Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[CH2:19][NH:18]/[C:17](=[N:20]\[C:21]([C:23]2[C:28]([NH2:29])=[N:27][C:26]([NH2:30])=[C:25]([Cl:31])[N:24]=2)=[O:22])/[NH:16]1)C1C=CC=CC=1.I[Si](C)(C)C.CO>C(Cl)Cl>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[CH2:19][NH:18]/[C:17](=[N:20]\[C:21]([C:23]2[C:28]([NH2:29])=[N:27][C:26]([NH2:30])=[C:25]([Cl:31])[N:24]=2)=[O:22])/[NH:16]1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCCNC(=O)OCc3ccccc3)N2)nc1Cl
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Product: NCCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a suspension of (4-{(S)-2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-imidazolidin-4-yl}-butyl)-carbamic acid benzyl ester (Ex. 5) (0.110 g, 0.239 mmol) in dry DCM (20 ml) is added iodotrimethylsilane (0.130 ml, 0.956 mmol). The reaction mixture is stirred at room temperature for 3.5 hours. MeOH is added to the suspension yielding a solution. Purification by catch and release resin (SCX-2) eluting with MeOH and 7 M NH3 in MeOH yields the title compound as a brown oil; [M+H]+ 327.1
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=3[F:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1cc(F)ccc1F
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3F)cccc2c1N
Yield: 69.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2,5-difluoro-phenylboronic acid (160 mg, 1.00 mmol) were reacted to afford the title compound (116 mg, 70% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 7.97-7.91 (m, 1H), 7.83-7.69 (m, 2H), 7.27-7.05 (m, 3H), 3.46 (apparent quartet, J=7.0 Hz, 2H), 1.74-1.59 (m, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=343 (M+H). HPLC 2.01 min.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[N:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[N:16](C(OC(C)(C)C)=O)[C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[N:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[NH:16][C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1[C@H](Nc1ncc(C(F)(F)F)cn1)C2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2N3)nc1
Reaction time: 8 h

Procedure:
To the title compound of step A (355 mg, 1 mmol) in DCM (9.7 mL) was added 4M HCl in dioxane (1.2 mL). The reaction was allowed to proceed overnight then concentrated and neutralized with 5% Na2CO3 (aq) and extracted with DCM (2×). The combined organics were dried (Na2SO4) to give the title compound of step B that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:13][NH2:14].[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)[CH:20]=O.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:11])([F:12])[F:10])=[CH:4][C:3]=1[CH2:13][NH:14][CH2:20][C:19]1[CH:22]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=1
Reactant: Cc1cc(Br)c(CN)cc1C(F)(F)F
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
A mixture of (2-bromo-4-methyl-5-(trifluoromethyl) phenyl) methanamine (189 mg, 0.705 mmol) and 3,5 bistrifluoromethyl benzaldehyde (170 mg, 0.705 mmol) in anhydrous toluene (10 mL) was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (25 mL). Sodium triacetoxyborohyride (373.5 mg, 1.76 mmol) was added and the mixture was stirred for 18 hours at room temperature. The mixture was poured into a mixture of saturated NaHCO3 (50 mL) and ethyl acetate (50 mL) and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried with anhydrous sodium sulfate, filtered and concentrated to give the title compound (98.4%). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 2H) 7.76(s, 1H) 7.58(s, 1H) 7.41 (s, 1H) 3.92(s, 2H) 3.89(s, 2H) 2.44(s, 3H)
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.[CH3:9][CH:10]([CH3:18])[C:11](=[O:17])[CH2:12][C:13](OC)=[O:14].[O-]CC.[Na+].Cl>C(O)C>[C:11]([CH:12]1[CH2:2][C:3]2([CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)[O:1][C:13]1=[O:14])(=[O:17])[CH:10]([CH3:18])[CH3:9]
Reactant: C1CC2(CCO1)CO2
Reactant: COC(=O)CC(=O)C(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)C(=O)C1CC2(CCOCC2)OC1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
6.6 g 1,6-Dioxaspiro[2.5]octane and 8.2 ml methyl 4-methyl-3-oxopentanoate are dissolved in 30 ml ethanol, cooled to 0° C. and treated in portions with 3.9 g sodium ethoxide. After completion of the addition the mixture is warmed to room temperature and stirred for 18 hours. Then the mixture is poured in 200 ml ice water, acidified to pH 3 by addition of 1 M hydrochloric acid and extracted for three times with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 50:50).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[CH2:5](N)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.O.C1(C=C(O)C=C(O)C=1)O.O>CS(C)=O>[N+:1]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5])([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=N[O-]
Agent: Oc1cc(O)cc(O)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCC[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Sodium nitrite (14.0 g, 0.2 mol) was added to a solution of the dibromide 2 (17.25 g, 0.05 mol) and phloroglucinol dihydrate (16.2 g, 0.1 mol) in DMSO (100 mL) and stirred for 8 h. The reaction mixture was poured into water and extracted with ethyl acetate (3×150 mL). The ethyl acetate solution was washed with water (2×100 mL) sodium chloride solution (2×100 mL), and dried (Na2SO4). Evaporation of ethyl acetate gave an oil, which was purified by silica gel chromatography, (hexane/ethyl acetate, 7/3). Fractions (Rf=0.73 were collected and evaporated to give 3 as a foamy solid. Yield: 2.8 g (22%).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=3)[C:32]=2[C:51](O)=[O:52])=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=3)[C:32]=2[C:51]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[O:52])=[CH:27][CH:26]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1ccc(-c2c(C(=O)O)n(Cc3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2c(C(=O)NS(=O)(=O)c3ccccc3)n(Cc3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Reaction time: 18 h
Yield: 78 %

