Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH3:9].ClN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([O-:39])=[O:38])=[CH:33][CH:32]=1.[Na+].C([O-])(=O)C.[K+]>C(Cl)(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][S:37]([C:34]1[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Cc1cnccc1Cl
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cc1cnccc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A carbon tetrachloride (15 ml) suspension of 4-chloro-3-methylpyridine hydrochloride (402 mg, 2.45 mmol), N-chlorosuccinic acid imide (327 mg, 2.45 mmol) and 2,2′-azobis(2-methylpropionitrile) (30 mg, 0.183 mmol) was heated under reflux for 13 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in butanol (10 ml), followed by the addition of sodium 4-chlorophenylsulfinate (487 mg, 2.45 mmol) and potassium acetate (481 mg, 4.90 mmol). The mixture was stirred at 70° C. for 24 hours. The reaction mixture was cooled to room temperature, followed by concentration under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and then, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure, whereby the title compound (130 mg, 18%) was obtained as a white solid.
Reaction SMILES: O[CH:2]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].Cl>O1CCCC1>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[CH2:4][CH:3]=[CH:2][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(CCCC2OC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CC=Cc1ccc(CCCC2OC(=O)NC2=O)cc1
Yield: 27.6 %

Procedure:
A mixture of 5-[3-[4-[1-hydroxy-3-(5-methyl-2-phenyl-4-oxazolyl)propyl]phenyl]propyl]-2,4-oxazolidinedione (0.17 g), 9N HCl (10 ml) and tetrahydrofuran (THF) (10 ml) was heated under refluxing conditions for 2 hours. The reaction mixture was concentrated under reduced pressure; the residue was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure; the residue was purified by silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:2), 5-[3-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-propenyl]phenyl]propyl]-2,4oxazolidinedione (0.045 g, 28%) was obtained, which was then recrystallized from ether-isopropyl ether to yield colorless needles having a melting point of 136°-137° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)(=[O:25])=[O:24])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: Nc1cc(OC(F)(F)F)cc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(OC(F)(F)F)cc2cccnc12)c1ccccn1
Yield: 56.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-trifluoromethoxy-quinolin-8-ylamine (Intermediate 46) (110 mg, 0.48 mmol), pyridine-2-sulfonyl chloride (Intermediate 18) (102 mg, 0.57 mmol), pyridine (0.08 ml, 0.96 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (100 mg, 56%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH:12]1[CH2:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:15][CH2:14][CH2:13]1
Reactant: C1CNC1
Reactant: N#Cc1cc(F)cnc1Cl
Agent: Cl
Product: N#Cc1cc(F)cnc1N1CCC1
Yield: 78 %

