Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(N([CH:7]([C:9]1[C:10]([CH3:21])=[C:11]2[C:15](=[C:16]([CH3:18])[CH:17]=1)[NH:14][C:13](=O)[C:12]2=O)[CH3:8])CC)C.[F:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][C:28]2[N:29]([NH2:34])[C:30]([NH2:33])=[N:31][N:32]=2)=[CH:25][CH:24]=1>C(O)CO.O.C(NCC)C>[ClH:1].[CH2:13]([N:14]([CH2:15][CH3:11])[CH2:8][CH2:7][C:9]1[C:10]([CH3:21])=[C:11]2[C:15](=[C:16]([CH3:18])[CH:17]=1)[NH:14][C:13]1[C:12]2=[N:34][N:29]2[C:28]([CH2:27][C:26]3[CH:35]=[CH:36][C:23]([F:22])=[CH:24][CH:25]=3)=[N:32][N:31]=[C:30]2[N:33]=1)[CH3:12]
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Reactant: CCN(CC)C(C)c1cc(C)c2c(c1C)C(=O)C(=O)N2
Agent: Cl
Solvent: O
Solvent: OCCO
Solvent: CCNCC
Product: CCN(CC)CCc1cc(C)c2[nH]c3nc4nnc(Cc5ccc(F)cc5)n4nc3c2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.60 mmol of 5-(N,N-diethylamino-2-ethyl)-4,7-dimethyl-1H-indole-2,3-dione hydrochloride (186.5 mg) and 0.70 mmol of (4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine (145 mg) in 1.5 mL of ethylene glycol was stirred at 125° C. for 1 day. The mixture was cooled to room temperature, diluted with water (5 mL), and neat diethylamine 0.5 mL was added. Stirred for 3 hours, the precipitate was collected by filtration, washed with water and dried on highvac. The obtained free base was suspended in water (10 mL), 2M HCl 0.5 mL was added, heated to boil, sonicated briefly while hot and then allowed to crystallize in a refrigerator (+5° C.) overnight. The precipitate was collected by filtration, washed with ice-cold water (2×1 mL) and dried on high vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.O.[NH2:20][NH2:21]>O>[NH:20]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1)[NH2:21]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: NN
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1ccc(NN)nc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
A suspension of 2-bromo-5-(methanesulfonyl)-pyridine (27.5 g, 116 mmol), triethylamine (14.7 g. 145 mmol), and hydrazine hydrate (7.26 g, 145 mmol) in water (205 ml) was heated to 70° C. The reaction mixture became homogenous before the product started to precipitate out of this mixture (after 90 minutes). The reaction mixture was stirred at 70° C. for total of 5 hours and then was allowed to cool to room temperature and stirred for 18 hours. The precipitated product was collected by filtration, dried and triturated with hot ethanol to afford 2-hydrazino-5-(methanesulfonyl)-pyridine in 86% yield. 1H NMR (300 MHz, CDCI3) δ3.12 (s, 3H), 4.44 (br s, 2H), 6.80 (br d, J=8.7 Hz. 1H), 7.81 (dd. J1=9.0 Hz, J2=2.4 Hz, 1H), 8.38 (d, 2.3 Hz, 1H), 8.57 (br s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([F:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[CH2:4][C@@H:3]1[OH:12].[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14]>CN(C=O)C>[F:8][C@H:7]1[C@H:2]2[NH:1][C:13](=[S:14])[O:12][C@H:3]2[CH2:4][C@H:5]([CH2:10][OH:11])[C@H:6]1[OH:9]
Reactant: N[C@@H]1[C@H](F)[C@H](O)[C@@H](CO)C[C@@H]1O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: OC[C@H]1C[C@@H]2OC(=S)N[C@@H]2[C@H](F)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a solution of (1S,2S,3S,4R,5R)-2-amino-3-fluoro-5-(hydroxymethyl)cyclohexane-1,4-diol (480 mg, 2.68 mmol) in DMF (5 mL) at room temperature was added thiocarbonyldiimidazole (549 mg, 3.08 mmol). The mixture was stirred at room temperature for 1.5 h. Solvent was evaporated and the residue was purified by silica gel column chromatography, eluted with 10%-35 MeOH in DCM to give the product (3aS,4S,5R,6R,7aS)-4-fluoro-5-hydroxy-6-(hydroxymethyl)hexahydrobenzo[d]oxazole-2(3H)-thione (494 mg, 83%) as a pale yellow solid. 