Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH:17]1[N:21]2[C:22]3[C:28]([CH:29]=O)=[CH:27][NH:26][C:23]=3[N:24]=[CH:25][C:20]2=[N:19][N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].O>O.CN(C=O)C.C1COCC1>[C:12]([O:11][C:10](=[O:16])[NH:9][CH2:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:29][C:28]2[C:22]3[N:21]4[CH:17]=[N:18][N:19]=[C:20]4[CH:25]=[N:24][C:23]=3[NH:26][CH:27]=2)[CH2:3][CH2:4]1)([CH3:13])([CH3:15])[CH3:14]
Reactant: O=Cc1c[nH]c2ncc3nncn3c12
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](NCc2c[nH]c3ncc4nncn4c23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl trans-4-aminocyclohexylmethylcarbamate (0.059 g, 0.258 mmol, AMRI) was added to a mixture of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carbaldehyde (0.0403 g, 0.215 mmol, Preparation #38) and THF (1.0 mL). The mixture was stirred at ambient temperature for about 90 min. Sodium triacetoxyborohydride (0.068 g, 0.32 mmol) was added. After about 3 h, DMF (0.500 mL) was added. After about 15 h, Na(OAc)3BH (0.091 g, 0.43 mmol) was added. After about 24 h, Na(OAc)3BH (0.091 g, 0.43 mmol) was added. The mixture was warmed to about 40° C. After about 22 h, the mixture was allowed to cool to ambient temperature. Saturated aqueous NaHCO3/water (1:1, 2 mL) was added. After vigorously stirring for about 1 h, the solution was diluted with water (3 mL) and then extracted with EtOAc (6×10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified silica gel chromatography eluting with a gradient of 10-100% [(1% 7 N NH3 in MeOH) in 10% MeOH/DCM]/DCM to give tert-butyl(trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)methylamino)cyclohexyl)methylcarbamate (0.0476 g, 53%): LC/MS (Table 1, Method a) Rt=1.24 min; MS m/z 400 (M+H)+.
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[C:5]([O:7]C)=O.C[O-].[Na+].Cl.[C:23]([NH2:26])(=[NH:25])[CH3:24]>CO>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][C:4]1[C:3]([OH:18])=[N:25][C:23]([CH3:24])=[N:26][C:5]=1[OH:7]
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(C)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A solution of 10 g of dimethyl-(o-methoxyphenoxy)malonate (Example 1b) in 80 ml dry methanol was cooled to 0° C. 6.71 g of sodium methylate was added portionenwise. To the suspension was added 2.84 g of acetamidine hydrochloride and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was suspended in 100 ml of diethyl ether. The solid was filtered off, washed with another portion of 100 ml of diethyl ether and dissolved in 50 ml of water. The pH was adjusted to 4 by adding 25 ml of glacial acetic acid. The white precipitate that formed was filtered off, washed with water and dried to yield 5.17 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl-pyrimidine (or a tautomer) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:47][C:48]([F:62])([F:61])[C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:51][CH:50]=1>C1COCC1>[CH:13]([O:12][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=1[C:8]([N:58]1[CH2:57][CH2:56][N:55]([C:52]2[CH:51]=[CH:50][C:49]([C:48]([F:61])([F:62])[F:47])=[CH:54][CH:53]=2)[CH2:60][CH2:59]1)=[O:10])([CH3:15])[CH3:14]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C#N)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.6 mmol 5-cyano-2-isopropoxy-benzoic acid (compound 1.13) in 20 ml THF were added 4.0 mmol TBTU, 21.6 mmol N-ethyldiisopropylamine and 4.0 mmol 1-(4-trifluoromethyl-phenyl)-piperazine (commercial). The reaction was then stirred at RT for 16 h, concentrated in vacuo, and purified by chromatography on silica gel (eluant: ethyl acetate/heptane 1:1) to afford the title compound. MS (m/e): 418.3 (M+H+, 100%)
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[CH2:34][NH2:35]>>[CH3:18][N:15]1[C:14]([C:19](=[O:21])[NH:35][CH2:34][C@H:30]2[CH2:31][CH2:32][CH2:33][O:29]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Reactant: NC[C@H]1CCCO1
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)NC[C@H]1CCCO1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (30 mg, 79 μmol; example 236, step 3) and (R)-(tetrahydrofuran-2-yl)methanamine (15 μl, 142 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (35 mg, 96%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]([F:18])=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.[Ni]>[CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]([F:18])=[C:13]([CH:14]=1)[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc(F)c(N)cc1OCc1ccccc1
Yield: 100.1 %

Procedure:
