Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH:17]1([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>N1C=CC=CC=1>[CH:17]1([C:23]2[CH:24]=[CH:25][C:26]([S:29]([NH:16][C:13]3[S:14][CH:15]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=4)[N:12]=3)(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: O=S(=O)(Cl)c1ccc(C2CCCCC2)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccc(C4CCCCC4)cc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.46 g of 4-cyclohexyl-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the organic phase was separated and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated as an oil upon neutralization. Thereupon, 20 ml of ethanol were added, the mixture was boiled and insoluble material was filtered off. Crystals separated upon cooling and, after recrystallization from 40 ml of 50% ethanol, yielded 0.15 g of 4-cyclohexyl-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as beige crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]([O:14]C)=[O:13])[CH:8]=[C:7]2[S:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])(=[O:18])=[O:17].[CH:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:30][CH:29]=1)=[CH2:27]>>[C:12]([CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2/[CH:27]=[CH:26]/[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:30][CH:29]=2)[C:7]([S:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:18])=[O:17])=[CH:8]1)([OH:14])=[O:13]
Reactant: COC(=O)CCCS(=O)(=O)c1cn(CC(=O)OC)c2c(Br)cccc12
Reactant: C=Cc1ccc(OCCCCOc2ccccc2)cc1
Product: O=C(O)CCCS(=O)(=O)c1cn(CC(=O)O)c2c(/C=C/c3ccc(OCCCCOc4ccccc4)cc3)cccc12

Procedure:
Except for using the compound prepared in Example 103 in place of the compound prepared in Example 2 and 1-ethenyl-4-{[4-(phenyloxy)butyl]oxy}benzene in place of 4-vinylphenyl acetate, the same operation as in Example 3→Example 6 was conducted to obtain the titled compound having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].N>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: N#Cc1cc(Cl)ccc1-n1cnnn1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1cc(Cl)ccc1-n1cnnn1
Yield: 50.3 %

Procedure:
A solution of 5-chloro-2-(1H-tetraazol-1-yl)benzonitrile (113 mg, 0.55 mmol) in ethanol saturated with ammonia (20 mL) was stirred in the presence of Raney nickel (50% slurry in water, washed with ethanol, catalytic amount) under a hydrogen atmosphere for 1 h. The reaction mixture was filtered through Celite and concentrated to give 5-chloro-2-tetrazol-1-yl-benzylamine (58 mg, 50%); 1H NMR (400 MHz, CDCl3): δ 9.24 (s, 1H), 7.64 (d, J=2.2 Hz, 1H), 7.46 (m, 1H), 7.38 (m, 1H), 3.68 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14](C)C)=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:8]=1)#[N:2].[CH3:17][O:18][C:19](=[O:42])[C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][CH:28]=2)=[C:22](N)[CH:21]=1.C(OCC)(=O)C.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.O>[CH3:17][O:18][C:19](=[O:42])[C:20]1[CH:21]=[CH:22][C:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[CH:29][CH:28]=2)=[C:24]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH:9]([CH3:10])[CH3:11])=[N:5][C:4]=3[N:12]=[CH:13][N:14]=2)[CH:25]=1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Temperature: 25 °C

Procedure:
A suspension of N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine (2.00 g, 9.3 mmol) and the product from Example 1C (3.46 g, 9.3 mmol) in AcOH (40 mL) was heated at 120° C. for 20 minutes under N2. After cooling to room temperature, the reaction mixture was portioned between ethyl acetate (150 mL) and H2O (200 mL), and then made basic to pH 9 with K2CO3 under stirring. The organic layer was separated, washed with 10% NaHCO3, H2O and brine, dried over MgSO4, and evaporated to give a pale brown oil. The oily residue was separated by silica gel column chromatography (ethyl acetate/n-hexane=5/1) gave yellow crystal. Further purification by washing with cold ethyl acetate (15 mL) gave the title compound as slightly yellow crystal (3.27 g, 65% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:12][N@@:11]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>>[Si:1]([O:8][CH2:9][C@@H:10]([NH:11][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:12][O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC1CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1)CO[Si](C)(C)C(C)(C)C
Yield: 29.9 %