1H NMR (500 MHz, MeOD) δ 4.74-4.77 (m, 1H), 4.56 (ddd, J=52.8 Hz, 3.8 Hz, 1.7 Hz, 1H), 3.98 (ddd, J=23.3 Hz, 7.0 Hz, 3.9 Hz, 1H), 3.59-3.64 (m, 2H), 3.45 (ddd, J=29.6 Hz, 10.6 Hz, 1.5 Hz, 1H), 2.22-2.27 (m, 1H), 1.95-2.02 (m, 1H), 1.69-1.75 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[C:16](Cl)[C:15]([F:19])=[CH:14][N:13]=1>CO.O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:12]2[N:17]=[C:16]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)[C:15]([F:19])=[CH:14][N:13]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)O)cc3)n2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 4-Aminobenzoic acid (410 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) in methanol (10 mL) and water (1 mL) was stirred at 100° C. for 24 h to yield N2,N4-bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine after methanol was removal. This residue was redissolved in DMF (10 mL) and to it was added potassium carbonate (1.65 g, 12 mmol) and iodomethane (0.37 mL, 6 mmol), stirred at room temperature overnight, and then diluted with 1 N HCl (80 mL) and ethyl acetate (80 mL). The ethyl acetate layer was washed with 1N HCl (60 mL) and water (60 mL). The organic layer was separated, dried, evaporated and the resulting residue was recrystallized from ethyl acetate/hexanes to give N2,N4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (150 mg, 63%). 1H NMR (acetone-d6): δ 3.85 (s, 3H), 3.88 (s, 3H), 7.88-7.97 (m, 4H), 7.98-8.05 (m, 4H), 8.18 (d, J=3.0 Hz, 1H), 9.00 (br, 1H, NH), 9.04 (br, 1H, NH); LCMS: ret. time: 27.07 min.; purity: 95.54%; MS (m/e): 397.04 (MH+).
Reaction SMILES: [Br-].[Br-].[Br-].[C:4]1([N+:10](C)(C)C)[CH:9]=CC=CC=1.[C:14]1([N+](C)(C)C)[CH:19]=CC=C[CH:15]=1.C1([N+:30](C)(C)C)C=CC=CC=1.O1CCCC1.O=[C:40]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]([C:51]([C:53]2[CH:70]=[CH:69][C:56]([NH:57][C:58](=[O:68])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3C(C)C)=[CH:55][CH:54]=2)=[O:52])[CH2:43][CH2:42][CH2:41]1.[OH2:71]>>[CH:14]([O:71][C:64]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[C:58]([NH:57][C:56]1[CH:55]=[CH:54][C:53]([C:51]([N:44]2[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[C:40]3[NH:30][C:4]([CH3:9])=[N:10][C:41]=3[CH2:42][CH2:43]2)=[O:52])=[CH:70][CH:69]=1)=[O:68])([CH3:19])[CH3:15]
Reactant: C[N+](C)(C)c1ccccc1
Reactant: CC(C)c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Reactant: O
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccccc3OC(C)C)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With cooling on an ice bath, a 793 mg portion of phenyltrimethylammonium tribromide was added to 20 ml of tetrahydrofuran solution containing 1.0 g of 4'-[(5-oxo-2,3,4,5-tetrahydro1H-1-benzazepin-1-yl)carbonyl]-2-isopropylbenzanilide, and the mixture was warmed up to room temperature. Filtration was carried out when disappearance of the color of bromine was confirmed after about 60 minutes. The filtered material was washed with tetrahydrofuran, and the filtrates were combined and concentrated. The thus obtained residue was dissolved in chloroform, washed with a sodium bicarbonate aqueous solution and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was further evaporated to dryness using a vacuum pump. The thus obtained solid substance was dissolved in 40 ml of chloroform, and the resulting solution was mixed with 1.11 g of acetamidine hydrochloride and 2.26 g of potassium carbonate and subjected to 20 hours of heating under reflux in a stream of argon. The resulting reaction solution was mixed with water to effect phase separation, and the organic layer was separated and dried over anhydrous magnesium sulfate. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was crystallized from toluene to obtain 640 mg of 2-isopropoxy-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]benzanilide. A 563 mg portion of this compound was dissolved in 5.5 ml of ethyl alcohol, mixed with 0.45 ml of 4N hydrochloric acid-ethyl acetate and recrystallized to obtain 400 mg of 2-isopropyl-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]benzanilide hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[C:20]([CH2:22]Cl)[N:21]=1.O>O1CCCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[C:20]([CH2:22][N:3]2[C:2]([CH3:1])=[CH:6][N:5]=[CH:4]2)[N:21]=1
Reactant: COc1ccccc1-c1nc(CCl)cs1
Reactant: Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1nc(Cn2cncc2C)cs1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