Procedure:
Prepared in 78% yield from the product of Example 169A and azetidine hydrochloride according to the procedure described for Example 178A. MS (ESI+) m/z 177.8 (M+H)+; 1H NMR (DMSO-d6) δ 2.28-2.38 (m, 2H), 4.17-4.22 (m, 4H), 8.07 (dd, J=8.3, 2.9 Hz, 1H), 8.66 (dd, J=8.1, 3.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:11][C:10]=1[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-benzyloxy-3-cyclopentyl-benzaldehyde (1.3 g, 4.64 mmol) and ethyl 2-triphenylphosphoranylideneacetate (1.6 g, 4.64 mmol) in dichloromethane (12 mL) was heated at reflux for 24 h. The reaction was cooled to room temperature and concentrated in vacuo. Purification by silica gel chromatography (0-10% ethyl acetate/hexanes) yielded ethyl 3-(4-benzyloxy-3-cyclopentyl-phenyl)prop-2-enoate (1.2 g, 81% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.61-7.57 (m, 2H), 7.52 (dd, J=2.1, 8.5 Hz, 1H), 7.46-7.39 (m, 4H), 7.33 (t, J=7.1 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.49 (d, J=16 Hz, 1H), 5.18 (s, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.32-3.27 (m, 1H), 1.99-1.92 (m, 2H), 1.74-1.67 (m, 2H), 1.65-1.58 (m, 4H), 1.24 (t, J=7 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].[OH-].[Na+].[CH2:27]([NH:30][C:31](=[O:36])C(Cl)(Cl)Cl)[CH2:28][CH3:29]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:31]([NH:30][CH2:27][CH2:28][CH3:29])=[O:36])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: CCCNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCNC(=O)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Yield: 14.1 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 160 mg (4 mmol) of sodium hydroxide were heated in 5 ml of N-methyl-2-pyrrolidone with 410 mg (2 mmol) of N-(n-propyl)trichloroacetamide at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction and washed with water until neutral. Purification by chromatography (silica gel; toluene/ethanol/ethyl acetate 8/1/1) resulted in 65 mg (14%) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:18])[CH2:9][CH:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])[CH3:2].[C:19](OC([O-])=O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CCCCCC.C(OCC)(=O)C.Cl>C(O)C.C(N(CC)CC)C.O[Mo](O)(=O)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][CH:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCOC(=O)C1(N)CC(OCc2ccccc2)C1
Agent: O=[Mo](=O)(O)O
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
7.64 g of 1-amino-3-benzyloxycyclobutane-1-carboxylic acid ethyl ester was dissolved in 250 mL of a mixed solution of ethanol/triethylamine=9/1. After the solution was cooled in an ice bath for 15 minutes, 8.6 mL (corresponding to 37.5 mmol) of t-butyl dicarbonate was added to the solution and stirred at room temperature overnight. The completion of the reaction was confirmed by TLC analysis using a mobile solvent of hexane/ethyl acetate=1:1 (Rf value of the target reaction product=around 0.6) (confirmed by coloration with UV and molybdic acid). After the completion of the reaction was confirmed, the reaction solution was concentrated under reduced pressure to yield white crystals as a residue. To the residue, 150 mL of cooled ethyl acetate and 150 mL of 0.5 mol/L cooled hydrochloric acid were added, stirred in an ice bath for 5 minutes, and left to stand at room temperature until separation occurred. The organic layer was extracted and washed with 150 mL of water twice, with 150 mL of a saturated aqueous solution of sodium hydrogencarbonate, with 150 mL of water twice and with 150 mL of a saturated saline solution twice in this order, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to yield yellow oily matter. Separately, the water layer was extracted and washed with 150 mL of ethyl acetate twice, with 150 mL of water twice and with 150 mL of saturated saline solution in this order, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to recover a small amount of yellow oily matter. By the series of operations, 8.82 g of light yellow oily matter was obtained. Since it was confirmed with TLC analysis, that there were reagents remaining in the residue, it was briefly purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to yield 4.9282 g (corresponding to 14 mmol) of 1-(N-(t-butoxycarbonyl)amino)-3-benzyloxy-cyclobutane-1-carboxylic acid ethyl ester as white crystals.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:53][C:54]1[S:55][C:56]2[CH2:62][CH2:61][CH2:60][CH2:59][C:57]=2[N:58]=1>CN(C)C=O.O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:53][C:54]2[S:55][C:56]3[CH2:62][CH2:61][CH2:60][CH2:59][C:57]=3[N:58]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nc2c(s1)CCCC2
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(s1)CCCC2)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 77.8 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (50 mg, 0.17 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (83 mg, 0.19 mmol), triethylamine (0.048 mL, 0.34 mmol), and 2-amino-4,5,6,7-tetrahydrobenzothiazole (40 mg, 0.26 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 25° C. for 14 h. The reaction mixture was then diluted with water and ethyl acetate, and the layers were separated. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium chloride solution, and water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-propionamide (56 mg, 79%) as a white solid: mp 170-171° C.; EI-HRMS m/e calcd for C21H24Cl2N2OS (M+) 422.0986, found 422.0982.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[K+]>C1COCC1.CO>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cnc(Nc2ccc(Cl)cc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(Nc2ccc(Cl)cc2)s1
Temperature: 50 °C

Procedure:
A mixture of 3.0 g (11.1 mmol) 2-(4-Chloro-phenylamino)-thiazole-5-carboxylic acid ethyl ester and 6.7 ml 5M KOH in 50 ml THF and 10 ml MeOH was heated to 50° C. for 4 h and subsequently concentrated. The residue was taken up in water, acidified with acetic acid and extracted with ethyl acetat. The combined organic layers were washed with water, dried with MgSO4 and evaporated. The residue was recrystallised from ethyl acetate to obrain 2.0 g (70%) of the title compound as white crystals. (m/e): 254.9 (M+H+, 100%)
Reaction SMILES: [CH:1]1([N:7]([CH3:26])[C:8]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=3)[N:12]=[CH:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C.CO>[NH2:23][C:17]1[CH:16]=[C:15]([C:13]2[N:12]=[CH:11][N:10]([C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:26])=[O:9])[CH:14]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCCCC3)cn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCCCC3)cn2)cc1N

