Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:37])[N:16]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:26][CH:25]=3)[CH:21]=[CH:22][CH:23]=2)[CH3:17])=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH3:6]>O1CCCC1.CO>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:37])[N:16]([C:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH3:17])=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ccc(NC(=O)N(C)c2cccc(-c3ccc(CCC(=O)OCC)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(NC(=O)N(C)c2cccc(-c3ccc(CCC(=O)O)cc3)c2)cc1
Yield: 71 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, 4.8 eq) of sodium hydroxide and 490 mg (1.03 mmol, 1 eq) of ethyl 3-{3′-[3-(4-butoxyphenyl)-1-methylureido]biphenyl-4-yl}propanoate in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after recrystallization from ethyl acetate/heptane, 330 mg of 3-{3′-[3-(4-butoxyphenyl)-1-methylureido]biphenyl-4-yl}propanoic acid are obtained in the form of white crystals. (m.p.=165° C.). Yield=71%
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:30][S@:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[NH:33])=[O:32]>C1COCC1>[CH3:30][S:31](=[O:32])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N:33][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[N:11][CH:12]=1
Reactant: C[S@](=N)(=O)c1ccccc1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=NC(=O)c1cncc(C#Cc2ccccc2)c1)c1ccccc1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 262.7 %

Procedure:
To a slurry of 5-(2-phenyleth-1-ynyl)nicotinic acid (339 mg, 1.5 mmol) in 6.0 mL THF at room temperature was added 1,1′-carbonyldiimidazole (271 mg, 1.7 mmol). After stirring 1.25 hour, a solution of (S)-(+)-S-methyl-5-phenylsulfoximine (260 mg, 1.7 mmol) in 1.5 mL THF was added and the mixture heated at 50° C. for 22 hours. Then an additional 50 mg (0.32 mmol) (S)-(+)-S-methyl-S-phenylsulfoximine was added and heating continued at 60° C. for 3.5 hours. The reaction was quenched with NaHCO3 solution and then extracted into EtOAc. The EtOAc layer was washed with NaHCO3 solution, H2O, brine, dried with anhydrous Na2SO4 and concentrated. The yellow oil obtained was chromatographed eluting with hexane/EtOAc to give N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide as a white foam (303 mg, 55%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([NH:11]C(=O)OC(C)(C)C)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O>ClCCl>[N:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[NH2:11])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(N=[N+]=[N-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=Nc1cc(N)cc(Cl)c1
Reaction time: 0.25 h

