Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][OH:5])(=O)C.CC(C)([O-])C.[K+].F[C:13]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[NH:24][C:23](=[O:38])[N:22]=2)=[CH:17][C:14]=1[C:15]#[N:16]>CN(C=O)C>[NH2:16][C:15]1[C:14]2[CH:17]=[C:18]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[NH:24][C:23](=[O:38])[N:22]=3)[CH:19]=[CH:20][C:13]=2[O:5][N:4]=1
Reactant: CC(=O)NO
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc(F)c(C#N)c2)nc(=O)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccccc1-c1cc(-c2ccc3onc(N)c3c2)nc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
To a solution of acetohydroxamic acid (53 mg, 0.7 mmol) in DMF (5 mL) was added potassium tert-butoxide (80 mg, 1.76 mmol). The mixture was stirred at room temperature for 20 min, followed by the addition of solution of 2-fluoro-5-(6-(2-isobutoxyphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzonitrile (100 mg, 0.27 mmol) (Example 1, Step 4) in DMF (4 mL). The reaction was stirred at room temperature for 16 h. The mixture was quenched by acid and the product was purified by Prep-HPLC to give 75 mg (74%) of 4-(3-amino-1,2-benzisoxazol-5-yl)-6-{2-[(2-methylpropyl)oxy]phenyl}pyrimidin-2(1H)-one. 1H NMR (400 MHz, d6-DMSO): δ 11.80 (s, br, 2H), 8.78 (s, 1H), 8.37 (d, 1H), 7.66-7.45 (m, 3H), 7.24-7.00 (m, 3H), 6.60 (s, 2H), 3.83 (d, 2H), 2.05-1.97 (m, 1H), 0.98 (d, 6H). MS (EI) for C21H20N4O3: 377 (MH+).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH3:23][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[C:20]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][C:11]([C:20](=[O:21])[C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([CH3:23])[CH:15]=4)=[CH:10][C:8]=3[C:9]=2[CH:1]=1)=[O:21]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cccc(C(=O)c2ccc3oc4ccc(C(=O)c5cccc(C)c5)cc4c3c2)c1

Procedure:
2,8-Bis(3-methylbenzoyl)dibenzofuran is prepared according to the procedure of Step 1, Example 1. Dibenzofuran (42 g, 0.25 mole), m-toluoyl chloride (82 g, 0.53 mole), and anhydrous aluminum chloride (73 g, 0.55 mole) are reacted in carbon disulfide (250 ml) for twenty-four hours at 20°. The desired compound is obtained after recrystallization of the crude product from toluene, yield 22 g (23% of theory), mp 180°-1°.
Reaction SMILES: [C:1]12([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]([OH:23])[CH2:15][CH2:14]3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH2:26]1COC[CH2:27]1>O>[C:1]12([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]([O:23][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C1CCOC1
Reactant: O=C(N1CCC(O)c2ccccc21)C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC1CCN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 0.1 g (0.32 mmol) adamantan-1-yl-(4-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-methanone and 35 mg (55% in oil, 0.8 mmol) NaH in 5 mL THF at 0° C. was treated with 0.15 g (0.99 mmol) iododethane and allowed to stir to room temperature and subsequently heated to 50° C. overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried with MgSO4, filtered and evaporated. The residue was subjected to column chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 24.5 mg (22%) of the title compound as colourless solid. MS(m/e): 340.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:7]1[C:8]2[C:3](=[C:2]([Br:1])[C:11]([F:12])=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH:6]1[CH3:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCc2c(ccc(F)c2Br)N1
Product: CC(=O)N1c2ccc(F)c(Br)c2CCC1C

Procedure:
The 5-bromo-6-fluoro-1,2,3,4-tetrahydroquinaldine intermediate of Formula IV is reacted in step (3) with acetic anhydride to provide the novel intermediate 1-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroquinaldine of Formula V. The reaction is conducted by heating the reaction mixture, for example, using a steam bath.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][C@H:14]1[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17](=[O:24])[CH2:16][CH2:15]1>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][C@H:14]3[N:18]([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:17](=[O:24])[CH2:16][CH2:15]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)CCN1C(=O)CC[C@H]1CN
Reactant: Fc1ccc2ncc(Br)n2n1
Product: CC(C)CCN1C(=O)CC[C@H]1CNc1ccc2ncc(Br)n2n1
Yield: 60 %

