Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)[CH3:2].Br[CH2:24][C:25]([CH3:27])=[CH2:26]>O1CCCC1>[CH2:1]([O:3][C:4]([CH:5]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:26][C:25]([CH3:27])=[CH2:24])=[O:22])[CH3:2]
Reactant: C=C(C)CBr
Reactant: CCOC(=O)CC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48.9 %

Procedure:
Lithium hexamethyldisilylazide (1.0 M in THF; 18.0 mL, 18.0 mmol) was added to a solution of benzyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (5.0 g, 16.4 mmol) in tetrahydrofuran (90 mL) at −78° C. After 40 min, 3-bromo-2-methylprop-1-ene (1.81 mL, 18.0 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 16 h, the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. Purified by silica gel chromatography (100% hexanes→40% hexanes/ethyl acetate) to give the title compound (2.88 g). MS 360.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1.[CH3:38][O:39][CH2:40][C@H:41]1[CH2:43][O:42]1>CO>[OH:42][C@@H:41]([CH2:40][O:39][CH3:38])[CH2:43][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]4[N:18]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:11][CH2:12]1
Reactant: COc1cc(CN2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Reactant: COC[C@H]1CO1
Solvent: CO
Product: COC[C@H](O)CN1CCN(Cc2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)c(OC)c2)CC1
Temperature: 25 °C

Procedure:
Into an 8-dram vial, N-{2-[2-(2-Methoxy-4-piperazin-1-ylmethyl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide (70.0 mg, 0.134 mmol), (R)-2-Methoxymethyl-oxirane (0.0154 g, 0.174 mmol), and Methanol (5.00 mL) were added. The reaction was stirred at room temperature over the weekend. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The selected fractions were concentrated. The residue was partitioned with DCM and sat. NaHCO3. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered wand washed with DCM. The solvent was removed under vacuum to give N-[2-(2-{4-[4-((R)-2-Hydroxy-3-methoxy-propyl)-piperazin-1-ylmethyl]-2-methoxy-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide a yellow solid (32 mg, 39%). LCMS (E/I+) 610.15 (M+H). NMR 1H (DMSO-d6)-8.95 (s, 1H), 7.92-7.98 (m, 1H), 7.88 (d, 1H, J=8.26 Hz), 7.72 (s, 1H), 7.60-7.67 (m, 1H), 7.50-7.78 (m, 2H), 7.00 (d, 1H, J=4.66 Hz), 6.96 (d, 1H, J=4.66 Hz), 6.92 bs, 1H), 6.72 (d, 1H, J=8.26), 4.47 (bs, 1H), 3.82 (s, 3H) 3.71 (bs, 1H), 3.39 (bs, 2H), 3.25-3.31 (m, 2H), 3.24 (s, 3H), 3.17-3.23 (m, 1H) 3.04 (s, 3H), 2.88 (s, 3H), 2.20-2.42 (m, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O.[OH-].[Li+]>O1CCCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Methyl 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylate (580 mg, 1.243 mmol) was dissolved in tetrahydrofuran (15 mL) and water (5.00 ml) was added. Lithium hydroxide (78 mg, 1.865 mmol) was added and the mixture stirred under argon at room temperature overnight. The THF was evaporated off and the aqueous residue was adjusted to ˜pH of 6 with 1N HCL. A white solid slowly formed. The white solid was filtered and washed 2× with water (5 mL). The pH of the filtrate was checked and was found to be 8. The pH was gradually lowered to 4 with 1N HCl. At this point no additional solid appeared to be forming. The solid was filtered and washed 2× with water (5 mL). The combined solid was dried at 50° C. in a vacuum oven for 6 hours to give 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (533 mg, 1.178 mmol, 95% yield) as a white solid. LC-MS m/z 453 (M+H)+, 0.71 min (ret time).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][CH2:32][C:3]1=2.CO.C(Cl)[Cl:43].Cl>C(OCC)C>[ClH:43].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][C:3]1=2
Reactant: ClCCl
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CNCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of tert-butyl 6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (80 mg, 0.20 mmol) in 5:1 MeOH/CH2Cl2 (6.0 mL) was treated with anhydrous 1.0 M HCl in diethyl ether (32 mL), and the resulting suspension was stirred at ambient temperature for 1 h. The solids were collected by filtration, washed with Et2O and dried to yield the title compound (58 mg, 85%) as a yellow powder: mp 264-270° C. decomp.; 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.89 (s, 2H), 8.39 (dd, J=8.5, 2.0 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 7.11 (dd, J=8.0, 1.5 Hz, 1H), 7.07 (d, J=7.5, 2.0 Hz, 1H), 4.47 (s, 2H), 3.74 (s, 3H), 3.47-3.45 (m, 2H), 3.11 (t, J=5.0 Hz, 2H), 2.08-2.06 (m, 2H); ESI MS m/z 439 [M+H]+; HPLC (Method A) 95.1% (AUC), tR=14.7 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9][CH2:8][C:7]2=[O:18])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9][CH2:8][C:7]2=[O:18]
Reactant: CCC(=O)N1CCC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N1CCC(=O)c2cc(N)ccc21
Yield: 90.1 %

