Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:35][C:36]1[CH:41]=[C:40]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)C=C(c1cccc(F)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Yield: 102.2 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.05 mmol), 3-fluoro-phenylboronic acid (2.1 g, 15 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.42 g, 0.6 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated at 90° C. in a microwave for 2 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×50 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (40 g, 17% ethyl acetate/petroleum ether) afforded 2-(1-(3-fluoro-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.6 g, 88%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.50 (dd, 1H, J1=5.1 Hz, J2=1.8 Hz), 7.89 (dd, 1H, J1=7.5 Hz, J2=1.5 Hz), 7.69 (dd, 2H, J1=8.4 Hz, J2=1.2 Hz), 7.46-7.40 (m, 1H), 7.27-7.13 (m, 5H), 7.01-6.89 (m, 2H), 6.85-6.80 (m, 1H), 6.53 (s, 1H), 6.14 (d, 1H J=10.2 Hz), 2.71-2.59 (m, 1H), 1.15-1.10 (m, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C.O1CCCC1>[NH2:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][O:28][C:19]2[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)(=[O:13])=[O:12])[C:20]=2[C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cc2)cc1
Yield: 98.7 %

Procedure:
A mixture of 4-tert-butyl-N-{5-(4-methylphenyl)-6-[2-(4-nitrophenoxy)ethoxy]pyrimidin-4-yl}benzenesulfonamide (383 mg), 10% palladium-carbon (50 mg) and ethanol-tetrahydrofuran (6 ml-3 ml) is subjected to catalytic hydrogenation at room temperature under hydrogen atmosphere (1 atm) for two hours. The catalyst is removed by filtration, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=10:1), and recrystallized from ethyl acetate/diisopropyl ether to give N-{6-[2-(4-aminophenoxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (358 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([NH2:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:25][CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCN
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Product: CCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1

Procedure:
This compound was prepared by a procedure similar to that described in Example 40 starting with 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and ethylamine gas; mp 180°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13](I)[C:8]2=[C:7]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])[N:6]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH2:36][CH3:37])=[C:30](B(O)O)[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([C:28]3[CH:27]=[C:26]([F:25])[CH:31]=[CH:30][C:29]=3[O:35][CH2:36][CH3:37])[C:8]2=[C:7]([NH:15][CH2:16][C@H:17]([OH:19])[CH3:18])[N:6]=1
Reactant: CCOc1ccc(F)cc1B(O)O
Reactant: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1ccc(F)cc1-c1n[nH]c2nc(Oc3ccc(F)cc3F)nc(NC[C@@H](C)O)c12
Temperature: 180 °C
Yield: 30.6 %

Procedure:
1-[6-(2,4-Difluoro-phenoxy)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (200 mg, 0.447 mmol), 5-fluoro-2-ethoxyphenyl boronic acid (246 mg), K3PO4 (285 mg), and Tetrakis(triphenylphosphine)palladium(0) CH2Cl2 (73 mg) were added to 2 mL dioxane in a microwave vial. The vial was sealed and the reaction mixture was heated to 180° C. for 10 minutes. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was filtered through silica gel using 10% MeOH in methylene chloride, then purified by preparative scale thin layer chromatography using 10% MeOH in methylene chloride, to give 62.9 mg of (R)-1-[6-(2,4-Difluoro-phenoxy)-3-(2-ethoxy-5-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=460.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][CH3:11].S(Cl)([Cl:14])=O>ClCCl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([CH2:8][Cl:14])=[CH:6][N:7]=1
Reactant: COc1cc(CO)cnc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCl)cnc1Cl
Reaction time: 5 h

Procedure:
To a solution of (6-chloro-5-methoxypyridin-3-yl)methanol (0.50 g, 2.9 mmol) in dichloromethane (14 mL) at 25° C. was added thionyl chloride (230 μL, 3.2 mmol) dropwise. Let stir for 5 h, then the reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (3×). The combined organic layer were dried over MgSO4 and concentrated to furnish the product 2-chloro-5-chloromethyl-3-methoxypyridine that was 96% pure by GC-MS. The product was used immediately in the next step without further purification. GC-MS: Exact mass calcd for C7H7Cl2NO [M]+, 191. Found 191.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[H][H]>N.CO.[Ni]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc(F)cc(F)c1
Yield: 87.1 %

