde product (14.0 g, 82%). The product is directly subjected to the next reaction.
Reaction SMILES: C1(N2CCN(C3C(N)=CC=CN=3)CC2)CCCC1.[CH:19]1([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][N:31]=3)[CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[N:31]=[CH:32][C:33]([NH2:36])=[CH:34][CH:35]=3)[CH2:28][CH2:29]2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3CCCC3)CC2)nc1
Agent: Nc1cccnc1N1CCN(C2CCCC2)CC1
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)nc1
Yield: 98 %

Procedure:
According to the procedure described for the synthesis of intermediate 2-(4-cyclopentyl-piperazin-1-yl)-pyridin-3-ylamine was synthesized from 1-cyclopentyl-4-(5-nitro-pyridin-2-yl)-piperazine through hydrogenation to yield 98% of the title compound as colorless crystals. (m/e): 247.1 (MH+; 100%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O>>[Si:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H](O)c1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN(C(C(=O)OCc2ccccc2)c2ccccc2)C[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenyl pyrrolidine (prepared above as Pyrrolidine 1) and (S)-mandelic acid, benzyl ester using a procedure analogous to that described in the preparation given above of Aldehyde 1. The title compound was obtained as a mixture of diastereomers: RF: 0.68 (4:1 v/v hexanes/EtOAc).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].[CH3:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][NH2:25]>CO.C(O)(=O)C>[CH3:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][N:25]=[C:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: Cn1c(NN)nc2ccccc21
Reactant: CC(=O)c1cc2ccccc2cn1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NNc1nc2ccccc2n1C)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 3-acetylisoquinoline (1.01 g, 5.9 mmol) and 1-methyl-2-hydrazinobenzimidazole (0.96 g, 5.55 mmol) in 15 ml of methanol is stirred for approximately 7 days at room temperature after the addition of 5 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: petroleum ether:ethyl acetate (3:7)). The reaction mixture is stored over night in the freezer at approximately −20° C. The precipitate is filtered, washed with ether and dried. The product is recrystallized from a mixture of ethylacetate and petroleum ether. Yield: 1.66 g (95% of theory).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([N:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([O:9]C)=[O:8]>CO>[Cl:3][C:4]1[C:5]([N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:21])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)N(C)c1c(C(=O)OC)ccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N(C)c1c(C(=O)O)ccc(Cl)c1Cl
Yield: 108 %

Procedure:
Sodium hydroxide solution (2M, 44.6 ml) was added dropwise during 5 minutes to a stirred solution of methyl 3,4-dichloro-2-(N-methyl-N-ethoxycarbonylamino)benzoate (9.1 g) in methanol. After 0.5 hours the methanol was evaporated, the residue diluted (water), washed (ether), acidified with potassium bisulphate and extracted (ethyl acetate). The extract was dried (magnesium sulphate) and evaporated to give 3,4-dichloro-2-(N-methylethoxycarbonylamino)benzoic acid (9.38 g) as a brown oil, NMR 1.2(m,3H), 3.1(s,3H), 4.0(m,2H), 7.4(m,1H), 7.9(m,1H).