Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31](O)=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]=23)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c6) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24](Cl)[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:9][CH:10]=2)[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(-c2ccc(N)cc2)ccn1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Nc3nc(C)cc(Cc4ccccc4)n3)cc2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 from 4-(2-methyl-pyridin-4-yl)-phenylamine and 4-benzyl-2-chloro-6-methyl-pyrimidine (example 43a). Obtained as a yellowish solid (Yield=48%). MS ISP (m/e): 367.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.77 (s, 1H), 8.45 (d, 1H), 7.93 (d, 2H), 7.71 (d, 2H), 7.55 (s, 1H), 7.47 (d, 1H), 7.35-7.20 (m, 5H), 6.67 (s, 1H), 3.95 (s, 2H), 2.51 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][CH:19]([NH2:21])[CH3:20].CCO>C(CC(C)(C)C)(C)C>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH:19]([CH3:20])[CH3:18])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: CC(C)N
Solvent: CC(C)CC(C)(C)C
Solvent: CCO
Product: CC(C)NCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), propan-2-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 303 (M+, 0.3), 95 (10), 86 (14), 75 (8), 72 (bp), 58 (9).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].P(C#N)(OCC)(OCC)=O.[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[OH:4][CH2:3][CH2:2][NH:1][C:27](=[O:28])[C@@H:26]([NH:25][C:23](=[O:24])[O:22][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:33][CH:32]=1
Reactant: NCCO
Reactant: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)OCc1ccccc1
Reaction time: 0.75 h
Yield: 90 %

Procedure:
2-Aminoethanol (1.62 mL, 26.9 mmol) and diethyl cyanophosphate (4.37 mL, 26.9 mmol) were added to a DMF (82 mL) solution of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (9.37 g, 24.4 mmol) prepared in Reference Example 6 (6a), at room temperature. Then, to the resulting mixture was dropwise added a DMF (10 mL) solution of triethylamine (3.75 mL, 26.9 mmol) under ice-cooling with stirring over 45 minutes. The mixture was stirred at room temperature for 3 hours, and ethyl acetate (480 mL) was added to this reaction solution. The mixture was sequentially washed with water (480 mL, four times), 1 N sodium hydroxide, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dried under reduced pressure to give 9.36 g of the title compound (white powder, yield: 90%).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:29][C:25]1([CH3:28])[CH2:24][CH2:23][N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[CH:12]=[N:11][C:6]4[NH:7][C:8]5[CH:9]=[N:10][C:2]([C:34]6[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=6)=[CH:3][C:4]=5[C:5]=4[CH:14]=3)=[CH:16][CH:17]=2)[CH2:27][CH2:26]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCC(C)(C)CC5)cc4)cc23)cn1
Temperature: 130 °C
Yield: 38.5 %

Procedure:
A degassed mixture of 6-bromo-3-[4-(4,4-dimethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (200 mg, 0.45 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (185 mg, 0.89 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol) in 2N aqueous sodium carbonate solution (5 mL) and acetonitrile (5 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 10 g column, Biotage, 0-15% methanol in DCM) to afford the title compound as a white solid (78 mg, 38%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.79 (d, J=2.2 Hz, 1H), 8.33 (d, J=1.1 Hz, 1H), 8.08 (s, 1H), 8.06 (d, J=08 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 4.00 (s, 3H), 3.63 (s, 2H), 2.51 (t, J=5.0 Hz, 4H), 1.46 (t, J=5.6 Hz, 4H), 0.96 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[S:18][C:19]([SH:22])=[N:20][N:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C(C(C)=O)C>[NH2:16][C:17]1[S:18][C:19]([S:22][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:15])[C:6]=2[CH2:12][CH2:13][CH3:14])=[N:20][N:21]=1
Reactant: Nc1nnc(S)s1
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCCc1c(CSc2nnc(N)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a mixture of 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride, 0.22 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 0.22 g of anhydrous potassium carbonate and 3 ml of methyl ethyl ketone were added catalytic amounts of potassium iodide and tetra-n-butylammonium bromide followed by stirring at 60° C. for 2 hours. Ethyl acetate was added to the reaction mixture. After insoluble matters were filtered off, the filtrate was washed with an aqueous sodium hydroxide solution and then dried over anhydrous magnesium sulfate The solvent was then removed by distillation to give 0.44 g of 2-amino-5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazole.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([O:22]COCC2C=CC=CC=2)([CH2:17][C:18]([F:21])([CH3:20])[CH3:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].CO>[F:21][C:18]([CH3:20])([CH3:19])[CH2:17][C:14]1([OH:22])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: CC(C)(F)CC1(OCOCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(F)CC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round bottom flask was added benzyl-4-(benzyloxymethoxy)-4-(2-fluoro-2-methylpropyl)piperidine-1-carboxylate (50 mg, 0.12 mmol), Pd/C (20 mg), and methanol (5 mL). The mixture was stirred at room temperature for 16 hrs under hydrogen atmosphere. The reaction mixture was filtered to get a solution, which was concentrated to give the desired product. The crude product was used directly for the next step. LC-MS: m/z 176.2 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=1)=[O:6])[CH3:3].O.[NH2:17][NH2:18]>C(O)C>[CH3:1][CH:2]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]([NH:17][NH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)NC(=O)c1ccc(C(=O)NN)s1
Yield: 45 %

