Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][CH2:12][O:10][C:8]1[CH:9]=[C:4]([C:2]([CH3:1])=[O:3])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(C(C)=O)c1
Temperature: 23 °C
Yield: 97.6 %

Procedure:
Commercially available 3-hydroxyacetophenone (25 g, 184 mmol) was stirred with ethyl iodide (17.8 mL, 220 mmol) and potassium carbonate (126.89 g, 918 mmol) in acetone (500 mL) at 55° C. for 16 h. Cooled to 23° C., filtered the solids off and the solvent was removed in vacuum. The residue was purified by silica gel column chromatography with heptane/ethyl acetate 4:1 to give the title compound as a light yellow liquid (29.5 g, 98%). MS (ISP) 165.2 [(M+H)+].
Reaction SMILES: F[C:2]1[C:7](F)=[C:6](I)C=C[C:3]=1[C:10]1C=[CH:14][C:13](C2C=CC(CCC)=CC=2)=[CH:12][C:11]=1F.OCC(C)(CO)C.CC(C)=O>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:6][CH2:7][CH2:2][CH2:3][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCc1ccc(-c2ccc(-c3ccc(I)c(F)c3F)c(F)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(CO)CO
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCCCCCCCC
Yield: 65 %

Procedure:
A solution of (0.1 mmol) of 10, (0.12 mmol) of 12, 14 mg (0.13 mmol) of neopentyl glycol, 95 mg (0.3 mmol) of Ba(OH)2.8H2O, 80 μl (6.08 mmol, 5 mol %) of a 76 mM acetone solution of Pd(OAc)2 in 2 ml of 95% i-PrOH is stirred at 80° C. for 12 hours. The solvent is subsequently removed under reduced pressure. 2 ml of 2 M HCl are added to the residue, and the mixture is extracted with dichloromethane (3×2 ml). The combined organic phases are dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, and the residue is purified by recrystallisation twice from nonane (yield: 65%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.[CH3:27][NH:28]CC1C=CC=CC=1.COC1C=CC(C2NC(C(N)=O)=C(C3C=CC(OC)=CC=3)N=2)=CC=1>CO.[Pd]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:28][CH3:27])=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Reactant: CNCc1ccccc1
Agent: [Pd]
Agent: COc1ccc(-c2nc(-c3ccc(OC)cc3)c(C(N)=O)[nH]2)cc1
Solvent: CO
Product: CNCCOc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1

Procedure:
The title compound was prepared by reaction of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide with N-methylbenzylamine, according to the procedure described in example S-1, step c, followed by deprotection with the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 60° C., 0.05M in MeOH). 1H NMR (DMSO) δ 2.35 (3H, s), 2.87 (2H, t), 4.10 (2H, t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.55 min; m/z (ES+) 374.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[N:6][CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc(N)c(N)c1
Reaction time: 14 h
Yield: 94.5 %

Procedure:
A suspension of 5.97 g (30 mmol) 6-amino-5-nitro-nicotinic acid methyl ester in 30 ml methanol and 600 mg Pd/C (10%) cat was added and hydrogenated at room temperature during 14 h. The catalyst was filtered off and the solution was concentrated to yield 4.74 g (94%) of the title compound as white amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:17]([C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1)#[N:18]
Reactant: CN(C)C=O
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)C1=Cc2cc(C#N)ccc2OCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (1416 mg, 5.00 mmol), zinc cyanide (352 mg, 3. 00 mmol), tetrakis(triphenylphosphine)-palladium (347 mg, 0.30 mmol) and DMF(10 ml) was stirred at 80° C. for 3 hours. The mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate. Insoluble materials were filtered off, which were washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting crude product was recrystallized from ethyl acetate to give methyl 7-cyano-2,3-dihydro-1-benzoxepine-4-carboxylate (800 mg, 3.49 mmol, 70%). IR (KBr): 2222, 1721 cm−1.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH3:13])[CH2:10][C:9](=[O:14])[NH:8][C:5]2=[N:6][CH:7]=1.[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[N:21]1[CH:25]=[N:24][N:23]=[C:22]1[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:12]([N:11]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([C:22]4[N:21]([CH:16]5[CH2:17][CH2:18][CH2:19][CH2:20][O:15]5)[CH:25]=[N:24][N:23]=4)=[CH:27][CH:28]=3)[N:3]=2)[NH:8][C:9](=[O:14])[CH2:10]1)[CH3:13]
Reactant: CCN1CC(=O)Nc2ncc(Br)nc21
Reactant: CC1(C)OB(c2ccc(-c3nncn3C3CCCCO3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CC(=O)Nc2ncc(-c3ccc(-c4nncn4C4CCCCO4)cc3)nc21
Temperature: 120 °C
Yield: 45 %

