Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2S(C1C=CC=CC=1)(=O)=O.N1C=CC=CC=1.[CH3:37][C:38]1[S:39][CH:40]=[C:41]([C:43](Cl)=[O:44])[N:42]=1>C(Cl)Cl>[CH3:37][C:38]1[S:39][CH:40]=[C:41]([C:43]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][NH:6]3)=[O:44])[N:42]=1
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: CS(=O)(=O)Nc1cncc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cc(-c3cncc(NS(C)(=O)=O)c3)cc3[nH]ncc23)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-3-pyridinyl}methanesulfonamide (50 mg) was dissolved in DCM (1 ml) and pyridine (0.014 ml) was added. A solution of 2-methyl-1,3-thiazole-4-carbonyl chloride (22 mg) in DCM (1 ml) was added to the reaction and the mixture was stirred at RT for 30 min. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (10 mg) was added to the reaction and stirring continued for 30 min. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (40 mg) was added then the reaction was quenched with water and passed through a hydrophobic frit. The organic layer was evaporated to dryness and the residue was dissolved in DMSO:MeOH (1 ml, 1:1, v/v) and purified by MDAP (method E). The compound was dissolved in MeOH containing a few drops of 2M NaOH and stirred for 5 mins at RT. The residue was dissolved in MeOH and loaded onto an SAX SPE cartridge pre-conditioned with MeOH. After eluting with MeOH and evaporating to dryness, the residue was dissolved in DMSO and purified by MDAP (method E) to give the title compound (9 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH3:23])=[C:9]2[CH3:24])=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[CH3:24][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][O:25][CH:26]=3)=[CH:3][CH:4]=2)[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:11][C:10]=1[CH3:23]
Reactant: OB(O)c1ccoc1
Reactant: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(Br)cc2)c1C
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(-c3ccoc3)cc2)c1C

Procedure:
The title compound was prepared according to the procedure of Example 35 using 1-(4-bromophenyl)-2,3-dimethyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole instead of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole and 3-furanboronic acid instead of 2-furanboronic acid in step 4.
Reaction SMILES: ClC1C=C(Cl)C=C(Cl)C=1[O:10][C:11](=O)[CH2:12][C:13](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:14].[NH2:26][C:27]([CH:34]([CH3:36])[CH3:35])=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>BrC1C=CC=CC=1.CCOC(C)=O.CCOCC>[OH:14][C:13]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([CH:34]([CH3:35])[CH3:36])[NH:26][C:11](=[O:10])[CH:12]=1
Reactant: CCOC(=O)C=C(N)C(C)C
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Brc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1c(O)cc(=O)[nH]c1C(C)C

