Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[N:18]=[C:17]([N:19]([CH3:39])[CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[C@H:29]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:28][CH2:27]3)[C:16](Cl)=[CH:15][N:14]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:12][C:13]1[N:18]=[C:17]([N:19]([CH3:39])[CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[C@H:29]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:28][CH2:27]3)[C:16]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][N:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3Cl)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3-c3ccc(OC)cc3)ccc21
Temperature: 75 °C
Yield: 79.3 %

Procedure:
To mixture of 4-methoxyphenylboronic acid (28.5 mg, 0.183 mmol) and ethyl ((1S)-5-{3-[(2,5-dichloro-4-pyrimidinyl)(methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 442, 80 mg, 0.183 mmol) in toluene (6.72 mL) and 1,4-dioxane (1.68 mL) was added PdCl2(dppf).CH2Cl2 (15 mg, 0.018 mmol). The mixture was purged with argon for 15 min after which a 2 M Na2CO3 aqueous solution (1.68 mL, 1.83 mmol) was added. The mixture was stirred and heated at 75° C. for 2 h, the reaction mixture was allowed cool to rt, and then washed with a saturated aqueous solution of NaHCO3. The organic layer was separated and the aqueous phase extracted with EtOAc (2×). The combined organic phases were dried, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (1:3 EtOAc/Hexanes) to give the product (74 mg, 79%). 1H NMR (400 MHz, CDCl3): δ 1.25 (t, 3H), 1.70-1.79 (m, 1H), 2.15-2.20 (m, 2H), 2.28-2.42 (m, 2H), 2.66 (dd, 1H), 2.72-2.90 (m, 2H), 3.31 (s, 3H), 3.44-3.54 (m, 1H), 3.82 (s, 3H), 3.84 (t, 2H), 3.95 (t, 2H), 4.16 (q, 2H), 6.65 (d, 1H), 6.72 (s, 1H), 6.91 (d, 2H), 7.05 (s, 1H), 8.15 (s, 1H), 8.25 (d, 2H); LC-MS: RT=3.51 min, (M+H)+ 510.5.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13]C)=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26][CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: CCOc1ccc(F)cc1Br
Product: CCOc1ccc(F)cc1C(=O)c1cnc(SC)nc1N

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-1-ethoxy-4-fluoro-benzene (prepared from 2-bromo-4-fluoro-phenol, Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(CC)CC>C(Cl)Cl>[CH3:19][C:13]1([CH3:20])[C@H:14]([C:16]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:18])[CH2:15][C@@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a stirred solution of (1R,3S)-3-(benzyloxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (Step 3, 0.9 g, 3.25 mmol) in DCM (5 ml) EDCI (0.747 g, 3.89 mmol) and HOBt (0.527 g, 3.89 mmol) were added at about 0° C., after 10 minutes morpholine (0.6 ml, 6.5 mmol) and Et3N (2.3 ml, 16.26 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 8 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt: 0.6 g; Yield: 53.4%; 1H NMR (300 MHz, CD3OD): δ 7.40-7.22 (m, 5H), 5.19 (d, 1H, J=8.7 Hz), 5.08 (q, 2H, J=12.0 Hz), 3.95 (q, 1H, J=9.0 Hz), 3.79-3.38 (m, 8H), 2.80 (t, 1H, J=8.4 Hz), 2.49-2.35 (m, 1H), 2.34-2.20 (m, 1H), 1.33 (s, 3H), 0.89 (s, 3H); Mass: [M+1]+ 347 (10%), [M+Na]+ 346 (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](C#N)[CH:5]=[C:4]([CH3:10])[C:3]=1[OH:11].C(C1N=NC(N2CCC(O)CC2)=CC=1)CC.CCOC(/N=N/C(OCC)=O)=O.[CH3:40][N:41]1[N:45]=[N:44][C:43]([C:46]2[CH:51]=[C:50]([CH3:52])[C:49]([OH:53])=[C:48]([CH3:54])[CH:47]=2)=[N:42]1>>[CH3:10][C:4]1[CH:5]=[C:6]([N:41]2[N:45]=[N:44][CH:43]=[N:42]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:11].[CH3:40][N:41]1[N:45]=[N:44][C:43]([C:46]2[CH:51]=[C:50]([CH3:52])[C:49]([OH:53])=[C:48]([CH3:54])[CH:47]=2)=[N:42]1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: CCCc1ccc(N2CCC(O)CC2)nn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cc1cc(-c2nnn(C)n2)cc(C)c1O
Product: Cc1cc(-n2ncnn2)cc(C)c1O