Procedure:
A solution of 3,5-difluorobenzonitrile (0.0345 mol) in ammonia saturated methanol (100 ml) and methanol washed Raney nickel were shaken together under 50 psi of hydrogen for 11/2 hours. The reaction mixture was filtered, the filtrate concentrated then dissolved in ethyl acetate. The product was extracted into 3N aqueous hydrogen chloride. The acidic solution was cooled and basified with 50% sodium hydroxide then was extracted into ethyl acetate. The organic extract was dried over sodium sulfate, filtered and concentrated to yield 4.3 g (86%) yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:20](OC)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:1]([C:3]1[N:4]=[C:5]([CH2:9][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccccc1
Reactant: Cc1cccc(C#N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(CC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
To a solution of 2-cyano-6-methylpyridine (9.7 g, 0.082 mol) in 400 ml of dry THF at -78° C. was added dropwise 90 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF. After stirring for 30 minutes a solution of methyl benzoate (30 ml, 0.245 mol) in 50 ml of THF was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0° C., quenched with 1N HCl, made basic with 15% NaOH solution, and extracted with ethyl acetate (3×). The organic layer was separated, dried, and concentrated to give crude material which was purified by chromatography on silica gel to give 2.5 g of the subtitle compound.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[N+:11]([C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)([O-:13])=[O:12].O>CN(C=O)C>[CH:2]([N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[N+:11]([O-:13])=[O:12])([CH3:4])[CH3:3]
Reactant: CC(C)Br
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 4 h

Procedure:
2-Bromopropane (7 mmol) and K2CO3 (13 mmol) were added to a solution of 2-nitroimidazole (4 mmol) in DMF (10 mL). The mixture was stirred at 60° C. for 4 h. The contents were cooled to room temperature and water (20 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined extracts were dried over MgSO4, filtered and the solvent was removed in vacuo to afford 1-isopropyl-2-nitro-1H-imidazole. The product used for further transformation without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:5]#[N:6].[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:20]3[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=3)[CH:24]=2)[CH2:12][CH2:11]1)[C:5]#[N:6]
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Product: N#Cc1ccc(N2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)c(F)c1
Yield: 38 %

Procedure:
This compound was synthesized from 3-fluoro-4-(piperazin-1-yl)benzonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (100 mg, yield 38%). 1H NMR (400 MHz, DMSO-d6) δ 8.17-8.15 (dt, J=6.6 Hz, 1.7 Hz, 1H), 8.09 (s, 1H), 7.75-7.72 (m, 3H), 7.61-7.58 (dd, J=8.5 Hz, 1.5 Hz, 1H), 7.17-7.13 (t, J=8.7 Hz, 1H), 3.81 (m, 2H), 3.52 (m, 2H), 3.19 (m, 4H). MS (ESI) m/z: Calculated for C21H15F4N5O2: 445.12. found: 446.2 (M+H)+
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[C:4]2[N:5]([C:19]([C:22](O)=[O:23])=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.O[NH:28][C:29](=[NH:40])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36](=[O:39])(=[O:38])[NH2:37])[CH:31]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[C:4]2[N:5]([C:19]([C:22]3[O:23][N:40]=[C:29]([C:30]4[CH:31]=[C:32]([S:36]([NH2:37])(=[O:38])=[O:39])[CH:33]=[CH:34][CH:35]=4)[N:28]=3)=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnc4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)cn34)n2)c1

Procedure:
The title compound was prepared from 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.32) (187 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane) as an off-white solid (117 mg, 42%). MS (ISN) 552.0 [(M−H)−]; mp 297° C.
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])/[C:5](=[O:14])[NH:6]2.C[Si](C)(C)N[Si](C)(C)C.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CN(C=O)C>[CH3:21][C:17]1[N:18]=[CH:19][NH:20][C:16]=1/[CH:15]=[C:4]1\[C:5](=[O:14])[NH:6][C:7]2[C:3]\1=[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=2
Reactant: OB(O)c1ccccc1
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccccc3)c21
Yield: 9 %

