Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([OH:12])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH3:13][C:14]1[N:15]=[N:16][S:17][C:18]=1[C:19](Cl)=[O:20]>O>[CH3:13][C:14]1[N:15]=[N:16][S:17][C:18]=1[C:19]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[C:3]([OH:12])=[O:11])=[O:20]
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1nnsc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nnsc1C(=O)Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
In 50 ml of water were dissolved 1.2 g (31 mmol) of sodium hydroxide and 4.2 g (31 mmol) of anthranilic acid. While cooling the solution with ice, 5 g (31 mmol) of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid chloride was dropwise added thereto over a period of 30 minutes. After the dropping, the resulting mixture was reacted with stirring at room temperature for 30 minutes. After the reaction was completed, the crystalline product deposited from the reaction mixture was collected by filtration and washed with methanol and ethyl acetate. Thus, 7.1 g of the objective compound was obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])#[N:14]>O1CCCC1>[N:1]1([S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]#[N:14])(=[O:23])=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccccc1S(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) To a mixture of pyrrolidine (4.92 ml) and triethylamine (6.91 ml) was added a solution of 2-cyanobenzene-1-sulfonyl chloride (10.0 g) in tetrahydrofuran (40 ml) at 0° C. The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was suspended in water, and the suspension was filtered. The filtered solid was dissolved in dichloromethane, and the solution was washed with water. The organic layer was dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 2-(pyrrolidin-1-ylsulfonyl)benzonitrile (11.3 g).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](Cl)(=O)[C:16](Cl)=O.C(O)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C=O>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:14])[C:9]([F:13])=[C:10]([O:11][CH3:12])[C:2]=1[F:1])[CH3:16]
Reactant: COc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(F)c(F)c(OC)c1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
A solution of 2,4,5-trifluoro-3-methoxybenzoic acid (2.513 g, 12.19 mmol) in dichloromethane (50 mL) at 0° C. is treated with oxalyl chloride (5.4 mL, 61.9 mmol) followed by N,N-dimethylformamide (4 drops). The mixture is stirred at 0° C. for 5 minutes and then at room temperature for 2.5 hours. The mixture is concentrated to near dryness and then co-evaporated from benzene. The resulting acid chloride is diluted with dichloromethane (50 mL), cooled to 0° C., and then anhydrous ethanol (7.30 mL, 124 mmol) is added dropwise. The resulting solution is stirred at room temperature for 4.5 hours, poured into saturated NaHCO3 solution, and extracted with dichloromethane. The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound as a light yellow liquid (2.82 g). 1H NMR (CDCl3): δ 7.47 (ddd, 1H), 4.39 (q, 2H), 4.05 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
To a solution of 3-bromophenol (0.500 g) in N,N-dimethylformamide (5.8 mL) was added potassium carbonate (1.20 g). Then 1-bromopentane (0.896 mL) was added, and the resulting mixture was stirred at room temperature for 18.5 hours. The reaction mixture was partitioned between diethyl ether (35 mL) and water (10 mL). The organic-layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (9.728 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=3)[N:18]=2)[C:10]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[N:9]1)(=O)=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CO>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C:10]1[C:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([CH:22]([CH3:23])[CH3:24])=[N:20][N:21]=3)[N:18]=2)=[CH:12][N:8]([CH2:7][CH2:6][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:9]=1
Reactant: CC(C)c1nnc2ccc(-c3cn(CCOS(C)(=O)=O)nc3-c3ccc(F)cc3F)nn12
Reactant: C1COCCN1
Solvent: CO
Product: CC(C)c1nnc2ccc(-c3cn(CCN4CCOCC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 70 °C
Yield: 42.4 %

Procedure:
The 2-(3-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (0.24 g, 0.52 mmol; Preparation #W.1) was dissolved in MeOH (4 mL) then morpholine (0.36 g, 4.2 mmol) was added. The mixture was heated at about 70° C. in an oil bath for about 2 h then cooled and concentrated under reduced pressure. The crude material was purified by RP-HPLC (Table 1, Method d). The appropriate fractions were concentrated under reduced pressure then basified with 2 N NaOH. Extraction of the solution with EtOAc followed by drying of the organic extract over MgSO4 and then filtration prior to concentrating under reduced pressure gave the title compound (0.10 g, 43%): LC/MS (Table 1, Method a) Rt=2.09 min; MS m/z: 454.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:3]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[C:3]=1[CH2:13][N:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(Cl)cccc2N2CCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(N2CCCC2)c1CN1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 132.7 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-chloro-6-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate (500 mg, 1.32 mmol, 1.00 equiv), dichloromethane (10 mL). The mixture was cooled to 0° C. Trifluoroacetic acid (1 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 490 mg (crude) of 1-[[2-chloro-6-(pyrrolidin-1-yl)phenyl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 280 [M+H]+.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([N:31]6[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]6)=[CH:42][CH:41]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CN1CCN(c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCC(c5cccc6c5CCO6)CC4)CC3)cc2)CC1