Procedure:
(S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)aziridine-1-carboxylate (5.0 g, 17.4 mmol), phenol (4.92 g, 52.3 mmol), K2CO3 (24 g, 174 mmol) and 150 mL of acetonenitrile were mixed, and heated to reflux for 48 h. The mixture was filtrated, and the filtrate was concentrated in vacuo. The residue was dissolved in 100 mL of EA, which was washed with water (50 mL×2), brine (50 mL) and dried with Na2SO4. The solution was concentrated in vacuo to give crude product, which was purified with flash column to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-phenoxypropan-2-ylcarbamate (2.0 g, 5.2 mmol, yield 30%) 1H NMR (CDCl3, 400 MHz) δ 0.0 (s, 6H), 0.87 (s, 9H), 1.45 (s, 9H), 3.71 (dd, 1H), 3.85 (dd, 1H), 3.98 (d, 2H), 4.05 (s, 1H), 6.93 (m, 3H), 7.28 (m, 2H). MS ESI +ve m/z 382 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:29])[N:16](COC(=O)C(C)(C)C)[CH:17]=[N:18]3)=[CH:13][CH:12]=2)[CH2:3][CH2:2]1>N>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:29])[NH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(OCCCN3CCOCC3)ccc2c1=O
Agent: N
Product: O=c1[nH]cnc2cc(OCCCN3CCOCC3)ccc12
Reaction time: 18 h
Yield: 97.2 %

Procedure:
7-(3-Morpholinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (680 mg, 1.6 mmol) was stirred in methanolic ammonia (20 ml) at 40° C. for 6 hours then for 18 hours at ambient temperature. The solvent was removed by evaporation, the residue was triturated with ether/isohexane and collected by filtration to give 7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (450 mg, 92%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]1([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)[CH2:6]2.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:20]1[O:21][C:8]2([C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH2:6][C:7]32[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[O:12][CH2:19]1
Reactant: OCCO
Reactant: COc1ccc2c(c1)CC1(CCC(=O)CC1)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CC1(CCC(=O)CC1)C21OCCO1
Yield: 73 %

Procedure:
A mixture of 4.89 g. (0.0196 M) of 6'-methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione [8] (prepared as in Example 15B), 1.21 g. of ethylene glycol and 0.2 g. of p-toluenesulfonic acid in 100 ml. of benzene is heated at reflux under a Dean-Stark trap for about 5 hours. The mixture is allowed to cool, washed with aqueous sodium bicarbonate solution and evaporated to dryness. The residue is recrystallized twice from methylene chloride: Skellysolve B to give 4.13 g. (73% yield) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9 ] having a melting point of 142° to 144° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[Cl:13]Cl.O>C(O)(=O)C>[Cl:13][C:11]1[C:2]([OH:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5][CH2:4]2
Reactant: ClCl
Reactant: O=C1CCc2c(O)cccc2N1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCc2c(ccc(Cl)c2O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.4 Grams of 5-hydroxy-3,4-dihydrocarbostyril are dissolved in 300 ml of acetic acid. This solution is stirred at room temperature, and 50 ml of acetic acid solution containing 7 g of chlorine are added dropwise and the reaction is continued for 3 hours with stirring The reaction mixture is poured into 500 ml of water and allowed to stand for 1 hour and the precipitate thus formed is separated by filtration, washed with water and then dried. Recrystallization from ethanolwater obtains 13.5 g of 6-chloro-5-hydroxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 209°-210° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH:20]=O)[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CC(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-]>CO>[CH2:1]([O:8][CH2:9][C:10]1([C:20]#[CH:22])[CH2:11][CH2:12][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:18][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=CC1(COCc2ccccc2)CCC2(CC1)OCCO2
Agent: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1(COCc2ccccc2)CCC2(CC1)OCCO2
Yield: 90.1 %

