Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:49]([O:56][C:57](=[O:60])[CH2:58]Br)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:37])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:58][C:57]([O:56][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:60])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccccc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 6.2 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester 80 ml of DMF, 4.3 g of cesium carbonate and 2.5 g of Bromo-acetic acid benzyl ester was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 4.4 g.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]2[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][F:19])[C:8]([CH2:10][O:11]C(=O)C)=[N:9][C:5]=2[CH:4]=1)#[N:2]>CO.CCO.Cl.[Pd]>[NH2:2][CH2:1][C:3]1[CH:21]=[CH:20][C:6]2[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][F:19])[C:8]([CH2:10][OH:11])=[N:9][C:5]=2[CH:4]=1
Reactant: CC(=O)OCc1nc2cc(C#N)ccc2n1CCCCF
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: NCc1ccc2c(c1)nc(CO)n2CCCCF
Yield: 28.3 %

Procedure:
To a solution of acetic acid 5-cyano-1-(4-fluoro-butyl)-1H-benzoimidazol-2-ylmethyl ester (1.3 g, 4.5 mmol) in MeOH (50 ml), EtOH (10 ml), concentrated HCl (10 ml) and 10% Pd/C (100 mg) was hydrogenated for 2 h. The solution was filtered and concentrated. The residue was dissolved in EtOAc and washed with aq NaHCO3. The product remains in the aqueous layer. The water was removed and the residue washed with hot EtOAc. The EtOAc extracts are concentrated to give 0.32 g (18%) of [5-aminomethyl-1-(4-fluoro-butyl)-1H-benzoimidazol-2-yl]-methanol as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([CH3:30])([CH3:29])[CH3:28])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:37]([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39]>C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([N:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([CH3:30])([CH3:29])[CH3:28])[P:37]([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)P(Cl)C(C)C
Reactant: Cc1ccc(C(=Nc2ccccc2C(C)(C)C)Nc2ccccc2C(C)(C)C)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(C(=Nc2ccccc2C(C)(C)C)N(c2ccccc2C(C)(C)C)P(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
N′-(2-tert-butylphenyl)-N-(2-tert-butylphenyl)-4-methylbenzamidine (NS Amidine II) (1.20 g, 3.0 mmol) was dissolved in 50 mL of diethylether and cooled to 0° C. Butyllithium (1.50 mL of 2.0 M solution in pentane, 3.0 mmol) was added dropwise, producing a light yellow solution. The solution was warmed to room temperature and stirred for 2 hours. Chlorodiisopropylphosphine (0.48 mL, 3.0 mmol) was added slowly at room temperature. A white suspension formed, which was stirred overnight at room temperature. The slurry was filtered to remove a small amount of white solid, presumably lithium chloride, and the solvent was removed in vacuo to produce 1.35 g (87%) of yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[N:11][CH:12]=1
Reactant: FC(F)(F)c1cncc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: Oc1cncc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 38.8 %

Procedure:
To a solution of 3-(benzyloxy)-5-(trifluoromethyl)pyridine (10 g, 39.5 mmol) in methanol (100 mL) was added Pd/C (0.500 g, 4.70 mmol). The reaction mixture was stirred at 50° C. under H2 (55 psi) for 24 h, filtered and concentrated under reduce pressure to afford the crude product (2.5 g).
Reaction SMILES: Cl[C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:4](=[O:14])[C:5]2[C:6]([N:13]=1)=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.O.[Cl-].[Na+].O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:3]1[C:4](=[O:14])[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:13]2[N:22]=[N:23][N:24]=[C:2]12
Reactant: [N-]=[N+]=[N-]
Reactant: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(Cl)nc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2c(=O)n(-c3ccccc3Cl)c3nnnn3c2n1

Procedure:
A mixture of Example 1B (0.175 g, 0.516 mmol) and sodium azide (0.037 g, 0.568 mmol) in N,N-dimethylformamide (5 mL) was heated at 70° C. for 1 hour. The reaction mixture was diluted with water and brine and extracted with ethyl acetate (2×). The combined organic layers were washed with brine (2×), dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (95:5 to 90:10) to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:15][C:16]([F:19])([F:18])[F:17])[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=O)[CH:10]=[CH:9]2)([O-])=O.[Sn](Cl)Cl>Cl>[F:19][C:16]([F:17])([F:18])[O:15][C:6]1[CH:7]=[C:8]2[C:13](=[C:4]([NH2:1])[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=c1ccc2cc(OC(F)(F)F)cc([N+](=O)[O-])c2[nH]1
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1cc(OC(F)(F)F)cc2cccnc12
Yield: 84.4 %