Procedure:
Step A-4. To a stirred solution of 3-azido-5-chlorophenylcarbamic acid, 1,1-dimethylethyl ester, (A-3, 1.26 g, 4.67 mmol) in 11 mL of dichloromethane is added 11 mL of trifluoroacetic acid. The reaction mixture is stirred at 20°-25° C. for 15 minutes and then concentrated. The residue is diluted with dichloromethane (250 mL) and washed with saturated aqueous NaHCO3 (1×75 mL). The organics are dried (MgSO4), filtered and concentrated. The organic residue is purified by flash chromatography using 20% ethyl acetate in hexane to afford 0.724 g of 3-azido-5-chloroaniline. (A-4, X is Cl). IR (mull) 3474, 3378, 2926, 2141, 2115, 1632, 1603, 1586, 1320, 1268, 1257, 880 cm-1 ; 1H NMR (CDCl3) δ6.42 (m, 2 H), 6.17 (m, 1 H), 3.81 (bs, 2 H); 13C NMR (CDCl3) δ148.5, 142.1, 135.9, 111.6, 109.1,103.5; Mass Spec (70eV, EI) m/z 168 (parent), 140, 107, 78 (base), 63, 52, 37; Exact Mass calculated for C6H5ClN4 : 168.0203. Found: 168.0193.
Reaction SMILES: Cl.CC(Cl)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH:27][C:28]([NH:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[O:29])[CH:21]=2)[CH2:15][CH2:14]1)=[O:12])(C)(C)C>O1CCOCC1>[CH3:6][O:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH:27][C:28]([NH:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[O:29])[CH:21]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: Cc1ccc(NC(=O)Nc2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2F)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCN(Cc2ccc(F)c(NC(=O)Nc3ccc(C)nc3)c2)CC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To 1.0 eq of 4-{4-fluoro-3-[3-(6-methyl-pyridin-3-yl)-ureido]-benzyl}-piperazine-1-carboxylic acid tert-butyl ester (2D) in MeOH (about 0.1 M 2D in MeOH) was added 2 volumes of HCl in dioxane (4 N) and the reaction mixture stirred at 50° C. for 15 min and evaporated to a solid. The solid was combined with DCM and treated with approximately 5 eq of TEA and split into 3 equal portions of reaction mixture A. One portion of the reaction mixture A was treated with 1.2 eq of methyl carbonyl chloride and stirred overnight. The resultant mixture was concentrated and purified by reversed phase HPLC to afford 4-{4-fluoro-3-[3-(6-methyl-pyridin-3-yl)-ureido]-benzyl}-piperazine-1-carboxylic acid methyl ester. MS 402 (M+H). A second portion of the reaction mixture A was treated with 1.2 eq of dimethylsulfamoyl chloride and stirred overnight. The resultant mixture was concentrated and purified by reversed phase HPLC to afford 4-{4-fluoro-3-[3-(6-methyl-pyrdin-3-yl)-ureido]-benzyl}-piperazine-1-sulfonic acid dimethylamide. MS 451 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:19][O:18][C:12]1[CH:17]=[CH:16][C:15]([C:4]([C:3]2[C:2]([Cl:1])=[C:10]([CH3:11])[CH:9]=[CH:8][CH:7]=2)=[O:5])=[CH:14][CH:13]=1
Reactant: COc1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(C)c2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of 2-chloro-3-methylbenzoyl chloride (18.05 mmol), [prepared as described above] in dry CH2Cl2 (60 ml) was cooled to 0° C. and AICl3 (2.41 g, 1 eq.) was added. After ten minutes, anisole (1.96 ml, 1 eq.) was added. The resulting orange colored reaction mixture was allowed to warm to room temperature, stirred for 3 h and then poured on ice. The product was extracted into ether, washed with brine, and dried over MgSO4 . The solvent was evaporated in vacuo to give 3-(4-methoxybenzoyl)-2-chlorotoluene (4.55 g, 97% yield) as a solid, mp 64.7°-65.8° C.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cs1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cs1
Temperature: 160 °C
Reaction time: 18 h

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide (200 mg, 0.563 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (338 mg, 1.69 mmol) in n-BuOH was stirred at 160° C. in a sealed tube. After 18 hours, additional (R)-tert-butyl piperidin-3-ylcarbamate (113 mg, 0.563 mmol) was added to the mixture and heating at 160° C. was continued for a further 18 hours. The mixture was concentrated in vacuo and purified by C-18 reverse phase column chromatography (Biotage Flash 25 M+ column) on Biotage SP4 unit eluting with a gradient of 10-85% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-methylthiazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate. This material was dissolved in neat TFA (3 mL), stirred at room temperature for 30 minutes and concentrated in vacuo. The oily residue was dissolved in a few drops of methanol and treated with 2M HCl in ether. The resulting precipitate was concentrated under reduced pressure, and the residue was dissolved in a few drops of methanol and CH3CN was added. The precipitate formed was filtered and dried under high vacuum to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide hydrochloride (25 mg, 10% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.87 (s, 1H), 10.64 (s, 1H), 8.34 (br s, 3H), 8.31 (s, 1H), 8.28 (s, 1H), 8.09 (d, 1H), 3.85-3.24 (m, 1H), 3.70-3.57 (m, 2H), 3.35-3.28 (m, 1H), 3.09-3.02 (m, 1H), 2.81 (s, 3H), 2.36-2.27 (m, 2H), 1.94-1.86 (m, 1H), 1.63-1.51 (m, 1H); LCMS (APCI+) m/z 435.0, 437.0 (M+H)+, Retention time=2.54 minutes (Method 2).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:28][C:29]2[N:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]=O)[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25].COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[CH3:15][O:14][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:31][C:30]2[C:29]([NH:28][C:20]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=3)=[N:36][CH:35]=[CH:34][CH:33]=2)[CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[O:12][CH3:13]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: COc1cc(Nc2ncccc2C=O)cc(OC)c1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
To a solution of 3,4,5-trimethoxyacetophenone (145 mg, 0.693 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 2-(3,4,5-trimethoxyphenylamino)nicotinaldehyde (200 mg, 0.693 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6v) (289 mg, 87% yield).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NC(=O)c1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (360 mg, 1 mmol) and commercially available 4-bromobenzamide (203 mg, 1 mmol) according to general procedure II. Obtained as a white solid (80 mg, 16%). MS (ISP) 474.2 [(M+H)+]; mp 286° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.BrC1SC(S(Cl)(=O)=O)=CC=1.[CH2:21]1[CH2:26][CH2:25][CH:24]([C@H:27]([NH2:31])[C:28](O)=[O:29])[CH2:23][CH2:22]1.CC(C1C=CC=CC=1)C(C(O)=O)N.N[C@H](C(O)=O)[C@@H](CC)C>>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:31][C@@H:27]([CH:24]2[CH2:25][CH2:26][CH2:21][CH2:22][CH2:23]2)[CH2:28][OH:29])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: N[C@H](C(=O)O)C1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: CC(c1ccccc1)C(N)C(=O)O
Agent: CC[C@@H](C)[C@H](N)C(=O)O
Agent: O=S(=O)(Cl)c1ccc(Br)s1
Product: O=S(=O)(N[C@H](CO)C1CCCCC1)c1ccc(Cl)s1