To a solution of 82 mg of 4-methylimidazole in 10 ml of tetrahydrofuran at 5° C. was added 50 mg of sodium hydride in 50% oil and the resulting mixture stirred at 5° C. for 20 minutes. 2-(o-Methoxyphenyl)-4-chloromethylthiazole (240 mg) in 5 ml of the same solvent was added and the reation mixture heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and treated with 1 ml of water. The water and solvent were removed in vacuo and the residue dissolved in chloroform. The chloroform solution was washed with a brine solution, dried over sodium sulfate and concentrated to give 250 mg of crude product. The product was obtained by chromatography on 7 g of silica gel (chloroform-methanol), 40:1-v:v), 100 mg.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:7][NH2:8].[Cl:14][C:15]1[C:16](=[O:25])[N:17]([CH2:22][CH2:23][CH3:24])[N:18]=[CH:19][C:20]=1Cl.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:14][C:15]1[C:16](=[O:25])[N:17]([CH2:22][CH2:23][CH3:24])[N:18]=[CH:19][C:20]=1[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([O:3][CH3:2])[CH:5]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: CCCn1ncc(Cl)c(Cl)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCn1ncc(NCc2ccc(OC)c(OC)c2)c(Cl)c1=O
Reaction time: 5 h

Procedure:
A mixture comprising 1.52 g of 3,4-dimethoxybenzylamine hydrochloride prepared in Reference Example 1, 0.62 g of 4,5-dichloro-2-n-propyl-3(2H)pyridazinone, 1.66 g of potassium carbonate, 10 ml of 1,4-dioxane and 30 ml of water was refluxed under stirring for 5 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained, and the mixture was extracted with ethyl acetate. The extract was washed successively with 2% diluted hydrochloric acid, water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off to obtain a pale yellow oily substance. This substance was crystallized from diethyl ether-n-hexane to obtain 522 mg of the above identified compound having a melting point of from 139 to 140° C. as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[N:25]#[C:26][NH2:27].C(N(CC)CC)C>CN(C=O)C.O>[CH3:22][C:20]([C:7]1[CH:8]=[C:9]([C:11]2[S:12][C:13]([NH:27][C:26]#[N:25])=[N:14][N:15]=2)[CH:10]=[C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])[C:6]=1[OH:24])([CH3:23])[CH3:21]
Reactant: N#CN
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(-c2nnc(NC#N)s2)cc(C(C)(C)C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl]phenol (5.0 g, 0.0136 mole) in a mixture of DMF (20 ml) and water (5 ml) is added cyanamide (5.0 g, 0.119 mole) and triethylamine (1.4 g, 0.0136 mole). The mixture is heated to 80° C. and stirred overnight. An additional portion of cyanamide (2.5 g, 0.059 mole) is added and the mixture is stirred six hours at 80° C. The reaction is cooled and partitioned between water and ether. The aqueous layer is acidified with 6M HCl (40 ml). The resulting precipitate is filtered and recrystallized from acetonitrile/water to provide 3.4 g of [5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]cyanamide (4.5 g theor., 76%) after drying in vacuo at 70° C., mp >250° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].Cl.[O:27]1CCC[CH2:28]1>O>[CH3:13][O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH:28]=[O:27])[C:18]=1[F:24]
Reactant: C1CCOC1
Reactant: COC(=O)Nc1ccc(F)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)Nc1ccc(F)c(C=O)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Into a reaction flask under nitrogen, diisopropylamine (24.87 g, 250 mmol) is combined with 160 mL of anhydrous tetrahydrofuran and the solution is cooled to −78° C. n-Butyllithium (154 mL, 1.6 M in hexanes, 250 mmol) is added dropwise, maintaining the temperature below −70° C. After stirring at −78° C. for 1 hour, (2,4-difluoro-phenyl)-carbamic acid methyl ester (2, 20.00 g, 110 mmol) in 40 mL of tetrahydrofuran is added dropwise, maintaining the temperature below −70° C. The reaction is stirred at −78° C. for 1 hour, then warmed to room temperature and stirred for 1 minute. The reaction is poured into 250 mL of water, the pH is adjusted to 1 with addition of 2M hydrochloric acid, and the mixture is extracted with 3×250 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is slurried in hexane and the resulting solid is collected by filtration and dried to provide the desired compound (3, 19.38 g, 84%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1F.[NH2:15][NH2:16]>C(O)C>[N+:10]([C:7]1[CH:6]=[C:5]2[C:4]([C:3](=[O:2])[NH:15][NH:16]2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: NN
