Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CO.C1COCC1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(F)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)O)CC1
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate (3.05 g, 8.64 mmol), 1 M aq LiOH (15 mL, 15 mmol), MeOH (15 mL), and THF (45 mL) was stirred overnight. The reaction mixture was diluted with EtOAc, washed with satd citric acid, dried over MgSO4, concentrated, and triturated with ether to give the acid as a white solid (2.23 g, 76%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][CH:35]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(C(F)(F)F)c2)c1
Temperature: 65 °C
Reaction time: 3.5 h

Procedure:
A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 112 mg, 0.25 mmol), (5-(trifluoromethyl)pyridin-3-yl)boronic acid (71.6 mg, 0.375 mmol) and Cs2CO3 (163 mg, 0.5 mmol) in degassed dioxane (3 mL) in a MW vial was evacuated/purged with argon. PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol) was added and the vial sealed. Water (0.6 mL) was added and the RM was stirred at 65° C. for 3.5 h. The solvent was evaporated off under reduced pressure to give a residue that was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4/charcoal, filtered and the filtrate was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (Silica gel column, 25 g, EtOAc). Palladium was removed using a SPE PL-Thiol MP cartridge (StratoSpheres™). The residue was dissolved in EtOAc and n-heptane was added. The solution was concentrated under reduced and the resulting suspension was stirred and filtered. The solid was washed with n-hexane then dried under HV at 45° C. to afford the title product as an amorphous white powder. UPLC-MS (Condition 3), tR=1.09 min, m/z=513.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.69-1.78 (m, 1H) 1.80-1.89 (m, 1H) 2.85 (d, J=10.92 Hz, 1H) 3.13-3.26 (m, 2H) 3.27-3.40 (m, 1H) 4.20 (br. s, 1H) 4.88 (br. s, 1H) 7.36 (d, J=8.66 Hz, 2H) 7.85 (d, J=8.85 Hz, 2H) 8.11 (s, 1H) 8.27 (br. s, 1H) 8.79 (s, 1H) 8.93 (s, 1H) 8.99 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.[CH2:19]=O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]1
Reactant: COc1ccc2[nH]cc(CC3CCCNC3)c2c1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2[nH]cc(CC3CCCN(C)C3)c2c1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of compound of Description 6 [5-methoxy-3-(piperidin-3-ylmethyl)-1H-indole] (2 g, 0.0082 mol) in methanol (50 ml) was added dropwise aqueous formaldehyde (40%) (5.63 ml; 0.082 mol). The mixture was heated at reflux for 2 hours. The reaction mixture was cooled at 10° C. and then sodium borohydride (0.93 g; 0.025 mol) was added. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction was then quenched with water and the solvent (methanol) was evaporated under vacuum. The product was extracted with ethyl acetate, the organic extract was dried (Mg SO4) and evaporated under vacuum, then the compound was triturated with diethyl ether and dried under vacuum giving the title compound as a solid (1.8 g)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][C:27]1[C:36](B2OC(C)(C)C(C)(C)O2)=[C:35]([CH3:46])[CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:36]5[C:27]([CH3:26])=[C:28]([CH:33]=[CH:34][C:35]=5[CH3:46])[C:29]([O:31][CH3:32])=[O:30])[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(C)c(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c1C
Temperature: 120 °C
Yield: 30.3 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (88 mg, 0.24 mmol) was dissolved in 1,2-dimethoxyethane (2.4 mL) in a reaction tube. Methyl 2,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (110 mg, 0.36 mmol), aqueous 2 M sodium carbonate (0.24 mL), and (Ph3P)4Pd (14 mg, 0.012 mmol) were added and the reaction mixture was heated at 120° C. under N2 atmosphere for 2 h in the microwave. The resulting material was cooled to room temperature, filtered, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (50-100% ethyl acetate in hexane) to yield methyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2,4-dimethylbenzoate (36 mg, 30%). ESI-MS m/z calc. 494.2, found 495.5 (M+1)+. Retention time 2.18 minutes.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:42]1(=O)[CH2:45][CH2:44][CH2:43]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH:42]1([N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]4\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]5[C:4]\4=[CH:3][C:2]([I:1])=[CH:11][CH:10]=5)=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)[CH2:45][CH2:44][CH2:43]1
Reactant: O=C1CCC1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCN(C3CCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60.6 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), cyclobutanone (0.195 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 32 mg (60%) of the title compound as a yellow solid. MS (ESI) m/z 529.4 (M+H)+1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:20][CH:21](C(O)=O)[C:22]([OH:24])=[O:23])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:12]=2)=[CH:4][CH:3]=1>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1)C(=O)O
Solvent: Clc1ccccc1
Product: O=C(O)CCc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Yield: 82.7 %