Procedure:
Malonic acid bis(2,4,6-trichlorophenyl) ester (1.4 g, 3.05 mmol) and ethyl 3-amino-4-methylpent-2-enoate (480 mg, 3.05 mmol) in bromobenzene (5 mL) was heated at 155° C. for 45 min. The reaction mixture was diluted with EtOAc/Et2O then concentrated in vacuo until a solid crashed out of solution. The solid was collected and rinsed with Et2O and ethyl acetate. The filtrate was concentrated in vacuo, diluted with DCM, and purified by flash chromatography (12-100% EtOAc/isohexane). The fractions containing pure product were concentrated in vacuo and the resulting solid triturated with Et2O and combined with the first batch of solid to give ethyl 4-hydroxy-2-isopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate. MS ESI calc'd. for C11H15NO4 [M+1]+ 226. found 226.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.O1CCCC1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.O1C2C=CC=CC=2N=C1>O>[F:24][C:23]([F:25])([F:26])[C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:18][CH:19]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: c1ccc2ocnc2c1
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
To a solution of 15.4 g. (0.1 mole) of 2-chlorobenzoxazole in 200 ml. of tetrahydrofuran was added dropwise a solution of 16.1 g. (0.1 mole) of p-aminobenzotrifluoride in 100 ml. of tetrahydrofuran with vigorous agitation. Following the addition, the reaction mixture was heated on a steam bath under reflux for 16 hours. Then the reaction mixture was cooled to about 25° C., and about 500 ml. of water was added. The tetrahydrofuran solvent was removed by distillation under vacuum, leaving an aqueous slurry of the reaction product. The solids were filtered off and dried. The dried residue was dissolved in a minimum amount of warm benzene. Then about 200 ml. of hexane was added to the benzene solution to crystallize the reaction product. The crystals were filtered off and dried, yielding 19.2 g. of 2-[4-trifluoromethyl)anilino]benzoxazole having a melting point of 180°-182° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].N1C(C)=CC=CC=1C.[CH3:17][C:18]([CH3:30])([O:20][C:21]([NH:23][C:24](=[CH2:29])[C:25]([O:27][CH3:28])=[O:26])=[O:22])[CH3:19]>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:29][C@@H:24]([C:25]([O:27][CH3:28])=[O:26])[NH:23][C:21]([O:20][C:18]([CH3:30])([CH3:17])[CH3:19])=[O:22]
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: Nc1ccccc1S
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@H](CSc1ccccc1N)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a mixture of 2-amino-thiophenol (1.9 g., 15.4 mmole), methylene chloride (15 ml.), and 2,6-lutidine (1.8 ml., 1.0 eq.) at -20° (chloroform dry ice) is added 2-[[(1,1-dimethylethoxy)carbonyl]amino]-2-propenoic acid, methyl ester (3.0 g., 1.0 eq.) dropwise over 5 minutes. After one hour the cooling bath is removed and the reaction mixture is stirred for an additional 16 hours. The reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, brine, dried (MgSO4), and evaporated. The residue (4.1 g.) is chromatographed on silica (125 g.) eluting with hexane/ethyl acetate (5:1) to give 2.5 g. of S-(2-aminophenyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-cysteine, methyl ester as an oil after evaporation.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:16]=[C:15]3[C:17]([C:28]([O:30]C)=[O:29])=[CH:18][N:19](COC(=O)C(C)(C)C)[C:14]3=[N:13][CH:12]=2)=[N:3]1.[OH-].[K+]>O.O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:16]=[C:15]3[C:17]([C:28]([OH:30])=[O:29])=[CH:18][NH:19][C:14]3=[N:13][CH:12]=2)=[N:3]1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4ccccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccccc21
Temperature: 25 °C
Yield: 113.7 %

Procedure:
A mixture of methyl 2-(1-methyl-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (150 mg, 0.36 mmol), potassium hydroxide (280 mg, 5 mmol) in 2.5 mL of water and 5 mL of 1,4-dioxane was heated to reflux for 90 mins. The reaction mixture was cooled to room temperature, evaporated, acidified with 1N HCl, then filtered and dried to give 2-(1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (120 mg, crude) as a brown solid. LCMS: (M+H)+=294. Used into the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Na].Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:12]([N+:23]([O-:25])=[O:24])=[CH:11][C:10]=1[C:26]([F:29])([F:28])[F:27]>CN(C=O)C>[CH2:21]([N:18]([CH2:19][CH3:20])[C:13]1[C:12]([N+:23]([O-:25])=[O:24])=[C:11]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[C:10]([C:26]([F:29])([F:28])[F:27])=[CH:9][C:14]=1[N+:15]([O-:17])=[O:16])[CH3:22]
Reactant: CCN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reactant: O=C1CCCN1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(N2CCCC2=O)c1[N+](=O)[O-]
Yield: 5 %

Procedure:
The residue, which contained sodium pyrrolidone, was cooled to 40°, and a solution of 34.2 g of 2-chloro-4-diethylamino-3,5-dinitrobenzotrifluoride (0.1 m) in 50 cc of DMF was added in 0.5 hr. at 40°-46°. The reaction mixture was heated at 112°-115° for 21.5 hr., cooled, and partitioned between 100 cc of tolune and 200 cc of water. The toluene phase was given 5 × 100 cc water washes, and the toluene was removed by rotary evaporation, leaving 21.0 g of residue. The residue then was vacuum distilled using a micro short-path distillation apparatus. The product (5.5 g) distilled at 170°-180° (0.1-0.2 mm). The yellow distillate was recrystallized twice from 1 part of methanol to yield 2.2 g, 5.0% yield; mp 94°-95°; IR(KBr) 3080 (CH aromatic), 2990 (CH aliphatic), 1710 (C=O), 1530 and 1340 cm-1 (NO2); NMR (CDCl3) δ 8.1 (1, s, CH aromatic), 3.6 (2, t, CH2NCO), 3.1 (4, q NCH2 -CH3), 2.6-2.1 (4, m, CH2CH2C=O), 1.1 (6, t, CH3).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CON(C)[C:8]([C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:14]=1)=[O:9]>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:13]2[CH:14]=[C:10]([C:8](=[O:9])[CH2:1][CH3:2])[CH:11]=[N:12]2)=[CH:21][CH:20]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc(Cn2cc(C(=O)N(C)OC)cn2)cc1
Solvent: C1CCOC1
Product: CCC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Reaction time: 1 h
Yield: 96.7 %