5-Benzyloxy-2-fluoro-4-methyl-1-nitrobenzene (500 mg, 1.9 mmol) in methanol (10 ml) was added to a suspension of Raney nickel (75 mg) and hydrazine hydrate (465 ml, 9.5 mmol) in methanol (10 ml) and heated at reflux. The mixture was maintained under reflux for 15 minutes and then the insoluble materials removed by filtration through diatomaceous earth. The filter pad was washed with methanol and the solvent removed from the filtrate by evaporation to give 5-benzyloxy-2-fluoro-4-methylaniline (440 mg, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([Cl:28])=[C:23]([F:29])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30]N1C(=O)CCC1=O>CC#N.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:30])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([F:29])[C:24]([Cl:28])=[C:25]([F:27])[CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(Cl)c(F)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(Cl)c(F)c1
Temperature: 70 °C

Procedure:
To a yellow homogeneous solution of 8-[2-(4-chloro-3,5-difluoro-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.150 g; 2.700 mmol) in anhydrous MeCN (40 ml) was added dropwise, at rt, a solution of N-chlorosuccinimide (0.367 g; 2.700 mmol; 1 eq.) in anhydrous MeCN (10 ml). The resulting solution was then heated to 70° C., under nitrogen, for 3 h30. Concentration to dryness afforded a yellow oily residue which was dissolved in EA (80 ml), and this organic layer was washed with aq. sat. NaHCO3 (2×120 ml), was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/EA=2/3) gave the expected 1-chloro-8-[2-(4-chloro-3,5-difluoro-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.724 g; 58%). LC-MS: tR=1.08 min.; [M+H]+=461.94 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]1[S:21][C:22]1[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1>C(O)C>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:27]([C:25]3[O:26][C:22]([S:21][C:13]4[NH:14][C:15]5=[N:16][CH:17]=[CH:18][CH:19]=[C:20]5[N:12]=4)=[CH:23][CH:24]=3)[C:30]3[C:31](=[O:35])[CH2:32][CH2:33][CH2:34][C:29]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=Cc1ccc(Sc2nc3ncccc3[nH]2)o1
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)c1[nH]ccc1N
Solvent: CCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cccnc3[nH]2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
A suspension of 69.2 mg (0.45 mmol) of 3-amino-2-ethoxycarbonylpyrrole and 110.0 mg (0.45 mmol) of 5-(1H-imidazo[4,5-b]pyridin-2-ylsulfanyl)-furan-2-carbaldehyde (obtained from step 1) in 5 mL of ethanol under argon is stirred at room temperature for 1 hour. 1,3-Cyclohexanedione (50.3 mg, 0.45 mmol) is then added and the reaction mixture is heated at reflux temperature for 16 h. The mixture is then cooled to room temperature and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 30 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol from 100/0 to 90/10 v/v). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a prepacked 30 g 15-40 μm silica gel cartridge (eluting solvent: toluene/2-propanol 85/15 v/v). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a prepacked 25 g 15-40 μm silica gel cartridge (eluting solvent: toluene/2-propanol 85/15 v/v). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a prepacked 15 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate/methanol/triethylamine 92/4/4 v/v/v). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. 37 mg of 9-[5-(3H-imidazo[4,5-b]pyridin-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester are obtained as a yellow powder. mp: 190-202° C. LCMS: m/z 476: [M+H]+ (base peak); m/z 474: [M−H]− (base peak).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=1.[Sn](Cl)[Cl:19]>O.Cl>[ClH:19].[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][NH2:1])=[CH:11][CH:10]=1)[CH3:17]
Reactant: O=N[O-]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1ccc(NN)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A solution of sodium nitrite (NaNO2, 4.04 g, 58.6 mmol) in H2O (20 mL) was added to a cooled (−5° C., ice-salt) solution of ethyl 4-aminophenylacetate (10 g, 55.8 mmol) in conc. HCl (55 mL), at a rate such that the temperature did not exceed 0° C. The mixture was stirred at 0° C. for 10 min and then added portion-wise to a cooled (−5° C., ice-salt) and rapidly-stirred solution of tin(II) chloride (SnCl2, 39.67 g, 209.2 mmol) in conc. HCl (30 mL), at a rate such that the temperature did not exceed 0° C. The resulting cream-colored suspension was warmed to 25° C. and stirred at room temperature for 2-3 hrs and then was filtered under vacuum. The collected solid was washed with water and ether and then air dried to afford the desired product as a pale solid (HCl salt). Precipitate that formed in the filtrates upon standing for 16 h was collected by filtration, washed with water and ether, and air-dried. The combined solids were obtained in 88% yield (11.28 g). 1H-NMR (DMSO-d6) δ 8.85 (broad, 2H), 7.73 (broad, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.03 (q, J=7.0 Hz, 2H), 3.53 (s, 2H), 1.16 (t, J=7.1 Hz, 3H); MS LC-MS [M+H]+=195.0, RT=1.11 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH2:8].C(OC)(OC)OC.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=O.[BH4-].[Na+]>CO>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][NH:8][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: O=Cc1ncc[nH]1