Procedure:
The following compounds (Examples 12-17, Table 4) were prepared using 5-chlorothiophene-2-sulfonyl chloride, and 5-bromothiophene-2-sulfonyl chloride with L-cyclohexylglycine, β-methyl-DL-phenylalanine, and L-allo-isoleucine and following the procedure outlined in Example 12.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:22]([N:25]=[C:26]=[S:27])[CH2:23][CH3:24]>CC(O)C>[CH2:22]([N:25]1[C:12](=[O:14])[C:3]2[C:2](=[CH:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=2)[NH:1][C:26]1=[S:27])[CH2:23][CH3:24]
Reactant: CCCN=C=S
Reactant: Nc1cc2ccccc2cc1C(=O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCn1c(=S)[nH]c2cc3ccccc3cc2c1=O
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a suspension of 1.88 g of 3-amino-2-naphthalic acid in 25 mL of 2-propanol was added 1.39 mL of triethylamine followed by 1.02 g of n-propyl isothiocyanate with stirring. The mixture was heated at reflux for 2 h, and then allowed to cool to room temperature. The resulting solid was collected by filtration and washed with cold 2-propanol to give 1.97 g of the title compound of Step A as a yellow solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH:20]([CH3:22])[CH3:21])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH:20]([CH3:21])[CH3:22])[N:16]([CH3:1])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)C1NS(=O)(=O)N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)C1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of potassium t-butoxide (3.53 g, 29 mmol) in THF was added a solution of 2-phenylmethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (7.7 g, 29 mmol) in THF at 0° C. and the mixture was stirred at this temperature for 1 hour. To the mixture was added methyl iodide (20.38 g, 0.143 mol) and the resulting mixture was allowed to stir at room temperature for 2.5 hours. The resulting mixture was quenched with brine, extracted with ether, and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 7.1 g (88%) of 2-phenylmethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =isopropyl; R3 =CH3) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][OH:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]#[N:10])([CH3:13])[CH2:11][O:12][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C#N)(CO)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)(C#N)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a stirred solution of 2-(4-bromo-phenyl)-3-hydroxy-2-methyl-propionitrile (25 g, 104.17 mmol) in pyridine (225 mL) was added para-toluene sulphonyl chloride (29.79 g, 156.25 mmol) and the reaction stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (300 mL), washed with a 2N aqueous hydrochloric acid solution (2×50 mL), water (2×100 mL), a saturated aqueous sodium bicarbonate solution (2×50 mL), dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (10% ethyl acetate/hexanes) afforded toluene-4-sulfonic acid 2-(4-bromo-phenyl)-2-cyano-2-methyl-ethyl ester as a colorless liquid (35 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:14]=3)=[O:26])=[C:2]([Cl:1])[CH:3]=2)=[O:6])[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CC1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-acetylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 4-(4-acetylpiperazine-1-carbonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 497 (M)+.
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[C:7](=O)[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[CH2:15]([NH2:18])[CH2:16][NH2:17]>CO.[Pt].[C]>[CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([NH:17][CH2:16][CH2:15][NH:18][CH:7]2[CH2:6][C:5]([CH3:11])([CH2:12][CH3:13])[NH:4][C:3]([CH3:14])([CH2:1][CH3:2])[CH:8]2[CH3:9])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: NCCN
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1
Agent: [Pt]
Solvent: CO
Product: CCC1(C)CC(NCCNC2CC(C)(CC)NC(C)(CC)C2C)C(C)C(C)(CC)N1
Reaction time: 106 h