Procedure:
2-Methyl-5-((3,5-dimethyl-4-hydroxyphenyl)-2H-tetrazole (Formula III: R2 =R3 =R4 =CH3) was prepared according to the procedure of Example 1b starting with 2,6-dimethyl-4-cyanophenol. 4.5 Mmol of 6-methyl-3-(4-hydroxyl-1-piperidinyl)pyridazine (Formula IV: R1 =methyl, Y=CH2), 1.14 g DEAD, 6.8 mmol TPP, 5 mmol of 2-methyl-5-(3,5-dimethyl-4-hydroxyphenyl)-2H-tetrazole (Formula III: R2 =R3 =R4 =CH3) were reacted as described in Example 1c. Recrystallization from ethyl acetate afforded a 71.9% yield of the compound of Formula I (R1 =R2 =R3 =R4 =methyl, Y=CH2) m.p. 183°-184° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.F[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CN1CCCC1=O.[NH4+].[Cl-]>[Cl:3][C:4]1[N:5]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: N#Cc1ccccc1F
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccccc1-n1c(Cl)c(C=O)c2ccccc21
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 7.7 %

Procedure:
NaH (60% in mineral oil, 223 mg, 5.57 mmol, Eq: 1.00) was added to a solution of 2-chloro-1H-indole-3-carbaldehyde (1 g, 5.57 mmol, Eq: 1.00) in 1-methyl-2-pyrrolidinone (NMP, 5 mL) in a microwave vial. After 10 min., 2-fluorobenzonitrile (3.37 g, 3.02 mL, 27.8 mmol, Eq: 5) was added. The reaction was sealed and heated at 150° C. After 16 h. the mixture was diluted with sat. NH4Cl solution, extracted with EtOAc and the combined extracts concentrated to give a residue that was purified by silica gel chromatography to afford 2-(2-chloro-3-formyl-1H-indol-1-yl)benzonitrile (120 mg, 8%) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[C:4]([CH3:10])[N+:3]=1[O-:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Cl)c(C)c(Cl)n1
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cc(C)[n+]([O-])c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.8 %

Procedure:
A mixture of 2,4-dichloro-3,6-dimethyl-pyridine (790 mg, 4.49 mmol) and 50% m-chloro-perbenzoic acid (1.544 g, 4.49 mmol) in 10 ml of chloroform was stirred at room temperature for 20 hours. The mixture was quenched with water, washed with saturated sodium thiosulfate and saturated sodium carbonate, brine and extracted with chloroform. The organic layer was dried and concentrated to give 954 mg of crude material. The material was purified through silica gel to give 662 mg of the title compound as a white crystals, mp 131-132° C. 1H NMR (CDCl3) δ 7.22 (s, 1H), 2.51 (s, 3H), 2.47 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[C:4]([F:22])[CH:3]=1.C(#N)C.[Br-].[Li+].CCN(CC)CC>CC(OC)(C)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[C:4]([F:22])[CH:3]=1
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: COC(C)(C)C
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(Cl)cc1F
Yield: 97.9 %

