Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+].[CH3:12]I>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: CI
Reactant: Oc1ccc(Br)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Br)cc1F
Yield: 80 %

Procedure:
2-Fluoro-4-bromophenol (1) (382.0 g, 2.0 mols) was dissolved in ethanol (1,000 ml), followed by adding potassium hydroxide (113.0 g, 2.0 mols) to the solution, sufficiently agitating the mixture, dropwise adding thereto methyl iodide (312.3 g, 2.2 mols), refluxing it for 4 hours, distilling off most of the ethanol, distilling the residue under reduced pressure and collecting a fraction of 65°-66° C. (4.5 mmHg) to obtain 2-fluoro-4-bromoanisole (2) (328.0 g). This compound was reacted with Mg (38.9 g) in diethyl ether to obtain 3-fluoro-4-methoxyphenylmagnesium bromide (3), followed by dropwise adding thereto cyclohexanone (157.0 g, 1.6 mol) at 7° C. or lower, agitating the mixture at room temperature for about 30 minutes, adding thereto 6N--HCl (350 ml), refluxing the mixture for one hour, washing the resulting organic layer with water, distilling off diethyl ether and recrystallizing the residue from ethanol to obtain (3'-fluoro-4'-methoxyphenyl)-cyclohexene-1 (4) (180.4 g) having a m.p. of 49.0°-50.0° C. This compound (112.0 g, 0.55 mol) was dissolved in xylene (700 ml), followed by adding p-chloranil (267.0 g, 1.1 mol) to the solution, refluxing the mixture for 4 hours, filtering off the resulting tetrachlorohydroquinone, washing the filtrate with 2N--NaOH aqueous solution, distilling off the solvent, subjecting the residue to column chromatography with a column filled with activated alumina and recrystallizing the resulting material from ethanol to obtain 3-fluoro-4-methoxybiphenyl (5) (69.2 g) having a m.p. of 84.5°-86.0° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[C:10]([NH:13][C:14]1[NH:18][N:17]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[C:15]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:12])[CH3:11]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:10]([NH:13][C:14]1[NH:18][N:17]=[C:16]([S:19]([NH:4][C:3]2[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=2[F:9])(=[O:20])=[O:21])[C:15]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:12])[CH3:11]
Reactant: Nc1c(F)cccc1F
Reactant: COC(=O)c1c(S(=O)(=O)Cl)n[nH]c1NC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)n[nH]c1NC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
23.63 g (177.5 mmol) of 97% 2,6-difluoroaniline and 1.48 g N,N-dimethyl-4-aminopyridine was dissolved in 225 ml pyridine and 25.0 g (88.75 mmol) 5-acetamido-4-methoxycarbonylpyrazole-3-sulphonyl chloride added portionwise. The mixture was stirred for 48 hours at 25° C. The pyridine was distilled and the residue dissolved in 510 ml methylene chloride washed twice with 370 ml 5N hydrochloric acid and twice with 370 ml water, dried over magnesium sulphate and concentrated. The residue was triturated with ether, the product suction filtered, washed with ether and dried.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[CH2:31][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[N:16]=1)([CH3:3])[CH3:2].CO.[BH3-]C#N.[Na+]>C(O)=O.O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[CH2:31][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[N:16]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=Nc2c(C(C)C)cccc2C(C)C)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Solvent: O
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(CNc2c(C(C)C)cccc2C(C)C)n1

