Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[CH:3]=1.[N:17]([O-])=[O:18].[Na+].Cl>CN(C)C=O.O>[NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[C:3]=1[N:17]=[O:18]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1Cc1ccccc1
Temperature: 70 °C

Procedure:
To a solution of 6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione (2.0 g, 9.2 mmol) in a mixture of 15 ml of N,N-dimethylformamide and 5 ml of water at 90° C. was added sodium nitrite (1.27 g, 69 mmol). To this reaction mixture was added concentrated hydrochloric acid until there was no deepening of color, and the mixture was heated at 70° C. for 1 hour. The solvent was removed under reduced pressure, the residue dissolved in water, and concentrated hydrochloric acid added to produce a pH of 4.0. The precipitate was filtered off, washed with water, and dried under reduced pressure, to provide 6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Br[C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30]>C(Cl)(Cl)Cl.CO>[CH3:32][C:28]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=3[O:2][CH3:1])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)([CH3:33])[C:29]([OH:31])=[O:30]
Reactant: CC(C)(Br)C(=O)O
Reactant: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(OC(C)(C)C(=O)O)cc2)cc1

Procedure:
0.5 gm (1.4 millimols) of 4-[2-(2-methoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl were heated at 90°-130° C for 90 minutes with 0.025 gm of 2-bromo-2-methyl-propionic acid. The reaction product was isolated by chromatography on silicagel with chloroform/methanol (9:1) as the eluant. M.P. 133° C. M + H = 433;
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([OH:37])[CH2:36][O:35][CH2:34]2)[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([C:33]4([OH:37])[CH2:36][O:35][CH2:34]4)=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(O)COC3)cc2F)n1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(O)COC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(3-hydroxyoxetan-3-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 193. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.30 (dd, J=8.7, 4.0 Hz, 1H), 8.23-8.12 (m, 1H), 7.90 (s, 1H), 7.49 (d, J=9.7 Hz, 2H), 4.81 (t, J=5.7 Hz, 3H), 4.73 (dd, J=7.0, 1.4 Hz, 2H), 4.41-4.17 (m, 1H), 4.10-3.87 (m, 2H), 3.76 (s, 3H), 3.19-3.09 (m, 1H), 2.11-2.02 (m, 1H), 1.69 (s, 3H). LCMS (ES+) m/z 536 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][CH3:11])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[Br:17][C:18]1[CH:19]=[C:20]([C:25](Cl)=[O:26])[C:21]([Cl:24])=[N:22][CH:23]=1.O>CC#N>[Cl:24][C:21]1[C:20]([C:25]([NH:1][C:2]2[C:3]([NH:9][CH2:10][CH3:11])=[N:4][C:5]([F:8])=[CH:6][CH:7]=2)=[O:26])=[CH:19][C:18]([Br:17])=[CH:23][N:22]=1
Reactant: CCNc1nc(F)ccc1N
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCNc1nc(F)ccc1NC(=O)c1cc(Br)cnc1Cl
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To a cooled solution (4° C.) of 3-amino-2-(ethylamino)-6-fluoropyridine (31.0 g, 200 mmol) in MeCN (160 mL) was added solid NaHCO3 (50.4 g, 600 mmol). After 15 min, a solution of 5-bromo-2-chloro-3-pyridinecarbonyl chloride (1 equiv., 200 mmol) in MeCN (155 mL) was added. After 60 min at room temperature, the reaction mixture was poured into water (1.2 L) and stirred for 30 min. The resulting solid was filtered, dried under reduced pressure at 50° C. overnight. The title compound (73.7 g, 99% yield) was obtained as a black solid.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:25]([NH:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O.[OH-].[Li+].O.Cl>C1COCC1>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([NH:26][C:25]2[C:16]([NH:15][S:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:7][CH:8]=3)(=[O:14])=[O:13])=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Nc2cc(OC)cc(OC)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CCC(=O)O)cc2)cc(OC)c1
Yield: 74.9 %

