Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][CH:14]([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:18]=[CH:19][C:20]([NH:22]C(=O)C)=[CH:21][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>Cl.CCO>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][CH:14]([F:17])[CH2:15][CH2:16]2)[C:8]2[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)CC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCC(F)CC1

Procedure:
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}acetamide (190 mg, 0.550 mmol) was heated in 5 mL of 2 M HCl/EtOH (1:1) at 120° C. for 1 h using a Personal Chemistry microwaves apparatus. The solvent was evaporated. The residue was basified with 2M NaOH and extracted (3×) with EtOAc. The organic phase washed with saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The solvent was evaporated. Yield: 154 mg (92%). 1H NMR (400 MHz, CD3OD) δ 1.28-1.39 (m, 2 H), 1.41-1.50 (m, 1 H), 1.53-1.59 (m, 1 H), 1.61-1.64 (m, 9 H), 1.69 (d, J=7.81 Hz, 2 H), 1.95-2.22 (m, 3 H), 4.37-4.83 (m, 3 H), 7.11-7.13 (m, 1 H), 7.15-7.18 (m, 1 H), 7.67-7.73 (m, 1 H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[OH:10][N:11]=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:13]#[N:14].C(N(CC)CC)C.O>C1C=CC=CC=1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2]([O:10][N:11]=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:13]#[N:14])=[O:3]
Reactant: N#CC(=NO)c1ccccc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: N#CC(=NOC(=O)OCC(Cl)(Cl)Cl)c1ccccc1
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A solution of 2,2,2-trichloroethyl chloroformate (2.2 g.) in benzene (10 ml.) was added dropwise to a solution of 2-hydroxyimino-2-phenylacetonitrile (1.5 g.) and triethylamine (1.40 ml.) in benzene (20 ml.) at room temperature, the mixture was stirred for 3 hours at the same temperature. Benzene and water were added to the reaction mixture layer was washed with water and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized by adding a small of ether and n-hexane. The crystals were collected by filtration and recrystallized from methanol to give 2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-phenylacetonitrile (2.7 g.), mp 82° to 84° C.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=3)[C@:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:15]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Br:24][C:20]1[CH:19]=[C:18]([C@@H:17]2[C@:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:15]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:40])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Br)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Br)c2)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 58.7 %

Procedure:
To a solution of rac-4-{[(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 340 (0.15 g, 0.25 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (1 N) of NaOH (9 mL, 9 mmol) and methanol (3 mL). The reaction mixture was heated at 80° C. for 2 h, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid as a white solid (90 mg, 60%).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C:31]([CH:41]=[O:42])([CH2:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C:31]([CH:41]([C:8]2[S:9][C:10]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=2)[OH:42])([CH2:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:30]1)=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(CC2CCOCC2)C1
Reactant: Fc1cccc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(CC2CCOCC2)(C(O)c2cc3cccc(F)c3s2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
To a solution of 7-fluoro-benzothiophene (0.22 g, 1.44 mmoles) in anhydrous tetrahydrofuran (10 ml) at −78° C. was added dropwise a solution of n-BuLi in hexane (1.6M, 0.9 ml, 1.44 mmoles). The reaction mixture was stirred at −78° C. for one hour, and then a solution of 3-formyl-3-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g, 1.01 mmoles) in anhydrous tetrahydrofuran (5 ml) was then added. The reaction mixture was stirred at −78° C. for 3 hours, quenched with saturated aqueous ammonium chloride, and partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10 to 45% ethyl acetate in hexane) to yield 3-[(7-Fluoro-benzo[b]thiophen-2-yl)-hydroxy-methyl]-3-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless semisolid (0.138 g, 30%). MS=450 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1
Reactant: COC(=O)c1c[nH]c2ncccc12
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccccn2)c2ncccc12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (22.70 mg, 0.568 mmol, 60% suspension in mineral oil) was added to a solution of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate (100 mg, 0.568 mmol) in DMF (1419 μl) at RT. After 10 min, 2-fluoropyridine (48.8 μl, 0.568 mmol) was added to the mixture and the mixture was heated at 100° C. for 14 h. After being cooled to RT, the reaction mixture was directly purified by HPLC followed by neutralization (aq. NaHCO3) to afford the title compound as a colorless film.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:34])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([Cl:33])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:10][N:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:33][C:25]1[CH:24]=[C:23]([C@@H:16]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:15]([NH:14][C:11]2[N:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)=[O:34])[CH:28]=[CH:27][C:26]=1[S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(=O)O)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 98.7 %