Procedure:
To a solution of 1.50 g (2.90 mmol) of (2,6-diisopropylphenyl){[6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl)pyridin-2-yl]methylene}amine in 20 ml of methanol 0.30 g (4.70 mmol) of NaBH3CN was added in one portion followed by addition of three drops of 88% formic acid. The reaction mixture was refluxed for 1 h and then poured into 50 ml of water. The crude product was extracted with 2×20 ml of ether. The organic extract was washed by water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes-ethyl acetate=5:1, vol.). Yield 1.00 g (67%) of yellow oil which crystallized at room temperature. Anal. calc. for C36H39N3: C, 84.17; H, 7.65; N, 8.18. Found: C, 84.25; H, 7.78; N, 8.00. 1H NMR (CDCl3): 7.91 (d, J=8.4 Hz, 1H, 4-H in naphthyl), 7.89 (m, 1H, 8-H in naphthyl), 7.79 (m, 1H, 4-H in Py), 7.66 (d, J=8.4 Hz, 1H, 3-H in naphthyl), 7.47 (m, 1H, 7-H in naphthyl), 7.36-7.42 (m, 4H, 3,5-H in Py and 5,6-H in naphthyl), 7.04-7.10 (m, 3H, 3,5-H in ortho-tolyl and 4-H in 2,6-diisopropylphenyl), 7.01 (m, 2H, 3,5-H in 2,6-diisopropylphenyl), 6.61 (m, 1H, 4-H in ortho-tolyl), 6.52 (m, 1H, 6-H in ortho-tolyl), 4.22-4.35 (m, 4H, CH2N), 4.02 (br. s, 1H, NH), 3.93 (br. s, 1H, NH), 3.28 (sept, J=6.8 Hz, 2H, CHMe2), 2.09 (s, 3H, Me in ortho-tolyl), 1.16 (d, J=6.8 Hz, 6H, CHMeMe′), 1.14 (d, J=6.8 Hz, 6H, CHMeMe′).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]12[CH2:16][S:15][CH:12]([S:13][CH2:14]1)[S:11][CH2:10]2)[CH2:7][CH3:8].Cl[CH2:18][O:19][CH2:20][CH2:21][C:22]#[CH:23].O>O1CCCC1>[CH2:20]([O:19][CH2:18][C:12]12[S:11][CH2:10][C:9]([CH2:6][CH2:7][CH3:8])([CH2:16][S:15]1)[CH2:14][S:13]2)[CH2:21][C:22]#[CH:23]
Reactant: CCCC12CSC(SC1)SC2
Reactant: C#CCCOCCl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C#CCCOCC12SCC(CCC)(CS1)CS2
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.3 ml, 1.6M solution in hexane) was added to a solution of 4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane (0.1 g) in dry tetrahydrofuran (5 ml) at -70° C., under nitrogen. The solution was stirred for 30 minutes and but-3-ynyl chloromethyl ether (0.058 g) in dry tetrahydrofuran (2.0 ml) was added and the reaction mixture was allowed to warm to 20°. Water (10 ml) was added and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by chromatography on alumina, eluting with 1:10 dichloromethane:hexane saturated with ammonia. 1-(But-3-ynyloxymethyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane was obtained as a waxy solid (0.032 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: NCC1COc2ccccc2O1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1COc2ccccc2O1
Temperature: 25 °C

Procedure:
Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (4.4 g, 26 mmol) and sulfamide (5.1 g, 53 mmol) were combined in 1,4 dioxane (100 mL) and refluxed for 2 h. The reaction was cooled to room temperature and a small amount of solid was filtered and discarded. The filtrate was evaporated in vacuo and the residue was purified using flash column chromatography (DCM:Methanol—10:1) to yield a white solid. The solid was recrystallized from DCM to yield the title compound as a white solid.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([CH:21]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[N:24]=[C:23]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl>C(OCC)(=O)C>[ClH:32].[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:25]1[CH:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)[CH:16]=2)[CH2:22][C:23]([C:33]([F:39])([F:38])[C:34]([F:36])([F:37])[F:35])=[N:24]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(N3CCCNCC3)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 216 %

Procedure:
5-[3-(4-BOC-homopiperazin-1-yl)-phenyl]-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (550.0 mg, 1.0 mmol) prepared in Example 124 was added to a saturated solution of hydrochloric acid in ethyl acetate (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give 550.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[CH:13]1([CH2:18][CH2:19][C:20](OC)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(CCC(O)=O)CCCC1.S(=O)(=O)(O)O>C1COCC1.CO>[CH:13]1([CH2:18][CH2:19][C:20](=[O:21])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CCC1CCCC1
Agent: O=C(O)CCC1CCCC1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCC1CCCC1)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a solution of dimethyl methylphosphonate (2.17 ml, 20 mmol) in anhydrous THF (20 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 13.7 mL, 22 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl 3-cyclopentylpropanoate (1.56 g, 10 mmol), prepared from 3-cyclopentylpropionic acid (Aldrich) and methanol at the presence of the catalytic amount of the concentrated sulfuric acid (the procedure described in Intermediate 17.1), was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (EtOAc:Hexanes=1:1) to give the product (1.80 g) with colorless oil in 82% yield. 1HNMR (CD3OD, ppm) δ 1.03 (m, 2H), 1.51 (m, 1H), 1.61 (m, 6H), 1.73 (m, 2H), 2.63 (t, J=7.4 Hz, 2H), 3.09 (d, J=22.7 Hz, 2H), 3.76 (s, 3H), 3.87 (s, 3H)
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:7]=2[O:6]1)#[N:2].S([O-])([O-])(=O)=O.[Ba+2]>O1CCCC1.[Pd]>[C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[O:6]1)#[N:2]
Reactant: N#CCCC1CCc2cc([N+](=O)[O-])ccc2O1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: N#CCCC1CCc2cc(N)ccc2O1
Reaction time: 48 h