Procedure:
A solution of 3 g of [4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolylmethyl]malonic acid in 50 ml of chlorobenzene is heated under reflux until the release of gas ceases (about 2.5 hours). The mixture is concentrated under vacuum, the residue is recrystallized from carbon tetrachloride, thus obtaining 2.2 g of 3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]propionic acid, mp 131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1[Cl:26]>>[Cl:26][C:19]1[CH:20]=[C:21]([C:22]#[N:23])[CH:24]=[CH:25][C:18]=1[CH2:17][NH:16][C:11](=[O:13])[CH:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[O:14][CH3:15]
Reactant: COc1ccc(C(OC)C(=O)O)c(F)c1
Reactant: N#Cc1ccc(CN)c(Cl)c1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2Cl)c(F)c1

Procedure:
(RS)-(2-Fluoro-4-methoxy-phenyl)-methoxy-acetic acid, described in example 15.1 was coupled with 4-aminomethyl-3-chlorobenzonitrile (CAS 202521-97-9) according to general procedure B to give (RS)-N-(2-chloro-4-cyano-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Light green solid. MS 361.1 ([M−H]−)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7]CC)=O.[C:13]1([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:29]=[C:28]([NH2:30])[NH:27][N:26]=3)[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:10][C:3]1([C:2]([F:1])([F:11])[F:12])[CH2:4][C:5](=[O:7])[NH:30][C:28]2[NH:27][N:26]=[C:25]([CH:22]3[CH2:21][CH2:20][N:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:24][CH2:23]3)[C:29]1=2
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cc(C2CCN(c3ccccc3)CC2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CC(O)(C(F)(F)F)c2c(C3CCN(c4ccccc4)CC3)n[nH]c2N1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Ethyl trifluoroacetoacetate (1.50 g, 8.15 mmol) was added to a solution of 3-(1-phenylpiperidin-4-yl)-1H-pyrazol-5-amine (648 mg, 2.67 mmol) produced in Reference Example 3 in acetic acid (10 mL), and the mixture was stirred at 60° C. for 2 hours and 30 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elute: ethyl acetate/methanol=100/0-96/4 (gradient)] and further purified by silica gel chromatography [elute: hexane/ethyl acetate=60/40-0/100 (gradient)] to obtain the title compound (430 mg, yield: 42%).
Reaction SMILES: I[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:24]#[N:25])[C:8]=2[NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:3]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].O>C(=O)(O)[O-].[Na+].COCCOC.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>[CH:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[S:10][C:9]3[C:4](=[N:5][CH:6]=[C:7]([C:24]#[N:25])[C:8]=3[NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[CH:3]=2)=[CH:30][CH:29]=1)=[O:27]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)cc(OC)c1OC
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)cc(OC)c1OC
Yield: 93.8 %

Procedure:
A mixture of 2-iodo-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.07 mmol), 4-formylphenylboronic acid (240.7 mg, 1.61 mmol), tetrakis(triphenylphosphine)palladium(0) (61.8 mg, 0.054 mmol) in 16 mL of saturated aqueous sodium bicarbonate and 20 mL of ethylene glycol dimethyl ether is heated at reflux for 3 h. After cooling, the mixture is treated with water. The precipitate is filtered, washed with water, ethyl acetate, and ether, then dried in vacuo to provide 447.2 mg of 2-(4-formylphenyl)-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 268-270° C.; 1H NMR (DMSO-d6) δ 3.73 (s, 3H), 3.75 (s, 6H), 6.69 (s, 2H), 7.94 (d, J=8 Hz, 2H), 8.00 (d, J=8 Hz, 2H), 8.10 (s, 1H), 8.64 (s, 1H), 9.64 (s, 1H), 10.00 (s, 1H); HRMS 446.11691 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH3:24])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:15][C:14]=1[CH3:24]
Reactant: COc1cc(C=O)ccc1OCc1sc(-c2ccccc2)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CO)ccc1OCc1sc(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of 3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzaldehyde (2.80 g) in tetrahydrofuran (50 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.31 g) at room temperature. After stirring the reaction mixture at room temperature for 2 hrs, water was added, and the precipitated crystals were collected by filtration to give {3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]phenyl}methanol as colorless crystals (2.57 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1O)([CH3:4])([CH3:3])[CH3:2].NC1C=CC=CC=1>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1O
Solvent: Nc1ccccc1
Product: CC(C)(C)c1ccccc1
Temperature: 25 °C

