Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([F:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:22][C:23]2[CH:24]=[C:25]([F:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cn1cc(N)cc(F)c1=O
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(C)c(C)c1C(Nc1cc(F)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 28.2) and 5-amino-3-fluoro-1-methylpyridin-2(1H)-one (Step 14.2). tR: 4.17 min (HPLC 1); tR: 0.93 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.77 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]2=[O:22])=[C:11]([CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1.[I-].[Mg+2].[I-]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[C:17](=[O:22])[CH:18]3[CH:19]([CH:25]4[O:24][CH:28]3[CH:27]=[CH:26]4)[C:20]2=[O:21])=[C:11]([CH3:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C=CC1=O
Reactant: c1ccoc1
Agent: [I-]
Agent: [Mg+2]
Solvent: CO
Product: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A suspension of 2-(4-benzyloxy-2,6-dimethylphenyl)cyclopent-4-ene-1,3-dione (1 g, 3.3 mmol), furan (20 ml) and magnesium iodide (50 mg) is stirred at room temperature for 5 days. The reaction mixture is diluted with methanol and silica gel is added. After evaporation of the solvent, the residue is purified by column chromatography on silica gel to give 4-(4-benzyloxy-2,6-dimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (0.531 g).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([OH:33])[C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:33][CH:17]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[CH:21][CH:22]=1)[CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][C:3]([O:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=[O:7])=[C:2]([F:1])[CH:14]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CCC(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CCC(Oc1ccc(CCC(OCc2ccccc2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F)C(=O)O

Procedure:
2-(4-(3-(Benzyloxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2-fluoro-phenoxy)butanoic acid is prepared from 2-(2-fluoro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)butanoic acid using 2.1 equivalents of sodium hydride and 2.1 equivalents of benzyl bromide according to general procedure H.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)=O.[NH2:16][C:17]1[CH:25]=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1>C(O)C>[C:22]([C:21]1[CH:25]=[C:17]([N:16]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[CH:8]=[C:6]2[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:19][C:20]=1[OH:26])([OH:24])=[O:23]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1CCCCC1=O)c1cccs1
Solvent: CCO
Product: O=C(O)c1cc(-n2c(-c3cccs3)cc3c2CCCC3)ccc1O

Procedure:
A mixture of 2.22 g. (0.01 mole) of 2-(2-thienoylmethyl)cyclohexanone, (1.53 g. (0.01 mole) of 5-aminosalicylic acid, and 25 ml. of ethanol was heated uder reflux under nitrogen for 4 hours and filtered. The filtrate was concentrated to an oil which solidified when triturated with petroleum ether. Recrystallization from acetonitrile gave 1.0 g. (29%) of yellow crystals, m.p. 211°-213°.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[C:25]([CH2:37][CH2:38][CH3:39])[N:24]=1.C(O)(C)C>CO>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[C:25]([CH2:37][CH2:38][CH3:39])[N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Reactant: CCCc1nc(Cl)c2cc(OC)c(OC)cc2n1
Agent: Br
Solvent: CC(C)O
Solvent: CO
Product: CCCc1nc(N2CCC(n3c(=O)c4cc(C)ccc4n(C)c3=O)CC2)c2cc(OC)c(OC)cc2n1
Yield: 35 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used, 4-chloro-6,7-dimethoxy-2-propylquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline, and isopropyl alcohol was used as a reaction solvent in place of methanol. As a result, 174.3 mg (yield: 35%) of Compound 82 was obtained as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N+:6]([O-:29])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ncc(F)cc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2cc(F)c[n+]3[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.1 %

Procedure:
To a solution of 6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridine (18 g, 62 mmol) in DCM (300 mL) was added MCPBA (16 g, 93 mmol). The mixture was stirred at RT overnight and then concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with DCM:MeOH (30:1) to afford 23 g (100%) of 6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridine 4-oxide as a solid. MS (ESI) m/z: 307.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([OH:12])=[CH:9][CH:8]=[CH:7]2.[CH3:13][O:14]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:12][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[C:7]([CH:13]=[O:14])=[CH:8][CH:9]=1
Reactant: COC(Cl)Cl
Reactant: Cc1cccc2cccc(O)c12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cccc2c(C=O)ccc(O)c12
Reaction time: 0.17 h