Solvent: CCO
Product: O=c1[nH][nH]c2cc([N+](=O)[O-])ccc12

Procedure:
The crude material, 2-fluoro-4-nitro-benzoic acid methyl ester, from above was treated with hydrazine (1.6 mL, 51 mmol) in ethanol under reflux for 14 hrs. After removal of solvent by evaporation, the residue was washed with water. The precipitate product was filtered and dried on the vacuum pump to give the title compound which was used without further purification (4.0 g, 85% for two steps). MS (ES+): m/e=180.1 (M+H), 178.0 (M-H); LC/Method A 1.83 min.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]=[CH:6][CH:5]1[CH3:12])=[O:3].[OH-].[K+].C1CCCCCCCCCCC1.[CH3:27][C:28]([C@@H:30]1[C:35]([CH3:37])([CH3:36])[CH2:34][CH:33]=[CH:32][C@H:31]1[CH3:38])=[O:29]>CS(C)=O>[CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][CH:6]=[C:5]1[CH3:12])=[O:3].[CH3:27][C:28]([C:30]1[C:35]([CH3:37])([CH3:36])[CH2:34][CH2:33][CH2:32][C:31]=1[CH3:38])=[O:29]
Reactant: CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Agent: C1CCCCCCCCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(=O)C1=C(C)CCCC1(C)C
Product: CC(=O)C1C(C)=CCCC1(C)C

Procedure:
In a 100-ml four-necked flask equipped with a thermometer, a condenser and a stirrer, placed were 2,6,6-trimethyl-3-cyclohexenyl methyl ketone (10 g) synthesized in Referential Example 1, potassium hydroxide (2.5 g), dimethyl sulfoxide (30 ml) and, as an internal standard substance for the analysis by gas chromatography, cyclododecane (3 g). They were reacted at 170 to 190° C. for 6 hours. The reaction mixture was treated in an usual manner. Analysis by gas chromatography showed that the content of trans-2,6,6-trimethyl-3-cyclohexenyl methyl ketone was 67.5%, while those of 2,6,6-trimethyl-2-cyclohexenyl methyl ketone and 2,6,6-trimethyl-1-cyclohexenyl methyl ketone produced by the above reaction were 20.1% and 12.4%, respectively. As a result of calculation, the yield of a mixture of these three methyl ketones was found to be 4.3 g.
Reaction SMILES: [S:1]1(=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][CH2:2]1.Cl[CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[C:30](=[O:33])([O-:32])[O-].[K+].[K+].O>C(C(C)=O)C.C(OCC)(=O)C>[C:4]([OH:11])(=[O:21])/[CH:5]=[CH:10]/[C:30]([OH:32])=[O:33].[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH:15]([N:3]2[C:4](=[O:11])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1](=[O:12])(=[O:13])[CH2:2]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:20]1
Reactant: O=C([O-])[O-]
Reactant: ClC(CCN1CCOCC1)c1ccccc1
Reactant: O=C1NCS(=O)(=O)c2ccccc21
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C(O)/C=C/C(=O)O
Product: O=C1c2ccccc2S(=O)(=O)CN1C(CCN1CCOCC1)c1ccccc1
Yield: 52.3 %

Procedure:
In methyl ethyl ketone (5 mL) were suspended 2H-1,3-benzothiazin-4(3H)-one 1,1-dioxide (100 mg, 0.518 mmol.), 1-chloro-3-morpholino-1-phenylpropane (130 mg, 0.54 mmol.), and potassium carbonate (180 mg, 1.3 mmol.). The suspension was heated overnight under refluxing. The reaction liquid was cooled, and the insolubles were filtered off. The solvent was distilled off to give a residue. To the residue were added water and ethyl acetate, and the organic layer was taken out. The organic solution was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was treated by silica gel column chromatography (chloroform/methanol=50/1) to give the free base of the desired compound (70 mg, yield 35%) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Oc1ccc2[nH]ccc2c1
Product: N#Cc1ccc(N(CCOc2ccc3[nH]ccc3c2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 5-hydroxyindole: MS (APCI) m/z 426 (M−1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([NH:19][C:20]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:21]=2[C:22]([OH:24])=O)=[CH:17][CH:16]=1.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:20]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:21]=2[C:22]([NH:42][O:41][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:24])=[CH:31][CH:32]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(Nc2cc(F)c(F)cc2C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2cc(F)c(F)cc2C(=O)NOCc2ccccc2)cc1