Procedure:
The 3-bromo-6-fluoroimidazo[1,2-b]pyridazine was reacted with (S)-5-(aminomethyl)-1-isopentylpyrrolidin-2-one under the amine displacement conditions described in example 5.6.42, Part A to afford 60% titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (d, J=6.32 Hz, 6H) 1.39-1.66 (m, 3H) 1.95-2.08 (m, 1H) 2.13-2.26 (m, 1H) 2.31-2.53 (m, 2H) 3.02 (ddd, J=13.89, 9.22, 4.93 Hz, 1H) 3.48 (dt, J=14.15, 5.18 Hz, 1H) 3.79 (ddd, J=13.77, 9.35, 6.95 Hz, 1H) 3.91 (ddd, J=14.08, 7.01, 2.91 Hz, 1H) 4.00-4.11 (m, 1H) 5.42 (t, J=5.31 Hz, 1H) 6.67 (d, J=9.60 Hz, 1H) 7.52 (s, 1H) 7.66 (d, J=9.85 Hz, 1H); LRMS (ESI) m/380.0 doublet [(M+H)+, calcd for C16H22BrN5O 379.0].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:5]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Solvent: CCO
Product: Cc1ccc(-c2nc(Cl)cc(N3CCN(C)CC3)n2)cc1

Procedure:
Repeating the procedure of Example XX 7.2 g. of 4,6-dichloro-2-(p-tolyl)-pyrimidine and 6.0 g. of N-methylpiperazine are reacted in 40 ml. of absolute ethanol. The crude product (8.4 g.) is separated and twice recrystallized from n-heptane to afford 4-chloro-6-(4-methyl-1-piperazinyl)-2-(4-tolyl)-pyrimidine, m.p. 93°-95°C.
Reaction SMILES: [CH2:1]([C@:8]1([C:23]([NH:25][CH2:26][C:27]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)=O)=O)[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:43]>C(O)(=O)C>[CH2:1]([C@:8]1([C:23]2[NH:25][CH:26]=[C:27]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=3)[N:43]=2)[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)cc(C(=O)CNC(=O)[C@@]2(Cc3ccccc3)OC(=O)N([C@H](C)c3ccccc3)C2=O)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(OC)cc(-c2c[nH]c([C@@]3(Cc4ccccc4)OC(=O)N([C@H](C)c4ccccc4)C3=O)n2)c1
Temperature: 100 °C

Procedure:
To the product from Step B (40 mg, 0.077 mmol) in acetic acid (1 mL) was added ammonium acetate (179 mg, 2.323 mmol) and the mixture heated at 100° C. for 40 h. The solvent was removed and the yellow oil was purified by reverse phase HPLC(YMC Pro-C 18 column, gradient elution, 20% to 90% acetonitrile/water with 0.1% TFA) to afford the title compound as a colorless amorphous solid. LC/MS 498.1 (M+1). IC50 value=B rating
Reaction SMILES: Br[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH:14]([CH3:16])[CH3:15].[C:17](=[O:19])=[O:18].Cl>>[CH:14]([C:3]1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]=1[C:17]([OH:19])=[O:18])([CH3:16])[CH3:15]
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Reactant: O=C=O
Agent: Cl
Product: CC(C)c1cc(C(C)C)c(C(=O)O)c(C(C)C)c1
Yield: 80 %

Procedure:
A Grignard reagent was prepared from 56.7 g of 1-bromo-2,4,6-triisopropylbenzene and poured to 300 g of dry ice, whereupon dry ice sublimated. Hydrochloric acid was added to the reaction mixture for quenching, followed by extraction with 200 g of toluene. The organic layer was taken out, washed with water, and combined with 10 wt % sodium hydroxide aqueous solution. The aqueous layer was taken out, combined with 50 g of 35 wt % hydrochloric acid, and extracted with 200 g of toluene. The organic layer was washed with water again, and concentrated under reduced pressure. The concentrate was crystallized from 150 g of hexane. The crystal precipitate was filtered and dried, obtaining the target compound, 2,4,6-triisopropylbenzoic acid. Amount 39.7 g, yield 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[I:9])N.C(ON=O)CC(C)C.[CH2:18]([S:20]SCC)[CH3:19]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:20][CH2:18][CH3:19])[CH:6]=[CH:7][C:8]=1[I:9]
Reactant: CCSSCC
Reactant: Nc1ccc(I)c(Cl)c1
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCSc1ccc(I)c(Cl)c1