Procedure:
A solution of 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid tert-butyl ester (3.29 g, 6.48 mmol) in methylene chloride (30 mL) was treated with trifluoroacetic acid (60 mL) and stirred at 25° C. for 65 min. The reaction solution was then concentrated in vacuo The resulting oil was diluted with ethyl acetate (500 mL), washed with water (2×250 mL) and a saturated aqueous sodium chloride solution (5×250 mL), dried over sodium sulfate, treated with decolorizing carbon, filtered through a pad of celite, and concentrated in vacuo to afford the 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid (2.89 g, 99%) as a light yellow foam: mp 121–127° C.; (ES)+-HRMS m/e calcd for C20H22ClN3O5S (M+H)+ 452.1042, found 452.1046. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][OH:13].[OH-].[Na+].S(OC)(O[CH3:20])(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[CH2:12][O:13][CH3:20]
Reactant: OCc1cc(C(F)(F)F)ccc1Cl
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
A mixture of (2-chloro-5-(trifluoromethyl)phenyl)methanol (COK) (11.55 g, 55 mmol), NaOH (8.00 g, 200 mmol) and dimethyl sulfate (6.25 mL, 65 mmol) in THF (100 mL) was stired for 5 hours at room temperature. The reaction was quenched with water (20 mL) and 25% ammonia (5 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was purred into water (100 mL) and extracted with petroleum ether (100 mL). The organic phase was washed with 1 M NaOH (aq) (100 mL), water (3×100 mL), brine (50 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to yield 1-chloro-2-(methoxymethyl)-4-(trifluoromethyl)benzene (COMK) as a colorless oil (11.54 g, 94%): 1H NMR (CDCl3) 3.50 (s, 3H), 4.57 (s, 2H), 7.46 (m, 2H), 7.77 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]([OH:20])([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.CCOC(C)=O>C(Cl)Cl.C(Cl)(Cl)Cl.CC(O)=O>[CH2:1]([O:8][C:9]([C:10]1([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:11][C:12](=[O:13])[O:20]1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=CCC(O)(CC(=O)O)C(=O)OCc1ccccc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)=CCC1(C(=O)OCc2ccccc2)CC(=O)O1
Reaction time: 1 h

Procedure:
A solution of hydroxyester 75 (100 mg, 0.342 mmol, 1.00 equiv) and triethylamine (166 μL, 1.20 mmol, 3.50 equiv) in CH2Cl2 (14 mL) was added via syringe pump over 4 h to a solution of 2,4,6-trichlorobenzoyl chloride (80 μL, 0.51 mmol, 1.5 equiv) and N,N-dimethylaminopyridine (DMAP) (46 mg, 0.38 mmol, 1.1 equiv) in CH2Cl2 (3.4 mL). The solution was then allowed to stir for 1 h after complete addition after which time it was quenched with H2O (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×10 mL). The organic phases were combined, dried over Na2SO4, and the solvent was removed via rotary evaporation to yield a red solid which was purified by silica gel column chromatography (CH2Cl2) to yield S10 (47 mg, 50%) as a pale yellow oil. Rf=0.79 (60:38:2 Hex:EtOAc:HOAc); 1H NMR (500 MHz, CDCl3) δ 7.37 (m, 5H, ArH), 5.25 (s, 2H, ArCH2), 5.09 (m, 1H, vinyl H), 3.61 (d, 1H, J=16.4 Hz, C(O)CH2), 3.36 (d, 1H, J=16.4 Hz, C(O)CH2), 2.79 (m, 2H, CHCH2), 1.70 (d, 3H, J=0.8 Hz, CH3), 1.60 (d, 3H, J=0.8 Hz, CH3); 13C NMR (100 MHz, CDCl3) δ 169.21, 165.84, 138.67, 134.67, 128.68, 128.38, 114.24, 76.28, 67.84, 45.56, 33.43, 25.87, 17.99; IR (neat film) 2966 (m), 2914 (m), 1842 (s), 1737 (s), 1452 (m) 962 (m) cm−1; HRMS (EI) m/z calcd for C16H18O4 (M+) 274.120509, observed 274.120646; [α]D=+1.2° (c 2.92, CHCl3).
Reaction SMILES: I[Si](C)(C)C.[CH2:6]([O:8][C:9]([C@@H:11]1[C@H:16]([NH:17]C(OCC2C=CC=CC=2)=O)[CH2:15][CH2:14][N:13]([CH2:28][CH2:29][S:30][C:31]2[CH:40]=[N:39][C:38]3[C:33](=[CH:34][C:35]([O:41][CH3:42])=[CH:36][CH:37]=3)[N:32]=2)[CH2:12]1)=[O:10])[CH3:7]>ClCCl>[CH2:6]([O:8][C:9]([C@@H:11]1[C@H:16]([NH2:17])[CH2:15][CH2:14][N:13]([CH2:28][CH2:29][S:30][C:31]2[CH:40]=[N:39][C:38]3[C:33](=[CH:34][C:35]([O:41][CH3:42])=[CH:36][CH:37]=3)[N:32]=2)[CH2:12]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)[C@H]1CN(CCSc2cnc3ccc(OC)cc3n2)CC[C@H]1NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CN(CCSc2cnc3ccc(OC)cc3n2)CC[C@H]1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 59.8 %

