Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22](C(O)=O)=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.SCC(O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Agent: O=C(O)CS
Solvent: O
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 170 °C
Yield: 23.7 %

Procedure:
A mixture of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (32) (102 mg, 0.22 mmol) and mercaptoacetic acid (2.2 mL) was heated to 170° C. for 1 h. At this time, the reaction mixture was cooled to room temperature and was diluted with water (120 mL) and was extracted with ethyl acetate (100 mL). The organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution (2×100 mL) and a saturated aqueous sodium chloride solution (100 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was dissolved in methylene chloride and was purified by flash chromatography (Biotage 40S) using silica gel eluted with 100% ethyl acetate to elute the impurity followed by 0.2% glacial acetic acid in ethyl acetate to elute the desired product. The desired fractions were collected and concentrated under vacuum. The resulting solid was slurried in hot methanol (2 mL), filtered and rinsed with petroleum ether. The solids were dried in a vacuum oven at 80° C. to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (33) (21.4 mg, 23%) as a yellow solid; EI(+)-HRMS m/z calcd for C16H13Cl2N5O4 (M+) 410.0418, found 410.0419. Molecular Weight=410.2191; Exact Mass=409.0345
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1cccc(C=O)c1
Yield: 848.3 %

Procedure:
A mixture of 1.00 g (0.82 mmol) of 3-hydroxybenzaldehyde, 1.70 g (12.2 mmol) of potassium carbonate and 2.16 g (9.00 mmol) of 1-iodooctane were warmed in acetonitrile at 80° C. for 16 h. The reaction was cooled, filtered and concentrated. The residue was purified using flash chromatography using 20:1 v/v hexane/ethyl acetate to afford 1.63 g of the title compound as a colorless oil: 1H-NMR (500 MHz) δ 0.89 (t, J=6.9, 3H), 1.24-1.39 (m, 8H), 1.42-1.50 (m, 2H), 1.80 (m, 2H), 4.01 (t, J=6.6, 2H), 7.19 (m, 1H), 7.40 (s, 1H), 7.44-7.46 (m, 2H), 9.99 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8](Cl)[N:7]=1.[NH3:15].C(O)C>S([O-])([O-])(=O)=O.[Cu+2].CCOCC>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([NH2:15])[N:7]=1
Reactant: N
Reactant: Cc1cc(Cl)nc(NCCN(C)C)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(N)nc(NCCN(C)C)c1

Procedure:
A mixture of 2-(2-dimethylaminoethylamino)-4-methyl-6-chloropyridine (from Example 77, Part A) (21.4 g., 0.1 mole), liquid ammonia (85 g) and copper sulfate catalyst (1.0 g) in 150 ml. ethanol is heated at 200° C. for 48 hours in a pressure vessel. The cooled reaction mixture is filtered and concentrated in vacuo. The residual oil is dissolved in 125 ml of chloroform, washed with excess sodium hydroxide and then with saturated sodium chloride solution, dried, filtered and concentrated in vacuo. The 16.0 g. of crude oil obtained is taken up in 100 ml of ether, filtered and extracted into dilute hydrochoric acid. The acidic extract is made basic and the product is extracted into ether. After drying and removing the ether in vacuo, the product (8.0 g.) is distilled. Purified material is collected at 125°-128° C. at 0.4 mm.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([O:16][CH2:17]C)=[O:15])=[CH:4]1.[CH:19]([C:22]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=1[S:34](Cl)(=[O:36])=[O:35])([CH3:21])[CH3:20].O>CCCCCC.CN(C=O)C>[CH:19]([C:22]1[CH:27]=[C:26]([CH:28]([CH3:29])[CH3:30])[CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=1[S:34]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4]1)(=[O:36])=[O:35])([CH3:20])[CH3:21]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: CCOC(=O)CCc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(S(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)c2ccccc12
Reaction time: 1 h
Yield: 102.1 %

Procedure:
Sodium hydride (60% oil 19.03 g 0.476 mol) was washed with n-hexane, and was suspended in DMF (500 ml). To the suspension was gradually added a solution of ethyl indole-3-propionate acid (64.79 g 0.317 mol) in DMF(100 ml). The mixture was stirred for one hour at 40°-50° C., and to the mixture was gradually added, under ice-cooling, 2,4,6-triisopropylphenylsulfonyl chloride (115.25 g, 0.38 mol), followed by stirring for one hour at room temperature. To the reaction mixture was added water (150 ml), and the mixture was subjected to extraction with n-hexane (500 ml). The extract solution was washed with water (100 ml) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to to leave the title compound (152 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.Cl[C:15]([CH3:22])([CH:17]([N:20]=[O:21])[CH2:18][CH3:19])[CH3:16]>C(#N)C>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:15]([CH3:22])([C:17](=[N:20][OH:21])[CH2:18][CH3:19])[CH3:16]
Reactant: NCCCCN
Reactant: CCC(N=O)C(C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(=NO)C(C)(C)NCCCCN