Procedure:
Methyl-3-{4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}propanoate (50 mg, 0.10 mmol, 1 eq.) and lithium hydroxide monohydrate (20.1 mg, 0.48 mmol, 5 eq.) are dissolved in THF (1 ml) and water (1 ml) and the yellow solution is heated up to 50° C. for 1 h. Aqueous HCl 1N is added until reaching acidic pH and the precipitate formed is filtered off then washed with water until neutral. The solid is dried under vacuum at 40° C. overnight, affording 38.1 mg (78%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 12.30-11.95 (m, 2H), 8.91 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.95-7.82 (br s, 1H), 7.60-7.50 (m, 1H), 7.48-7.23 (m, 6H), 6.23 (s, 1H), 3.75 (s, 6H), 2.88 (t, J=7.2 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H). HPLC (max plot) 100%; Rt 4.10 min. LC/MS: (ES+): 509.4; (ES−): 507.4.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: c1ccncc1
Product: CC1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Temperature: 80 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (910 mg), 2-methylpiperazine (320 mg), and pyridine (10 ml) was stirred at 80° C. for 1 hour. After evaporating the reaction mixture under reduced pressure, the residue was dissolved in dilute aqueous ammonia and treated with activated carbon. The filtrate was evaporated under reduced pressure and adjusted to pH 7-8. The resulting crystals were filtered, washed with water, and dried to give 1-cyclopropyl-5,6,8-trifluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (810 mg), m.p. 235°-237° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:47](Cl)([CH3:50])(=[O:49])=[O:48]>C(Cl)Cl>[O:27]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:3][CH:4]=1)[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:35][CH:36]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(N)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 2 °C

Procedure:
2-[6-([2-(4-aminophenyl)ethyl]{2-[(4-aminophenyl)oxy]ethyl}amino)hexyl]-1H-isoindole-1,3(2H)-dione (108.3 mg) was dissolved in DCM (5 ml) and cooled to 0-4° C. in an ice-bath. Hunig's Base (0.227 ml) was added followed by the dropwise addition of mesylchloride (0.051 ml). The reaction was maintained at 0-4° C. for 0.5 h and then allowed to warm slowly to room temperature. After 3 h the reaction mixture was evaporated to dryness and used crude in next step.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:12][C@H:13]1[C@H:17]([OH:18])[CH2:16][CH:15]=[CH:14]1.O1CCCC1.C[O:25][C:26]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])=O>C(N(CC)CC)C>[OH:18][C@@H:17]1[CH2:16][CH:15]=[CH:14][C@H:13]1[N:12]1[C:26](=[O:25])[C:28]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:29]2[C:30]1=[O:31]
Reactant: COC(=O)c1ccccc1C(=O)Cl
Reactant: N[C@@H]1C=CC[C@H]1O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=CC[C@H]1O

Procedure:
A 31.3 g. (0.115 M) quantity of dl-trans-3-amino-4-hydroxycyclopentene toluenesulfonate is dissolved in 240 ml. of tetrahydrofuran and 47 ml. (0.46 M) of triethylamine. The resultant stirred solution is cooled to 5° and treated dropwise with 22.8 g. (0.115 M) of o-methoxycarbonylbenzoylchloride. The reaction is then allowed to warm to 25°. After 48 hours the reaction is partitioned between Ethyl acetate and water. The ethyl acetate layer is dried over magnesium sulfate and concentrated in vacuo leaving 29.6 g. of residue. This residue is chromatographed over silica gel 60 eluted with 5 l. of (10-90) and 7.5 l. of (20-80) acetone-methylene chloride. Three hundred ml. fractions are collected. The product is isolated in fractions 25-35, which upon standing crystallizes to yield 14.2 g. of dl-trans-4-hydroxy-3-phthalido-cyclopentene, m.p. 114°-116°.
Reaction SMILES: [F:1][C:2]([F:28])([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)[C@H:3](OS(C(F)(F)F)(=O)=O)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH2:29][C@@H:30]([CH2:34][S:35][C:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:28][C:2]([F:1])([O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26][CH3:27])=[CH:24][CH:25]=1)[C@@H:3]([NH:29][C@@H:30]([CH2:34][S:35][C:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:31]([OH:33])=[O:32])[C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CSc1ccc(OC(F)(F)[C@H](OS(=O)(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Solvent: ClCCl
Product: CSc1ccc(OC(F)(F)[C@@H](N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 27.6 %

