Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH:6]=[CH2:7].[C:12]([Cl:16])(Cl)(Cl)[Cl:13].[OH2:17]>N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:13][C:12]([Cl:16])=[CH:7][CH:6]1[O:17][C:3](=[O:10])[CH2:4][C:5]1([CH3:9])[CH3:8]
Reactant: ClC(Cl)(Cl)Cl
Reactant: C=CC(C)(C)CC(=O)N(C)C
Reactant: O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl
Reaction time: 1.5 h

Procedure:
31 g (0.2 mole) of 3,3-dimethyl-pent-4 -enoic acid, N,N-dimethylamide are added dropwise, in the course of 3 hours, to a solution of 1 g of azo-bis-isobutyronitrile in 308 g (2 moles) of carbon tetrachloride at 75°-80° C. The mixture is stirred for 1.5 hours at 75°-80° C., a further 1 g of azo-bis-isobutyronitrile is added, and the temperature is maintained for a further 2 hours. After distilling off the unconverted starting materials at a bath temperature not exceeding 150° C., a residue is left, and this is stirred with 100 ml of water at 80°-90° C. for 1 hour. 17 g (0.08 mole) of 5-(2,2-dichlorovinyl)-4,4-dimethyl-tetrahydrofuran-2-one are thereby obtained as a water-insoluble phase.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH:26]=O)[CH:7]=1)[CH3:2].C(OC(=O)CC1C=C(C(F)(F)F)C=C(OC2C=CC([N+]([O-])=O)=CC=2CO)C=1)C.[F:57][C:58]([F:62])([F:61])[CH2:59][SH:60]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH2:26][S:60][CH2:59][C:58]([F:62])([F:61])[F:57])[CH:7]=1)[CH3:2]
Reactant: FC(F)(F)CS
Reactant: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2C=O)cc(C(F)(F)F)c1
Agent: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2CO)cc(C(F)(F)F)c1
Product: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)cc(C(F)(F)F)c1

Procedure:
[3-(2-Formyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester was reduced to [3-(2-hydroxymethyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester according to the procedure described in Example 21, Step 6 and then brominated as described in Example 21, Step 7 and then treated with 2,2,2-trifluoroethanethiol to give {3-[4-Nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester. The amine was reduced as described in Example 21, Step 9, and then treated with pivaloyl chloride as described in Example 21, Step 10 to provide {3-[4-(2,2-Dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester as described in Example 21, Step 11 provided the acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)(O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(O)c1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(Cl)ccc2C1c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Crude rac-6-chloro-3-(4-chloro-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one (from Example 7a supra) was suspended in a mixture of triethylsilane (5 mL, 31.3 mmol) (Aldrich) and trifluoroacetic acid (12.5 mL) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate (100 mL) and treated with solid sodium carbonate (10.5 g). After stirring for 30 minutes, mixture was extracted with water (2×100 mL) and brine (100 mL). Aqueous layers were back washed with ethyl acetate (100 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from ethyl acetate-hexanes to give rac-6-chloro-3-(4-chloro-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 2.20 g, 79.1% over two steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[N:10]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[C:11]=S>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:11]([NH:10][CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1N
Reactant: S=C=NC1CCCc2ccccc21
Product: Fc1ccc2nc(NC3CCCc4ccccc43)[nH]c2c1