Procedure:
A solution of 4.3 g (18.5 mmol) of 2-cyanoethyl-6-nitro-3,4-dihydro-2H-1-benzopyran in 80 ml of tetrahydrofuran is hydrogenated in the presence of 1 g of palladium on 5% barium sulfate. The mixture is stirred for 2 days, then it is filtered and the filtrate is concentrated under reduced pressure. By chromatography of the residue on a silica column using cyclohexane containing 30% ethyl acetate, 2.5 g of product are obtained.
Reaction SMILES: C([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:9]=1[N:22]1[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]2=[N:23]1)C=CCCC.[CH3:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(OCC)(=O)C>CN(C)C1C=CC=CC=1>[N:26]1[N:22]([C:9]2[CH:10]=[C:11]([C:14]([CH3:20])([CH3:21])[CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:12]=[C:13]([CH:33]([CH2:34][CH2:35][CH3:36])[CH:32]=[CH2:31])[C:8]=2[OH:7])[N:23]=[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=12
Reactant: CCCC=CCOc1ccc(C(C)(C)CC(C)(C)C)cc1-n1nc2ccccc2n1
Reactant: CCCCCC
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: C=CC(CCC)c1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Reaction time: 22 h
Yield: 84 %

Procedure:
5.6 g (13.8 mmol) of 2-(2-hex-2-enyloxy-5-(1,1,3,3-tetramethylbutyl)-phenyl)-2H-benzotriazole, prepared as described above, in 100 ml of N,N-dimethylaniline were heated to reflux. The reaction was traced by tlc. (hexane:ethyl acetate=7:3). After 22 hours the reaction was complete. N,N-dimethylaniline was distilled off and the product freed from residual amine in a high vacuum to yield 4.7 g (84%) of 2-(benzotriazole-2-yl)-4-(1,1,3,3-tetramethylbutyl)-6-(1-hexen-3-yl)-phenol as an orange liquid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[C:27]([CH3:28])=[CH:26][S:25][C:24]=12>CN(C=O)C>[CH3:28][C:27]1[C:23]2[C:24](=[C:19]([CH2:18][S:1][C:2]3[NH:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[N:20]=[CH:21][CH:22]=2)[S:25][CH:26]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1csc2c(CCl)nccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Reaction time: 2 h

Procedure:
To a suspension of 1.82 g of 2-mercaptobenzimidazole and 6.7 g of K2CO3 in 35 ml of DMF was added 2.4 g of 7-chloromethyl-3-methylthieno[2, 3-c]pyridine, and the mixture was stirred for 2 hr. DMF was evaporated under reduced pressure, and CHCl3 was added to the residue for extraction. The CHCl3 layer was washed with water and dried. Then, CHCl3 was removed by evaporation, and ether was added to he residue, whereby 3.41 g (Yield : 90.5%) of the objective product (Ia-11), 2-[(3-methylthieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole was obtained as crystals.
Reaction SMILES: [CH:1]([N:4]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:12](O)=[C:7]2[CH:6]=[N:5]1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:12]1[N:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:9]=[C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][C:7]=12
Reactant: CC(C)n1ncc2c(O)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)n1ncc2c(Cl)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Temperature: 25 °C
Yield: 100 %