Procedure:
Iodotrimethylsilane (26 μL, 0.18 mmol, 2.0 eq) is added at 0° C. to a stirred solution of (3S,4R)-4-benzyloxycarbonylamino-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester (50 mg, 0.09 mmol, 1.0 eq) in dichloromethane (5 mL). After 2 hours stirring at 0° C. and 4 hours at room temperature, the reaction mixture is quenched with methanol (2 mL) and extracted with dichloromethane (3×5 mL) and a 0.1N hydrochloric acid aqueous solution (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford (3S,4R)-4-amino-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester as a yellow oil (21 mg, 55% yield).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=3)[CH:18]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+].C(=O)(O)[O-].[Na+].Cl>CO>[CH:22]([C:19]1[N:17]2[CH:18]=[C:13]([O:12][CH:9]3[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:25])=[O:3])[CH2:7][CH2:8]3)[CH:14]=[CH:15][C:16]2=[N:21][N:20]=1)([CH3:24])[CH3:23]
Reactant: CCOC(=O)CC1CCC(Oc2ccc3nnc(C(C)C)n3c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nnc2ccc(OC3CCC(CC(=O)O)CC3)cn12
Yield: 59 %

Procedure:
A solution of Example 22 step a (50 mg, 0.145 mmol) and 1N sodium hydroxide (0.5 mL, 0.5 mmol) in MeOH (2 mL) was stirred at RT for 16 h. The reaction mixture was treated with sat. aq. sodium bicarbonate, evaporated to dryness, and purified on a reverse phase FCC (water/MeOH 100/0.0 to 0/100) to give two fractions. The first eluting fraction was acidified to pH 5 with 1N HCl solution and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, combined with the second eluting fraction from chromatography and concentrated in vacuo. The resulting residue was dissolved in MeOH/EtOAc (1:1, 10 mL), filtered and evaporated to dryness to give the title compound as a pale brown solid (27 mg, 59%). LCMS (Method 5): Rt 3.58-3.65 min, m/z 318 [MH+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][S:26]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27].CC(C)([O-])C.[K+].Cl>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]([CH2:25][S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:20]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(OC2CCCN(Cc3ccccc3)C2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: -40 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
A mixture of 1-benzyl-3-(4-nitrophenoxy)piperidine (1.0 g, 3.14 mmoles) and 1-chloromethanesulfonylnaphthalene (0.9 g, 3.8 mmoles) in THF at −78° C. was treated dropwise with a solution of 1M potassium t-butoxide (9 mL, 9 mmoles) over a 30 minute period, warmed to −40° C., stirred at −40° C. for 5 hours, poured into cold 2N HCl and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum. The resultant residue was purified by normal phase HPLC on a silica column, using as eluent 40% EtOAc/hexane, to afford the title compound as an off-white solid (1.2 g, 2.3 mmoles).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[C:7](O)=[O:8].O>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)[S:5][C:6]=1[CH2:7][OH:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Yield: 97.8 %

Procedure:
10.0 g of 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid were dissolved in 50 ml tetrahydrofuran under an atmosphere of argon. 69.7 ml of boran-tetrahydrofuran complex (1 molar solution in tetrahydrofuran) was added and the mixture refluxed for three hours. Water was added to the cooled reaction mixture and the solvent removed in vacuo. The residue was extracted five times with 50 ml portions of ethyl acetate. The combined extracts were dried over MgSO4. The solvent was removed in vacuo to obtain 9.3 g of [4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC(OC(C)C)=O>>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)C)CC2)cc1