Procedure:
The title compound was prepared from 4-fluorophenylenediamine and 1-isothiocyanato-1,2,3,4-tetrahydronaphthalene by Procedure D. The title compound was isolated by column chromatography as the free base and as a mixture of enantiomers (solid, mp 220-221° C.). MS(ES+) m/z 282 ([M+1]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:68][C:69]1[CH:82]=[CH:81][C:72]([CH2:73][S:74][CH2:75][C@H:76]([C:78]([OH:80])=[O:79])[NH2:77])=[CH:71][CH:70]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:77][C@@H:76]([C:78]([OH:80])=[O:79])[CH2:75][S:74][CH2:73][C:72]3[CH:81]=[CH:82][C:69]([CH3:68])=[CH:70][CH:71]=3)=[O:36])=[O:31])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: Cc1ccc(CSC[C@@H](N)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(CSC[C@@H](NC(=O)CNC(=O)COc2ccc([C@@H]3[C@@H](SCC(O)c4ccc(F)cc4)C(=O)N3c3ccc(F)cc3)cc2)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine, (19.9 mg, 0.037 mmol) in DMF (2.0 ml) was added N-methylmorpholine (15 μl, 0.14 mmol). TBTU (14.4 mg, 0.045 mmol) was added and the mixture was stirred at 30° C. for 45 minutes. S-(4-methylbenzyl)-D-cysteine (10.5 mg, 0.047 mmol) was added and the mixture was stirred at 30° C. for 1 hour. The formation of the ketone of the title compound was confirmed. M/z: 748.02 (M+1). Methanol (2 ml) and sodium borohydride (14.7 mg, 0.39 mmol) were added the mixture was stirred for 30 minutes. Ammonium acetate (20 mg) was added and the methanol was removed under reduced pressure. The remaining DMF-solution was purified with preparative HPLC on a C8 column, UV-detection 240/260 nm. A gradient from 20 to 50% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The combined organic phases were concentrated and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (8.7 mg, 31.5%). H-NMR (400 MHz, DMSO-d6): 2.24 (s, 3H), 2.60-2.68 (m, 1H), 2.72-2.79 (m, 1H), 2.86-2.94 (m, 2H), 3.68 (s, 2H), 3.82 (d, 2H), 4.25 (d, 0.5H), 4.27 (d, 0.5H), 4.39-4.46 (m, 1H), 4.52 (s, 2H), 4.67-4.77 (m, 1H), 5.03 (d, 0.5H), 5.06 (d, 0.5H), 5.60-5.67 (bs, 1H), 6.98 (d, 2H), 7.05-7.18 (m, 8H), 7.20-7.25 (m, 2H), 4.30-4.39 (m, 4H), 8.23-8.32 (m, 2H), 12.80-12.95 (bs, 1H). M/z: 748.04 (M−1).
Reaction SMILES: C([O:4][CH:5]1[CH:10]=[CH:9][CH2:8][N:7]([C:11](=[O:24])[C@@H:12]([CH:21]([CH3:23])[CH3:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6]1)(=O)C.[OH-].[Na+].C(O)(=O)C.C(Cl)(Cl)Cl>CCO>[C:14]([NH:13][C@@H:12]([C:11]([N:7]1[CH2:8][CH:9]=[CH:10][CH:5]([OH:4])[CH2:6]1)=[O:24])[CH:21]([CH3:23])[CH3:22])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(=O)OC1C=CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CC(O)C1

Procedure:
0.254 g of 3-acetoxy-N—(N-BOC-(R)-valyl)-1,2,3,6-tetrahydropyridine, dissolved in 5 ml of EtOH are treated with 2N ethanolic NaOH under ice-cooling. To the mixture obtained acetic acid is added in order to neutralize the reaction mixture and solvent is evaporated. The evaporation residue obtained is mixed with CHCl3, the mixture obtained is washed with NaCl-solution, the organic phase is dried and solvent is evaporated. N—(N-BOC-(R)-valyl)-1,2,3,6-tetrahydropyridin-3-ol is obtained. 1H-NMR: 5.9(m,2H,HIV, HV), 4.51, 4.45(2xdd,1H, NHCHCO,J=5.2 Hz,J=9.0 Hz), 1.4 (b,9H,(CH3)3), 0.9(m,6H,CH(CH3)2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([OH:28])=O)[CH:20]=[N:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:41][N:42](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN.Cl>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:40])=[C:4]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([NH:42][CH3:41])=[O:28])[CH:20]=[N:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[CH:36][CH:37]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ncc(CC(=O)O)cc1-c1cc2c(n1C(C)C)C(c1ccc(C#N)cc1)N(c1cccc(Cl)c1F)C2=O
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)Cc1cnc(OC)c(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cccc(Cl)c2F)C3=O)c1