Procedure:
101.9 g of 8-methyl-1-naphthol was dissolved in 815 ml of dichloromethane, in which 141.6 ml of titanium tetrachloride was gradually dropped under ice-cooling conditions. Thereafter, 93.7 ml of dichloromethyl methyl ether was gradually dropped under ice-cooling conditions. After agitation for 10 minutes, 200 ml of water was gently dropped under ice-cooling conditions. The reaction solution was extracted with ethyl acetate and the resultant organic phase was washed with water. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the resultant crystals were washed with chloroform to obtain 80 g of the captioned compound as brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]#[N:16])=[N:6]1.C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:29]>CO>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:29])[NH2:16])=[N:6]1
Reactant: [NH4+]
Reactant: Cc1ncc2c(C#N)nn(Cc3ccccc3F)c2n1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ncc2c(C(=N)N)nn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 994 mg (purity 81%, approx. 3.01 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile was dissolved in 15 ml of absolute methanol. 209 mg (3.72 mmol) of sodium methylate was added and it was stirred for 1 h at RT. Then a further 31 mg (0.56 mmol) of sodium methylate was added and it was stirred for 15 min at RT. 871 mg (14.50 mmol) of acetic acid and 489 mg (4.46 mmol) of ammonium chloride were added and the mixture was stirred for 45 min at 45° C. The reaction mixture was concentrated by evaporation, the residue was mixed with 1N sodium hydroxide solution, the precipitate was filtered with suction and dried under high vacuum. 918 mg (purity 91%, 97% of theor.) of the target compound was obtained.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2nccs2)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
N-Boc-4-hydroxy-aniline (3.9 g, 0.019 mol) was combined with 2-bromothiazole (2.4 mL, 0.027 mol) in DMSO (20 mL) at room temperature. K2CO3 (3.9 g, 0.028 mol) was added and with rapid stirring, the reaction mixture was heated at about 140° C. for 5 hours. After cooling to room temperature, the reaction mixture was poured into water (300 mL), extracted with ethyl acetate (2×) and the combined organics were dried over MgSO4. Decolorizing charcoal was added, stirred for 30 minutes and filtered through a plug of celite and silica (1:1) to obtain an amber filtrate. The solvent was removed by rotary evaporation and the residue was purified by flash column chromatography (ethyl acetate:hexanes; 5%-50% ethyl acetate gradient) to give the title compound (1.4 g, 4.8 mmol, 25%) MS (ESI APCI) m/z 293.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ 9.49 (s, 1H) 7.53 (d, J=9.0 Hz, 2H) 7.21-7.28 (m, 2H) 7.16-7.19 (m, 2H) 1.48 (s, 9H).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].Cl.[NH:6]1[CH2:9][CH:8]([NH:10][S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:13])=[O:12])[CH2:7]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[CH:2]([N:6]1[CH2:9][CH:8]([NH:10][S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:12])=[O:13])[CH2:7]1)([CH3:4])[CH3:3]
Reactant: CC(C)Br
Reactant: O=C(NCCS(=O)(=O)NC1CNC1)c1ccc(Cl)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N1CC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
85.3 mg (5 equiv.) 2-Bromo-propane were added to a mixture of 50 mg (0.14 mmol) 5-chloro-thiophene-2-carboxylic acid[2-(azetidin-3-ylsulfamoyl)-ethyl]-amide hydrochloride and 38 mg (2 equiv.) K2CO3 in 5 ml DMF. The resulting mixture was stirred for 2 h at 70° C., then diluted with 15 ml dichloromethane and washed with 3 ml of a saturated NaHCO3-solution. The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-azetidin-3-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: C[O-].[Na+].CO.CO.C([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:36])[NH:19][C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][C:21]=2[C:32]([O:34][CH3:35])=[O:33])=[C:14]([O:37]C(=O)C)[CH:13]=1)(=O)C.Cl>C(OCC)(=O)C>[OH:37][C:14]1[CH:13]=[C:12]([OH:11])[CH:17]=[CH:16][C:15]=1[C:18]([NH:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][C:21]=1[C:32]([O:34][CH3:35])=[O:33])=[O:36]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC(C)=O)cc1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Under ice-cooling, a 28% sodium methoxide-methanol solution (0.34 g) was added to a methanol (3.1 mL) suspension of 4-(2-(methoxycarbonyl)-5-phenylphenylcarbamoyl)-1,3-phenylene diacetate (0.31 g), followed by stirring at room temperature for 1 hour. The reaction mixture was added to 0.5 mol/L hydrochloric acid (20 mL) under ice-cooling, and then ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue to obtain 0.24 g of methyl 2-(2,4-dihydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]([Mg]Br)=[CH2:10].[Cl-].[NH4+]>O1CCCC1.O>[CH:1]1([CH:7]([OH:8])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)C1CCCCC1
Temperature: -20 °C
Yield: 37.8 %

