Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][CH2:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=3)[N:7]=2)[CH2:3]1.[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][CH:2]2[CH2:10][CH2:9][C:8]3[C:4](=[CH:5][N:6]([C:11]4[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=4)[N:7]=3)[CH2:3]2)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCOC(=O)c1sc(-n2cc3c(n2)CCC(N)C3)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(-n2cc3c(n2)CCC(NC(=O)c2nc(Cl)c(CC)[nH]2)C3)nc1C
Yield: 75.1 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-(5-amino-4,5,6,7-tetrahydro-2H-indazol-2-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (243a) (127 mg, 0.42 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (72 mg, 0.42 mmol), WSC hydrochloride (239 mg, 1.25 mmol), 1-hydroxybenzotriazole (56 mg, 0.42 mmol) and N-methylmorpholine (0.09 mL, 0.83 mmol), to obtain 146 mg of the title compound as a pale yellow solid (76%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:34]=1)=[O:4].[CH3:35][NH2:36].CO>C(#N)C>[CH3:35][NH:36][CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:34]=1)=[O:4]
Reactant: O=C(CCl)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CN
Solvent: CO
Solvent: CC#N
Product: CNCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 25 %

Procedure:
Using N-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide (92 mg, 0.187 mmol), methylamine/methanol (2 mL) solution and acetonitrile (1 mL) as starting materials and in the same manner as in Example 398, the title compound (22 mg, 25%) was obtained as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([C:15](=[O:33])[CH:16](C(OCC)=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH:8]=1)C.Cl>C(O)(=O)C>[CH2:34]([CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([C:15](=[O:33])[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=2)[CH:8]=1)[C:4]([OH:36])=[O:3])[CH3:35]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C(=O)C(Cc2ccc(C(F)(F)F)cc2)C(=O)OCC)c1
Agent: Cl
Solvent: CC(=O)O
Product: CCC(Cc1ccc(OC)c(C(=O)CCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A mixture of ethyl-3-[3-[2-ethoxycarbonyl-3-[4-(trifluoromethyl)phenyl]propionyl]-4-methoxyphenyl]-2-ethylpropanoate (2.62 g, 5.15 mmol), glacial acetic acid (10 mL) and concentrated hydrochloric acid (5 mL) was refluxed for 5 hours. After cooling, the mixture was poured into ice water, which was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate:acetic acid=400:100:1.5 v/v/v) to afford 1.47 g (70%) of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]#[N:4].[OH2:18]>Cl>[OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([NH2:4])=[O:18]
Reactant: O
Reactant: CCCCCCCCCCCCCC(O)C#N
Agent: Cl
Product: CCCCCCCCCCCCCC(O)C(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Hydroxypentadecanenitrile (1.0 g) was suspended in concentrated hydrochloric acid (15 ml), and this suspension was vigorously stirred at room temperature for 24 hours. Then, this mixture was diluted with water (45 ml). The insoluble powder was collected by filtration, washed with water (10 ml×3), and dried to give 2-hydroxypentadecanamide (1.06 g).
Reaction SMILES: [N+:1]([C:4](=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)C(=O)CCC)([O-:3])=[O:2].[H-].[Na+].[C:18](Cl)(=[O:20])[CH3:19]>C(COC)OC.C(Cl)(Cl)Cl>[C:18]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:4][N+:1]([O-:3])=[O:2])(=[O:20])[CH3:19]
Reactant: CCCC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: CC(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 23 g of 1-nitro-1-(tetrahydro-2H-1,3-thiazin-2-yl-idene)-2-pentanone in 200 ml of monoglyme was added dropwise at 0° C. to a suspension of 4.65 g of a 57% sodium hydride/mineral oil dispersion in 100 ml of monoglyme. The stirred mixture was allowed to warm to room temperature and stirred overnight. A solution of 8.2 g of acetyl chloride in 50 ml of monoglyme was added dropwise to the reaction at 0° C. The resulting mixture was stirred for one hour at 0° C., then allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with chloroform and extracted with 10% sodium hydroxide solution. The organic phase was separated, washed with water, then with saturated sodium chloride solution, and dried Na2SO4), and the solvent was evaporated under reduced pressure. The resulting liquid was chromatographed, using a wet column with silica gel. As eluent, there was first used 2 litres of a 98/2 chloroform/acetone mixture, then a 95/5 chloroform/acetone mixture was used. Three fractions were obtained. The last fraction was triturated with ether, then cooled, to give a solid yellow product, 3-acetyl-2-nitromethylene-tetrahydro-2-H-1,3-thiazine, m.p. 91°-92.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[SH2:12].C(NCC)C>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[S:12])[NH2:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1O
Reactant: S
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1cc(C(N)=S)ccc1O
Temperature: 70 °C