Procedure:
A mixture of {5-[5-(3-chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-6-methoxy-pyridin-3-yl}-acetic acid (Step 85.1) (0.054 mmol), HATU (0.161 mmol), NMM (0.215 mmol) and methylamine.HCl (0.081 mmol) in DMF (0.5 mL) at rt was stirred for 2 h. The reaction mixture was diluted with EtOAc and successively washed with a saturated aqueous solution of NaHCO3 (2×) and brine, dried (MgSO4), filtered and concentrated. The residue was purified using a silica gel column to afford the title compound as a white solid. tR: 4.96 min (HPLC 4); ESI-MS: tR=1.02 min, [M+H]+ 572/574 (LC-MS 1).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[S:26]1CC(O)S[CH2:28][CH:27]1O.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[NH2:5][C:4]1[S:26][CH:27]=[CH:28][C:3]=1[C:2]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[CH:10][CH:11]=1)=[O:1]
Reactant: OC1CSC(O)CS1
Reactant: COc1cc(CCc2ccc(C(=O)CC#N)cc2)cc(OC)c1OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(CCc2ccc(C(=O)c3ccsc3N)cc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 1.35 g of the compound prepared in (a) above in 8 ml of dry N,N-dimethylformamide was added, successively and under a nitrogen atmosphere, 0.6 g (4 mmol) of 1,4-dithiane-2,5-diol and 0.14 ml (1 mmol) of triethylamine, and the resultant mixture was heated to 50° C. and maintained at this temperature for 4 hours. After cooling the reaction mixture to 25° C., it was diluted with ethyl acetate and the resultant solution was washed successively with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to yield a crude product which was purified on silica gel employing a mixture of ethyl acetate and hexane in a 1:1 ratio as the eluent to yield a yellow foam.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([Cl:18])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OC)(C)(C)C>O.CS(C)=O>[Cl:17][C:16]1[C:6]([CH2:5][C:1]#[N:2])=[C:7]([C:13]([Cl:18])=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)ccc(Cl)c1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=O)c1c(Cl)ccc(Cl)c1CC#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
A solution of sodium cyanide (75.12 g, 1.53 mol) in water (300 mL) was added dropwise to a solution of ethyl 2-(bromomethyl)-3,6-dichlorobenzoate (253c, 320 g, 1.03 mol) in dimethylsulfoxide (2.4 L) at room temperature. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into a mixture of water (4 L) and methyl tert-butyl ether (2 L), and the layers separated. The organic layer was washed with water (2 L) and with saturated aqueous sodium chloride solution (2 L), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 30:1 petroleum ether/ethyl acetate), affording ethyl 3,6-dichloro-2-(cyanomethyl)benzoate (253d, 150 g, ˜75% pure, 47% yield) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>[Cu](I)I.CN(C=O)C>[CH3:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc2c(Br)cccc2n1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cc1ccc2c(C#C[Si](C)(C)C)cccc2n1
Temperature: 110 °C
Yield: 90 %

Procedure:
In a sealed tube were introduced 5-bromo-2-methyl-quinoline (1.0 g, 4.5 mmol, 1.0 eq), PdCl2(PPh3)3 (154 mg, 0.22 mmol, 5% mol), copper iodide (42 mg, 0.22 mmol, 5% mol), and triphenylphosphine (236 mg, 0.9 mmol, 20% mol). Then, DMF (10 mL) was added followed by diethylamine (9.5 mL, 68 mmol, 15 eq) and trimethylsilylacetylene (700 μL, 5.0 mmol, 1.1 eq). The mixture was heated at 110° C. overnight. After cooling down the solvent was evaporated and the crude product was purified by column chromatography (Florisil, Cyclohexane-EtOAc 95:5) to afford 2-methyl-5-trimethylsilanylethynyl-quinoline as a white solid (970 mg, 90%).
Reaction SMILES: [CH:1]12[N:9]([C:10]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=4)[N:13]=[C:12]4[N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:24]=[CH:25][C:11]=34)[CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][O:3][CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.[N:45]([C:48]1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C4COCC3COC4)N=2)=CC=1)=[C:46]=[O:47]>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH:5]12[N:9]([C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([NH:20][C:46]([NH:45][CH3:48])=[O:47])=[CH:21][CH:22]=4)[N:13]=[C:12]4[N:23]([CH2:26][C:27]([F:29])([F:28])[F:30])[N:24]=[CH:25][C:11]=34)[CH:1]([CH2:2][O:3][CH2:4]1)[CH2:8][O:7][CH2:6]2
Reactant: O=C=Nc1ccc(-c2nc(N3C4COCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: Nc1ccc(-c2nc(N3C4COCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(-c2nc(N3C4COCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
A solution of 4-(4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (47 mg, 0.11 mmol) in dichloromethane (2 mL) was treated triethylamine (140 μL), followed by triphosgene (25 mg, 0.08 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1.1 mL)—was added to the 9-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 1-(4-(4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea. MS (ES+): 478.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[C:4](Cl)[N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1
Reactant: Nc1ncc(-c2cc(Cl)nc(Cl)n2)cn1
Reactant: C1COCCN1
Solvent: CC#N
Product: Nc1ncc(-c2cc(N3CCOCC3)nc(Cl)n2)cn1

Procedure:
According to Method 6, the reaction of 2,6-dichloro-4,5′-bipyrimidin-2′-amine with morpholine in acetonitrile gave 2-chloro-6-morpholino-4,5′-bipyrimidin-2′-amine. LCMS (m/z): 293.0 (MH+); Rt 1.92 min.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:6]1.[Li+].[OH-]>C1COCC1.O.Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:28])=[O:2])[CH2:6][CH:7]2[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)CC1CCN(c2ccc(Cl)cc2)C(c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCN(c2ccc(Cl)cc2)C(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.1 %