Procedure:
10% Palladium on carbon (0.16 g, 0.15 mmol) was added to a stirred solution of N-cyclohexyl-4-(4-methoxy-3-nitrophenyl)-N-methyl-1H-imidazole-1-carboxamide (1.075 g, 3 mmol) in a mixture of ethyl acetate (50 mL) and methanol (50 mL) at room temperature under an argon atmosphere. Hydrogen was bubbled through the solution for 1 h. The solution was then filtered through celite and the pad was washed with ethyl acetate. The combined filtrate was evaporated to give a brown oily solid that was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:27])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]([NH:13][NH:14]S(C2C=CC(OC)=CC=2)(=O)=O)=[CH:10][C:9](=[O:26])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36](=O)[CH2:37][CH3:38]>CO>[Cl:1][C:2]1[S:3][C:4]([Cl:27])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]2[N:13]=[N:14][CH:35]=[C:36]([CH2:37][CH3:38])[C:10]=2[C:9](=[O:26])[CH2:8]1
Reactant: CCC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(Cl)sc3Cl)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cnnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
To a mixture of 5-(2,5-dichlorothiophen-3-yl)-1-[2-(4-methoxyphenylsulfonyl)hydrazino]cyclohexen-3-one (1.79 g), anhydrous potassium carbonate (0.718 g) and methanol (30 ml) was added under ice-cooling 1-bromobutan-2-one (0.785 g), and the mixture was stirred at room temperature for 2 hours. To the mixture was added anhydrous potassium carbonate (1.2 g), and the mixture was stirred for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified with silica gel column chromatography to give 7-(2,5-dichlorothiophen-3-yl)-4-ethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.26 g) as oil.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[N:10]=1>C(#N)C>[N:1]1([C:13]2[CH:12]=[C:11]([CH2:16][O:17][CH2:18][CH:19]3[CH2:20][CH2:21]3)[N:10]=[C:9]([Cl:8])[N:14]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cc(COCC2CC2)nc(Cl)n1
Reactant: C1CNC1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1nc(COCC2CC2)cc(N2CCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
To a mixture of azetidine (93 mg, 0.99 mmol) and sodium methoxide (30 wt % in methanol, 0.135 mL, 0.73 mmol) in acetonitrile (6 mL) was added 2,4-dichloro-6-((cyclopropylmethoxy)-methyl)pyrimidine (77 mg, 0.33 mmol). The reaction was stirred at rt for 30 minutes. The mixture was purified by preparative HPLC to give the title compound (44 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[F:16])=[CH:4][CH:3]=1.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([N:21]4[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]4)=[CH:32][CH:31]=3)=[CH:7][CH:6]=2)=[C:10]([F:16])[CH:11]=1
Reactant: Nc1ccc(Nc2ccc(N)cc2F)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: Nc1ccc(Nc2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2)c(F)c1

Procedure:
Compound 807 was prepared according to the procedure described in Scheme IV from N1-(4-aminophenyl)-2-fluorobenzene-1,4-diamine and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C24H25FN4O2: 421.20; found 420.98.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[C:3](=[O:13])[O:2]1.Cl[CH2:15][Cl:16].S(Cl)(Cl)=O>CO.CC(OC)(C)C>[CH3:1][O:2][C:3](=[O:13])[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:15][Cl:16])=[N:11][OH:12]
Reactant: ClCCl
Reactant: O=C1OCc2ccccc2C1=NO
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: COC(C)(C)C
Product: COC(=O)C(=NO)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of isochroman-3,4-dione 4-oxime (98% pure, 3.5 g, 0.02 mol) in methanol (35 g) and dichlormethane (32 g) was added dropwise at 20-30° C. thionyl chloride (24.0 g, 0.2 mol). The resulting mixture was stirred at ambient temperature for 3 d. The reaction was monitored by HPLC. After completion of the reaction, the mixture was concentrated in vacuo and a crude residue was obtained (5.5 g). A part of this residue (5.1 g) was dissolved in MTBE and was washed with water. The mixture was concentrated and the resulting residue was purified by silica column chromatography by yield (2-chloromethyl-phenyl)-hydroxyimino-acetic acid methyl ester as a colorless solid (3.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:11]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])([CH2:13][CH3:14])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[O:17])[CH:15]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:21](=[O:22])[NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)CC
Product: CCC(C)C1C(=O)NN(c2ccc(Cl)c(Cl)c2)C1=O
Yield: 76.2 %