Procedure:
A suspension of 1-isopropyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.76 g, 2.5 mmol) in phosphorus oxychloride (20 mL) was heated a sealed tube with a heat gun until all of the starting material was dissolved. After allowing the mixture to cool to room temperature it was concentrated to dryness under reduced pressure, leaving a pale yellow solid which was then triturated with water and collected by Buchner filtration. The solid was further washed with water and dried under house vacuum to provide 4-chloro-1-isopropyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.90 g, >100%) as a pale yellow solid. MS (ES+): 317.7, 319.8 (M+H)+
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[C:17]=3[CH2:21][CH2:22][CH3:23])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:31])(=O)=O>>[Cl:31][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[C:17]=2[CH2:21][CH2:22][CH3:23])[S:10]1(=[O:12])=[O:11]
Reactant: CCCc1c(OC)c(OC)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reactant: O=S(=O)(Cl)Cl
Product: CCCc1c(OC)c(OC)cc2c1C(=O)N(CCl)S2(=O)=O
Yield: 97 %

Procedure:
By the method of Example 22A 3,4-dimethoxy-2-propyl-N,N-dimethylbenzamide (9.2 g) was aminosulfonylated with sulfur dioxide and hydroxylamine-O-sulfonic acid (5.6 g) to give 2-aminosulfonyl-4,5-dimethoxy-6-propyl-N,N-dimethylbenzamide (7.4 g, 63% yield), which was cyclized in quantititive yield to 4-propyl-5,6-dimethoxysaccharin, phenylthiomethylation of which with chloromethyl phenyl sulfide (1.42 mL) gave 2-phenylthiomethyl-4-propyl-5,6-dimethoxy-saccharin (4.07 g), reaction of part (3.59 g) of which with sulfuryl chloride (2.12 mL) gave 2-chloromethyl-4-propyl-5,6-dimethoxysaccharin, 2.84 g, 97% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=O)=[CH:7][CH:6]=1.C(OP([CH:23]1[C:28](=[O:29])[NH:27][C:26]2[CH:30]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:32]=[CH:33][C:25]=2[S:24]1)(OCC)=O)C>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][CH:13]=[C:23]2[C:28](=[O:29])[NH:27][C:26]3[CH:30]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:32]=[CH:33][C:25]=3[S:24]2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1ccc2c(c1)NC(=O)C(P(=O)(OCC)OCC)S2
Reactant: COc1ccc(/C=C/C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)C(=CC=Cc1ccc(OC)cc1)S2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice-cooling, sodium hydride (4.65 g, content 60%) was added in small portions to a THF solution (300 ml) containing (2E)-3-(4-methoxyphenyl)acrylaldehyde (10 g) synthesized by the process described in Reference Example 1 and ethyl 2-(diethoxyphosphoryl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (21.7 g, synthesized according to the process disclosed in WO00/63197). The resulting mixture was slowly warmed up to room temperature and stirred overnight. The same aldehyde as above (1.5 g) was added thereto and stirred for another 2 hours. The resulting mixture was concentrated under reduced pressure, and ethyl acetate (30 ml), hexane (100 ml), a 1N aqueous hydrochloric acid solution (50 ml) and water (600 ml) were added to the residue, followed by stirring at room temperature for 6 hours. The solid was collected by filtration and dried under reduced pressure. Ethyl 2-[3-(4-methoxyphenyl)prop-2-en-1-ylidene]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (22.43 g) was obtained as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:13])[C:7]=2[C:6]([CH3:14])=[N:5]1.[C:15](=O)([O-:19])[O:16][CH2:17][CH3:18].C(O)(=O)C>C1C=CC=CC=1.O.C(O)C>[CH3:3][N:4]1[C:12]2[CH2:11][CH2:10][CH:9]([C:15]([O:16][CH2:17][CH3:18])=[O:19])[C:8](=[O:13])[C:7]=2[C:6]([CH3:14])=[N:5]1
Reactant: Cc1nn(C)c2c1C(=O)CCC2
Reactant: CCOC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CCc2c(c(C)nn2C)C1=O
Temperature: 25 °C
Reaction time: 11 h
Yield: 63.8 %