Procedure:
4-[4-(4-Acetylamino-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester was prepared was prepared according to General Procedure D by the reaction of 4-[4-(4-acetylamino-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 70) with trifluoroacetic acid, followed by reaction of the resulting amine with isopropyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]2[N:27]=[C:26]([O:28][C@@H:29]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[CH2:14]3)=[N:10][CH:9]=2)[CH:5]=[C:4]([NH:21][C:22]2[N:27]=[C:26]([O:28][C@@H:29]3[CH2:33][CH2:32][NH:31][CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(O[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(O[C@@H]3CCNC3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reaction time: 1 h

Procedure:
tert-Butyl (3R)-3-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]-phenyl}amino)pyrimidin-4-yl]oxy}pyrrolidine-1-carboxylate (80 mg, 0.14 mmol) was taken up in dichloromethane (1 mL). The mixture was treated with trifluoroacetic acid (0.2 mL, 2.6 mmol) and left to stir for 1 hour. The reaction was neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (×3). The combined organics were washed with brine, dried over sodium sulfate, concentrated, and purified by Combiflash (methanol/dichloromethane) to provide 4-{5-[3-methyl-5-({4-[(3R)-pyrrolidin-3-yloxy]-pyrimidin-2-yl}amino)phenyl]-1,3-thiazol-2-yl}-1,4-diazepan-2-one. MS APCI: [M+H]+ m/z 466.1. 1H NMR (500 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.22 (d, J=5.6, 1H), 7.63 (m, 2H), 7.49 (s, 1H), 7.38 (s, 1H), 6.96 (s, 1H), 6.25 (d, J=5.6, 1H), 5.56 (s, 1H), 4.16 (s, 2H), 4.10 (s, 1H), 3.80 (s, 2H), 3.44-3.05 (m, 5H), 2.27 (s, 3H), 2.21 (m, 1H), 2.06 (m, 1H), 1.77 (m, 2H). rhSyk=+++
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:23]=[C:22]([Cl:24])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:23]=[C:22]([Cl:24])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccccc1
Product: Clc1cc2c(NCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].CS(C)=O.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1.Br[CH2:21][CH2:22][CH2:23]Br>CC(OC)(C)C>[F:7][C:8]([F:18])([F:19])[C:9]1[CH:10]=[C:11]([C:15]2([C:16]#[N:17])[CH2:23][CH2:22][CH2:21]2)[CH:12]=[CH:13][CH:14]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
The mixture of sodium hydride (1.312 g, 54.7 mmol) and DMSO was stirred for about 10 minutes at room temperature. Then a solution of 2-(3-(trifluoromethyl)phenyl)acetonitrile (5 g, 24.86 mmol) and 1,3-dibromopropane (5.02 g, 24.86 mmol) in MTBE (80 mL) was added dropwise via dropping funnel. After addition, the mixture was stirred for about 12 hours, and quenched with 60 mL of water. The aqueous phase was extracted with MTBE (3×30 mL). The combined organic layers were washed with water (3×30 mL) and brine (3×30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel column (20:1 Hexanes/ethyl acetate) to obtain the title compound as a transparent liquid (3.8 g, 63.4%). LC-MS: m/z (M+H) 226.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]#[N:11])[CH:5]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Al]>C1COCC1.O>[CH:24](=[N:11][CH2:10][CH2:9][N:6]1[CH2:7][CH2:8][N:4]([CH2:3][CH2:1][N:2]=[CH:5][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: N#CCN1CCN(CC#N)C1c1ccccc1
Agent: [Al+3]
Agent: [Al]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: C(=NCCN1CCN(CCN=Cc2ccccc2)C1c1ccccc1)c1ccccc1
Temperature: 20 °C
Yield: 32 %

Procedure:
This Example demonstrates the reduction of (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile (5) with LiAlH4 and protection using benzaldehyde. As shown in Scheme 3, a solution of 1 equivalent of (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile (5) was added to a solution of 3 equivalents of LiAlH4 in THF at about −30° C. The reaction mixture was warmed to about 20° C. over 80 minutes, whereupon thin-layer chromatography showed complete conversion. The reaction mixture was treated with water (vigorous, exothermic reaction with H2-evolution) and aluminum salts were removed by filtration. Isolation of the amine intermediate 2-[3-(2-Amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine (8) as a pure compound was not readily achieved. To add protecting groups and allow isolation the amine intermediate (8) was reacted in situ with 2.2 equivalents of benzaldehyde after aqueous quench. After work-up and crystallization from acetonitrile, crystalline benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine (7) was obtained in 32% yield and with a purity of 95.8 area % by gas chromatography.