Procedure:
According to Scheme 2 Step 2: Ethylmagnesium bromide (3N, 37.2 mmol, 12.4 mL) was added dropwise at room temperature to a solution of N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide (33.8 mmol, 9.30 g) in THF (80 mL) and the reaction mixture was stirred for 1 hour. Then ethylmagnesium bromide (3N, 37.2 mmol, 12.4 mL) was added and the reaction mixture was stirred for 1 hour. Finally some more ethylmagnesium bromide (3N, 74.4 mmol, 24.8 mL) was added and the reaction mixture was stirred for 1.5 hour at 50° C. The reaction was quenched with HCl (1 N, 300 mL) and the aqueous phase was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was concentrated to yield 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)propan-1-one (32.7 mmol, 8.00 g, 97%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:19][NH2:20])=[O:18])[CH2:11][CH2:10]1.[CH2:21]1[CH2:26][CH2:25][CH:24]([CH2:27][N:28]=[C:29]=[O:30])[CH2:23][CH2:22]1.CCCCCC>C1(C)C=CC=CC=1>[CH:24]1([CH2:27][NH:28][C:29]([NH:20][NH:19][C:17](=[O:18])[CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)=[O:30])[CH2:25][CH2:26][CH2:21][CH2:22][CH2:23]1
Reactant: COc1ccccc1N1CCN(CCC(=O)NN)CC1
Reactant: O=C=NCC1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCC(=O)NNC(=O)NCC2CCCCC2)CC1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a suspension of 3-[4-(2-methoxyphenyl)piperazino]propanohydrazide D2 (0.30 g, 1.07 mmol) in anhydrous toluene (5 mL), cyclohexanemethyl isocyanate (0.16 g, 0.165 mL, 1.16 mmol) was added and the mixture was heated at reflux until all solid dissolved. The solution was allowed to cool slowly to room temperature. Hexane was added and the resulting oil was extracted with ethyl acetate, the organic phase was washed with water, dried over MgSO4 and evaporated under reduced pressure to afford 0.40 mg (87%) N-(cyclohexylmethyl)-2-{3-[4-(2-methoxyphenyl)piperazino]propanoyl}-1-hydrazinecarboxamide D4 as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)([N:18]1C=CN=C1)=O.N.C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: CCS(=O)(=O)c1ccc(Br)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Br)c(C(N)=O)c1
Reaction time: 0.17 h
Yield: 28 %

Procedure:
To 2-bromo-5-(ethylsulfonyl)benzoic acid (Preparation 73, 8.10 g, 27.6 mmol) dissolved in THF (200 mL) was added carbonyldiimidazole (8.72 g, 41.4 mmol). The reaction was left to stir for 5 minutes under nitrogen before ammonia was bubbled through the solution. A temperature rise from 22° C. to 41° C. was observed over 10 minutes. The temperature then started to fall, reaching 35° C. after 5 minutes, after which the flow of ammonia was stopped. The reaction mixture was left to stand as a saturated ammonia solution for 30 minutes before removal of the solvent under reduced pressure. The residue was partitioned between EtOAc (500 mL) and water (500 mL) and the layers separated. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure to give the crude product. Trituration with CH2Cl2 gave the title compound as a solid in 28% yield, 2.23 g. A further portion of the title compound was isolated by drying of the filtrate and further trituration, to give a further 8%, 650 mg.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([CH3:32])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[C:14]1[C:15]([CH3:31])=[N:16][N:17]2[C:22](=O)[C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:20]([CH3:30])[NH:19][C:18]=12.C(=O)(O)[O-].[Na+]>>[Cl:3][C:22]1[N:17]2[N:16]=[C:15]([CH3:31])[C:14]([C:7]3[C:8]([CH3:13])=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=3[CH3:32])=[C:18]2[N:19]=[C:20]([CH3:30])[C:21]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Reaction time: 1 h
Yield: 103.2 %