Procedure:
To a stirred solution of 1,4-diaminobutane (0.26 g; 2.9 mmol) and triethylamine (0.33 g; 3.2 mmol) in acetonitrile (5 ml) was added a solution of 2-chloro-2-methyl-3-nitrosopentane (0.485 g; 3.24 mmol) in acetonitrile (5 ml). After stirring for ca 10 minutes the product began to precipitate. The reaction mixture was stirred overnight and the product was filtered off and dried in vacuo to give a white powder, (0.5 g; 86%).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.C([O-])([O-])=O.[K+].[K+].[C:21]([O:25][CH3:26])(=[O:24])[CH2:22][SH:23]>>[CH3:26][O:25][C:21]([C:22]1[S:23][C:4]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:24]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,4-dinitrobenzaldehyde (6.45 g, 32.9 mol) and K2CO3 (5.45 g, 39.4 mmol) in DMIF (60 mL) was slowly added methyl thioglycolate (3.0 mL, 32.9 mmol). The mixture was stirred at RT for 1 h, then at 50° C. for 2 h. The resultant mixture was poured into H2O/ice and stirred until a precipitate formed. The solid was filtered and triturated with hot MeOH. The pale brown solid was filtered. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.33 (s, 1H), 8.30-8.17 (m, 2H), 3.89 (s, 3H). MS (EI): cal'd (MH+) 238.01, exp (MH+) 238.10.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]1([N:25]2[CH2:32][CH2:31][CH2:30][C@H:26]2[C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:27](=[O:28])[C@@H:26]2[CH2:30][CH2:31][CH2:32][N:25]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)[C@@H]1CCCN1c1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)[C@@H]2CCCN2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.30 g, 1.03 mmol), 1-phenylproline (Reference example 7, 0.22 g, 1.13 mmol), triethylamine (0.23 g, 2.26 mmol), EDCI (0.22 g, 1.13 mmol) and HOBt (0.17 g, 1.13 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50) and the resulting yellow solid was triturated with hexane-ethyl acetate to give the title compound (0.10 g, 25%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.I[CH2:23][CH3:24].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:23][CH3:24])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cncc(Cl)n2)CC1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(c1cncc(Cl)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of tert-butyl 4-[(6-chloropyrazin-2-yl)amino]piperidine-1-carboxylate (0.20 g, 0.64 mmol) in tetrahydrofuran (3 mL) at −70° C. was added iodoethane (0.26 mL, 3.2 mmol) and NaHMDS (1M solution in THF; 1.3 mL, 1.3 mmol). The reaction mixture was warmed to room temperature. Iodoethane (0.26 mL, 3.2 mmol) and NaHMDS (1M solution in THF; 1.3 mL, 1.3 mmol) were added. The reaction mixture was stirred at 65° C. After 18 h, the reaction was quenched with saturated aqueous ammonium chloride (25 mL) and extracted with EtOAc (3×25 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 4-[(6-chloropyrazin-2-yl)(ethyl)amino]piperidine-1-carboxylate as a yellow solid. LRMS (ESI) calculated for C16H25ClN4O2 [M+Na]+, 363.2; found 363.1.
Reaction SMILES: C1(OC)C=CC=CC=1.C(OC([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][C@H:25]([NH:32][C:33]([C:35]2[CH:43]=[C:42]3[C:38]([C:39]([Cl:44])=[CH:40][NH:41]3)=[CH:37][CH:36]=2)=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>>[Cl:44][C:39]1[C:38]2[C:42](=[CH:43][C:35]([C:33]([NH:32][C@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][O:23][CH2:22][CH:19]3[CH2:18][CH2:17][NH:16][CH2:21][CH2:20]3)=[O:34])=[CH:36][CH:37]=2)[NH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1
Solvent: COc1ccccc1
Product: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Yield: 135.3 %