Procedure:
A solution of 6-nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (6.076 g) in methanol (60 ml) was hydrogenated over 5% palladium on carbon (0.5 g) under atmospheric pressure at ambient temperature. After the theoretical amount of hydrogen gas was absorbed, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residual solid was washed with diethyl ether and dried to give 6-amino-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (4.815 g).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:8])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3CCCCC3)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use cyclohexanecarbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white solid (58% yield). 1H NMR (300 MHz, CDCl3) δ 8.06, 7.99, 6.99, 3.88, 3.79, 3.68, 3.56, 2.50, 1.67-1.84, 1.48-1.60, 1.24-1.34, 0.76, 0.47, 0.10. MS (ES+) m/z 386 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C1CCNCC1.CC=C(C)C.[C:37](Cl)(=[O:41])[CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl>[C:37]([N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)=[O:8])[CH2:25][CH2:24]1)(=[O:41])[CH2:38][CH2:39][CH3:40]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: CCCC(=O)Cl
Agent: CC=C(C)C
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 24 h
Yield: 12.5 %

Procedure:
A small sample of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (60 mg, 0.16 mmol) was weighed out in a 4 mL sealable vial, followed by (piperidinomethyl)polystyrene (0.12 g, 0.32 mmol). To this was added 10 mL of amylene-stabilized chloroform and butyryl chloride (18.0 μL, 0.17 mmol). The vial was capped and placed in a shaker, where it was kept at room temperature for 24 h, then at 50° C. for 36 h. The crude reaction mixture was then applied to a 2 g SCX column, washed with methanol and eluted with 1 N ammonia in methanol. The yellow fractions were combined and concentrated in vacuo to a dry residue, which was purified by preparative thin layer chromatography. Elution with 9:1 dichloromethane-methanol provided the title compound (9 mg, 13%), isolated in 98% purity by HPLC analysis (Method C: gradient from 50% acetonitrile-50% water with 0.1% trifluoroacetic acid to 90% acetonitrile-10% water with 0.1% trifluoroacetic acid over 10 min; hold 2 min; back to 50% acetonitrile-10% water with 0.1% trifluoroacetic acid over 1 min; hold 2 min; 0.5 ml/min; Waters Symmetry Cl18, 3.5 μM column, 4.6 by 75 mm; 25° C.).
Reaction SMILES: Br[CH2:2][C:3](=[O:7])[C:4](=O)[CH3:5].[C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])(=[S:10])[NH2:9]>CC(C)=O>[C:3]([C:4]1[N:9]=[C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])[S:10][CH:5]=1)(=[O:7])[CH3:2]
Reactant: CC(=O)NCC(N)=S
Reactant: CC(=O)C(=O)CBr
Solvent: CC(C)=O
Product: CC(=O)NCc1nc(C(C)=O)cs1
Yield: 92.9 %