Procedure:
A solution of 4-hydroxy-3-methoxybenzonitrile (15.0 g, 0.1 mol) in DMF (150 mL) was treated with a slow flow of gaseous hydrogen sulfide for 30 minutes at rt. Diethyl amine (15.6 mL, 11.0 g, 0.15 mol) was added and the solution was heated at 70° C. for 4 h. The solution was cooled to rt and the residual H2S was removed by passing argon through the solution for 30 minutes. The solvent was evaporated under reduced pressure and the residue was filtered through a plug of silica, followed by washing with EtOAc. Removal of the solvent resulted in a crude brown oil, which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7](F)[N:6]=[C:5]([F:11])[C:4]=1[F:12].[CH3:13][NH:14][CH3:15].O>C(O)C>[CH3:13][N:14]([CH3:15])[C:7]1[C:8]([F:9])=[C:3]([CH2:2][OH:1])[C:4]([F:12])=[C:5]([F:11])[N:6]=1
Reactant: OCc1c(F)c(F)nc(F)c1F
Reactant: CNC
Solvent: CCO
Solvent: O
Product: CN(C)c1nc(F)c(F)c(CO)c1F
Yield: 87.3 %

Procedure:
A mixture of 1.0 g (0.0055 mole) of 4-hydroxymethyl-2,3,5,6-tetrafluoropyridine (from Example 5) and 0.23 g (0.0050 mole) of dimethylamine in 25 ml of ethanol was refluxed for approximately twenty hours. The reaction mixture was cooled and was poured into water. This mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure, yielding 0.9 g of 2-dimethylamino-4-hydroxymethyl-3,5,6-trifluoropyridine as a yellow oil. The structure and nmr spectra are set forth in Table 1C below.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CN(C)CCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-(dimethylamino)ethylamine according to general procedure 1 providing the amino compound (456 mg, 74%) as a white solid; Rf=0.43 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J=9.6 Hz, 1H), 7.46 (s, 1H), 6.77 (d, J=9.7 Hz, 1H), 3.83 (t, J=5.9 Hz, 2H), 3.48 (t, J=6.0 Hz, 2H), 3.01 (s, 6H); ES-MS: (M+H)=284, 286 m/z.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.088 mmol), 4-aminobutyric acid (726 mg, 7.0 mmol) and NaOMe solution (10.6 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 526.32 (M+1).
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC=CCCC=CCCC1
Reactant: [H][H]
Agent: [Pd]
Product: O=C1CCCCCCCCCCC1