Procedure:
6-Bromo-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1.1 equiv), 4-(tetrahydro-2H-pyran-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-1,2,4-triazole (1 equiv) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (0.05 equiv) were combined in 1,4-dioxane followed by the addition of sodium carbonate (3 equiv) in water. The solution was heated in a Biotage Emrys Optimizer microwave reactor to 120° C. for 30 min. The solution was condensed under reduced pressure and purified using column chromatography (0-10% methanol in ethyl acetate) to afford the title compound in 45% yield. MS (ESI) m/z 406.6 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O.ClC1N=C2C(N=CN2CC2CCOCC2)=C(Cl)N=1>CN(C)C=O.C(OCC)(=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:37][CH:38]3[CH2:42][CH2:41][O:40][CH2:39]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCC1CCOC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Agent: Clc1nc(Cl)c2ncn(CC3CCOCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[(2-cyclopropylethyl)oxy]-8-(methoxy)-1H-purin-6-amine trifluoroacetic acid salt (2.89 g) in dry N,N-dimethylformamide (32 ml) under nitrogen and at room temperature, was added potassium carbonate (4.41 g) in one go. The reaction was heated to 60° C. and stirred for 90 minutes. A solution of tetrahydro-3-furanylmethyl methanesulfonate, Isomer 2 (1.869 g) in dry DMF (3 ml) was then added gradually via pipette. The reaction was heated to 70° C. and left to stir overnight. Still 22% starting material present by LCMS, therefore increased temperature to 90° C. and stirred for a further 3 hours at this temperature. The reaction was cooled and diluted with ethyl acetate (100 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was concentrated in vacuo to yield an orange oil. The product was purified by C18 reverse phase chromatography using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluant (10-60%) to afford the title compound as an orange viscous oil (1.45 g).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C-:12]#[N:13].[Na+].O>CS(C)=O>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:12]#[N:13]
Reactant: [C-]#N
Reactant: COc1cccc(CCl)c1F
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(CC#N)c1F

Procedure:
24.89 g (142.56 mmol) of 2-fluoro-3-methoxybenzyl chloride is stirred in 200 ml of DMSO with 8.38 g (171.07 mmol) of sodium cyanide for three hours at 90° C. The reaction mixture is poured into water and extracted four times with methyl tert-butyl ether. The combined organic phases are washed with brine, dried, the desiccant is suctioned off, and the solvent is spun off. First, only a portion of the residue (21.43 g) is incorporated in crude form into the next stage.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH:39]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:39][CH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: O
Product: COC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reaction time: 1 h

Procedure:
A suspension of 4.5 g of methoxymethyl-triphenylphosphonium chloride in 40 ml of t-butyl methyl ether was treated within 3 minutes with 1.5 g of potassium t-butylate while gassing with argon at -10° C. and the solution was stirred for a further 1 hour at 0°-5° C. The suspension was then treated dropwise within 5 minutes at 0° C. with a solution of 2.0 g of [trans-4-(p-cyanophenyl)cyclohexyl]-acetaldehyde in 20 ml of t-butyl methyl ether and the mixture was stirred for a further 2 hours at room temperature. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The resulting, viscous oil was dissolved in 15 ml of ethyl acetate and the clear solution was treated with 250 ml of petroleum ether. After leaving to stand for 10 minutes at -20° C. the precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the residue (3.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 2.04 g (91%) of p-[trans-4-(3-methoxy-2-propenyl)cyclohexyl]benzonitrile as a colourless oil; Rf-value (ethyl acetate/petroleum ether vol. 10:90) 0.33.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([CH:19]=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][OH:20])[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(C=O)cccc3n2)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc(CNc2ccc3c(CO)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinoline-5-carbaldehyde (150 mg, 0.56 mmol) was dissolved in 5 mL dichloroethan. Acetic acid (136 mg, 2.3 mmol) and sodium triacetoxy borohydride (258 mg, 1.2 mmol) were added. The reaction mixture was stirred at room temperature overnight and quenched by addition of 2N sodium carbonate solution (50 mL). The mixture was extracted three times with ethyl acetate (100 mL each). The organic phases were pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a light brown solid (105 mg, 69%), MS: m/e=269.5 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCc3ccccc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4- carboxylic acid ethyl ester (10.74 g, 24.13 mmol) dissolved in TBF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.67 g (47%); off white powder; mp 203° C.; MS: 418.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:35][CH3:36])[CH:10]=1.ClC1C(C2C3C(=CC=CC=3)N(C)C=2)=NC(NC2C=C([N+]([O-])=O)C(F)=CC=2OC)=NC=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:35][CH3:36])[CH:10]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CNCCN(C)C
Agent: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 62 %