Procedure:
A mixture of trifluoromethanesulfonic acid 2,2-difluoro-1(R)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethyl ester (1.70 g, 3.8 mmol), 2(R)-amino-3-tritylsulfanylpropionic acid (1.38 g, 38 mmol) and diisiopropylethylamine (2.65 ml, 15.2 mol) in DCM (35 ml) was stirred for 19 h at room temperature. The solvent was evaporated under vacuum and the residue dissolved in ethyl ether (20 ml). The solution was washed with 1N HCl solution and brine. After drying over sodium sulfate, the solvent was evaporated and the crude was purified by flash chromatography, using a mixture of EA/H (1/3) as eluent to give 2(R)-[2,2-difluoro-1(S)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethylamino]-3-tritylsulfanylpropionic acid (0.693 g, 27%) as a foam.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:16])[C:10]=2[F:15])[CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(N)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110 %

Procedure:
A mixture of 0.70 g (2.50 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.56 g (3.00 mmol) of 3-(t-butoxycarbonyl) aminopyrrolidine, 0.76 g (7.52 mmol) of triethylamine, and 25 mL of acetonitrile was refluxed for 4.5 hours, then stirred at room temperature overnight. The solids were collected by filtration and washed with acetonitrile and ether. The crude product was dissolved in 20 mL of 6N hydrochloric acid and 20 mL of acetic acid and was stirred at room temperature for 3 hours. The solution was concentrated to an oil which was triturated with 2:1 ether:isopropanol. The solids were removed by filtration, washed with ether, and dried to give 0.95 g of the title compound as the hydrochloride salt, mp>300° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)(=O)OCC)C.[CH3:20][C:21]([CH3:23])=O.O>O1CCCC1>[CH3:20][C:21]([CH3:23])=[CH:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[C:18]#[N:19]
Reactant: CCOP(=O)(Cc1cccc(C#N)c1)OCC
Reactant: CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=Cc1cccc(C#N)c1
Temperature: 25 °C
Yield: 28 %

Procedure:
Sodium hydride (0.40 g, 10 mmol, 60% in oil) was suspended in tetrahydrofuran (5 mL), (3-cyanobenzyl)phosphonic acid diethyl ester obtained in Preparation Example 135 (2.53 g, 10 mmol) was added dropwise under stirring at room temperature. After stirring for 1 hour at 60° C., the solution was allowed to room temperature, acetone (0.92 g, 20 mmol) was added dropwise, and the solution was further stirred for 30 minutes at room temperature. Water (100 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL). The organic layer was washed with water, then, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3), and the title compound (0.44 g, 2.80 mmol, 28%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17](=[O:25])[C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cc(F)ccc1SCC2
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cc(F)ccc1S(=O)CC2
Temperature: 25 °C

Procedure:
To a solution of 1.8 g of 2-(4-chlorophenyl)-10-fluoro-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)one, prepared in Example 22, in 20 ml of acetic acid is added 1.3 ml of 35% hydrogen peroxide with stirring at room temperature and furthermore stirred for 5 hours at the same temperature. To the resultant mixture is added water, and the precipitated crystals are collected by filtration and recrystallized from dimethylformamide-water to give 1.3 g of 2-(4-chlorophenyl)-10-fluoro-5,6-dihydro[1]benzothiepino[5,4-c]pyridazin-3(2H)-one 7-oxide, melting at 233°-235° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccco1
Reactant: CCc1c(Cl)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCc1c(Cl)ncnc1-c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A mixture of 4,6-dichloro-5-ethylpyrimidine (10 g), 2-furylboronic acid (6.33 g) tetrakis(triphenylphosphine)palladium (1.94 g), dimethoxyethane (100 ml), and sodium carbonate solution (2 mol/l) (60 ml) was stirred at 70° C. for 2 hours and at 80° C. for 2 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, water was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6.06 g of 4-chloro-5-ethyl-6-(furan-2-yl)-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([CH:12]=O)=[C:10]([CH3:11])[C:4]=2[O:3]1.O.[OH-].[Na+].[CH3:20][C:21]([CH3:23])=[O:22]>>[CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([CH:12]=[CH:20][C:21](=[O:22])[CH3:23])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1C=O)OC(C)(C)C2
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c(C)c2c(c1C)OC(C)(C)C2

Procedure:
To a solution of 37 g of the 2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-carboxaldehyde in 125 ml of acetone was added 60 ml of water and 68 g of 2% aqueous solution of sodium hydroxide. After refluxing for 20 hours, the reaction mixture was quenched with 10 ml of 2N aqueous solution of hydrochloric acid and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product. Final purification was carried by recrystallization to afford 42.4 g of 4-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-3-butene-2-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[C:10](=O)([O:19]N1C(=O)CCC1=O)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O>[CH2:12]([O:11][C:10]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: O=C(O)[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Yield: 191.6 %