Procedure:
15 g (0.1 mol) of t-butylphenol, 6.31 g (0.21 mol) of p-formaldehyde and 10.24 g (0.11 mol) of aniline were added to a 100 ml one-neck round-bottom flask and mixed in an oil bath at 90° C. When the initially opaque mixture became a dark brown transparent gel type material after about 30 minutes, the reaction was quenched using tetrahydrofuran (THF), and then the mixture was cooled to room temperature. The cooled crude product was base-washed twice through a solvent extraction using a 1N NaOH aqueous solution, and washed once with deionized water. After washing, the organic layer was dried with MgSO4 and filtered. The residual solution was dried using a rotary evaporator to remove the solvent, and the purified product was dried in a vacuum oven at 40° C. for 6 hours to obtain t-BuPh-a.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:21]N1C(=O)CCC1=O>C(#N)C.O>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:21])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.900 g, 2.67 mmol) in acetonitrile (30 mL) was treated with N-chlorosuccinimide (0.357 g, 2.67 mmol) and stirred overnight at 70° C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases washed with brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in 0.399 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.17 (s, 1H), 6.68 (m, 1H), 3.88 (s, 3H), 3.78 (m, 1H), 3.6-3.3 (m, 2H), 3.2-2.9 (m, 4H), 1.34 (m, 3H). MS calculated for C14H15ClF3NO2+H: 322, observed: 322.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](/[CH:26]=[CH:27]/[C:28](=O)[CH3:29])=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O>C(O)(=O)C.C(O)C.[Fe]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[C:28]([CH3:29])[CH:27]=[CH:26]4)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)ccc4c3O2)cc1

Procedure:
To a solution of {(2R)-7-nitro-8-[(E)-3-oxo-1-butenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (3.40 g, 7.83 mmole) in 200 mL of acetic acid/ethanol (3:2) was added 2.25 g (40.2 mmole) of iron powder and the mixture was heated at reflux under nitrogen for 6 hours. After the reaction was complete, 150 mL of water was added and the mixture filtered through a pad of celite. The filtrate was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel using a gradient elution commencing with 20% ethyl acetate/hexane and ending with 70% ethyl acetate/hexane to give 2.5 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 8.1 δ (1H); doublet 7.6 δ (2H); doublet 7.45 δ (1H); multiplet 7.2 δ (4H); multiplet 4.6 δ (1H); multiplet 4.3 δ (3H); multiplet 4.1 δ (1H); singlet 2.5 δ (3H); singlet 2.4 δ (3H).
Reaction SMILES: C([Si](CC)(CC)[O:4][C@H:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:7][CH:8]([C:13]([O:15]C)=O)[C:9]([O:11]C)=O)C.[O:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[NH:34])[CH2:28][CH2:27]1.CC[O-].[Na+].Cl.O1CCOCC1>CCO>[CH2:20]([O:19][C:17](=[O:18])[C@@H:5]([OH:4])[CH2:6][CH2:7][C:8]1[C:9]([OH:11])=[N:34][C:33]([NH:32][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[N:35][C:13]=1[OH:15])[CH3:21]
Reactant: N=C(N)NC1CCOCC1
Reactant: CCOC(=O)[C@H](CCC(C(=O)OC)C(=O)OC)O[Si](CC)(CC)CC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](O)CCc1c(O)nc(NC2CCOCC2)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A solution of 398 (3.75 g, 9.46 mmol), 24 (1.63 g, 11.4 mmol), EtOH (30 mL) and NaOEt (3.86 g, 11.4 mmol) was heated to 85° C. and stirred overnight. The reaction was cooled to RT and quenched reaction by addition of 4N HCl in dioxane (2.37 mL, 9.46 mmol) and the solution concentrated. The crude product was purified by reverse phase chromatography (Biotage 40 M C18 using a C18 samplet loaded using water) eluting with a MeCH/H2O chromatography (0-60% MeCN) over 30 column volumes to afford 1.25 g (37%) of (S)-ethyl-4-(4,6-dihydroxy-2-(tetrahydro-2H-pyran-4-ylamino) pyrimidin-5-yl)-2-hydroxybutanoate (400): MS m/z (APCI-pos) M+1=342.1.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[CH3:11][Si:12]([CH3:21])([CH3:20])[C@@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1>>[CH2:9]([C:6]1([NH:19][C@H:16]2[CH2:15][CH2:14][C@@H:13]([Si:12]([CH3:21])([CH3:20])[CH3:11])[CH2:18][CH2:17]2)[NH:5][CH:4]=[N:3][CH:2]=[C:7]1[I:8])[CH3:10]
Reactant: CCc1ncnc(Cl)c1I
Reactant: C[Si](C)(C)[C@H]1CC[C@@H](N)CC1
Product: CCC1(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)NC=NC=C1I