Procedure:
In a similar fashion using route 1 general procedure 4, 8-nitro-6-(trifluoromethoxy)quinolone (Intermediate 34) (1.1 g, 4.26 mmol), tin (II) chloride (2.42 g, 12.8 mmol) and 6 N HCl (13 drops) gave the title compound (820 mg, 84%) which was used in the next step without purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:23]O>>[O:17]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([O:13][CH3:23])=[O:12])[CH2:6][CH2:7]1
Reactant: O=C(O)c1cccc(N2CCS(=O)(=O)CC2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1
Yield: 90 %

Procedure:
3-(1,1-dioxidothiomorpholino)benzoic acid (100 mg, 0.392 mmol) was refluxed in the presence of con. Sulfuric acid (2.53 mg, 0.020 mmol) in methanol (5 mL) at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 3-(1,1-dioxidothiomorpholino)benzoate (99 mg, 0.353 mmol, 90% yield). 1H NMR (CDCl3, 400 MHz): δ 7.58 (m, 2H), 7.36 (t, 1H, J=8.0 Hz), 7.09 (m, 1H), 3.91 (s, 3H), 3.89 (m, 4H), 3.11 (m, 4H). Mass [M+H]+: 270.1
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9](F)[CH:10]=1)[C:6]#[N:7].[F:14][C:15]([F:44])([F:43])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([OH:42])[C@@H:24]([C:28]2[CH:41]=[CH:40][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:29]=2)[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=1>>[F:14][C:15]([F:43])([F:44])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([O:42][C:9]2[CH:10]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=2)[C@@H:24]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:40][CH:41]=2)[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@@H](O)c1ccc(OC(F)(F)F)cc1
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@@H](Oc1cc(C#N)cc(C(F)(F)F)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
Using the procedure from EXAMPLE 75, 3-trifluoromethyl-5-fluorobenzonitrile and N-(4-{(1R)-1-[(R)-(4-trifluoromethoxyphenyl)(hydroxy)methyl]butyl}benzoyl)-β-alanine were converted to the title compound. LC3 4.01 min. (M+H)+ 609.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[N:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:6])[CH:16]=[N:15]2
Reactant: COc1ccc(CNc2cnc3cc(OC)ccc3n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2nc(N)cnc2c1
Yield: 99.4 %

Procedure:
N-(2,4-Dimethoxybenzyl)-6-methoxyquinoxalin-2-amine (2.8 g, 8.61 mmol) was stirred in TFA (10 mL, 130 mmol) and dichloromethane (10 mL) at ambient temperature for 30 min. The solvents were removed in vacuo. Saturated aq. sodium hydrogen carbonate (200 mL) was added to the red residue, which then precipitated a yellow solid. The mixture was extracted extensively with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 6-methoxyquinoxalin-2-amine (1.50 g, 8.56 mmol, 99% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (1 H, s), 7.54-7.58 (1 H, m), 7.25-7.29 (2 H, m), 4.71 (2 H, br. s.), 3.90 (3 H, s). MS (LC/MS) R.T.=0.86; [M+H]+=176.23.
Reaction SMILES: [Li].[CH3:2][C:3]1[CH:4]=[C:5]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH:6]=[C:7]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:33][C:34]1([CH3:44])[CH2:39][C:38](=[O:40])[CH2:37][CH2:36][CH:35]1[C:41]([OH:43])=[O:42].S1C=CN=C1>C1COCC1.O.CO>[OH:40][C@:38]1([C:12]2[S:13][C:9]([C:7]3[CH:6]=[C:5]([NH:14][C:15]4[N:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][N:16]=4)[CH:4]=[C:3]([CH3:2])[CH:8]=3)=[CH:10][N:11]=2)[CH2:37][CH2:36][C@H:35]([C:41]([OH:43])=[O:42])[C:34]([CH3:44])([CH3:33])[CH2:39]1
Reactant: CC1(C)CC(=O)CCC1C(=O)O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Temperature: -78 °C
Yield: 428.6 %