Procedure:
The title compound, white solid (106 mg, 80%), MS (ISP) m/z=531.3 [(M+H)+], mp 241° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-(4-methyl-piperazin-1-yl)-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH3:23][O:24][CH2:25]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:23][O:24][CH3:25])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1
Reactant: COCCl
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COCOc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and chlorodimethyl ether with sodium carbonate in acetone there is obtained 1-[4-chloro-2-fluoro-5-(methoxymethoxy) -phenyl]-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 97°-98° C.;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.[CH3:31][N:32]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[N:34]=[CH:33]1>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[S:37]([C:35]2[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=2)(=[O:39])=[O:38])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)S(=O)(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a stirred solution of the product from Example 1 (80 mg) dissolved in DCM (5 mL) was added 1-methylimidazole-4-sulfonyl chloride (38.4 mg) and TEA (0.032 mL) under nitrogen. The resulting solution was stirred at rt for 16 h, the solvents were evaporated and the residue redissolved in MeOH and the crude product purified by RPHPLC to afford the title compound 69 mg.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=3[F:29])[CH:13]=2)=[N:10][CH:11]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:44])[C:38](=[O:43])[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[F:29][C:23]1[CH:24]=[C:25]([NH:26][C:40](=[O:41])[CH2:39][C:38]([N:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)[CH3:44])=[O:43])[CH:27]=[CH:28][C:22]=1[O:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:3])=[CH:11][N:10]=3)[S:20][C:19]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Reactant: CN(C(=O)CC(=O)O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(C=O)cn4)sc23)c(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To intermediate 38 (0.35 g, 0.86 mmol) in dry DMF (25 mL) was added 3-((4-fluorophenyl)(methyl)amino)-3-oxopropanoic acid (44) [US 2007/0004675 A1] (0.36 g, 1.7 mmol) [Met-036], and EDC.HCl (0.33 g, 1.7 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was then partitioned between ethyl acetate and water; the organic phase was collected, washed with water, saturated NaHCO3, and brine, dried (anhydrous MgSO4), filtered and concentrated. The crude product was dissolved in acetone (50 mL) to give a colorless solution. The solution was diluted with water (20 mL) and TFA (2 mL), and heated to reflux for 3 h. It was then cooled and concentrated. The residue was then partitioned between ethyl acetate and water, the organic phase was collected, washed with water, saturated NaHCO3, and brine, dried (anhydrous MgSO4), filtered and concentrated to produce intermediate 45 (0.27 g, 57% yield). MS (m/z): 559.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:26][SiH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:20]([OH:24])([CH3:23])[CH:21]=[CH2:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:50](Br)[CH:51]=[CH2:52]>CN(C)C=O.C(OCC)(=O)C>[CH2:52]([N:18]([CH:19]([C:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[O:26][SiH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:20]([OH:24])([CH3:23])[CH:21]=[CH2:22])[S:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:17])=[O:16])[CH:51]=[CH2:50]
Reactant: C=CCBr
Reactant: C=CC(C)(O)C(NS(=O)(=O)c1ccc(OCc2ccccc2)cc1)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN(C(C(C)(O)C=C)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 24 h
Yield: 102.6 %

Procedure:
To a solution of 4-benzyloxy-N-[1-(tert-butyl-diphenyl-silanyloxymethyl)-2-hydroxy-2-methyl-but-3-enyl]-benzenesulfonamide (compound of formula VI, 1.6 g, 2.6 mmol) in 5 ml of dimethylformamide was added cesium carbonate (1.7 g, 5.2 mmol) and allyl bromide (0.63 g, 5.2 mmol). After stirring at a temperature of about 20 to about 25° C. for about 24 hours, an additional 0.4 g of cesium carbonate and 0.2 ml of allyl bromide was added, and the mixture was stirred at a temperature of about 20° C. to about 25° C. for about 24 hours. The mixture was diluted with ethyl acetate, washed 4 times with water, dried over sodium sulfate, filtered and concentrated in vacuo to afford 1.75 g of N-allyl-4-benzyloxy-N-[1-(tert-butyl-diphenyl-silanyloxymethyl)-2-hydroxy-2-methyl-but-3-enyl]-benzenesulfonamide (compound of formula VII) as a colorless syrup.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.CI.[C:12]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][N:3]1[C:2]([CH3:1])=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c([N+](=O)[O-])cnn1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
To a solution of 3-methyl-4-nitro-1H-pyrazole (4.01 g, 31.6 mmol) in DMF (60 mL) were added CH3I (8.93 g, 63.0 mmol) and K2CO3 (8.73 g, 63.2 mmol). The reaction mixture was stirred at 60° C. in a sealed tube overnight and concentrated in vacuo. The residue was diluted with water (50 mL), and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a beige solid (1.01 g, 22.7%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:15][C:14]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])=[CH:11][N:10]([CH3:33])[C:5]2=[C:6]([O:8]C)[N:7]=1.[ClH:34].O1CCOCC1>>[Cl:34][C:2]1[NH:7][C:6](=[O:8])[C:5]2[N:10]([CH3:33])[CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:15][C:14]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[C:4]=2[CH:3]=1
Reactant: Cl
Reactant: COc1nc(Br)cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(CS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(Cl)[nH]c(=O)c21
Temperature: 70 °C
Yield: 74 %