Reactant: Cn1ccnc1CN
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: Cn1ccnc1CNCc1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
The compound (201 mg) obtained in Example 14-7 was dissolved in methanol (4.0 ml) and added with trimethyl orthoformate (200 μl) and 2-imidazole carboxaldehyde (115 mg) and the whole was stirred at room temperature for 30 minutes. After having been cooled to 0° C., the solution was added with sodium borohydride (89.6 mg) and then the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with water, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (137 mg) as a pale-yellow oily substance.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)(=[O:3])[CH3:2].[CH2:11]([NH2:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(OCC)(=O)C>[CH2:11]([NH:33][C:6](=[O:8])[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCOC(=O)CNC(C)=O
Reactant: CCCCCCCCCCCCCCCCCCCCCCN
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCCCCCNC(=O)CNC(C)=O
Temperature: 150 °C

Procedure:
A mixture consisting of 1.13 gm (0.01 mol) of ethyl N-acetyl-glycinate and 2.50 gm (0.0078 mol) of n-docosyl-amine was heated for 90 minutes at 150°C., while stirring. Thereafter, ethyl acetate was added to the hot reaction mixture, and upon cooling of the mixture a crystalline substance separated out which was collected and again recrystallized from ethyl acetate in the presence of activated charcoal and silicagel. 1.5 gm (55% of theory) of the compound of the formula ##EQU6## having a melting point of 135°-137°C. were obtained.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([OH:21])[CH:15]=1)[CH3:11].Cl[CH2:24][O:25][CH3:26]>ClCCl.CCOCC>[CH2:10]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH2:24][O:25][CH3:26])[CH:15]=1)[CH3:11]
Reactant: COCCl
Reactant: CCOC(=O)c1ccc(C)c(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C)c(OCOC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N,N-Diisopropylethylamine (5.3 mL, 30.5 mmol) (Aldrich) was added to a suspension of ethyl 3-hydroxy-4-methylbenzoate (5.0 g, 27.75 mmol) (from Example 2 supra) in dichloromethane (20 mL) with cooling in an ice-water bath. Chloromethylmethyl ether (4.2 mL, 55.5 mmol) (Aldrich) was then added dropwise and the mixture stirred at room temperature for 5 hours. The mixture was then diluted with ether (100 mL) and washed with mixture of water (100 mL), followed by 0.1 N HCl (2×100 mL) and brine (100 mL). Aqueous layers were back washed with ether (100 mL). Organic solutions were combined, dried (MgSO4), filtered and concentrated. Residue was filtered through silica gel (Biotage 40 L) eluting with dichloromethane. Fractions were combined and concentrated to give 3-methoxymethoxy-4-methyl-benzoic acid ethyl ester as colorless oil. (Yield 4.88 g, 78.4%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]#[C:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:13]=[CH:12][C:11]=1[O:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[O:26][C:11]1[CH:12]=[CH:13][C:14]([C:16]#[C:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:15][C:10]=1[CH2:9][NH:7][CH3:6]
Reactant: CN(Cc1cc(C#CCCN2CCOCC2)ccc1Oc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(C#CCCN2CCOCC2)ccc1Oc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a solution of [2-(3,4-dichloro-phenoxy)-5-(4-morpholin-4-yl-but-1-ynyl)-benzyl]-methyl-carbamic acid tert-butyl ester (95.6 mg, 0.18 mmol) in DCM (2 mL) was added TFA (1 mL). After 30 min, the mixture was concentrated and the residue was purified by FCC to give the desired product (67.7 mg, 89%). MS (ESI): mass calcd. for C22H24Cl2N2O2, 418.12; m/z found, 419.3 [M+H]+. 1H NMR (CDCl3): 7.49-7.47 (m, 1H), 7.37 (d, J=8.8, 1H), 7.27 (dd, J=8.3, 2.0, 1H), 7.02 (d, J=2.8, 1H), 6.82-6.78 (m, 2H), 3.75-3.69 (m, 6H), 2.70-2.64 (m, 2H), 2.62-2.57 (m, 2H), 2.55-2.51 (m, 4H), 2.42 (s, 3H), 1.80-1.69 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[CH:3]1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[NH2:31][C:32]([NH2:34])=[O:33].Cl>CCO>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17]
Reactant: Cn1cnc(C(=O)Cc2ccccc2)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cn(C)cn3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 30.7 %

Procedure:
A mixture of 1-(1-methyl-1H-imidazol-4-yl)-2-phenylethanone (Intermediate 40) (130 mg, 0.65 mmol), compound 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (165 mg, 0.78 mmol), and urea (117 mg, 1.95 mmol) in anhydrous EtOH (5 mL) was added concentrated HCl solution (0.2 mL), the reaction mixture was refluxed for 16 hours. The reaction mixture was concentrated under reduced pressure, and purified by column chromatograph and preparative HPLC to afford Compound 80 as a yellow solid (87 mg, yield: 30.8%). 1H NMR (DMSO-d6 400 MHz): δ 10.31 (s, 1H), 8.62 (m, 2H), 7.68 (s, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.19-7.22 (m, 3H), 7.06 (m, 2H), 6.97-7.00 (m, 2H), 5.25 (d, J=2.4 Hz, 1H), 3.95-4.07 (m, 2H), 3.67 (s, 3H), 1.29-1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 436.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.N1CCCC1=O.[CH3:57][C:58]([OH:62])([C:60]#[CH:61])[CH3:59]>>[OH:62][C:58]([CH3:59])([CH3:57])[C:60]#[C:61][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1CN1CCCC1=O)CCOc1ccc(Br)cc1-2
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: O=C1CCCN1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CN3CCCC3=O)n1CCO2
Yield: 63 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((2-oxopyrrolidin-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with 2-pyrrolidinone) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (64 mg, 63%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:6]=[CH:5]2.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH2:13]([CH:12]([CH2:15][CH3:16])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:25][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH3:14]
Reactant: CCC(CC)Cn1ccc2cc(Br)ccc21
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCC(CC)Cn1ccc2cc(-c3ccc(OC(F)(F)F)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-(2-ethylbutyl)-1H-indole and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (APCI, [M+H]+) m/z 362. 1HNMR (300 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.77 (d, 2H, J=8.56 Hz), 7.51 (d, 1H, J=8.50 Hz), 7.44-7.39 (m, 4H), 6.49 (d, 1H, J=3.12 Hz), 4.07 (d, 2H, J=7.32 Hz), 1.80 (hep, 1H), 1.24 (p, 4H), and 0.85 ppm (t, 6H).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].[C:13](O)(=O)[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>Cl>[CH:14]([C:16]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:2])=[O:12])[C:5]=2[N:11]=1)([CH3:15])[CH3:13]
Reactant: CC(C)C(=O)O
Reactant: COC(=O)c1cccc(N)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1nc2c(C(=O)O)cccc2[nH]1
Temperature: 10 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A slurry of 2,3-diaminobenzoic acid methyl ester (21.5 g, 0.13 mol) and isobutyric acid (36.2 mL, 0.39 mol) in aqueous hydrochloric acid (4M, 210 mL) was stirred under reflux for 24 h to afford a homogenous solution. The solution was cooled to 10° C. and the pH raised to 3.5 using aqueous sodium hydroxide solution (4M, approx. 210 mL), while maintaining the temperature below 30° C. The reaction mixture was stirred at room temperature for 2 h, cooled to 10° C., and the resultant precipitate filtered off. The solid cake was transferred to a beaker and acetonitrile (300 mL) was added. The slurry was stirred at room temperature for 1 h then and filtered to afford a grey solid. The solid was dried under vacuum to afford the title intermediate (23 g, 0.11 mol, 87%). (m/z): [M+H]+ calcd for C11H12N2O2 calcd. 205.09; found 205.3. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.27 (d, 6H), 3.39 (m, 1H), 7.29 (t, 1H), 7.78 (m, 2H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:27])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10](Br)[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[N-:33]=[N+:34]=[N-:35].[Na+].O>C(OCC)(=O)C>[C:1]([NH:5][C:6](=[O:27])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([N:33]=[N+:34]=[N-:35])[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)NC(=O)CN1C(=O)C(Br)CC(c2ccccc2)c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)CN1C(=O)C(N=[N+]=[N-])CC(c2ccccc2)c2ccccc21
Temperature: 75 °C

Procedure:
To a 250 ml round-bottomed flask equipped with N2 inlet were added N-tert-butyl-2-[3-bromo-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide, (8.317 g, 19.37 mmoles), 90 ml dimethylformamide (DMF), and sodium azide (5.25 g, 80 mmoles, under nitrogen), and the mixture was heated at 75° C. for 20 hours with stirring. The reaction mixture was then cooled and distributed between water and ethyl acetate, separated, and the aqueous phase was again extracted. The combined extracts were washed with water three times, with bicarbonate solution once, and then dried with brine and sodium sulfate and filtered and evaporated, leaving a gummy residue, 8.58 g (100%), containing some solvent.