Procedure:
A suspension of 1-bromo-2,3-butanedione (47 g) and N-[(thiocarbamoyl)methyl]acetamide (30 g) in acetone (600 ml) was refluxed for 3 hours. The resulting precipitate was collected by filtration to afford 4-acetyl-2-(acetylaminomethyl)thiazole (41.8 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:37][O:38][C:39]1[CH:59]=[CH:58][C:42]([CH2:43][N:44]2[C:56]3[CH:55]=[CH:54][CH:53]=[C:52]([OH:57])[C:51]=3[C:50]3[C:45]2=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:41][C:40]=1[O:60][CH3:61].Cl>[Cu](I)I.O1CCOCC1>[CH3:61][O:60][C:40]1[CH:41]=[C:42]([CH:58]=[CH:59][C:39]=1[O:38][CH2:37][C:27]1[N:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:30][C:26]=1[CH3:25])[CH2:43][N:44]1[C:56]2[CH:55]=[CH:54][CH:53]=[C:52]([O:57][C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])[C:51]=2[C:50]2[C:45]1=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: COc1cc(Cn2c3ccccc3c3c(O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C(O)c1ccccc1Br
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(Cn2c3ccccc3c3c(Oc4ccccc4C(=O)O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
3.53 g of 2-bromobenzoic acid, 2.23 g of copper iodide, 1.63 g of N,N-dimethylglycine hydrochloride, and 15.2 g of cesium carbonate were added to 1,4-dioxane (50 mL) suspension of 5.74 g of 9-{4-[(5-methyl-2-phenyloxazole-4-yl)methoxy]-3-methoxybenzyl}-9H-carbazole-4-ol, and refluxed overnight. 1 N hydrochloric acid was added to the reaction mixture, extracted with ethyl acetate, and washed with brine. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=2:1), and 1.4 g of the subject compound was prepared as white crystal.
Reaction SMILES: [CH2:1]([C:8]1([OH:26])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16](N)[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].[ClH:31]>O>[ClH:31].[CH2:1]([C:8]1([OH:26])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([Cl:31])[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(CCN1CCC(O)(Cc2ccccc2)CC1)C(=O)c1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccccc1)C(Cl)CCN1CCC(O)(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a cooled solution of 3.6 g of γ-(4-benzyl-4-hydroxypiperidino)-2-aminobutyrophenone in 35 ml of 2N hydrochloric acid was added dropwise a solution of 0.74 g of sodium nitrite in 5 ml of water with stirring below 0° C. The resulting diazonium salt solution was added all at once to a cold suspension of 1.5 g of cuprous chloride in 5 ml of concentrated hydrochloric acid with vigorous stirring. The mixture was stirred for 30 minutes under cooling with ice, and stirring was continued for 2 hours at room temperature and then for 1 hour at 55°-60° C. After cooling, the reaction mixture was made alkaline, and extracted with chloroform. The extract was washed with water, dried and concentrated to a residue. The residue was treated with methanolic hydrogen chloride and recrystallization of the resulting solid matter from isopropanol gave γ-(4-benzyl-4-hydroxypiperidino)-2-chlorobutyrophenone hydrochloride.8c
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Li])CCC.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[CH:20]=[O:21].CC(O)C>C1COCC1.O>[CH3:26][O:25][C:23]1[CH:22]=[C:19]([CH:20]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)[OH:21])[CH:18]=[C:17]([O:16][CH3:15])[CH:24]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2cc(OC)cc(OC)c2)c1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A solution of 1-bromo-3-methoxybenzene (2.48 g, 13.24 mmol) in anhydrous THF (10 ml) was cooled to −78° C., evacuated and refilled with nitrogen for ten cycles. To this clear solution was slowly added n-butyl lithium (5.30 ml, 13.24 mmol) and stirred for 30 min. Then a solution of 3,5-dimethoxybenzaldehyde (2.00 g, 12.04 mmol) in anhydrous THF (10 ml) was added via a syringe. The mixture was stirred at −78° C. under nitrogen for 4 h then quenched with 2-propanol (2.1 ml, 27 mmol) and stirred overnight. To the orange colored mixture was added 30 ml of water and extracted with ether (3×60 ml). The combined ether extracts was washed with water (2×60 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography to give (3,5-dimethoxy-phenyl)-(3-methoxy-phenyl)-methanol as an off-white oil (2.69 g, 82%), HPLC purity was 98.3% at 2.81 min. (50/50 ACN/0.1% H3PO4): 1HNMR (CDCl3) δ 7.26-7.29 (m, 1H, Ar), 6.95-6.92 (m, 2H, Ar), 6.81-6.77 (m, 1H, Ar), 6.53 (d, J=2 Hz, 2H, Ar), 6.34 (t, J=2 Hz, 1H), 5.68 (d, J=3 Hz, 1H, CH), 3.77 (s, 3H, single OCH3 group), 3.74 (s, 6H, 2OCH3 groups), 2.45 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([N+:15]([O-])=O)=[CH:10][C:9]=1[OH:18])=[O:6]>C(OCC)(=O)C.CN(C)C=O.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([NH2:15])=[CH:10][C:9]=1[OH:18])=[O:6]
Reactant: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(O)c(NC(=O)c2ccc(Cl)c(Cl)c2)cc1Cl
Reaction time: 15 h
Yield: 81.4 %