Procedure:
50 g of 3,4-dichlorophenylhydrazine (85%) and 122.5 g of diethyl sec-butyl-malonate were heated for 10 hours at 180° C. (external temperature) while distilling 21.3 g of ethanol. The remainder was taken up in 200 ml of methylene chloride, and the solution was extracted with 2N sodium hydroxide, then with water. The combined aqueous phases were washed with methylene chloride and acidified to pH 1 by concentrated hydrochloric acid. The precipitate was separated, washed with water, separated, dried under reduced pressure at 40° C. to obtain 64.8 g of 1-(3,4-dichlorophenyl)-4-(sec-butyl)-pyrazolidine-3,5-dione melting at 118°-120° C.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][N:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([C:35]([O:37]C)=[O:36])[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][N:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([C:35]([OH:37])=[O:36])[CH:29]=[CH:28]4)=[CH:23][CH:24]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CC4)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CC4)cc3)ccc2n1
Temperature: 120 °C
Yield: 76.6 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (70 mg, 0.13 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.19 mL, 0.19 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. Then (0.19 mL, 0.19 mmol) 1 N hydrochloric acid was added and the solution was concentrated. The residue was taken up with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine and concentrated. The resulting solid was dried under a nitrogen stream at 45° C. over 48 hours to afford 6-[4-({[5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a yellow solid (53 mg, 78%). 1H-NMR (400 MHz, DMSO-d6) δ 13.37 (br s, 1H), 8.81 (s, 2H), 8.53 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.18-8.08 (m, 3H), 7.74 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 5.02 (s, 2H), 2.52-2.46 (m, 1H), 1.23-1.10 (m, 4H). HRMS (ESI) C28H19Cl2N3O4 calculated: 532.0825 [M+H]+, found: 532.0823 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH3:17])[C:14](O)=[O:15])[CH:12]=2)=[CH:4][C:3]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH3:17])[C:14]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:15])[CH:12]=2)=[CH:4][C:3]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: C1COCCN1
Reactant: CC(C(=O)O)n1cc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)N1CCOCC1)n1cc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-propionic acid (5.00 mg, 0.0142 mmol), morpholine (10.0 mg, 0.11 mmol), TBTU (9.14 mg, 0.0284 mmol), DIPEA (0.02 mL, 0.1 mmol) and DMF (2 mL, 0.03 mol) was stirred at rt for 10 min. The solution was transferred to a separatory funnel, diluted with EtOAc and washed 3× with water. The organic layer was concentrated in vacuo and loaded onto a prep TLC plate, eluting with 5% MeOH/DCM. The band containing the pure product was filtered off using 1:1 MeOH/DCM, and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.74 (d, J=7.1 Hz, 3H), 3.50-3.72 (m, 8H), 5.62 (q, J=7.1 Hz, 1H), 7.42-7.47 (m, 1H), 7.50-7.56 (m, 1H), 7.88 (s, 1H), 8.01 (dd, J=10.7, 8.2 Hz, 2H), 8.17 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.3 Hz, 1H). MS (ES+): m/z=435.16 (100) [MH+]. HPLC: tR=2.89 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:26])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:34][C:33]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[C:38]#[N:39])=[CH:32][C:31](=O)[O:30]1>>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:26][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:42]=[CH:41][CH:40]=[C:37]([C:38]#[N:39])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(-c3ccccc3)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(-c3ccccc3)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 66.7 %

Procedure:
Prepared from (3″-amino-[1,1′;4′,1″]terphenyl-4″-yl)-carbamic acid tert.-butyl ester (Example G32) (159 mg, 0.44 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (111 mg, 0.49 mmol) according to the general procedure K. Obtained as an off-white solid (156 mg).