Procedure:
A mixture of (R)-piperidine-3-carboxylic acid (3.0 g, 23 mmol), benzyl 2,5-dioxopyrrolidin-1-yl carbonate (5.79 g, 23.2 mmol) and Na2CO3 (6.15 g, 58.1 mmol) was stirred in water and 1,4-dioxane (1:1, 200 mL) at ambient temperature for about 96 h. The organic solvent was removed under reduced pressure. The aqueous layer was acidified with 1 N aqueous HCl and extracted with EtOAc (2×100 mL). The organic phase was washed with brine (150 mL), dried over anhydrous MgSO4 and concd under reduced pressure to yield crude (R)-1-(benzyloxycarbonyl)-piperidine-3-carboxylic acid (11.6 g, 191%) as a white solid: LC/MS (Table 1, Method a) Rt=1.80 min; MS m/z 264 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([C:15]1[CH:24]=[CH:23][C:18]([CH2:19][NH:20][O:21][CH3:22])=[CH:17][CH:16]=1)#[N:14]>>[C:13]([C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]([O:21][CH3:22])[C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)=[CH:17][CH:16]=1)#[N:14]
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(C#N)cc1
Product: CON(Cc1ccc(C#N)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 99 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-cyanobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (99% yield): mp 148–149° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.72 (3H, s, OCH3), 4.86 (2H, s, NCH2), 6.39 (1H, s, CH), 7.46 (2H, m, aromatics), 7.63 (2H, m, aromatics). Anal. calcd. for C16H16N2O5: C, 60.75; H, 5.10; N, 8.86. Found: C, 60.60; H, 4.91; N, 8.78.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]([O:10][CH:11]3[CH2:14][NH:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]([O:10][CH:11]3[CH2:12][N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[CH2:14]3)=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: c1cc(OC2CNC2)ccc1OCC1CC1
Reactant: CC(=O)NC(C)(C)c1ccc(Br)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NC(C)(C)c1ccc(N2CC(Oc3ccc(OCC4CC4)cc3)C2)cc1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
To 35 mg (0.16 mmol) 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1) in THF (2.0 mL) are added under an argon atmosphere 41 mg (0.16 mmol) N-[1-(4-bromo-phenyl)-1-methyl-ethyl]-acetamide, 63 mg (0.64 mmol) NaOtBu, 19 mg (0.064 mmol) 2-(di-tert-butylphosphino)biphenyl and 15 mg (0.016 mmol) tris-(dibenzylidene-acetone)-dipalladium(0). The mixture is stirred for 12 h at 45° C. The mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (Zorbax, acetronitrile/H2O (+0.15% HCOOH)) to yield the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[N:19]=[CH:18]3)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25][CH2:26][OH:27])[N:19]=[CH:18]3)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ncc2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCCO)c1
Yield: 88 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridine-2(1H)-one (200 mg, 0.63 mmol) in DMSO (5 mL) was added Cs2CO3 (1.03 g, 3.15 mmol) and (3-bromopropoxy)-tert-butyldimethylsilane (0.15 mL, 0.66 mmol). After stirring overnight at ambient temperature under argon, the reaction mixture was filtered through a layer of Celite and concentrated. Purification by flash column chromatography (silica gel, EtOAc/hexanes, 50:50) gave 4-(benzyloxy)-1-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indazol-5-yl)pyridin-2(1H)-one (90 mg, 29%). To a solution of 4-(benzyloxy)-1-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indazol-5-yl)pyridin-2(1H)-one in THF (3 mL) was added TBAF (0.75 mL, 0.75 mmol, 1.0 M). After the reaction was complete, the mixture was treated with H2O, extracted with CH2Cl2, and the combined organics were concentrated. Purification by flash column chromatography (silica gel, EtOAc/hexanes, 50:50) gave 4-(benzyloxy)-1-(1-(3-hydroxypropyl)-1H-indazol-5-yl)pyridin-2(1H)-one (50 mg, 88%) as a white solid. In accordance with the procedure of Example 1, the HCl salt was made to give the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.73-7.71 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.48-7.36 (m, 5H), 7.33 (dd, J=9.0, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 4.50 (t, J=7.0 Hz, 2H), 3.38 (t, J=6.5 Hz, 2H), 2.01-1.96 (m, 2H); ESI MS m/z 376 [M+H]+.