Procedure:
Lithium diispropylamide (1.31 M, 10.0 mL, 13.1 mmol) was cooled to −78° C. and N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 4, 2.0 g, 5.95 mmol) in THF (20 mL) was added portionwise. While stirring at −78° C. additional lithium diisopropylamide (1.31 M, 4.55 mL, 5.95 mmol) was added. In a separate flask, lithium diisopropylamide (1.31 M, 10.0 mL, 13.1 mmol) was cooled to 0° C. and 2,2-dimethyl-4-oxo-cyclohexanecarboxylic acid (2.02 g, 11.9 mmol) in THF (20 mL) was added. The resulting solution of the carboxylate anion was transferred via cannula to the previously prepared thiazole anion solution, maintaining an internal reaction temperature below −68° C. The resultant mixture was stirred at −78° C. for 1 h, then methanol (5 mL) was added and the reaction mixture allowed to warm to room temperature. The reaction mixture was poured into water (200 mL) and extracted with MTBE (2×). The layers were separated and the aqueous portion was acidified to pH=3 with 2 N aqueous HCl then extracted with ethyl acetate (2×). The combined organic portions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide a yellow foam. The foam was then purified and the enantiomers separated via supercritical fluid chromatography (30% MeOH:CO2) to give (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (Example 42(1), 12.9 g, 25.5 mmol, 21%) as a yellow solid. MS ESI: [M+H]+ m/z 507.1. 1H NMR (500 MHz, DMSO-d6) δ 12.13-11.86 (br s, 1H), 10.24 (s, 1H), 8.82 (m, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 7.27 (m, 1H), 7.14 (s, 1H), 5.89 (s, 1H), 2.31 (s, 3H), 2.16 (d, J=12.7, 1H), 2.02 (m, 1H), 1.86 (m, 3H), 1.64 (d, J=13.8, 1H), 1.57 (d, J=13.1, 1H), 1.11 (s, 3H), 0.99 (s, 3H). rhSYK activity=+++.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.FC(F)C(OC(=O)C(F)F)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:8][C:9]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:2](=[O:1])[CH:4]([F:7])[F:5])[CH:28]([CH3:32])[C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2C
Agent: O=C(OC(=O)C(F)F)C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)C(F)F)C2C

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol), 2,2-difluoroacetic anhydride (7.4 mg, 0.042 mmol), and DIPEA (10.94 mg, 0.085 mmol) in DCM (141 μL) was stirred at room temperature for 1 h. Purification by HPLC Method A gave the title compound as a TFA salt (8.2 mg) as an off-white film. 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.27 (dd, J=7.6, 6.6 Hz, 6H), 1.51 (d, J=6.8 Hz, 2.1H), 1.62 (d, J=6.8 Hz, 0.9H), 1.90-2.00 (m, 2H), 2.09-2.17 (m, 2H), 2.65-2.75 (m, 1H), 2.80-3.03 (m, 3H), 3.25 (td, J=12.9, 3.9 Hz, 0.3H), 3.34-3.42 (m, 2H), 3.52-3.61 (m, 0.7H), 4.11-4.21 (m, 1.7H), 4.46 (dt, J=7.3, 3.7 Hz, 1H), 4.66 (dd, J=13.4, 5.6 Hz, 0.3H), 4.91-4.98 (m, 0.3H), 5.25 (q, J=6.7 Hz, 0.7H), 6.44-6.69 (m, 1H), 6.84-6.92 (m, 1H), 6.99 (ddd, J=11.3, 8.4, 3.2 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 496.90.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[CH:7]=[CH:6]2.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:49])(=O)=O)=CC=1.Cl>O1CCCC1.CCOCC>[F:49][C:31]1[S:30][C:29]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[O:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:27][CH:28]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccs3)ccc2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)s3)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Add 1-(2-(4-(6-methoxy-2-(thiophen-2-yl)naphthalen-1-yloxy)phenoxy)ethyl)piperidine (153 mg, 0.4 mmol) and tetrahydrofuran (3.3 mL) to a screw-cap vial under argon. Cool the resulting solution to −78° C. Add n-butyl lithium (1.6M in hexanes; 230 μL, 0.4 mmol) dropwise. Warm the resulting solution to 0° C. and stir for 30 min. Add a solution of N-fluorobenzenesulfonimide (210.0 mg; 0.6 mmol) in tetrahydrofuran (500 μL). Allow the resulting mixture to warm to room temperature and stir for 2 hours. Add 1M HCl, dilute with ether and pass through an SCX acidic ion exchange column. Flush the column with methanol then elute desired material with 2M ammonia in methanol. Concentrate the ammonia containing eluent to give a yellow solid. Purify the yellow solid on a silica gel flash chromatography to obtain the title compound (59.0 mg, 0.1 mmol): mass spectrum (m/z): 478 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]([CH2:9][C:10]2[N:11]([CH2:27][CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)[C:12](=[N:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[S:13][CH:14]=2)[CH3:8])=[CH:4][CH:3]=1.Cl>>[NH2:30][CH2:29][CH2:28][CH2:27][N:11]1[C:10]([CH2:9][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:39][CH:38]=2)[CH3:8])=[CH:14][S:13][C:12]1=[N:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:20][CH:21]=1
Reactant: CN(Cc1ccc(Cl)cc1)Cc1csc(=Nc2ccc(OC(F)(F)F)cc2)n1CCCNC(=O)OC(C)(C)C
Agent: Cl
Product: CN(Cc1ccc(Cl)cc1)Cc1csc(=Nc2ccc(OC(F)(F)F)cc2)n1CCCN