Procedure:
Dimethyl 2-(4-chloro-2-fluorophenyl)piperidine-1,4-dicarboxylate (7.77 g, 23.56 mmol) was dissolved into acetonitrile (100 mL) and water (2.000 mL), then lithium bromide (16.37 g, 188.51 mmol) was added. Et3N (13.14 mL, 94.25 mmol) was added and the resulting yellow suspension was heated under reflux for 2 h. Water (200 mL) and MTBE (300 mL) were added. The phases were separated and the organic layer was extracted with water (2 times). The pooled water layers were acidified to pH 1 with 3.8 M HCl and extracted with MTBE (2 times). The combined organic layer was dried over MgSO4, filtered and evaporated yielding 2-(4-chloro-2-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.28 g, 98%) as a yellow semi-solid. MS m/z 316 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][N:23]3[CH:26]=[CH:27][N:28]=[C:22]3[CH:21]=2)O1>>[N:28]1[CH:27]=[CH:26][N:23]2[CH:24]=[CH:25][C:20]([C:2]3[N:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][CH:3]=3)=[CH:21][C:22]=12
Reactant: CC1(C)OB(c2ccn3ccnc3c2)OC1(C)C
Reactant: CC(=O)Cc1cccc(Cl)n1
Product: CC(=O)Cc1cccc(-c2ccn3ccnc3c2)n1

Procedure:
Prepare from 1-(6-chloro-pyridin-2-yl)-propan-2-one and 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridine using conditions similar to Preparation 21 step A. MS(ES), m/z 170 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=O)[CH2:7][CH:8]2[CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1>C(O)(=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[N:17]([C:18]3[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([C:23]([OH:25])=[O:24])[CH:26]=3)[C:9]3[CH2:10][CH2:11][CH2:12][C:8]=3[CH:7]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1CCCC1=O)c1ccc(Br)cc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc(Br)cc3)cc3c2CCC3)ccc1O

Procedure:
A solution of 20.8 g. (0.07 mole) of 2-(p-bromophenacyl)cyclopentanone, 10.71 g. (0.07 mole) of 5-aminosalicylic acid, and 88 ml. of glacial acetic acid was heated under reflux under nitrogen for 31/2 hours, cooled and filtered. The collected solid was chromatographed on silica gel. The solid eluted with benzene was recrystallized from ethanol-water to provide tan crystals, m.p. 215°-216°.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30]CC4C=CC=CC=4)[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(O)C.CO>C(OCC)(=O)C.[Pd]>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([OH:30])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cnc(NC(=O)c2cc(O)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Reaction time: 16 h
Yield: 99 %

Procedure:
3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(phenylmethyl)oxy]benzamide (3.9 g, 7.9 mmol) was dissolved in ethyl acetate (200 mL) and ethanol (200 mL) then 10% palladium on charcoal added. The reaction was stirred under an atmosphere of hydrogen for 16 hours. Methanol (150 mL) was added to aid solubilisation of the material and the suspension filtered, the residue taken up in DMF, filtered and the combined filtrates evaporated to dryness to give the desired material (3.17 g). 1H NMR δ (d6-DMSO): 2.33 (quin, 2H), 2.53 (s, 3H), 4.13 (t, 2H), 4.64 (t, 2H), 6.81 (s, 1H), 7.31 (s, 1H), 7.34 (s, 1H), 7.62 (d, 1H), 8.05 (d, 1H), 8.40 (s, 1H), 8.47 (s, 1H), 9.26 (s, 1H), 10.35 (s, 1H), 11.02 (s, 1H); m/z 406 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1cccc(C(=O)OC)c1
Yield: 86.7 %