Procedure:
In a reactor battery consisting of a tubular reactor with liquid circuit and a postreactor, cyclododeca-4,8-dien-1-one was hydrogenated continuously (30 bar, temperatures 130°, each reactor in trickle mode, catalyst 0.2% Pd on alumina), which also comprised approx. 0.5% polyunsaturated C12-aldehydes. The entire amount of hydrogen (2.1 molar equivalents based on reactant, i.e. 5 mol % hydrogen excess) was introduced into the main reactor and transferred together with the product stream into the postreactor. Downstream of the postreactor, the residual gas was discharged as offgas. At a total catalyst hourly space velocity of 0.5 kg of dienone/liter of catalyst×h, the conversion was 99.8%, i.e. the reaction effluent still contained 0.2% of unconverted olefin. In a subsequent distillation, it was possible to obtain cyclododecanone in a purity of 99.4%; 0.2% of unsaturated cyclododecanone was undesired secondary constituent.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([CH:26]([CH2:29][CH3:30])[CH2:27][NH2:28])[CH3:25]>>[CH2:24]([CH:26]([CH2:29][CH3:30])[CH2:27][NH:28][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH3:25]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CCC(CC)CN
Product: CCC(CC)CNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 95 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2-ethylbutylamine instead of methylamine, to the title compound (121 mg, 95%) which was obtained as an off white solid. MS: m/e=394.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[N:11]([O-])=O.[Na+]>Cl>[C:5]([C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][N:11]=1)#[N:6]
Reactant: N#CCc1ccccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of o-aminobenzyl cyanide (0.5 g) in aqueous hydrochloric acid 1N (9.6 mL), was treated with a solution of aqueous sodium nitrite 1N (3.85 mL). After stirring at room temperature for 15 minutes, the reaction mixture was filtered. The solid was recrystallised from ethanol to give the title compound (0.4 g) as a yellow solid, m.p. 138-140° C. 1H NMR [(CD3)2SO]: δ 7.89 (d, 1H, J=7.7 Hz); 7.76 (d, 1H, J=7.9 Hz); 7.48 (t, 1H); 7.41 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:20][N:19]=[C:18]2[CH2:28][O:29][CH3:30])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13]C)[C:6]([O:15]C)=[N:5]2.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:17]2[C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:20][N:19]=[C:18]2[CH2:28][O:29][CH3:30])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:15])[NH:5]2
Reactant: COCc1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: Cl
Solvent: C1COCCO1
Product: COCc1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Yield: 71.2 %

Procedure:
A mixture of (±)-6,7-dichloro-2,3-dimethoxy-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (3.0 g, 6.7 mmol), 2M aqueous hydrochloric acid solution (10 ml) and 1,4-dioxane (50 ml) was heated under reflux for 9 hours, cooled, and concentrated under reduced pressure. The residue was dissolved in 1M aqueous sodium hydroxide solution and acidified to pH 4.5 with concentrated hydrochloric acid to afford a thick white precipitate. This was collected by filtration and washed with water to give (±)-6,7-dichloro-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,3(1H,4H)-quinoxalinedione (2.0 g, 68%) as an off-white solid. mp 230-232° C.
Reaction SMILES: [C:1]1([C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24](=O)[CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][C:44]([NH2:46])=[S:45])[CH:38]=1>>[ClH:36].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][C:44]2[S:45][C:23]3[CH2:22][CH2:21][N:20]([C:18]([C:15]4[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]5[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=5[C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:13][CH:14]=4)=[O:19])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24]=3[N:46]=2)[CH:38]=1
Reactant: NC(=S)Cc1cccnc1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: Cl
Product: O=C(Nc1ccc(C(=O)N2CCc3sc(Cc4cccnc4)nc3-c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 18.3 %

Procedure:
Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide and 400 mg of 3-pyridylthioacetamide hydrochloride, the procedure of Example 5 was repeated to obtain 100 mg of 4'-[[2-(3-pyridylmethyl)-5,6-dihydro-4H-thiazolo[5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide hydrochloride as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26]>>[CH:28]1([O:27][C:25](=[O:26])[NH:1][C:2]2[C:3]([C:7]3[NH:23][C:10]4=[CH:11][C:12]5[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=5[CH:17]=[C:9]4[N:8]=3)=[N:4][NH:5][CH:6]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)OC1CCCC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OC4CCCC4)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid cyclopentyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and cyclopentyl chloroformate (126 μl, 0.97 mmol). The title compound was obtained as yellow powder (116 mg, 34%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH2:9][CH3:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCc1cc(Br)ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(Br)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
4-Bromo-2-ethylaniline (500 mg, 2.50 mmol) was dissolved in toluene (25 mL), sodium carbonate (397 mg, 3.75 mmol) and benzyl chloroformate (0.428 mL, 3.00 mmol) were added and the mixture stirred under nitrogen at room temperature. After 20 hours water (25 mL) was added, the aqueous phase separated and washed with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. Chromatography (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I38) (708 mg, 85%) as a pink solid; 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.44-7.28 (m, 7H), 6.43 (s, 1H), 5.20 (s, 2H), 2.54 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H). LCMS Method C: rt 6.46 min; 258.0 [M-PhCH2O+CH3OH]+.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O)(=O)[CH3:2].Cl.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C.O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:5]3[C:6]4[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[CH:10][C:11]=4[CH2:12][CH2:13][C:4]=3[C:1]([CH3:2])=[N:33]2)=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc2c(c1)C(=O)C(C(C)=O)CC2
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)-c1c(c(C)nn1-c1ccc(OCc3ccccc3)cc1)CC2
Yield: 32.1 %