Procedure:
A solution of cyclohexanecarbaldehyde (4.79 mL, 39.8 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of vinylmagnesium bromide (47.8 mL, 1M in tetrahydrofuran, 47.8 mmol) stirring at −20° C. The solution was stirred for 30 minutes at −20° C. at which time saturated ammonium chloride solution (75 mL) was added and the reaction was allowed to warm to 25° C. The solution was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, followed by 5% and 10% ethyl acetate in hexane to give the title compound (2.11 g, 38%). 1H NMR (300 MHz, CDCl3): δ ppm 1.40 m, 11 H) 3.85 (m, 1 H) 5.17 m, 2 H) 5.86 m, 1 H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14]2)=[O:10]>C1COCC1>[O:20]=[C:15]1[CH2:14][C:13]2[C:17](=[CH:18][CH:19]=[C:11]([C:9]([C:8]3[CH:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[CH:23]=[CH:22][CH:21]=3)=[O:10])[CH:12]=2)[NH:16]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
A dry 25 mL flask was charged with acetyl chloride (0.273 g, 3.48 mmol) and THF (5 mL). 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 1, 0.675 g, 2.67 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The tan precipitate was filtered to afford N-[3-(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.478 g, 1.48 mmol, 61%).
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[N:27][CH:28]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[N:27][C:26]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:49])=[CH:50][CH:51]=3)(=[O:43])=[O:44])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Yield: 91.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (140 mg, 0.199 mmol) was deprotected with TFA/DCM (2/1 ml). This afforded 110 mg (91.6% yield) of the titled compound. MS: m/z=604.1 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[C:16]1([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][C:30]#[N:31])(=[O:28])=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:29](/[S:26]([NH:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:28])=[O:27])\[C:30]#[N:31])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)NCCCc2ccccc2)cc(C(C)C)c1O

Procedure:
M44 was prepared with 3,5-diisopropyl-4-hydroxybenzaldehyde and N-3-phenyl-n-propyl cyanomethylsulfonamide under similar conditions as described for M40.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][NH:15][C:4]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9]
Reactant: NCC(O)CO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1NCC(O)CO

Procedure:
23 g (0.10 moles) 4-chloro-3-nitro-1-trifluoromethyl-benzene are heated with 30 g 1-amino-2,3-propandiol for 3 hours to 100° C. After cooling, the product is precipitated with water, vacuumed off and dried. One obtains 26.7 g (93% of the theoretical yield) of a yellow product with a melting range of 117°-118 C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Reactant: NCCc1cccs1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1c(NCCc2cccs2)ccnc1Cl

Procedure:
A mixture of 2,4-dichloro-3-nitropyridine (1.5 g), 2-aminoethylthiophene (1 g) and triethylamine (5 ml) is heated to reflux in EtOH (60 ml). The reaction mixture is cooled, the solvent evaporated and the residue chromatographed on silica gel (10% hexane/CH2Cl2) to yield the desired addition product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:24]([NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])=[O:36])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCNCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of tert-butyl 4-(6-bromo-4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1H-indazol-1-yl)piperidine-1-carboxylate (1 mmol) in DCM (5 mL) was cooled to 0° C. and TFA (2 mL) was added to it. The reaction mixture was stirred at room temperature for 1 h. On completion, the reaction was concentrated to dryness and the residue basified with aqueous sodium bicarbonate till pH 8 and aqueous layer extracted with 20% MeOH/DCM. The combined organic layers were dried over sodium sulfate and concentrated to afford 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-1H-indazole-4-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1

Procedure:
For example, N-benzyloxycarbonyl-L-aspartic acid is dissolved in a large excess of acetic anhydride, the acetic acid formed by the reaction and the excess acetic anhydride are distilled off under reduced pressure and the effect of any acetic acid remaining in the residue is removed by the addition of an organic solvent to give N-benzyloxycarbonyl-L-aspartic anhydride [J. Am. Chem. Soc., 81, 167-173 (1959)].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]2)=[C:32]2[C:36]=1[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]2>>[CH2:21]([P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C@H:39]4[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]4)=[C:32]4[C:36]=3[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH2:24][CH2:25][CH3:26])=[O:20])[CH2:22][CH3:23]
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Reactant: CCCP(=O)(CCC)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Product: CCCP(=O)(CCC)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cc1

Procedure:
The title compound was prepared according to the procedure for Example 102 using 4-chloro-N-[4-(dipropylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine Compound 198A, (75.0 mg, 0.185 mmol) and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (48.1 mg, 0.185 mmol). The reaction mixture was concentrated in vacuo purified on an ISCO Combiflash unit (0-5% MeOH/DCM) to isolate the desired product as 66 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) d 0.93 (t, J=7.33 Hz, 6H), 1.24-1.40 (m, 4H), 1.42-1.58 (m, 4H), 1.79 (d, J=12.88 Hz, 2H), 1.82-1.89 (m, 2H), 1.89-1.98 (m, 4H), 3.08 (s, 3H), 3.42-3.54 (m, 1H), 4.54 (s, 2H), 4.64 (br. s., 1H), 7.26 (br. s., 1H), 7.63-7.72 (m, 2H), 7.79 (d, J=6.57 Hz, 2H), 8.52 (s, 1H), 8.62 (br. s., 1H), 10.14 (s, 1H), 10.59 (br. s., 1H). MS (ES+): m/z=630.27 [MH+]. HPLC: tR=3.17 min (ZQ3, polar—5 min)