Procedure:
The compound (80 mg) obtained in the above (1) was treated in a similar manner to in Example 9 (2) to give the title compound (83 mg) as hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])=[S:11])=[C:5]([OH:20])[CH:4]=1)#[N:2].N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])=[S:11])=[C:5]([O:20][Si:30]([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=S)Nc2ccccc2Br)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1NC(=S)Nc1ccccc1Br
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of N-(4-cyano-2-hydroxyphenyl)-N′-(2-bromophenyl)thio urea (3.5 g, 10 mmol) in THF (50 mL) at 0° C. was added imidazole (1.0 g, 15 mmol) and TBSCl (1.5 g, 10 mmol). After 1 h, the reaction mixture quenched with water (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude material was crystallized from ethyl acetate to give 3.9 g (84%) of N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)thio urea as a yellow solid. 1H NMR (400 MHz, DMSO) δ 9.9 (s, 1H), 9.2 (s, 1H), 8.1 (d, 1H), 7.7 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 7.4 (t, 1H), 7.35 (s, 1H), 7.2 (t, 1H); MS(EI) m/e 347 (100 (M+)), 175 (40), 461 (40).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:5]=[CH:6][CH:7]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:4]4[N:5]=[CH:6][CH:7]=[N:3]4)=[CH:13][CH:14]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(COCCn2nccn2)cc1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4nccn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25 mg (1.0 mmol) 95% Sodium hydride were given to a solution of 219 mg (1.00 mmol) 4-(2-[1,2,3]triazol-2-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 304 mg (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 254 mg (52%) colorless powder.
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:17])[CH2:16][CH2:15][CH2:14]1)[N:8]([CH3:18])[C:7]2=[O:19].[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[F:20][C:3]1[C:2]([C:28]2[NH:27][C:26]3[C@@H:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=3[CH:29]=2)=[C:11]2[C:6]([C:7](=[O:19])[N:8]([CH3:18])[C:9]([NH:12][C:13]3([CH3:17])[CH2:16][CH2:15][CH2:14]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cn1c(NC2(C)CCC2)nc2c(Br)c(F)ccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1NC(=O)c2cc(-c3c(F)ccc4c(=O)n(C)c(NC5(C)CCC5)nc34)[nH]c21
Temperature: 80 °C
Yield: 17.3 %

Procedure:
A mixture of 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (502a, 120 mg, 0.353 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 237 mg, 0.705 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium (II) (12.49 mg, 0.018 mmol), and potassium phosphate (225 mg, 1.058 mmol) in 1,4-dioxane (2.82 mL)/water (0.70 mL) was sparged with nitrogen for 3 min at RT; the red reaction mixture was then heated to 80° C. for 45 min. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (2×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-5% 2 M ammonia in MeOH/DCM to give (R)-7-fluoro-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (502, 24 mg, 0.061 mmol, 17% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.58 (s, 3H) 1.78 (s, 3H) 1.98-2.15 (m, 2H) 2.27-2.42 (m, 3H) 2.42-2.52 (m, 1H) 3.56 (s, 3H) 4.69 (q, J=6.65 Hz, 1H) 5.08 (s, 1H) 6.01 (s, 1H) 7.00 (dd, J=11.54, 8.80 Hz, 1H) 7.08 (d, J=4.11 Hz, 1H) 8.01 (dd, J=8.80, 6.06 Hz, 1H) 12.76 (br. s., 1H). 19F NMR (376 MHz, CDCl3) δ ppm −99.57 (s, 1F). MS (ESI, pos. ion) m/z: 369.0 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH:5]([O:38][CH2:39][CH3:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:21]2[S:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH3:36])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH3:37])C.[Li+].[OH-]>>[CH2:39]([O:38][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:21]2[S:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH3:36])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[CH3:37])[C:4]([OH:41])=[O:3])[CH3:40]
Reactant: CCOC(=O)C(Cc1ccc(OC(c2ccccc2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OC(c2ccccc2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], 2-ethoxy-3-(2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-phenyl-methoxy}-phenyl)-propionic acid ethyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 2-ethoxy-3-(2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-phenyl-methoxy}-phenyl)-propionic acid as a mixture of two diastereomeric racemates as off-white gum.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[F:1][C:2]1[C:9]([O:10][C:11]([F:13])([F:14])[F:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cccc(OC(F)(F)F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(OC(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a stirred solution of 2-fluoro-3-(trifluoromethoxy)benzaldehyde (1.00 g, 4.81 mmol) in methanol (20 mL) is added Sodium borohydride (0.36 g, 9.61 mmol) at 0° C. After stirring at room temperature for 16 hours, the reaction mixture is quenched with water. The mixture is diluted with ethyl acetate (100 mL) and washed with water. The organic layer is dried over sodium sulfate, and concentrated under reduced pressure to give 0.97 g (96% yield) of the title compound as colorless syrup. This material is used for the next reaction (Step-2) without further purification.