Procedure:
A suspension of sodium hydride (14.6 g, 0.365 mol, 60% oil dispersion) in dry benzene at 5° to 10° C. is treated with 1,5,6,7-tetrahydro-1,3-dimethyl-4H-indazole-4-one (30.0 g, 0.183 mol). The reaction mixture is treated dropwise with ethyl carbonate (45.0 mL, 0.365 mol) and ethanol (1.0 mL) with cooling, stirred for 11 hours at reflux temperature, cooled to room temperature and treated with acetic acid (24.1 g, 0.400 mol) and water. The phases are separated, the organic phase is set aside and the aqueous phase is extracted with ether. The organic phases are combined, washed with water, dried (Na2SO4) and concentrated in vacuo. The resultant residue is chased twice with toluene, recrystallized from (2:1) methylene chloride:heptane and a second time from 50% tetrahydrofuran:heptane to afford the title product (27.6 g, 63.9%), mp 76.5°-79° C.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:1][C:2]3[N:6]([CH3:7])[N:5]=[N:4][N:3]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Cn1nnnc1S
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nnnn3C)C(=O)O)cc2)cc1

Procedure:
Example 30 is prepared from 5-mercapto-1-methyltetrazole and 1d using the procedure described for compound 20.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:11]=[C:12]=[O:13])[CH2:9][CH3:10].[NH2:14][C:15]([NH:17][C:18]1[NH:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24])=[O:16]>CN(C)C=O>[NH2:14][C:15]([NH:17][C:18]1[NH:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][C:12]([NH:11][CH2:8][CH2:9][CH3:10])=[O:13])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24])=[O:16]
Reactant: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Reactant: CCCN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNC(=O)Oc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Triethylamine (43 μL, 0.31 mmol) and propyl isocyanate (17 μL, 0.18 mmol) were added to a solution of 2-aminocarbonylamino-5-(2-hydroxyphenyl)pyrrole-3-carboxamide (Compound No. 3-1, 40 mg, 0.15 mmol) in anhydrous N,N-dimethylformamide (2 mL), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated in vacuo, the residue was purified by silica gel column chromatography to give the target compound (29 mg) as a pale blue solid (Yield 54%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5])C.C[O-].[Na+]>CO>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1csc(N)n1
Yield: 44.6 %

Procedure:
A mixture of 2-amino-thiazole-4-carboxylic acid ethyl ester (38 g, 221 mmol) in methanol (400 mL) was cooled in an ice bath and to it was added 25% sodium methoxide over 30 minutes. The ice bath was removed after 30 minutes. A few small particles were filtered off and to this yellow solution was added saturated aqueous ammonium chloride and it was concentrated to remove excess methanol. The mixture was adjusted to pH=9.0 with sodium bicarbonate and extracted using 1:1 ether/tetrahydrofuran (3×200 mL). The combined organic extracts were washed with water, dried over sodium sulfate and concentrated to give a pale yellow solid which still contained some solvent. It was taken into hexanes, filtered on a 5.5 cm funnel then dried in vacuo to give 2-amino-thiazole-4-carboxylic acid methyl ester as a pale yellow solid (15.6 g, 45%).
Reaction SMILES: Cl[C:2]1[CH:22]=[N:21][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:9][CH:8]=3.[N+:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[NH:6][C:5]2[N:21]=[CH:22][C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([N+:23]([O-:25])=[O:24])[CH:31]=4)=[CH:3][C:4]3=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc3[nH]c4ncc(Cl)cc4c3c2)cc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COc1ccc(-c2ccc3[nH]c4ncc(-c5cccc([N+](=O)[O-])c5)cc4c3c2)cc1
Reaction time: 8 h
Yield: 68.8 %

Procedure:
3-chloro-6-(4-methoxyphenyl)-9H-pyrido[2,3-b]indole (50 mg, 0.16 mmol, 1 equiv.), 3-nitrophenylboronic acid (81 mg, 0.48 mmol, 3 equiv.), K3PO4 (136 mg, 0.64 mmol, 4 equiv.), S-PHOS (13.1 mg, 0.032 mmol, 0.2 equiv.), Pd(OAc)2 (4.0 mg, 0.016 mmol, 0.1 equiv.) are introduced in a schlenk tube which is flushed with N2. Freshly distilled dioxane (0.433 ml) is then injected and the reaction is carried out at 100° C. overnight. The mixture is filtered through celite and concentrated under reduced pressure. The crude product is purified over silica gel chromatography (eluant CH2Cl2/AcOEt 6:4). The white solid obtained is washed with methanol to give the product as a white solid (43 mg, 0.11 mmol) in 69% yield.