Procedure:
To a solution of methyl 3-aminobenzoate (6.0 g) and triethylamine (4.5 g) in methylene chloride (90 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (4.8 g). The mixture was stirred for one hour. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, dilute hydrochloric acid and water, followed by drying and concentration to dryness. The concentrate was crystallized from ethyl acetate - hexane to afford colorless prisms (8.1 g, 87%), m.p. 101°-102° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[N:17]=[CH:18][C:19]3[C:25](=[O:26])[N:24]([C:27]4[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:28]=4[CH3:36])[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.C1COCC1>[Pd].CO>[NH2:33][C:31]1[CH:30]=[CH:29][C:28]([CH3:36])=[C:27]([N:24]2[CH2:23][CH2:22][C:20]3[N:21]=[C:16]([NH:15][C:4]4[CH:5]=[CH:6][C:7]([N:8]5[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]5)=[C:2]([CH3:1])[CH:3]=4)[N:17]=[CH:18][C:19]=3[C:25]2=[O:26])[CH:32]=1
Reactant: Cc1cc(Nc2ncc3c(n2)CCN(c2cc([N+](=O)[O-])ccc2C)C3=O)ccc1N1CCN(C)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2ncc3c(n2)CCN(c2cc(N)ccc2C)C3=O)ccc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
To a solution of 2-[3-Methyl-4-(4-methyl-piperazin-1-yl)-phenylamino]-6-(2-methyl-5-nitro-phenyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (100 mg, 0.198 mmol) in the mixed solvent of THF (5 ml) and methanol (5 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 6-(5-Amino-2-methyl-phenyl)-2-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [19] (Yield: 81.72 mg, 86.9%) as a off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH:24]=O)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[NH2:26][CH2:27][CH:28]1[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1.CN(C=O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][NH:26][CH2:27][CH:28]3[NH:32][C:31](=[O:33])[CH2:30][CH2:29]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C=O)s2)c1
Reactant: NCC1CCC(=O)N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CNCC3CCC(=O)N3)s2)c1
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a flask was added 4 Å molecular sieves (200 mgs) and the product from Step 1 (0.050 g, 0.14 mmol), 5-(aminomethyl)pyrrolidin-2-one (0.016 g, 0.21 mmol) and a 95:5 solution of DMF: acetic acid (1.4 mL). The mixture was stirred overnight. Resin-bound sodium cyanoborohydride (0.44 g, 0.41 mmol, 0.93 mmol/g loading) was added and the reaction was stirred for 72 hours. The mixture was filtered and purified by reverse phase HPLC (12-100% acetonitrile gradient with water over 6 minutes with 0.1% formic acid buffer) to yield 5-[({[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}amino)-methyl]pyrrolidin-2-one (0.016 g, 25%). MS ESI: [M+H]+ m/z 463.1. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.81 (d, J=5.2, 1H), 7.96 (s, 2H), 7.61 (s, 1H), 7.42 (s, 1H), 7.26 (d, J=5.1, 1H), 7.14 (s, 1H), 4.03 (s, 2H), 3.63 (s, 1H), 2.74-2.53 (m, 1H), 2.47 (m, 1H), 2.29 (s, 3H), 2.20-1.98 (m, 3H), 1.80-1.59 (m, 1H). rhSYK activity=+++
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[Cl:16][O-:17].[Na+:18]>ClC(Cl)=C(Cl)Cl>[Cl:16][O-:17].[Na+:18].[CH:3]1[C:4]2[C:13](=[CH:12][C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:2]=1
Reactant: Cc1ccc2cc3ccccc3cc2c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClC(Cl)=C(Cl)Cl
Product: c1ccc2cc3ccccc3cc2c1

Procedure:
A vessel was charged with 4.81 grams of 2-methylanthracene which is 96.7% pure, 50 milliliters of distilled tetrachloroethylene, and 173 grams of a sodium hypochlorite aqueous solution containing 8.04 grams of sodium hypochlorite, providing for a mole ratio of sodium hypochlorite to anthracene of 4.34:1. 4.5 Milliliters of concentrated hydrochloric acid were added to the stirred mixture to adjust the pH to about 7. During the resulting reaction about 12 milliliters of 3 N sodium hydroxide was added to maintain the pH at about 7. Reaction temperature was about 30° C. After about three hours the aqueous layer was removed and the organic layer was found to contain 95% of 2-methylanthraquinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=O)[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)([N:21]1C=CN=C1)=O.[OH-].[NH4+]>>[NH2:21][C:16]([CH:14]([O:13][C:10]1[N:11]=[CH:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[N:9]=1)[CH3:15])=[O:18]
Reactant: CC(Oc1ncn(-c2cccc(Br)c2)n1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Product: CC(Oc1ncn(-c2cccc(Br)c2)n1)C(N)=O
Yield: 53.5 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 38, 2.3 g of carbonyldiimidazole and 0.7 g of ammonium hydroxide. A yield of 1.6 g of the desired product, in unrecrystallized form, m.p. 141°-144°, was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2C(C)=CC=C2C)[N:5]=[C:4]([N:19]2C(C)=CC=C2C)[CH:3]=1.O.Cl.NO.[OH-].[K+]>C(O)C>[NH2:19][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[N:5]=1
Reactant: Cc1cc(CCCCn2c(C)ccc2C)nc(-n2c(C)ccc2C)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)nc(CCCCN)c1
Temperature: 100 °C
Yield: 75 %