Procedure:
Phosphorus oxychloride (1.7 g) was added to ethyl 2-(3-mesityl-2,5-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)acetate (120 mg) of Reference Example 27 at room temperature, followed by stirring for one hour under heating under reflux. After cooling, the reaction solution was poured onto ice. The reaction mixture was basified with an aqueous saturated solution of sodium bicarbonate, and then extracted twice with ethylacetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (130 mg) as a reddish brown oil.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:21]3[CH:22]=[CH:23][C:24]4[O:28][N:27]=[C:26]([NH:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]=4[CH:35]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:10][CH2:9]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH:8]1([N:11]([CH2:12][C:13]2[CH:14]=[C:15]([C:21]3[CH:22]=[CH:23][C:24]4[O:28][N:27]=[C:26]([NH:29][CH2:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C:25]=4[CH:35]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2ccc3onc(NCC(C)(C)C)c3c2)cc1CNC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2ccc3onc(NCC(C)(C)C)c3c2)cc1CN(C1CC1)S(C)(=O)=O
Temperature: -70 °C
Reaction time: 15 h
Yield: 69.5 %

Procedure:
Triethylamine (0.14 mL, 0.99 mmol, 1.5 equiv.) was added to a solution of 5-(3-((cyclopropylamino)methyl)-4-methoxyphenyl)-N-neopentylbenzo[d]isoxazol-3-amine (exemplary compound 45) (0.25 g, 0.66 mmol, 1 equiv.) in DCM (10 mL) and the mixture was subsequently cooled to −70° C. Methanesulphonic acid chloride (0.06 mL, 0.79 mmol, 1.2 equiv.) was added in drops and the mixture was heated slowly to RT and stirred for 15 hours. The reaction mixture was diluted with DCM (50 mL) and extracted with sat. aq. sodium hydrogen carbonate sol. (1×10 mL) and sat. aq. NaCl solution (1×10 mL), dried (MgSO4) and the solvent removed in a vacuum. After column-chromatographic purification (EtOAc/DCM; 1:1), the desired product (0.21 g, >99%) is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]3)[CH:16]=[CH:15][C:14]=2[NH2:27])=O)=[N:2]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:26][C@H:21]1[O:22][C@@H:23]([CH3:25])[CH2:24][N:19]([C:17]2[CH:16]=[CH:15][C:14]3[N:27]=[C:10]([C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][N:2]=4)[NH:12][C:13]=3[CH:18]=2)[CH2:20]1
Reactant: C[C@@H]1CN(c2ccc(N)c(NC(=O)c3n[nH]c4ccccc34)c2)C[C@H](C)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H]1CN(c2ccc3nc(-c4n[nH]c5ccccc45)[nH]c3c2)C[C@H](C)O1

Procedure:
1H-Indazol-3-yl-N-[5-((6S,2R)-2,6-dimethyl-morpholin-4-yl)-2-aminophenyl]carboxamide (1.0 equivalent) was dissolved in acetic acid, and sodium acetate (1.1 equivalents) was added. The solution was heated at reflux for 1 hour and then cooled. The acetic acid was removed, and the residue was triturated with ethyl acetate and filtered. The filtrate was concentrated to provide a green foam which was purified by reverse phase HPLC. LC/MS (m/z) 348.1 (MH+), Rt 2.23 minutes.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH:38](=O)[CH:39]([CH3:41])[CH3:40]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)C=O
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure F using isobutyraldehyde. The final product was obtained in 41% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][N:13]=[CH:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])=[C:4]([F:21])[CH:3]=1.N1CCCCC1.[CH3:28][CH:29](C(O)=O)[C:30](O)=[O:31].C(O)(=O)C>N1C=CC=CC=1>[F:21][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]=1[N:12]1[C:30](=[O:31])[C:29]([CH3:28])=[C:15]([C:16]([F:19])([F:18])[F:17])[CH:14]=[N:13]1
Reactant: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: CC(C(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1c(C(F)(F)F)cnn(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 57.2 %