Procedure:
The product from Example 91E (0.064 g, 0.119 mmol) and 4 M hydrogen chloride in dioxane (2 mL, 8.00 mmol) were combined and heated at 70° C. for 2 hours, cooled and concentrated. Purification by trituration (1:1 dichloromethane/heptane) afforded the title compound (0.042 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H) 7.60 (s, 1H) 7.57 (d, J=2.03 Hz, 1H) 7.43-7.52 (m, 1H) 7.19-7.30 (m, 2H) 7.05-7.15 (m, 1H) 6.82 (d, J=8.14 Hz, 1H) 6.68 (s, 1H) 4.53 (s, 2H) 4.07 (s, 3H) 2.94 (s, 3H). MS (ESI+) m/z 479 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[C:5]2[CH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH:25]([CH:31]([CH3:33])[CH3:32])[CH2:24]1.O.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:23]1[CH2:28][CH2:27][S:26](=[O:29])(=[O:30])[CH:25]([CH:31]([CH3:33])[CH3:32])[CH2:24]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(C(C)C)C3)cn(C(=O)OC(C)(C)C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C1CC(c2c[nH]c3c(C(=O)O)cc(Br)cc23)CCS1(=O)=O
Temperature: 80 °C

Procedure:
1-(1,1-dimethylethyl) 7-ethyl 5-bromo-3-[2-(1-methylethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]-1H-indole-1,7-dicarboxylate (1.46 g, 2.69 mmol) was dissolved in methanol (12 mL) and then water (6.00 mL) was added and then 6 N aqueous NaOH (6.73 mL, 40.4 mmol was added and the mixture was heated in a microwave 30 mins at 80° C. The mixture was neutralized with 1 N aqueous HCl until pH=1 and a small amount of yellow solid precipitated which was set aside. The aqueous solution was extracted with ethyl acetate, the organic layers were combined, dried (MgSO4) and solvent was removed under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[N:7]=[CH:8][C:9]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[N:10][CH:11]=1.[ClH:26].O1CCOCC1.C(OC(C)C)(C)C>O1CCOCC1>[ClH:26].[ClH:26].[NH:15]1[CH2:16][CH2:17][C@@H:13]([NH:12][C:9]2[N:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:25])=[N:7][CH:8]=2)[CH2:14]1
Reactant: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cn1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate (830 mg) in dioxane (8.3 mL) was added 4N HCl/dioxane (6.0 mL), which was stirred at room temperature for 1 hour. To the reaction mixture was added diisopropylether, and the precipitate was filtered to give methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylate dihydrochloride (742 mg) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.Cl.[N:24]1([C:29]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:24]1([C:29]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[CH:35][CH:36]=2)=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (50 mg, 0.16 mmol) and 4-(pyrrolidinylcarbonyl)phenylamine hydrochloride (43 mg, 0.19 mmol) in pyridine (3 mL) cooled in ice-bath, POCl3 (0.028 mL, 0.31 mmol) was added. The mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (15 mg). MS 491.4 and 493.4 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][C:31]([NH:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.[OH-].[Na+].C(O)(=O)C>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][C:31]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1
Reactant: CCOC(=O)CNC(=O)CC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cn3)CC2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)NCC(=O)O)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
Ethyl [2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetamido]acetate (221 mg) was dissolved in methanol (5 mL). A 2N aqueous sodium hydroxide solution (2.1 mL) was added to the solution, and it was stirred at room temperature for 16 hours. The solution was neutralized by addition of acetic acid (0.25 mL) (to pH of about 6). The solvent was distilled off under reduced pressure, and the resulting residue was extracted with 20% ethanol/chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give the title compound (170 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COc1ccc(N)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(Cl)nc(Cl)n2)cn1
Yield: 53.2 %

Procedure:
A solution of 2,4,6-trichloropyrimidine (2.0 mL, 17.4 mmol), 3-amino-6-methoxypyridine (1.5 mL, 19.1 mmol) and diisopropylethylamine (6.1 mL, 34.8 mmol) in acetonitrile (100 mL) was stirred at 55° C. under N2 for 15 hours. The reaction mixture was then partitioned between EtOAc (400 mL) and NaHCO3(sat.) (100 mL). The organic layer was separated, washed with brine (75 mL), dried over Na2SO4, concentrated, and purified by silica gel chromatography (20-30% EtOAc/hexanes) to yield 2,6-dichloro-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (2.51 g, 53%) as an off-white solid. LCMS (m/z): 270.9 and 272.9 (MH+); 1H NMR (CDCl3): δ 8.13 (d, J=2.7 Hz, 1H), 8.55 (dd, J=8.5, 2.7 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.84(bs, 1H), 6.35 (s, 1H), 3.97 (s, 3H).