Procedure:
Methyl 5-(2-propylcarbamoyl)thiophene-2-carboxylate (1.22 g, 5.37 mmol) in ethanol (40 mL) was heated with hydrazine monohydrate (2.7 g) at 85° C. for 16 hours with reflux. After cooling, the solvent was evaporated, the resulting solid was recrystallized from chloroform to give 549.2 mg of the desired product (yield 45%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]([CH3:31])[CH2:29][NH2:30]>C(#N)C>[CH3:27][CH:28]([CH3:31])[CH2:29][NH:30][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: CC(C)CN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC(C)CNCC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), 2-methylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 6), 256 (20), 86 (bp), 70 (6), 57 (8).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]2[CH3:16])=[CH:6][C:5]=1[CH3:17].C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:3][C:4]1[C:5]([CH3:17])=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]2[CH3:16])=[CH:8][C:9]=1[Br:1]
Reactant: BrBr
Reactant: Cc1cn(-c2ccc(N)c(C)c2)c(C)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(C)c(N)c(Br)c2)c(C)n1
Reaction time: 0.5 h

Procedure:
A solution of bromine (5.6 cm3) in glacial acetic acid (50 cm3) was added dropwise over 0.5 hours to a stirred solution of 1-(4-amino-3-methylphenyl)-2,4-dimethylimidazole (20.3 g) and sodium acetate (9.02 g) in glacial acetic acid (200 cm3). After a further 0.5 hours, volatile material was removed in vacuo, and the residue was partitioned between chloroform (200 cm3) and 10% aqueous sodium hydroxide solution (to pH 10). The aqueous phase was further extracted with chloroform (2×100 cm3) and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to afford a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 19:1. Combination and evaporation of the appropriate fractions gave an oil which was triturated with ether to afford the title compound, m.p. 176°-180.5°. The mother liquors were evaporated and the residue was rechromatographed on silica, as before, to give a further crop of material (total yield 17.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=1.[Cl:17][C:18]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:19]=1[CH2:20][NH:21][CH2:22][CH:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:21]([CH2:20][C:19]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34]([F:37])([F:35])[F:36])[C:18]=2[Cl:17])[CH2:22][CH:23]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH3:24])[CH:6]=1
Reactant: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1cccs1
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2cccs2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.1 %

Procedure:
A solution of (3-{3-bromo-propoxy}-phenyl)acetic acid methyl ester (41 mg, 0.14 mmol) and (2-chloro-3-trifluoromethyl-benzyl)-(2-thiophen-2-yl-propyl)-amine (50 mg, 10.14 mmol) in acetonitrile (10 ml) was treated with solid potassium carbonate (24.9 mg, 0.18 mmol). The reaction was heated to reflux and stirred for 48 h. Upon cooling to room temperature, the reaction was filtered through a pad of celite, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil (25 mg, 30%). MS m/e 540.6 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[O:12].[BH4-].[Na+].Cl.[CH2:17](Cl)Cl>CO>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[O:12][CH3:17]
Reactant: ClCCl
Reactant: Cc1c(Br)ccc2c1C(=O)CCS2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC1CCSc2ccc(Br)c(C)c21
Temperature: 0 °C