Procedure:
Using deprotection method B, but without addition of anisole, 4-{(R)-2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-phenylethoxymethyl}piperidine-1-carboxylic acid tert-butyl ester (4.6 g crude, 8.97 mmol) afforded 5 g (100%) of the title compound as a crude residue, which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[O:20][CH3:21])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:24])=[CH:6][C:7]([CH3:23])([CH3:22])[NH:8]2.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[S:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:3]([CH2:2][O:32][C:30](=[S:31])[C:29]3[CH:33]=[CH:34][C:26]([CH3:25])=[CH:27][CH:28]=3)=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([CH3:22])([CH3:23])[CH:6]=[C:5]3[CH3:24])=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Reactant: Cc1ccc(C(O)=S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccc2c(c1COC(=S)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 48.4 %

Procedure:
5-Chloromethyl-6-(4-fluoro-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-2, 50.0 mg, 0.145 mmol), 4-methylthiobenzoic acid (73.2 mg, 0.435 mmol), and potassium carbonate (80.2 mg, 0.580 mmol) were suspended in anhydrous N,N-dimethylformamide (1 mL), and the reaction mixture was stirred at 80° C. for 2.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the whole was washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (32.4 mg) as a colorless amorphous product. (Yield 47%)
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:26]1([CH2:32]O)([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27]1.OCC1CCN(CC2(C(OC)=O)CCCC2)CC1>>[OH:31][CH2:30][C:26]1([CH2:32][O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: OCC1(CO)CCC1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Agent: COC(=O)C1(CN2CCC(CO)CC2)CCCC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC4(CO)CCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 9 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, Step 2) and cyclobutane-1,1-diyldimethanol (DE 19735574) instead of 4-[(4-methoxybenzyl)oxy]-1,2-benzisoxazol-3-ol and methyl 1-{[4-(hydroxymethyl)piperidin-1-yl]methyl}cyclopentanecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:27]([CH3:33])[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])(=[O:26])=[O:25])(=[O:17])=[O:16])[CH:5]=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][NH2:12].[ClH:34].[N:35]1([C:40](N)=[NH:41])C=CC=N1>CN(C)C=O>[ClH:34].[CH3:1][C:2]1[CH:3]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:27]([CH3:33])[CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])(=[O:26])=[O:25])(=[O:16])=[O:17])[CH:5]=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][NH:12][C:40]([NH2:41])=[NH:35]
Reactant: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)CCN(C)C)c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)CCN(C)C)c1
Yield: 90.7 %

Procedure:
A mixture of 3-[5-methyl-3-(2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine (94 mg, 0.19 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (57 mg, 0.39 mmol), in N,N-dimethylformamide (8 mL) was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was dissolved in acetonitrile, filtered, and the filtrate concentrated to an oil. This was dissolved in dilute HCl (pH 3), washed with diethyl ether, basified with aqueous NaHCO3, and extracted with CH2Cl2. The CH2Cl2 layer was washed with pH 7 buffer and brine, dried over Na2SO4 and filtered. The filtrate was acidified with HCl-methanol and concentrated giving the title compound as a white solid (100 mg, 92%). 1H NMR (300 MHz, CDCl3) δ8.20 (m, 2H), 7.93 (td, 1H, J=7.7, 1.4 Hz), 7.78 (td, 1H, J=7.7, 1.2 Hz), 6.62 (m, 2H), 6.51 (t, 1H, J=2.2 Hz), 4.05 (t, 2H, J=6.1 Hz), 3.99 (t, 2H, J=6.0 Hz), 3.87 (t, 2H, J=6.9 Hz), 3.44 (t, 2H, J=6.9 Hz), 3.04 (s, 3H), 2.96 (s, 6H), 2.27 (s, 3H), 2.10 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C22H33N5O7S2: 544.2 (M+H). Found: 544.0.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[C:13]([N+:22]([O-])=O)=[C:12]2[CH3:25])[CH:18]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]>[Pd]>[F:7][C:4]([F:5])([F:6])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[C:13]([NH2:22])=[C:12]2[CH3:25])[CH:18]=1)([OH:8])[C:2]([F:27])([F:26])[F:1]
Reactant: Cc1c([N+](=O)[O-])c(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Agent: [Pd]
Product: Cc1c(N)c(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Yield: 61.9 %