Procedure:
N1,N1,N2-trimethylethane-1,2-diamine (80 mg, 0.79 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, (which may be prepared by the method described for Intermediate 87); 350 mg, 0.79 mmol) and DIPEA (0.342 mL, 1.97 mmol) in 2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled reaction mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (230 mg, 62%) as an orange solid; 1H NMR: 2.16 (6H, s), 2.45-2.49 (2H, t, obscured by DMSO peak), 2.86 (3H, s), 3.26 (2H, t), 3.87 (3H, s), 3.95 (3H, s), 6.85 (1H, s), 7.11 (1H, t), 7.21 (1H, d), 7.25 (1H, t), 7.52 (1H, d), 8.10 (1H, s), 8.31 (1H, d), 8.33 (1H, s), 8.36 (1H, d), 8.62 (1H, s); m/z: ES+ MH+ 476.40.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2ccccc2N1
Agent: O=S(=O)(O)O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
2-Oxindole (6.5 g) was dissolved in 25 mL concentrated sulfuric acid and the mixture maintained at −10 to −15° C. while 2.1 mL of fuming nitric acid was added dropwise. After the addition of the nitric acid the reaction mixture was stirred at 0° C. for 0.5 hr and poured into ice-water. The precipitate was collected by filtration, washed with water and crystallized from 50% acetic acid. The crystalline product was then filtered, washed with water and dried under vacuum to give 6.3 g (70%) of 5-nitro-2-oxindole.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1CBr
Temperature: 25 °C

Procedure:
A stirred mixture of ethyl 2-methylbenzoate (30 grams, 0.183 mole) and N-bromosuccinimide (35 grams, 0.194 mole) in carbon tetrachloride (200 ml) was irradiated with an infrared lamp and heated at reflux for 20 minutes. The reaction mixture was allowed to cool to room temperature, then filtered. The filtrate was evaporated under reduced pressure to give ethyl 2-bromomethylbenzoate as a yellow oil.
Reaction SMILES: [C:1]1([CH3:12])[C:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:1]1[C:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1CBr

Procedure:
A mixture of 100 g. of ethyl o-toluate, 100 g. of N-bromosuccinimide, and 0.3 g. of benzoyl peroxide in 1 liter of carbon tetrachloride is heated under reflux for 3 hours with stirring and filtered. The filtrate is washed with 3% aqueous sodium hydroxide and then with water, dried over magnesium sulfate, and concentrated under reduced pressure to provide ethyl α-bromo-o-toluate as an oil.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11]O)=[C:6]([F:13])[CH:5]=1.[BrH:15]>C(OCC)C>[Br:15][CH2:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([O:3][CH:2]([F:14])[F:1])=[CH:5][C:6]=1[F:13]
Reactant: Br
Reactant: OCc1c(F)cc(OC(F)F)cc1F
Solvent: CCOCC
Product: Fc1cc(OC(F)F)cc(F)c1CBr
Temperature: 25 °C
Yield: 66.3 %