Procedure:
Benzenesulfonamide (155 mg, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (96 mg, 0.50 mmol), and 4-(dimethylamino)pyridine (20 mg, 0.16 mmol) were added to a stirred solution of 3-(4-methoxyphenyl)-1-{[3-(trifluoromethyl)phenyl]methyl}indole-2-carboxylic acid (Lit: WO94/14434, 213 mg, 0.50 mmol in dichloromethane (5 mL). The resulting mixture was stirred for 18 h and then quenched with hydrochloric acid (1N). The mixture was extracted with ethyl acetate (2×20 mL) and the combined organic extracts was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified with silica gel flash chromatography using hexane/ethyl acetate (2/1) as the eluant to give a white solid. It was further purified by trituration with diethyl ether to afford (3-(4-methoxyphenyl)-1-{[3-(trifluoromethyl)phenyl]methyl}indol-2-yl)-N-(phenylsulfonyl) carboxamide as a white solid (220 mg, 78%): mp>250° C.; MS (electrospray, MH+) calcd for C30H24F3N2O4S 565.1, found 565.0; 1H NMR (DMSO-d6) δ 7.51-8.31 (m, 17 H), 7.03 (br s, 1H), 6.17 (s, 2H), 4.36 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(OCc2ccccc2)cc1
Yield: 64.6 %

Procedure:
4-Bromophenol (17.3 g, 0.1 mol), 19.03 g (0.15 mol) benzyl chloride, and 27.64 g (0.2 mol) pulverized K2CO3 were suspended in 150 mL Me2CO and heated to reflux 2 h. The resulting suspension was concentrated on a rotary evaporator. The mixture was then diluted with 200 mL 5% NaOH and extracted with 100 mL Et2O. The organic layer was washed with an additional 100 mL 5% NaOH, dried (MgSO4), filtered, and concentrated to give a yellow oil, which was crystallized and recrystallized from boiling EtOH to yield 17 g (65%) of Benzyl 4-bromo phenyl ether as white needles, mp: 60°-61° C. NMR δ 7.35 and 6.82 (AA'BB', c, 4H, C6H4), 7.36 (s, 5H, C6H5), 5.0 (s, 2H, OCH2).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:13]C1CC(C(C)C)CCC1=O>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([Br:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: CCOC(=O)C1CCC(=O)C(Br)C1