Procedure:
Using Method S above, (Z)-4-bromo-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (100 mg, 0.29 mmol) (Starting Material 9 above) was first treated with 1,1,1,3,3,3-hexamethyidisilazane (1.53 g, 9.5 mmol) (Aldrich) then coupled with phenyl boronic acid (52.4 mg, 0.43 mmol) (Aldrich) using DPPFPdCl2 (11.7 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.29 mL, 0.58 mmol), DMF (3 mL) and DME (3 mL) at reflux for 1 day to yield (Z)-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-4-phenyl-2H-indol-2-one (yield 9 mg, 9%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[C:3]1[C:12]([O:14]CC)=O.C(O[C:20](OCC)([CH3:23])[C:21]#[N:22])C.CC1C=CC(S(O)(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:21]([C:20]1[CH:23]=[N:1][N:2]2[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[C:3]2[C:12]=1[OH:14])#[N:22]
Reactant: CCOC(C)(C#N)OCC
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(O)c(C#N)cnn2c1
Temperature: 125 °C
Yield: 50 %

Procedure:
To a round bottom flask was added diethyl 1-amino-1H-pyrrole-2,4-dicarboxylate (40 g, 177 mmol), diethoxypropionitrile (53 mL) and p-TSA (10 g, 0.052 mmol). The reaction was heated at 125° C. for 3 hours and the EtOH was removed. The reaction was cooled to room temperature before DBU (30 g, 340 mmol) was added. The reaction was then heated at 80° C. for 2 hours. The reaction was cooled to room temperature and diluted with CH2Cl2. The mixture was washed with 5% citric acid solution (2×), water and brine solution. The organic layer was concentrated and the residue was purified by flash silica gel column chromatography (10% MeOH in CHCl3) to yield 20 g (50%) of the title compound as a brown oil. LCMS (condition A): m/z=230.2 −ve. H1 NMR (400 MHz, CDCl3) δ ppm: 9.53 (1H, br s), 8.32 (1H, s), 7.75 (1H, s), 6.75 (1H, s), 4.25 (2H, q), 1.28 (3H, t).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[K+:11]>O>[NH2:1][CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([O-:9])=[O:8].[K+:11]
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC(N)C(=O)[O-]

Procedure:
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 7.87 g (60 mmol) of Leucine is dissolved in 300 ml of water. To this is added 72 ml of 1M potassium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, potassium 2-amino-4-methylpentanoate, shown below.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[H-].[Na+].[CH3:12]I>C1COCC1.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:12])[CH:3]=1
Reactant: OCc1cc(I)ccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cc(I)ccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (4-iodo-pyridin-2-yl)-methanol 6AN (0.51 g, 2.16 mmol) in THF (7.5 ml) was added in a dry NaH (0.17 g, 4.32 mmol). Reaction mixture was stirred for 20 min at r.t. It was cooled to 0° C. and CH3I 0.16 ml, 2.59 mmol) was added drop wise. After 30 mins at 0° C., it was warmed up to r.t. and stirred further for 2 hr. Then it was diluted with EtOAc (50 ml) and washed with water (2×10 ml) and brine (1×15 ml). Organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified on silica gel eluting with 1/2 EtOAc/Hexane to give the desired product 4-Iodo-2-methoxymethyl-pyridine 7AN (0.39, 72%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:23]1[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[N:24]=1>O1CCCC1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:23]3[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]4[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=4)[N:24]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Brc1ccc(C2CCNCC2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(c3ccc(Br)cc3)CC2)nc(-c2ccncc2)cc1=O
Yield: 93.1 %

Procedure:
A solution of (4-(4-bromophenyl)-piperidine hydrochloride (279 mg, 1.01 mmol) and triethylamine (554 mg, 5.47 mmol), 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (206 mg, 0.929 mmol) in tetrahydrofuran (20 mL) was stirred for 3 hr. The resulting solution was diluted with tetrahydrofuran and filtrated. After removal of the solvents under reduced pressure and the purification of the resulting residue by CHEM ELUT CE1010 (manufactured by VARIAN) eluting dichloromethane/ethanol (15/1, v/v) and wash with ethyl acetate afforded 2-(4-(4-Bromophenyl)-piperidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (368 mg, 93%) as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>O1CCOCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: NCc1ccccn1
Solvent: C1COCCO1
Product: COc1cc2c(NCc3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.7 %