Procedure:
Prepared as in Example 1 from 4-chloro-5-iodo-6-ethylpyrimidine and cis-4-trimethylsilylcyclohexylamine (yellow oil). The following compounds were further prepared analogously:
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][C:5]2([O:9][CH2:8][C:7](=O)[CH2:6]2)[CH2:4][CH2:3]1.Cl.[NH2:14][OH:15]>CO>[CH3:1][N:2]1[CH2:12][CH2:11][C:5]2([O:9][CH2:8][C:7](=[N:14][OH:15])[CH2:6]2)[CH2:4][CH2:3]1
Reactant: NO
Reactant: CN1CCC2(CC1)CC(=O)CO2
Agent: Cl
Solvent: CO
Product: CN1CCC2(CC1)CC(=NO)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 2 (0.6 g, 3.5 mmol) was dissolved in methanol (50 ml) and placed under nitrogen. Hydroxylamine hydrochloride was added and the reaction was stirred at room temperature overnight.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2].[O:31]=[C:32]1[NH:36][CH2:35][CH2:34][N:33]1[CH2:37][C:38]#[CH:39].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>[Cu]I.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.O.C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:39]#[C:38][CH2:37][N:33]3[CH2:34][CH2:35][NH:36][C:32]3=[O:31])[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(I)cc2C(F)(F)F
Reactant: C#CCN1CCNC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(C#CCN1CCNC1=O)cc2C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 875.7 %

Procedure:
A mixture of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-chlorophenyl)oxindole (720 mg, 0.13 mmol), 3-(2-oxo-1-imidazolidinyl)-1-propyne (280 mg, 0.226 mmol), triethylamine (1 mL), CuI (12.8 mg, 0.0372 mmol), and (PPh3)2PdCl2 (22.6 mg, 0.0322 mmol) in a mixed solvent of THF (0.5 mL) and toluene (0.5 mL) was stirred for 3 h at 50° C. Water and sat. aqueous NaHCO3 were added and the mixture was extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 30:1 to 20:1 chloroform/methanol to give the title compound (625 mg). The compound was dissolved in dioxane (4 mL) and 4 N HCl in dioxane (1.5 mL) was added. The solvent was evaporated azeotropically with toluene. The residual solid was washed with ether and dried in vacuo to give the hydrochloride (583 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[N:3]=1.[Cl:15]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([Cl:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[N:3]=1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Nc1nc(Cl)c(Cl)c(-c2ccccc2)n1
Temperature: -20 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To 1.5 g (7.3 mM) of 4-chloro-6-phenyl-2-pyrimidinamine is added 40 ml of glacial acetic acid and 1.05 g of N-chlorosuccinimide. The reaction is stirred at ambient temperature (-20° C.) for 18 hours. The reaction mixture is evaporated to dryness, dissolved in acetone and 10.0 g of silica gel added and the mixture evaporated to a powder under vacuum. The powder is chromatographed on 50 g silica gel and eluted with 35% ethyl acetate/hexane. A fraction containing material with a TLC r.f. of 0.7 35% ethylacetate/hexane is collected and evaporated to dryness, recrystallized from acetone/Skellysolve B (1:10), evaporated to dryness(?) to yield 0.90 g of 4,5-dichloro-6-phenyl-2-pyrimidinamine.