Procedure:
197.3 g of 2,6-diethyl-2,3,6-trimethylpiperidine-4-one and 30.0 g of ethylenediamine are dissolved in one liter of methanol. 10 g of a platin-carbon catalyst (5% b.w. Pt) are added, and the solution is hydrogenated at 30°-35° C. and normal pressure. Hydrogenation is completed after 106 hours. The catalyst is filtered off, the solvent is evaporated in vacuo, and the oily residue is purified by molecular distillation at 150° C. and 0.005 mm Hg. N,N'-Bis-(2,6-diethyl-2,3,6-trimethyl-4-piperidyl)-ethylenediamine (compound no. 7) is obtained as a practically colourless oil. If, instead of 30.0 g of ethylenediamine an equivalent amount of 1,6-hexamethylenediamine is used and otherwise the procedure described above is followed, after molecular distillation at 180° C. and 0.002 mm Hg. N,N'-Bis-(2,6-diethyl-2,3,6-trimethyl-4-piperidyl)-hexamethylene-1,6-diamine (compound no. 8) is obtained in the form of a thick colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[N:38][C:37]([NH2:40])=[CH:36][N:35]=2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:40][C:37]3[N:38]=[CH:39][C:34]([N:31]4[CH2:30][CH2:29][NH:28][CH2:33][CH2:32]4)=[N:35][CH:36]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)cn2)CC1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3cnc(N4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 55.1 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.342 mmol) and 5′-amino-2,3,5,6-tetrahydro-[1,2]bipyrazinyl-4-carboxylic acid tert-butyl ester (114 mg, 0.408 mmol), followed by deprotection using General Procedure A to give 7-cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (82 mg, 45%). MS (ESI) m/z 436.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].O[CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C(F)(F)F
Temperature: 75 °C
Yield: 30891.9 %

Procedure:
To a solution of 1-chloro-2-nitrobenzene (10.0 g, 0.063 mmol) in conc. sulphuric acid (150 mL) was added N-hydroxy methyl trifluoro acetamide (9.98 g, 0.069 mmol). The reaction mixture was heated at 70-80° C. for 24 h. The reaction mass was quenched in ice cold water, neutralised with sodium hydroxide and extracted with DCM. The organic layer was concentrated and the obtained crude product was purified by column chromatography on silica gel eluting with 4% EtOAc: pet. ether to afford 5.5 g of desired product. 1H NMR (300 MHz, DMSO d6): 4.48 (d, J=3.9 Hz, 2H), 7.62-7.64 (m, 1H), 7.72-7.78 (m, 1H), 7.97-8.01 (m, 1H), 10.09 (brs, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CNC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To 5-aminomethyl-6-chloro-3-(1-BOC-2-(S)-azetidniylmethoxy)pyridine from step 92b (0.262 g, 0.80 mmol) was added CH2Cl2 (10 mL), triethylamine (0.1619 g, 1.60 mmol) and benzoyl chloride (0.1349 g, 1.0 mmol). The mixture was stirred at room temperature overnight, then concentrated under vacuum. The residue was chromatographed (silica gel; CH2Cl2 /MeOH, 9/1) to afford a light brown foam (0.267 g, 77%). MS (CI/NH3) m/z 432.00 (M+H+), 449.00 (M+NH4+). 1H NMR (CDCl3, 300 MHz): 1.57 (s, 9H), 2.25-2.37 (m, 2H), 3.87 (t, J=7.1 Hz, 2H), 4.11 (dd, J=2.7, 9.80 Hz, 1H), 4.31-4.39 (m, 1H), 4.49-4.55 (m, 1H), 4.68 (d, J=8.5 Hz, 2H), 6.75 (m, 1H), 7.42-7.56 (m, 4H), 7.79-7.82 (m, 2H), 8.03 (d, J=3.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[CH:19]=2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH3:26][O:25][C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[C:15]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: COc1ccc2cc(Br)cnc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3c2)cc1

Procedure:
Followed Step 1 of Compound IV-1, starting from 4-(methoxycarbonyl)phenylboronic acid and Intermediate 13, and where the base used was Na2CO3, the solvent DME/H2O (8: 2), and the reaction was run at 100° C. for 2 h.