Procedure:
A solution of 3-chloro-4-iodo-aniline (5.6 g), isoamylnitrite (8.8 ml) and ethyldisulphide (13.4 ml) in acetonitrile (100 ml) was heated at 60° C. for 24 h. The solvent was removed under reduced pressure and the residue purified by chromatography on silica eluting with 1% ethylacetate/isohexane. Yield 4.02 g
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][NH2:32])[CH:28]=[CH:29][CH:30]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:32][CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=3)=[O:20])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: NCc1cccc(Cl)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)NCc2cccc(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (17 mg, 0.054 mmol) and (3-chlorophenyl)methanamine (8.34 mg, 0.059 mmol) in THF (268 μL) was added PyBroP (27.5 mg, 0.059 mmol), DIEA (28.1 μL, 0.161 mmol) and HOBT (9.02 mg, 0.059 mmol). The reaction mixture was stirred overnight at room temperature. All volatile material was removed in vacuo and dissolved in DCM. The crude product dissolved in DCM was loaded to flash chromatography column (gradient EtOAc in heptane) providing 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(3-chlorobenzyl)-2-fluorobenzamide in 87% yield. LCMS (m/z): 441.1 (MH+), 0.79 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (s, 1H), 7.74 (m, 1H), 7.63 (m, 2H), 7.35 (m, 4H), 6.14 (s, 1H), 4.48 (m, 2H), 3.92 (m, 2H), 3.43 (m, 2H), 1.73 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][C:27]=3[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[O:37][C:36]([F:48])([F:47])[F:35])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2ccccc2OC(F)(F)F)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-trifluoromethoxyphenyl boronic acid as in Example 38 to afford 0.058 g (39%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C31H25O5F6 591.1606, found 591.1619.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][CH2:29][CH2:28][CH2:27][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCCCN1CCCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 3-(pyrrolidin-1-yl)propan-1-amine (32.1 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light brown solid, 73.3 mg, (77% yield) MS (ES+): 378.2, (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:30]([CH2:34][C:35]([OH:37])=O)([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:35](=[O:37])[CH2:34][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)CC(=O)O
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)CC(C)(C)C)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3,3,N-trimethyl-butyramide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using tert-butylacetic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 536.3 [M]+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH3:19])[CH:13]=[CH:12][CH:11]=1>FC(F)(F)S(O)(=O)=O>[F:9][C:10]1[C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH3:19])[C:13]([I:1])=[CH:12][CH:11]=1
Reactant: Cc1cccc(F)c1C(=O)O
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c(I)ccc(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Iodosuccinimide (7.47 g, 33.2 mmol) was added dropwise to a stirred solution of 6-fluoro-2-methylbenzoic acid (5.12 g, 33.2 mmol) in trifluoromethanesulfonic acid (50 mL) at room temperature. The mixture was stirred at room temperature overnight, poured into ice/water and stirred for 3 h until solid produced. The precipitate was collected, washed with water, and air dried to give the title compound as a yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:45])[C@@H:7]([NH:13][C:14](=[O:44])[CH2:15][CH2:16][C:17](=[O:43])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28](=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])(C)(C)C.[B-](F)(F)(F)F.CN(C(O[N:59]1[C:64](=[O:65])[CH2:63][CH2:62][C:60]1=[O:61])=[N+](C)C)C>>[O:61]=[C:60]1[CH2:62][CH2:63][C:64](=[O:65])[N:59]1[O:5][C:6](=[O:45])[C@@H:7]([NH:13][C:14](=[O:44])[CH2:15][CH2:16][C:17](=[O:43])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28](=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:8][CH2:9][C:10]([O:12][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:11]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCC(=O)NCCOCCOCCNC(=O)CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)CCCCCCC(=O)NCCOCCOCCNC(=O)CCC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O