Procedure:
To a solution of 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (Reference Example 86) (100 mg, 0.344 mmol) in methanol (5.2 mL), potassium carbonate (143 mg, 1.03 mmol) and dimethyl-1-diazo-2-oxopropylphosphonate (165 mg, 0.861 mmol) were added with stirring under ice-cooling, and the obtained solution was stirred at room temperature for 1 hour. The reaction was quenched by adding water to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (88.9 mg, 0.310 mmol, 90%) as a colorless oily compound.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[C:43]([S:45]([CH3:48])(=[O:47])=[O:46])[C:42]([F:49])=[CH:41][C:40]=1[CH3:50]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[C:43]([S:45]([CH3:48])(=[O:47])=[O:46])[C:42]([F:49])=[CH:41][C:40]=1[CH3:50])([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1cc(F)c(S(C)(=O)=O)cc1Br
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: Cc1cc(F)c(S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-bromo-4-fluoro-5-methanesulfonyl-2-methyl-benzene (Ger. Offen. 2000; DE 19919349), the title compound was obtained as a brown oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([C@H:15]1[O:19][C:18](=[O:20])[C@@H:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:16]1)([CH3:14])([CH3:13])[CH3:12].[C:27]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1.[Cl-].[NH4+]>C1COCC1>[C:11]([C@H:15]1[O:19][C:18](=[O:20])[C@@:17]([C:27]2([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28]2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:16]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)[C@H]1OC(=O)[C@@H](c2ccccc2)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)(C2(O)CCCC2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium hexamethyldisilazide (0.8 g, 4.7 mmol; 4.7 mL of 1.0 M in hexanes) was added to anhydrous THF (5.3 mL, 65 mmol) at −78° C. Intermediate (1a) (800 mg, 3.6 mmol) in 5.3 mL anhydrous THF was added to the solution dropwise over 15 minutes. After 30 minutes cyclopentanone (451 μL, 5.1 mmol) was added dropwise over less than 1 minute. After 2 hours, 0.8 mL of saturated aqueous Na2HPO4 was added, and the mixture stirred at room temperature for 5 minutes. The mixture was added to 8 mL saturated aqueous ammonium chloride. The aqueous layer was washed (2×80 mL EtOAc), and the organic layers were combined, dried over Na2SO4, filtered, and concentrated. The crude product (780 mg) was purified by flash chromatography (5-15% EtOAc gradient over 30 minutes with hexanes) to yield intermediate (1b).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([CH:28]=[CH:29][N:30]=2)[CH:5]=[C:6]([C:8]2[C:9]([CH3:27])=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.Cl[C:32]1[N:37]=[CH:36][C:35]([C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:39])=[CH:34][CH:33]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:32]4[CH:33]=[CH:34][C:35]([C:38]([N:40]5[CH2:41][CH2:42][O:43][CH2:44][CH2:45]5)=[O:39])=[CH:36][N:37]=4)[C:3]4[N:4]([CH:28]=[CH:29][N:30]=4)[CH:5]=3)[C:9]=2[CH3:27])=[O:26])=[CH:17][CH:18]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c2nccn2c1
Reactant: O=C(c1ccc(Cl)nc1)N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c2nccn2c1
Temperature: 200 °C
Reaction time: 1.67 h

Procedure:
A mixture of N-[3-(8-Amino-imidazo[1,2-a]pyridin-6-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (0.69 g, 1.73 mmol), (6-Chloro-pyridin-3-yl)-morpholin-4-yl-methanone (1.17 g, 5.19 mmol), sodium t-butoxide (0.23 g, 2.42 mmol), Pd(II)acetate (19 mg, 0.08 mmol) and 2-(dicyclohexyl-phosphino)biphenyl was stirred at 200° C. in a microwave for 100 min.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[N:27]([CH2:28][CH2:29][O:30][C:31]4[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][C:32]=43)[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]>C(Cl)Cl>[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[C:32]4[CH:35]=[C:36]([S:39]([N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)(=[O:41])=[O:40])[CH:37]=[CH:38][C:31]=4[O:30][CH2:29][CH2:28][N:27]3[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCN(S(=O)(=O)c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of 1-isopropylpiperazine (50 mg, 0.39 mmol) and NEt3 (90 μL, 0.65 mmol) in DCM (8 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (0.13 mmol) in DCM (8 mL) and the resulting mixture warmed to RT after 10 min then stirred for 2 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-7% 2M NH3/MeOH in DCM) affording 128 (41 mg, 65%) as a white solid. LCMS: RT 2.90 min [M+H]+ 486.3. 1H NMR (DMSO, 400 MHz): δ 8.79 (1H, d, J=2.41 Hz), 8.00 (1H, s), 7.94 (1H, d, J=0.61 Hz), 7.63 (1H, dd, J=8.62, 2.43 Hz), 7.28 (1H, d, J=8.62 Hz), 5.76-5.69 (1H, m), 4.64-4.62 (4H, m), 2.94-2.87 (4H, m), 2.62-2.61 (1H, m), 2.54-2.43 (4H, m), 1.49 (6H, d, J=6.62 Hz), 0.89 (6H, d, J=6.53 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH:6]2[CH2:14][C:15]([O:17][CH3:18])=[O:16].[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:21])[C:8](=[O:13])[CH2:7][CH:6]2[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: CI
Reactant: COC(=O)CC1CC(=O)Nc2ccc(OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1CC(=O)N(C)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 40.8 g of 1,2,3,4-tetrahydro-6-methoxy-2-oxo-4-quinoline acetic acid, methyl ester in 500 ml of dimethyl formamide was added over 1 hour to a chilled (0° C.) suspension of 4.6 g of sodium hydride in 300 ml of dimethyl formamide. After stirring for 1 hour at ambient temperature, 27.5 g of methyl iodide was added and the mixture stirred for an additional hour. The mixture was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to an oil. Column chromatography on silica gel (elution with hexane-ethyl acetate) afforded 1,2,3,4-tetrahydro-6-methoxy-1-methyl-2-oxo-4-quinoline acetic acid, methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N-:8][S:9](N1C=CC(=[N+](C)C)C=C1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([N:22]([CH3:21])[S:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:10])=[O:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNCc1ccccc1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 61 %