Procedure:
4.4 Grams (0.017 mol) of 6-bromo-5-methylthiochroman-4-one was dissolved in 10 ml of methylene chloride and 10 ml of methanol. The solution was cooled to 0° C. with a salt water-ice bath. 0.32 Grams (0.0085 mol) of sodium borohydride was gradually added so that the temperature did not exceed 10° C. While the mixture was cooled with the ice bath, it was allowed to react for 1 hour. Then, the reaction mixture was poured into 100 ml of 5% hydrochloric acid, and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Added to the resultant oil were 20 ml of methanol and 0.3 g of concentrated sulfuric acid, arid the mixture was refluxed under heat for 2 hours. The reaction mixture was allowed to cool, poured into 200 ml of water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 4.3 g of 6-bromo-4-methoxy-5-methylthiochroman as oil.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:19])[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.CO.[NH4+].[Cl-]>C1COCC1.[Zn]>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[C:10]3=[C:11]([CH3:19])[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:13][N:9]3[N:8]=[CH:7][N:6]=2)=[C:2]([F:1])[CH:23]=1
Reactant: CCOC(=O)c1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ncnc(Oc3ccc(N)cc3F)c2c1C
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (36 mg, 0.1 mmol) in THF (1.0 mL) was added MeOH (0.7 mL) followed by Zn (130 mg, 2.0 mmol) and NH4Cl (53 mg, 1.0 mmol). The reaction was heated at 70° C. overnight. LC/MS analysis indicated mostly starting material. The solution was shaken vigorously and then heated to 75° C. LC/MS analysis after 4 h showed the desired product and many other peaks. The reaction was filtered through a coarse filter, and the filtrate was concentrated to a give 55 mg of a brown residue. The residue was suspended in THF and passed through an HPLC filter resulting in a clear filtrate. The filtrate was concentrated in vacuo to give 54 mg of the title compound as a crude mixture which was used in the next step without further purification.
Reaction SMILES: [Na].[C:2]([CH2:6][C:7]([O:9]CC)=[O:8])(=O)[CH2:3][CH3:4].[CH2:12]([N:19]=[N+:20]=[N-:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C.O>[CH2:12]([N:19]1[C:2]([CH2:3][CH3:4])=[C:6]([C:7]([OH:9])=[O:8])[N:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)CC
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1c(C(=O)O)nnn1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4.3 g (187 mmoles) of sodium pellets in 80 ml of absolute ethanol under nitrogen was added 18.0 g (125 mmoles) of ethyl propionylacetate followed by 16.6 g (125 mmoles) of benzyl azide. The resulting reaction mixture was stirred under reflux for two days. Upon cooling to room temperature, 45 ml of 4M aqueous sodium hydroxide was added dropwise and the mixture was refluxed for 3 hours. The reaction was again cooled to room temperature and concentration in vacuo gave a gummy solid. This residue was dissolved in 125 ml of water and extracted with ether. Acidification (pH 1) with 12N hydrochloric acid caused precipitation of 25.1 g (87%) of 1(2 or 3)-benzyl-5-ethyl-1H-1,2,3-triazole-4-carboxylic acid as a tan solid. The structure was confirmed by n.m.r. and I.R.
Reaction SMILES: Br[C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]([CH2:15][CH3:16])[N:5]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:35]=[O:36]>O1CCCC1.C(Cl)Cl>[CH2:15]([CH:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:14][C:2]([CH:35]=[O:36])=[CH:3][C:4]=2[N:5]1[S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH3:16]
Reactant: CCC1c2ccccc2-c2sc(Br)cc2N1S(=O)(=O)c1ccc(OC)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC1c2ccccc2-c2sc(C=O)cc2N1S(=O)(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A solution of 2-bromo-4-[(4-methoxyphenyl)sulfonyl]-5-ethyl-4,5-dihydrothieno[3,2-c]isoquinoline (2.3 g, 5.0 mmol) in dry tetrahydrofuran (45 mL) was cooled to −78° C. and treated with a solution of butyllithium in hexanes (1.35 M, 3.7 mL, 5.0 mmol) during ca. 2 min followed immediately by the fast addition of dry dimethylformamide (1.9 mL, 25 mmol). After 30 min further at −78° C., the reaction was quenched with 10% aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (75 mL), dried (MgSO4), and concentrated in vacuo to give the crude product as a light orange solid (2.0 g) which was taken up in methylene chloride (ca. 8 ML) and pre-adsorbed on silica gel (8 g). Flash chromatography on silica gel (72 g) eluting 50-, then 75% methylene chloride-hexane, and then methylene chloride gave the title compound (1.7 g, 81%, m.p. 129-32° C.) as a pale yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:15]([C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1.Cl[C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[N:2]1[CH2:5][CH:4]([C:6]2[C:15]([C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1
Reactant: Clc1ccc2ccccc2n1
Reactant: Cc1cccc(-c2nc3ccccc3nc2C2CNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2nc3ccccc3nc2C2CN(c3ccc4ccccc4n3)C2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 2-azetidin-3-yl-3-m-tolyl-quinoxaline hydrochloride (311 mg, 1 mmol) and 2-chloro-quinoline (163 mg, 1.0 mmol) in DMF (6 mL) was added Cs2CO3 (650 mg, 2 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give 2-(1-quinolin-2-yl-azetidin-3-yl)-3-m-tolyl-quinoxaline (256 mg, 0.64 mmol yield 63.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][C:3]=1[OH:26].[C:27]([O:32]C)(=[O:31])[C@@H:28]([CH3:30])O.BrBr>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][C:3]=1[O:26][C@@H:28]([CH3:30])[C:27]([OH:32])=[O:31]
Reactant: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)ccc1Br
Reactant: COC(=O)[C@@H](C)O
Agent: BrBr
Product: C[C@H](Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)ccc1Br)C(=O)O

Procedure:
Prepared from of 2-bromo-5-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (Example 68) and commercially available (R)-lactic acid, methyl ester. White solid: mp 132-134° C.: MS (+EI): [M+], 2 bromine isotope pattern, 554, 556, 558; Anal. Calc. for C25H16Br2O3S: C, 53.98, H, 2.90, N, 0.00. Found: C,52.97, H, 2.98, N, 0.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[NH2:38][CH:39]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:38][CH:39]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40]1)=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NC2Cc3ccccc3C2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-aminoindane hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:24]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: COc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
3-Fluorophenylacetic acid (4.90 g, 32.07 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (3.5 ml, 40.08 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 50 ml dichloromethane. To this mixture, 4-bromoanisole (5.0 g, 26.72 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (5.3 g, 40.08 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (6.6 g, 80% yield. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 12.02(s,1H), 7.94(d, J=2.4 Hz, 1H), 7.57(dd, J=8.9,2.4.1 Hz, 1H), 7.36(m,1H), 7.04(m, 3H), 6.90(d, J=8.9 Hz, 1H),4.28(s, 2H).