Procedure:
A mixture of 3.0 g. (0.0075 mole) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-6-methyl-5-nitro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, 150 ml. of alcohol, and 0.5 g. of 10% palladium on charcoal is hydrogenated at an initial pressure of 3 atmospheres in a Parr shaker apparatus until uptake is complete. The catalyst is filtered off, and the filtrate is evaporated. Recrystallization of the residue from alcohol gives 1.7 g (62% ) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-5-amino-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 292°-293°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]([O:26]CC)=[O:25].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=CC=CC=1C(OC)=O>>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Agent: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 11.30 and making non-critical variations using ethyl (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetate to replace methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate, (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetic acid was obtained (83%): mp 193-196° C. (water); 1H NMR (300 MHz, DMSO-d6) δ 7.26-7.21 (m, 1H), 7.09-7.07 (m, 1H), 6.99-6.91 (m, 2H), 6.45 (s, 1H), 6.27 (s, 1H), 4.66 (ABq, 2H), 4.29-4.05 (m, 6H); MS (ES+) m/z 353.7 (M+1).
Reaction SMILES: [I-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:23]=[CH:22][C:14]3[NH:15][C:16](=[O:21])[O:17][C:18]([CH3:20])([CH3:19])[C:13]=3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)#[CH:4].Cl[Si](C)(C)C.Cl.[C:30](#[N:32])C>O.CS(C)=O>[CH3:19][C:18]1([CH3:20])[O:17][C:16](=[O:21])[NH:15][C:14]2[CH:22]=[CH:23][C:11]([C:7]3[CH:6]=[C:5]([C:3]#[C:4][C:30]#[N:32])[CH:10]=[CH:9][CH:8]=3)=[CH:12][C:13]1=2
Reactant: C#Cc1cccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1
Reactant: CC#N
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#CC#N)c3)cc21
Temperature: 50 °C
Yield: 4.6 %

Procedure:
To a stirred mixture of DMSO, acetonitrile and water (9 mL/3 mL/0.5 mL) was added at rt under nitrogen cuprous cyanide (0.193 g, 2.2 mmol), sodium iodide (11 mg, 0.072 mmol), and 6-(3-ethynyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.2 g, 0.72 mmol). Chlorotrimethylsilane was then added to the above mixture in a dropwise manner. After addition, the mixture was heated at 50° C. for 72 hours. The reaction mixture was then cooled to rt and treated with 0.5 N aqueous HCl cold solution (50 mL). The precipitate obtained was collected on a filter and washed with water. The solid was purified on a silica gel column (hexane:ethyl acetate/2:1) to give the title compound as an off-white solid (10 mg, 4.6 %): mp 212-213° C.; 1H-NMR (CHCl3-d6) δ7.96 (s, 1H), 7.77 (s, 1H), 7.65 (d, 1H, J=7.8 Hz), 7.60 (d, 1H, J=7.69 Hz), 7.51 (d, 1H, J=7.77 Hz), 7.45 (dd, 1H, J=8.67, 2.21 Hz), 7.31 (d, 1H, J=1.55 Hz), 6.91 (d, 1H, J=8.19 Hz), 1.8 (s, 6H); MS (EI) m/z 302 ([M+], 30%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:32][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:26])([F:1])[F:27])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C
Reactant: NC1CCC1
Product: CC(C)S(=O)(=O)C(C#N)=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCC1
Yield: 89 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.500 g, 1.16 mmol) was stirred in cyclobutylamine (2 ml) for 24 h at 80° C. under nitrogen in a sealed flask. Work up as described in Example 40, 2) gave 470 mg (89%) of the title compound as white crystals. Mp 148-150° C. 1H NMR (200 MHz, CDCl3): δ=1.38 (d, 6H), 1.49-1.85 (m, 2H), 2.02 (q, 4H), 3.26 (heptet, 1H), 3.53-3.77 (m, 1H), 7.46 (s, 2H), 7.64 (s, 1H), 7.96-8.14 (m, 1H), 9.17 (br s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH:10]1OC=CO1>ClC1C=CC=CC=1>[Br:1][C:2]1[C:3]2[S:8][CH:9]=[CH:10][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccccc1SCC1OC=CO1
Solvent: Clc1ccccc1
Product: Brc1cccc2ccsc12
Temperature: 25 °C
Yield: 40.1 %

Procedure:
To a mixture of 2-bromothiophenol (5 g) and 2-bromomethyl-1,3-dioxolane (2.98 mL) in N,N-dimethylformamide (50 mL) was added potassium carbonate (5.48 g) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract washed with water, 1 mol/L sodium hydroxide aqueous solution, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (2-bromophenylthiomethyl)-1,3-dioxolane (7.25 g). To a mixture of poly phosphoric acid (20 g) and chlorobenzene (40 mL) was added a solution of (2-bromophenylthiomethyl)-1,3-dioxolene (7.25 g) in chlorobenzene (20 mL), and the mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature and supernatant solution was collected by decantation. Toluene was added to the residue, and the supernatant was collected by decantation after the mixture was stirred. The supernatant was combined and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution washed with a saturated sodium hydrogencarbonate aqueous solution, water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (2.27 g).