Procedure:
The bromination of 4-oxo-cyclohexane carboxylic acid ethyl ester takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[N:11]=[C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:33])[CH2:22][N:23]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[N:24]3)[CH2:17][CH2:16]2)[S:13][CH:14]=1)#[CH:9].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:9]#[C:8][C:10]1[N:11]=[C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:33])[CH2:22][N:23]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([F:30])([F:32])[F:31])=[N:24]3)[CH2:17][CH2:16]2)[S:13][CH:14]=1
Reactant: C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reactant: COc1ccccc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (25 mg), copper(I) iodide (7 mg) and triethylamine (48 mg) are added to a solution of 1-[4-(4-ethynyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (I-86, 150 mg) and 1-iodo-2-methoxybenzene (101 mg) in degassed N,N-dimethylformamide (1.5 ml). After 2 hours of stirring at 85° C., the reaction mixture is then diluted with water and extracted with ethyl acetate. The organic extracts are dried over sodium sulphate and concentrated under reduced pressure. After chromatographic purification, this gives 1-(4-{4-[(2-methoxyphenyl)ethynyl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (100 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:19][CH2:20][C@H:21]2[C@H:25]([CH3:26])[CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[CH3:34][N:35]1[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][C@H:25]1[C@H:21]([CH2:20][O:19][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[N:7]=[C:2]([NH:40][C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)[N:3]=2)[CH2:22][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1
Reactant: Cn1cc(N)cn1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1COc1nc(Cl)nc2c1ccn2COCC[Si](C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1COc1nc(Nc2cnn(C)c2)nc2c1ccn2COCC[Si](C)(C)C
Yield: 59.8 %

Procedure:
To a mixture of tert-butyl trans-3-{[(2-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]methyl}-4-methylpyrrolidine-1-carboxylate (1.34 g, 2.7 mmol), 1-methyl-1H-pyrazol-4-amine (0.397 g, 4.05 mmol), Cs2CO3 (2.7 g, 8.4 mmol) and Xantphos (138 mg, 0.27 mmol) in 1,4-dioxane (30 mL) was added Pd2(dba)3 (247 mg, 0.27 mmol). The reaction was irradiated at 140° C. in three microwave tubes for 1 hr. TLC (petroleum ether/EtOAc=5:1) showed the reaction was complete. The mixture was concentrated and diluted with water (20 mL), then extracted with EtOAc (two×20 mL). The combined organic layers were washed with brine (four×20 mL), dried over Na2SO4 and concentrated. The residue was purified by Biotage flash chromatography (petroleum ether/EtOAc=1:1, Rf: 0.3) to yield the title compound (0.9 g, 59% yield) as a brown oil. m/z (APCI+) for C27H43N7O4Si 558.3 (M+H)+.
Reaction SMILES: Cl[C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11].CC([O-])(C)C.[K+]>C(O)(C)(C)C>[Cl:11][C:5]1[C:6]([Cl:10])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]#[C:2][C:12]([F:15])([F:13])[F:14]
Reactant: FC(F)(F)C(Cl)=Cc1cccc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: FC(F)(F)C#Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 31.7 g of (2-chloro-3,3,3-trifluoropropen-1-yl)-2,3-dichlorobenzene in 50 ml of tert-butanol, there is added dropwise at RT a solution of 14.1 g of potassium tert-butylate in 750 ml of tert-butanol in such a manner that the temperature of the reaction solution does not exceed 30° C. After continued stirring at RT for 18 h, the mixture is taken up in ice-water and extracted with ether. The organic phases are combined, washed with water and sodium chloride solution, and concentrated by evaporation. There is thus obtained, after distillation in vacuo, 2,3-dichloro-(3,3,3-trifluoropropyn-1-yl)-benzene in the form of colourless oil, b.p. 92°-98° C. at 22 mb (compound No. 2.27).
Reaction SMILES: [CH2:1]([O:3][C:4]([S:6][C:7]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=1[CH2:9][OH:10])=[S:5])[CH3:2].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([S:6][C:7]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=1[CH2:9][O:10][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)=[S:5])[CH3:2]
Reactant: CCOC(=S)Sc1ccc(C)cc1CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=S)Sc1ccc(C)cc1COC1CCCCO1