Procedure:
N,N-dialkyl sulfamides were prepared according to the published procedures: Winum, J-Y; Toupet, L.; Barragan, V.; Dewynter, G.; Montero, J.-L. Org. Letters 2001, 3, 2241-2243 and Casini, A.; Winum, J.-Y.; Montero, J.-L.; Scozzafava, A.; Supuran, C. Bioorganic & Medicinal Chemistry Letters 2003, 13, 837-840. A flask was charged with N-tert-butoxycarbonyl-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (500 mg, 1.66 mmol) and methylbenzylamine (0.21 mL, 1.66 mmol) in 10 mL of CH2Cl2. After 2 h, the solution was concentrated in vacuo and purified by flash column chromatography (5-70% EtOAc/hexanes) to afford 304 mg of tert-butyl {[benzyl(methyl)amino]sulfonyl}carbamate.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][C:9]1([CH3:31])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:31])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc([N+](=O)[O-])c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a suspension of methanesulfonamide (2.6 g, 27.2 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (1.1 g, 27.5 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.79 g, 5.5 mmol) and 1,1′-carbonyldiimidazole (1.78 g, 11 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70° C. for 1 h. Then the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. The reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford N-[3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (2 g, 90%) as a brown solid which was used for next step without further purification: LC/MS m/e calcd for C19H21N3O5S (M+H)+: 404.46, observed: 404.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:23])=[CH:16][C:17]([NH:18][C:19](=O)[CH2:20][Cl:21])=[C:12]2[N:11]=[C:10]1[CH3:24]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:23])=[CH:16][C:17]([NH:18][CH2:19][CH2:20][Cl:21])=[C:12]2[N:11]=[C:10]1[CH3:24]
Reactant: Cc1cc(NC(=O)CCl)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Solvent: C1CCOC1
Product: Cc1cc(NCCCl)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
Treat a solution of N-[3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl]-2-chloroacetamide (1.0 g, 2.6 mmol) in THF (5 mL) with borane-methyl sulfide complex (0.8 mL, 7.8 mmol). Heat the mixture to reflux for 3 h and quench at ambient temperature with a large excess of MeOH followed by 5 N HCl (2 mL). Re-heat the mixture to reflux for 1 h, then concentrate under reduced pressure. Purify by flash column chromatography (50% EtOAc-hexane) to obtain the title compound as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.C([Li])CCC.[CH:17](=[O:19])[CH3:18]>O1CCCC1.O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([CH:17]([OH:19])[CH3:18])[O:9][C:8]=12
Reactant: CC=O
Reactant: COc1nccc2ccoc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nccc2cc(C(C)O)oc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 7-methoxyfuro[2,3-c]pyridine (1.5 g) in dry tetrahydrofuran (50 ml) was stirred at −78° C. under dry nitrogen. n-Butyllithium (1.6N solution in hexanes, 6.9 ml) was added dropwise and the resulting solution stirred at −78° C. for 60 minutes. Acetaldehyde (5.7 ml) was added and stirring continued at −78° C. for 90 minutes before warming to room temperature. The mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave the title compound (1.8 g) as a brown oil.