Yield: 102 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (3.6 g, 22.4 mmol), 2-(4-methoxy-anilino)-4,5-difluorobenzoic acid (Example O, 5.72 g, 20.4 mmol), O-benzylhydroxylamine hydrochloride (3.26 g, 20.4 mmol), and triethylamine (3.1 mL, 22.4 mmol) provided 8.0 g of the crude title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[CH:17][C:16]=3[CH3:24])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O>[N:28]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[CH:17][C:16]=3[CH3:24])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26])=[N+:29]=[N-:30]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)c(C)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)c(C)cc1Cl
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To 1.1 g (2.7 mmol) of 7-chloro-4-(4-chloro-5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile in 5 mL of anhydrous dimethyl sulfoxide (DMSO) is added 1.77 g (27 mmol) of sodium azide under a flow of nitrogen. The mixture is stirred at 55° C. for 3 hours. The reaction is cooled to room temperature and poured onto 30 g of crushed ice. This mixture is stirred for 30 minutes and the suspended solid collected by filtration. After drying, a 1 g portion of 7-azido-4-(4-chloro-5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile is obtained as a dark solid. The solid is dissolved in a 1:1 mixture of ethanol/tetrahydrofuran (50 mL) and to this is added 200 mg of 10% palladium on carbon under a flow of nitrogen. After hydrogenation of the mixture for 1.5 hours using a Parr shaker at 40 psi, the crude product is filtered through diatomaceous earth and the filtrate evaporated in vacuo. The residue obtained is purified by flash chromatography, eluting with 85:15 methylene chloride/methanol to provide a 0.638 g of a brown solid, mp 232-235° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[S:12][C:13]=1[CH3:14].[BH4-].[Na+].[OH-].[Na+]>CCOCC>[CH2:15]([C:11]1[S:12][C:13]([CH3:14])=[C:9]([CH3:8])[CH:10]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(C(O)c2ccccc2)sc1C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1cc(Cc2ccccc2)sc1C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (50 mL) was added dropwise over a 60 minute period to a stirred, 0° C. suspension of 4,5-dimethylthiophene-2-yl-(phenyl)-methanol (7.7 g, 35.3 mmol), sodium borohydride (6.67 g, 177 mmol) and ether (600 mL). After an additional 1.5 hours the reaction mixture was added to 10% aqueous sodium hydroxide (600 mL) and stirred for 30 minutes. The layers were separated and the ether phase was washed with 10% aqueous sodium hydroxide, brine and dried (magnesium sulfate). The ether phase was concentrated to provide the title compound as a an oil (6.73 g, 94%): NMR (CDCl3); δ7.33-7.19 (m, 5H), 6.47 (s, 1H), 4.03 (s, 2H), 2.27 (2, 3H), 2.06 (s, 2H); MS (EI) (M+) 202 (45%, MI).
Reaction SMILES: [Pb]=O.[CH2:3]([NH:7][C:8](=S)[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])[CH:11]=1)[CH:4]([CH3:6])[CH3:5].[NH3:28]>C(O)C>[ClH:26].[CH2:3]([NH:7][C:8](=[NH:28])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])[CH:11]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CNC(=S)Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Reactant: N
Agent: O=[Pb]
Solvent: CCO
Product: CC(C)CNC(=N)Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 168 h

Procedure:
Lead oxide (PbO, 0.8 g.) is added to a solution of 1-(3-isobutylthioureido)-3-(3-p-chlorophenylureido)benzene (1.13 g.) in ethanol which has been saturated with ammonia gas (50 ml.). The mixture is stirred at room temperature for 7 days, the solids are filtered off, washed thoroughly with boiling ethanol and the combined filtrates are evaporated to dryness. The residual gum is dissolved in ethanol (5 ml.) and saturated ethereal hydrochloric acid (3 ml.) is added, followed by dry ether (150 ml.). The precipitated white solid is filtered off, washed with dry ether followed by cold isopropanol, and dried under reduced pressure, to give 1-(3-isobutylguanidino)-3-(3-p-chlorophenylureido)benzene hydrochloride, m.p. 212° C.