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitroquinoline (1.5 g, 3.5 mmol) and 2-(aminomethyl)pyridine (1.46 g, 13.5 mmol) in dioxan (10 ml) was stirred at room temperature for 2 h. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed [50-100% ethyl acetate/cyclohexane] to give the title compound as a yellow solid (1.5 g, 3.70 mmol, 82% yield). LCMS (formate) Rt 0.86 min, MH+ 406.
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][C:9](=[O:20])[C:8]=2[CH:7]=[C:6]([CH3:21])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[OH:3][CH:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][C:9](=[O:20])[C:8]=2[CH:7]=[C:6]([CH3:21])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(C)cc2c(=O)cc(-c3ccncc3)oc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(C(C)O)c2oc(-c3ccncc3)cc(=O)c2c1
Yield: 86.2 %

Procedure:
A mixture of 8-acetyl-6-methyl-2-(4-pyridinyl)-4H-1-benzopyran-4-one (4.6 g, 16.5 mmol) in methanol (100 ml) was treated with sodium borohydride (1.22 g, 33 mmol) and heated to reflux overnight. Upon cooling water (2 ml) was added and the solution concentrated to near-dryness in vacuo. Water (100 ml) was added and a precipitate formed which was filtered yielding a tan/orange solid (4.0 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:11]#[N:12])=[CH:6][CH:5]=1
Reactant: Brc1ccccn1
Reactant: N#CCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#CC(c1ccc(F)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
A sample of sodium hydride (60%, 1.60 g, 0.04 mole) was washed with dry hexanes. After removal of hexanes a 100 ml portion of dimethyl sulfoxide was added. To this mixture was added a solution of 4-fluorophenylacetonitrile (5.41 g, 0.04 mole). The mixture was stirred 3 hrs at room temperature under nitrogen. 2-Bromopyridine (6.32 g, 0.04 mole) was added to the mixture, the reaction mixture was then stirred overnight at 65° C. The reaction mixture was poured into 1200 ml of water and the aqueous phase was extracted several times with chloroform (the chloroform layer was filtered using Celite). The combined chloroform layer was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a red oil. The oil was subjected to flash chromatography on silica gel using 10% ethylacetate-90% hexanes and 20% ethylacetate-80% hexanes for elution. Fractions of similar purity was combined and solvent removed in vacuo. The oil obtained was dried in vacuo overnight at 80° C. to give 2.43 g (28.6%) of clear oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:18])[CH3:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].COCCO.Cl.C(=O)([O-])[O-]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:18])[CH3:17])=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: CC(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NC(C)=O)n3)cc2CC1
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 68.7 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide (170.0 mg, 0.5607 mmol) was added into a Vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (103.0 mg, 0.5413 mmol) in 2-Methoxyethanol (7 mL, 90 mmol). 4 M of Hydrogen chloride in 1,4-Dioxane (0.20 mL) was added and the reaction was heated at 120° C. After 4.5 h, the reaction was cooled to room temperature, Macroporous carbonate resin (3.16 mmol/g loading; 530 mg, 1.68 mmol) was added and stirred 30 min. The polymer was filtered off, and the solvent removed in vacuo. The residue was dissolved in DCM, concentrated onto Celite, then chromatographed (2×12 g SiO2, ISCO, 0-10% (5% NH4OH:MeOH):DCM) to afford N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-acetamide as a beige solid (170 mg, 69%). m.p.=248-250° C.; LCMS (m/e) 457 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.88 (s, 1H), 7.28 (m, 2H), 7.04 (d, 1H, J=7.5 Hz), 6.77 (s, 1H), 6.02 (s, 1H), 5.73 (s, 1H), 3.81 (m, 2H), 2.81-2.91 (m, 4H), 2.5-2.6 (m, 6H), 2.26 (m, 1H), 2.13 (m, 1H), 1.81 (m, 2H), 1.71 (s, 3H), 1.2-1.4 (m, 4H), 1.10 (t, 3H, J=7 Hz).