Procedure:
(S)-2-[3-(2-{2-[2-(7-tert-Butoxycarbonylheptanoylamino)ethoxy]ethoxy}-ethylcarbamoyl)propionylamino]pentanedioic acid 1-tert-butyl ester (0.6 g, 0.93 mmol) was activated with TSTU using the procedure described above.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:45]([CH3:46])=[CH:44][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[C:30]([NH:35]C(C4CCCCC4)=O)[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[NH2:35][C:30]1[CH:29]=[CH:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([C:21]3[CH:20]=[C:19]([C:17]4[S:18][C:14]5[C:13]([C:47]6[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=6)=[C:12]([C@H:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:7]([OH:9])=[O:8])[C:45]([CH3:46])=[CH:44][C:15]=5[N:16]=4)[CH:24]=[CH:23][N:22]=3)[CH:26]=2)[N:31]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5nc(NC(=O)C6CCCCC6)ccc5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-c4ccc5nc(N)ccc5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(2-(cyclohexanecarboxamido)quinolin-6-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (12.0 mg, 0.016 mmol) in THF (0.4 mL) and methanol (0.4 mL) was added 1N NaOH solution (0.4 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H30ClN4O3S: 609.2; found: 609.2. 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J=5.6 Hz, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.16 (d, J=9.2 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.59-7.45 (m, 3H), 6.94 (d, J=8.8 Hz, 1H), 5.36 (s, 1H), 2.62 (s, 3H), 1.03 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[CH3:31][C:32]1[CH:36]=[C:35]([C:37](O)=[O:38])[O:34][N:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:37]([C:35]5[O:34][N:33]=[C:32]([CH3:31])[CH:36]=5)=[O:38])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: Cc1cc(C(=O)O)on1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)n1
Product: Cc1cc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5nnn(C)n5)cnc43)CC2)on1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 55) was coupled with 3-methyl-isoxazole-5-carboxylic acid to yield the title compound as light yellow solid. MS: 537.2 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccoc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccoc2c1
Yield: 80.8 %

Procedure:
A mixture of 6-methylbenzofuran (3.44 g, 0.026 mol), N-bromosuccinimide (4.63 g, 0.026 mol), dibenzoyl peroxide (trace) and carbon tetrachloride (50 cm3) was refluxed for 5 hr. The mixture was filtered and the solvent was removed from the filtrate. The residue was distilled to give 6-bromomethylbenzofuran (4.38 g, 0.021 mol, 80.0%) b.p. 84°-88° C./0.7 mm Hg.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C(O)(=O)C>CO.[Fe]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(c2ncc(N)cn2)CC1
Yield: 78.1 %

Procedure:
A mixture of 2-(4-methyl-piperazin-1-yl)-5-nitro-pyrimidine (446 mg, 2 mmol), iron powder (432 mg, 7.6 mmol), acetic acid (0.884 mL, 14 mmol) in methanol (8 mL) is heated at 65 C for 2 h. It is worked up as before to yield 302 mg (78%) of the title compound. MS (ESI) m/z 194 (M+H)+1.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][N:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[CH3:19][O:20][CH2:21]Cl>O1CCCC1>[CH3:19][O:20][CH2:21][O:1][C:2]1[C:3]2[CH:16]=[CH:15][N:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCCl
Reactant: Oc1c(-c2ccccc2)sc2cnccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(-c2ccccc2)sc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
A solution of 1.1 g (4.8 mmol) 3-hydroxy-2-phenyl-6-azabenzo[b]thiophene and 0.116 g (4.8 mmol) of sodium hydride in 15 mL of tetrahydrofuran was stirred at room temperature for 15 minutes. Then 0.37 mL (5.0 mmol) of chloromethyl methyl ether was added and the solution was stirred at room temperature for 2 hours. The solution was partitioned between ether and water and the ether extract was concentrated to afford 1.2 g (92%) of white crystalline material, m.p. 55°-56° C.