Procedure:
162 mg [4-(difluoromethoxy)-2,6-difluorophenyl]methanol (0.769 mmol, 1.0 eq.) were dissolved in 0.348 mL hydrogen bromide (2.12 mmol, 2.8 eq.). and stirred at rt over night. The reaction mixture was diluted with diethylether and stirred for 5 minutes. The aqueous layer was washed twice with diethylether. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo to provide the 149 mg (0.51 mmol, 67%) of the crude product, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4](=[O:16])[CH:3]=1.[S-:17][C:18]#[N:19].[K+].N1C=CC=CC=1.BrBr>CN(C)C=O>[NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:5][C:4](=[O:16])[C:3]=1[S:17][C:18]#[N:19]
Reactant: Nc1cc(=O)nc(SCc2ccccc2)[nH]1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#CSc1c(N)[nH]c(SCc2ccccc2)nc1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
6-Amino-2-[(phenylmethyl)thio]-4(1H)-pyrimidinone (10.5 g) [preparation as described in WO 9635678] and potassium thiocyanate (25 g) in N,N-dimethylformamide (200 ml) were heated together at 65° C. Pyridine (6.3 ml) was added and the solution cooled to 5° C. Bromine (2.2 ml) was added slowly and the reaction mixture stirred for 2 hours at 5-10° C. The reaction mixture was poured onto ice water, stirred for 1 hour and the solid was isolated by filtration. After washing with water and ether, a pure sample was obtained after trituration with hot methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)COc1cccc(N)c1
Yield: 76.1 %

Procedure:
A solution of (3-nitrophenoxy)-acetic acid ethyl ester (500 mg, 2.22 mmol) in methanol (20 ml) was hydrogenated over 10% Pd—C (50 mg) at atmospheric pressure until no further gas uptake was observed. The reaction mixture was then filtered over celite and concentrated to yield a residue which was purified over neutral alumina using ethyl acetate-hexane to give (3-amino-phenoxy)-acetic acid ethyl ester (330 mg, 77%) as oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:19][C:18]4[C:13](=[N:14][C:15]([F:21])=[N:16][C:17]=4[NH2:20])[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C(=O)N([I:29])C(=O)C1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:11]([CH2:10][C:8]3[C:7]([I:29])=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12]2)=[C:17]([NH2:20])[N:16]=1
Reactant: Nc1nc(F)nc2nc(Cc3ccc4c(c3)OCO4)[nH]c12
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(F)nc2nc(Cc3cc4c(cc3I)OCO4)[nH]c12

Procedure:
A solution of 8-Benzo[1,3]dioxol-5-ylmethyl-2-fluoroadenine (50 mg, 0.17 mmol), NIS (94 mg, 0.4 mmol), TFA (20 mg, 13.4 L, 0.17 mmol) in CH2Cl2 (200 L) was stirred at room temperature overnight. After solvent removal, the desired product 18 (6 mg, 8.5%) was purified by silica gel column chromatography (CHCl3:EtOAc at 9:1 to 4:6). 1H NMR (400 MHz, DMSO-d6) 7.6 (bs, 2H), 7.38 (s, 1H), 6.95 (s, 1H), 6.03 (s, 2H), 4.12 (s, 2H); MS m/z 414.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH:34](=O)[CH:35]([CH3:37])[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:34][CH:35]([CH3:37])[CH2:36][NH:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CNc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichlorothane. Acetic acid (8 μL, 0.14 mmol) followed by isobutyraldehyde (11.7 μL, 0.13 mmol) and solid NaBH(OAc)3 (37.3 mg, 0.18 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 16.1 mg (29%) of the desired 3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C22H26F7N2O2: 483.1883 [M+H]+, found: 483.1932. 1H NMR (CDCl3) δ1.0 (m, 6H), 2.0 (m, 1H), 3.0 (m, 2H), 3.6 (dd, 1H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.7 (d, 1H), 6.9-7.4 (m, 6H).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([NH2:10])=O)[CH2:4][CH2:3]1.[Li+].[BH4-]>C1COCC1>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([CH2:8][NH2:10])[CH2:4][CH2:3]1
Reactant: NC(=O)C1CCC(F)(F)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of compound 4,4-difluorocyclohexanecarboxamide (1.8 g, 13 mmol) in 100 mL THF was added LiBH4 (1.1 g, 50 mmol) under N2 stirred for overnight. Then the reaction mixture was refluxed for 4 h. After cooled to r.t, it was poured into ice-water slowly. After filtration, the product was extracted with DCM from filtrate. Combined organic layers washed with water, brine, dried over Na2SO4, filtered and condensed to afford compound (4,4-difluorocyclohexyl)methanamine (0.8 g, crude) as a colorless oil.