Procedure:
A solution of methyl{1-(4-chlorophenyl)-2-[4(trifluoromethyl)phenyl]piperidine-4-yl}acetate (34 mg, 0.08 mmol) in THF (2 ml) and H2O (2 ml) was treated with LiOH (19 mg, 0.8 mmol) and the mixture was stirred at room temperature for 20 hours. The reaction was diluted with hydrochloric acid (1N, 20 ml) and extracted with EtOAc (2×20 ml). The combined extracts were washed with brine (×1), then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 7.5% MeOH/DCM give the acid as a clear gum (15 mg, 45%). 1H NMR (400 MHz, CD3OD) δ: 1.34-1.40 (1H, m), 1.54-1.67 (1H, m), 1.84-2.12 (3H, m), 2.24-2.30 (2H, m), 2.86 (1H, dt, J 12.1, 2.4), 3.47-3.54 (1H, m), 4.15 (1H, dd, J 11.5, 2.7), 6.95 (2H, d, J 8.8), 7.06 (2H, d, J 8.8), 7.44 (4H, s).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([O:16][CH3:17])(=[O:15])[C:12]([CH3:14])=O.S([O-])([O-])(=O)=O.[Mg+2].[H][H]>CO.[Pd]>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][CH:12]([CH3:14])[C:11]([O:16][CH3:17])=[O:15]
Reactant: [H][H]
Reactant: COC(=O)C(C)=O
Reactant: Nc1ccc(F)c(F)c1F
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Yield: 95.3 %

Procedure:
2,3,4-Trifluoroaniline (2.94 g) and methyl pyruvate (2.04 g) were dissolved in methanol (30 ml). After adding 5% Pd—C (2.0 g) and anhydrous magnesium sulfate (2.65 g), the mixture was stirred at 50° C. in a hydrogen atmosphere for 16 hours. After filtering off Pd—C and magnesium sulfate, the obtained filtrate was concentrated under reduced pressure. The crystals thus precipitated were filtered while washing with hexane. Thus the title compound (4.44 g) was obtained as slightly yellowish crystals. Various spectral data of this product was identical with those obtained in Example 5.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=2[CH3:16])[N:17]=1
Reactant: CC(=O)Nc1cc(C)c(C(=O)CBr)c(C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: CC(=O)Nc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 86.5 %

Procedure:
A mixture of N-(4-(2-bromoacetyl)-3,5-dimethylphenyl)acetamide (7.34 g, 25.8 mmol) and thiourea (1.97 g, 25.9 mmol) in 95% EtOH (36.9 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (50 mL). The solids were filtered and dried under vacuum to give N-(4-(2-aminothiazol-4-yl)-3,5-dimethylphenyl)acetamide (5.83 g) as yellow solids in 86% yield: 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1 H), 7.26 (s, 2 H), 6.90 (bs, 2 H), 6.30 (s, 1 H), 2.06 (s, 6 H), 2.02 (s, 3 H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][CH:9]2O)=[CH:5][CH:4]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:20][NH2:21].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.C(OCC)(=O)C>[F:15][C:16]([F:29])([F:30])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1)[CH2:20][NH:21][CH2:9][C:10]1[CH:11]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: OC1OCc2ccc(C(F)(F)F)cc21
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: OCc1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
6-Trifluoromethyl-1,3-dihydro-isobenzofuran-1-ol (4.12 g) is dissolved in 1,2-dichloroethane (75 ml), and thereto are added 3,5-bis-trifluoromethyl-benzylamine (5.89 g), triacetoxy-sodium borohydride (9.0 g) and acetic acid (2.3 ml), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) to give {2-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-methanol (7.06 g). MS (m/z): 432 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].CO[C:19]([CH3:21])=[CH2:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CCOC(C)=O.C(O)(=O)C>[CH3:10][C:9]([CH3:11])([CH3:12])[C:8]#[C:7][C:5]1[S:4][C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]([NH:1][CH:19]([CH3:21])[CH3:20])[CH:6]=1
Reactant: C=C(C)OC
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Methyl 3-amino-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate (see WO 2008058393) (12.0 g, 50.6 mmol) in dichloromethane (150 mL) was placed in a cool water bath (12 deg C.) and treated dropwise with 2-methoxyprop-1-ene (14.6 mL, 152 mmol) over about 6 minutes followed by acetic acid (8.7 mL) over about 5 minutes. Sodium triacetoxyborohydride (16.1 g, 152 mmol) was added portionwise over about 30 minutes. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 h. The resulting light orange solution was poured into cold sodium bicarbonate (sat aq, 200 mL). The organic layer was separated and the aqueous layer was extracted twice with dichloromethane (150 mL each). The combined organic layers were washed with sodium bicarbonate (sat aq) and brine, dried over sodium sulfate (anhyd), filtered and concentrated to an orange oil. Silica gel chromatography (0-15% EtOAc:Hex) afforded 13.0 g (92% yield) of the desired methyl 5-(3,3-dimethylbut-1-ynyl)-3-(isopropylamino)thiophene-2-carboxylate as a light yellow oil which solidified upon standing to a waxy crystalline solid, and was used in the subsequent step.