Procedure:
Under a stream of nitrogen gas, 0.399 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone), compound 3-3 was dissolved in 2.4 ml of pyridine at room temperature. To this solution were added 0.133 ml of piperidine and 0.159 g of methylmalonic acid, and the mixture was heated to 70° C. and stirred for 3.5 hours. Then, 2.4 ml of acetic acid was added, and stirring was further continued at 130° C. for 8 hours. The reaction solution was left cooling to room temperature and concentrated under reduced pressure. The residue was diluted with 100 ml of diethyl ether. The diluted solution was washed twice with 20 ml of 3 N hydrochloric acid and once with 30 m of saturated sodium bicarbonate solution, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography to give 0.255 g of 2-(2-fluoro-4-chloro-5-isopropoxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one, compound 5-2.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[C:19]([O:18][C:16]([NH:15][C@@H:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc2c(c1)SCC[C@@H]2NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)O)ccc21
Yield: 96.2 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using (S)-4-(tert-butoxycarbonylamino)thiochromane-7-carboxylic acid methyl ester (5.75 g) and potassium carbonate (4.91 g), the objective (S)-4-(tert-butoxycarbonylamino)thiochromane-7-carboxylic acid (5.29 g) was obtained as colorless crystals.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)CCl.[CH:12]1[CH:13]=[CH:14][C:15]2[N:20](O)N=[N:18][C:16]=2[CH:17]=1.NCC1C=CC=CN=1>C1COCC1>[N:18]1[CH:14]=[CH:13][CH:12]=[CH:17][C:16]=1[CH2:15][NH:20][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: On1nnc2ccccc21
Agent: NCc1ccccn1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCCCC(=O)NCc1ccccn1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of pentanoic acid (5.3 mL, 48.7 mmol) in THF (50 mL) was added EDC (11.2 g, 58.4 mmol) and HOBt (7.88 g, 58.4 mmol). The mixture was stirred for 10 min. then 2-(aminomethyl)pyridine (4.7 mL, 46.3 mmol) was added. The solution was allowed to stir for 3 h then quenched with water (100 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield pentanoic acid (pyridin-2-ylmethyl)-amide (8.60, 92%).
Reaction SMILES: [CH:1]1([C:13]([O:15]C)=[O:14])[CH2:5][CH2:4][N:3]2[CH:6]=[CH:7][C:8]([C:9]([O:11]C)=[O:10])=[C:2]12.[OH-].[Na+].Cl>O>[CH:8]1([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][N:3]2[CH:4]=[CH:5][C:1]([C:13]([OH:15])=[O:14])=[C:2]12
Reactant: COC(=O)c1ccn2c1C(C(=O)OC)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccn2c1C(C(=O)O)CC2
Temperature: 0 °C
Yield: 71.7 %

Procedure:
Dimethyl 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (1.26 g, 5 mmol) and sodium hydroxide (1.00 g, 25 mmol) were heated in water (10 mL) at reflux for 1 hour. The resulting solution was cooled to 0° C. and acidified with hydrochloric acid (12 M) to pH 1. 2,3-Dihydro-1H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylic acid (0.70 g, 71.4% yield) was collected by filtration and dried.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([Cl:28])[C:19]=1[C:20](Cl)=[O:21]>C1C=CC=CC=1>[CH3:16][O:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([Cl:28])[C:19]=1[C:20]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)=[O:21]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Reactant: O=C1CCCC(=O)C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1c(Cl)ccc(Cl)c1C(=O)OC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1,3-Cyclohexanedione (11.2 grams; 0.10 mole), benzene (100 ml) and triethylamine (11.1 grams; 0.10 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer. 2-Methoxy-3,6-dichlorobenzoyl chloride (23.85 grams; 0.10 mole) dissolved in benzene (20 ml) was then added dropwise with stirring. After the addition was completed the reaction mixture was first stirred at ambient temperature for a period of about one hour and then at about 75°C for a period of about 20 minutes. After this time the mixture was cooled to room temperature and was filtered. The filtrate was stripped of benzene under reduced pressure to yield an oil as the residue. This oil was distilled under reduced pressure to yield the desired product 3-oxocyclohex-1-enyl 2-methoxy-3,6-dichlorobenzoate having a boiling point of 199° to 200°C at 0.45 mm of Hg pressure.