Procedure:
2-Acetyl-7-methoxy-3,4-dihydro-2H-naphthalen-1-one (72.5 mg, 0.33 mmol) and 4-benzyloxyphenylhydrazine hydrochloride (90 mg, 0.36 mmol) were heated in ethanol at 70° C. for 2.5 days. The reaction was diluted with water and extracted with ethyl acetate. The organic extracts were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, dried over MgSO4, and concentrated. SiO2 chromatography with 5-20% ethyl acetate/hexanes gave 42 mg of the desired product. LC-MS (C26H24N2O2 calculated 396) m/z 397 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:21](=[O:22])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2c(Cl)c(NC(=O)Cc3ccc(Cl)cc3)ccc2s1
Yield: 76 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-chlorophenylacetyl chloride (65 mg, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave N-(4-chloro-2-methyl-benzothiazol-5-yl)-2-(4-chloro-phenyl)-acetamide (65 mg, 0.19 mmol, 80% yield) as a white powder after crystallisation in hexane/DCM.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[N+:29]([O-])([O-:31])=[O:30].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[CH:6]=[CH:5][C:4]=1[N+:29]([O-:31])=[O:30]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cccc2c1CCCC(=O)N2C
Agent: [K+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
To a solution of 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-1) (538 mg, 2.62 mmol) in acetonitrile brought to 0° C. in an ice bath was added 1.8 mL TFAA (2.7 g, 13.1 mmol), followed by KNO3 (320 mg, 3.14 mmol). After approximately 5 minutes, the reaction was allowed to warm to room temperature. Conversion of starting material to product was monitored by LC/MS. Upon completion, the reaction was cooled to 0° C. in an ice bath and quenched with sat. NaHCO3 (aq), 1N NaOH (aq), and ice until pH ˜9-10 was achieved. The aqueous mixture was extracted 3× with EtOAc and the organic layers were washed with brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-2) as an orange solid (530 mg, 82%). By NMR, the product showed a 4:1 mixture of nitration products, 80% of which was the desired product. By TLC, the products appeared inseparable, so the material was taken on for reduction crude. Data for Major Isomer: 1H-NMR (CDCl3) δ 7.83 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 3.37 (s, 3H), 2.87 (br m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.24 (m, 2H); LC/MS (ESI-pos) m/z 251.03 (M+H).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([N:13]([CH3:43])[C:14]([N:16]([CH3:42])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:46]C(C)([O-])C.[K+].CI>CN(C=O)C>[F:45][C:2]([F:44])([F:1])[C:3]1[CH:4]=[C:5]([N:13]([CH3:43])[C:14]([N:16]([CH3:42])[C@H:17]2[C@H:21]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:32][CH2:33][C@H:34]([N:37]([CH3:46])[S:38]([CH3:41])(=[O:39])=[O:40])[CH2:35][CH2:36]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](NS(C)(=O)=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](N(C)S(C)(=O)=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the compound (0.23 g) obtained in Example 242 in DMF (7.0 mL) were added potassium tert-butoxide (0.079 g) and methyl iodide (0.055 mL) at 0° C. The mixture was stirred at room temperature for 12 hr, diluted with ice water, and extracted with ethyl acetate. The extract was washed with water, 1N aqueous potassium hydrogen sulfate solution and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (0.17 g, 70%) as a white powder.