Procedure:
4-Methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2,5-dimethylpyrrol-1-yl)butyl)pyridine (429 mg, 1.28 mmol) was dissolved in 6.5 mL of 95% ethanol and 2.5 mL of water was added followed by 818 mg (11.8 mmol) of hydroxylamine hydrochloride and 450 mg (6.96 mmol) of 87% potassium hydroxide. The mixture was heated in a 100° C. oil bath for 18 h. After cooling the reaction to room temperature, most of the ethanol was removed on a rotary evaporator. The residue was partitioned between 10 mL of 2 N aqueous hydrochloric acid and 20 mL of ethyl ether. The aqueous layer was made strongly basic by the addition of solid 87% potassium hydroxide and then extracted with 3×20 mL of ethyl ether. The combined ethyl ether extracts were dried over potassium hydroxide and sodium sulfate, decanted, and evaporated. The residue was purified by flash column chromatography on 6 g of silica gel eluting with 100 mL of 1% ammonium hydroxide and 7% methanol in dichloromethane followed by 100 mL of 2% ammonium hydroxide and 10% methanol in dichloromethane to give 172 mg (75% yield) of 2-amino-6-(4-aminobutyl)-4-methylpyridine as a light amber oil.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[C:8](O)(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:7][C:8](=[O:12])[CH:9]=[CH:10][CH3:11])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6]
Reactant: C/C=C/C(=O)O
Reactant: CCC=CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OCCC=CCC
Temperature: 125 °C
Yield: 82.2 %

Procedure:
Hex-3-en-1-ol (179 g), crotonic acid (181 g), PTSA (7.2 g), and toluene (250 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 120-130° C. Water was removed azeotropically. The reaction was aged at reflux for about 4-5 hours until no more water evolved. The reaction mixture was cooled to room temperature and quenched with water (400 mL). The organic layer was separated and subsequently washed with sodium carbonate (5%, 300 mL), and further distilled to provide but-2-enoic acid hex-3-enyl ester (247 g) with a boiling point of 109° C. at 20 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15][OH:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[C:10](=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15][O:16][CH3:26])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[C:10](=[O:25])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CI
Reactant: Cc1cccc(N2C[C@H](CCO)N(C(=O)OC(C)(C)C)CC2=O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC[C@H]1CN(c2cccc(C)c2C)C(=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from Step E (0.241 g, 0.699 mmol) was dissolved in DMF (10 mL) containing methyl iodide (0.21 mL, 3.44 mmol) and the stirred solution cooled to 0° C. under nitrogen. Sodium hydride (0.070 g, 60% dispersion in oil, 1.72 mmol) was added and the reaction stirred for 1 h. The reaction was quenched with water, and the DMF removed under vacuum. The residue was partitioned between ethyl acetate and water, and the organic phase washed with saturated brine and dried over magnesium sulfate. The crude product was chromatographed on silica gel with 40% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[S:21][CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[S:21]([CH3:22])=[O:28])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 68 %

Procedure:
3-Benzenesulfonyl-2-methylsulfanyl-pyrido[1,2-a]pyrimidin-4-ylideneamine (50 mg, 0.15 mmol) was dissolved in anhydrous methylenechloride (2 ml) to which 3-chloroperoxybenzoic acid powder (32 mg, 50-60%, ˜0.11 mmol) was added at 0° C. and stirred for 2 hours. In order to neutralize the reaction mixture, 2,6-tert-butyl-4-methylpyridine (38 mg, 90%, 0.17 mmol) was added. After concentration, the crude mixture was purified by preparative HPLC (XTerra™ MS C18 5.0 mM, MeOH/H2O as the eluent) to yield 26 mg of product as a pale yellow solid.