Procedure:
The nitrophenol (3) (36.0 g, 0.1 mol) was dissolved in ethyl acetate (250 ml) and dimethylformamide (DMF) (50 ml). The solution was hydrogenated over Raney Nickel at 3040 kPa (30 atm)/25 C. for 15 h. The catalyst was removed by filtration through a pad of Kieselguhr and the ethyl acetate removed in vacuo. The residual solution of aminophenol (4) in DMF was poured on to an ice/water mixture (1.51) to precipitate aminophenol (4) (27 g, yield 84%), which was collected by filtration and dried. This was stored under a blanket of nitrogen while the ballast acid chloride was prepared.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([CH:26]3[CH2:28][CH2:27]3)[C:10]([N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:6]=2[O:5][C:4]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)#[N:2].[NH2:36][OH:37]>C(O)C>[CH:26]1([C:9]2[C:10]([N:12]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:6]3[O:5][C:4]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)=[C:3]([C:1](=[N:36][OH:37])[NH2:2])[C:7]=3[CH:8]=2)[CH2:28][CH2:27]1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C#N)c3cc2C2CC2)S(C)(=O)=O)cc1
Reactant: NO
Solvent: CCO
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C(N)=NO)c3cc2C2CC2)S(C)(=O)=O)cc1
Temperature: 140 °C

Procedure:
To a 20 mL microwave tube was added the product from Example 8B (340 mg, 0.693 mmol) and hydroxylamine (50 weight % in water, 6.0 mL, 102 mmol) in ethanol (6 mL). The vial was sealed and heated in a microwave reactor (Personal Chemistry (Biotage), Emrys Creator, 300 W maximum) at 140° C. for 30 minutes. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound which was used without purification (363 mg, quantitative yield). MS (ESI+) m/z 524 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]([CH:22]([CH3:24])[CH3:23])[C:19](=[O:21])[NH:20][C:16]=3[CH:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[CH3:27]I>CN(C)C=O>[Cl:3][C:4]1[C:5]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]([CH:22]([CH3:23])[CH3:24])[C:19](=[O:21])[N:20]([CH3:27])[C:16]=3[CH:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: CI
Reactant: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)n(C)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
0.23 g of an 80% strength by weight suspension of sodium hydride in mineral oil was added at 23° C. to 25 ml of anhydrous dimethylformamide. The mixture was then treated dropwise with a solution of 2.50 g of 5-(3-chloro-5-trifluoromethylpyridin-2-yl)-1-(1-methylethyl)benzimidazol-2-one in 25 ml of dimethylformamide and, after stirring for 15 minutes, with 1.05 g of methyl iodide. After stirring for 6 hours, the reaction mixture was poured into 300 ml of ice water. The aqueous phase was extracted three times with 100 ml of tert-butyl methyl ether each time, after which the combined organic phases were washed twice with 50 ml of water each time, dried over sodium sulfate and concentrated. Chromatography on silica gel using cyclohexane/ethyl acetate (4:1) as the eluent gave 2.1 g of colorless crystals. Yield: 75%; m.p.: 108-109° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25](=O)[C:26]#[CH:27])[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Cl.[OH:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[NH:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][N:36]=[C:34]([C:33]([OH:32])([CH3:38])[CH3:37])[N:35]=3)[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 75 °C
Yield: 61.2 %

Procedure:
To a solution of the 5-bromo-6-(2,4-difluoro-benzyloxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one of Step E (80 mg, 0.17 mmol) in acetonitrile (3 mL) was added 2-hydroxy-2-methylpropionamidine HCl (35 mg, 0.25 mmol) and potassium carbonate (70 mg, 0.50 mmol) and the slurry was heated at 75° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (58 mg, 61% yield). MS (M, M+2): 557, 559; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.17 (s, 3H), 2.20 (s, 3H), 5.50-5.60 (m, 2H), 6.87-6.94 (m, 2H), 7.54-7.58 (m, 3H), 7.92 (s, 1H), 8.13 (d, J=7.04 Hz, 1H), 8.77 (d, J=4.30, 1H).
Reaction SMILES: OC[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7]C(=O)CC1.C1([NH2:19])CC1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[CH2:7]1[C@@H:8]([NH2:19])[C@@H:3]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(CO)(c2ccccc2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-(hydroxymethyl)-4-phenylcyclohexanone (5.0 g, 24.5 mmol, 1.0 equiv.) in 1,2-dichloroethane (50 mL) was treated at 0° C. with cyclopropylamine (4.2 g, 74.0 mmol, 3.0 equiv.), 1 mL acetic acid and NaBH(OAc)3 (15.6 g, 74.0 mmol, 3.0 equiv.) successively. After being stirred at 25° C. for 12 h, the reaction mixture was diluted (EtOAc), washed (1×1 N aqueous NaOH and 2× brine), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 50% EtOAc/n-Hexane with 5% TEA) gave the trans amine isomer (the bottom spot on the TLC).