Procedure:
38.2 g (0.158 mol) of the compound from Example 7, dissolved in 500 ml of abs. methylene chloride, are treated with 19.8 g (0.24 mol) of dihydropyran and a spatula tipful of p-toluenesulphonic acid and the mixture is stirred at 25° C. for 14 h. It is washed with aqueous sodium hydrogen carbonate solution and water, dried over sodium sulphate and concentrated in vacuo, and the residue is chromatographed on a silica gel column using petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:21]([O:23]C)=O)[CH2:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:12]#[N:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C(=O)([O-])[O-].[K+].[K+]>C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:12][NH:13][C:21]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](CC(C#N)c1ccccc1F)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Ni]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2ccccc2F)CNC1=O
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-4-(2-fluorophenyl)-5-nitrilonorvalinate (3.88 g, 11.5 mmol) in ethanol (50 mL) was added Raney nickel (slurry in water, ca. 10 g). The mixture was placed under a balloon of hydrogen and the reaction was stirred at 23° C. for 4 hours. The mixture was filtered and concentrated to afford a mixture of 4 diastereomers. A solution of this residue in ethanol (100 mL) was stirred in the presence of solid potassium carbonate (1.30 g, 9.44 mmol) at 60° C. for 2 h. The bulk of the ethanol was removed under reduced pressure and the remaining slurry was diluted with water to afford a white precipitate. The precipitate was filtered, washed with water and then dried under vacuum at 40° C. for 18 hours. The enantiomers were separated using normal-phase HPLC using a ChiralPak® AD column, eluting with 40% hexane in ethanol (0.1% diethylamine used as a modifier) to afford the title compound as the second major enantiomer to elute. MS: m/z=331.1 (M+Na).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:43]([C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:22]4[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:32][CH:31]=2)[C:35]([CH3:47])=[C:36]3[CH3:46])=[O:44])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc(C(C)(C)C)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)(C)C)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (S)-1-(3-(tert-butyl)phenyl)ethanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 559 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([Cl:27])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:27][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(Cl)c2c(CC(=O)O)csc2c1
Yield: 92.4 %

Procedure:
To a mixture of methyl(4-chloro-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (160 mg) and THF (2 mL) was added 1N NaOH (1 mL) at room temperature. The mixture was refluxed for 1 h. The mixture was neutralized with 1N HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (143 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[C:25]1[C:26]2[C:33]([CH3:34])=[CH:32][S:31][C:27]=2[N:28]=[CH:29][N:30]=1>C(O)(C)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:13]=2)=[O:11])=[CH:3][C:2]=1[NH:1][C:25]1[C:26]2[C:33]([CH3:34])=[CH:32][S:31][C:27]=2[N:28]=[CH:29][N:30]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: Cc1csc2ncnc(Cl)c12
Solvent: CC(C)O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ncnc2scc(C)c12
Temperature: 88 °C
Yield: 25.4 %

Procedure:
N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide (0.056 g), 4-chloro-5-methylthieno[2,3-d]pyrimidine (Maybridge Chemical Company, Trevillet, Tintagel, Cornwall, PL34 0HW, GB; 0.037 g) and isopropanol (2 ml) and the reaction mixture was stirred and heated to 88° C. for 18 hours. The reaction mixture was cooled to ambient temperature and the precipitate was isolated and washed in turn with isohexane and diethyl ether. There was thus obtained the title compound (0.021 g); Mass: M+H+ 461.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][N:18]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[N:8][C:7]=1[CH3:30])=[O:5])C.O.[OH-].[Li+].C(O)C.Cl>O.[Cl-].[Na+]>[CH3:30][C:7]1[N:8]=[C:9]([NH:11][C:12](=[O:29])[CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][N:18]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[S:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(NC(=O)Cc2cccc3c2cnn3C2CCCCO2)nc1C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: Cc1nc(NC(=O)Cc2cccc3c2cnn3C2CCCCO2)sc1C(=O)O
Yield: 72.2 %

Procedure:
A mixture of 4-Methyl-2-{2-[1-(tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carboxylic acid ethyl ester (800 mg, 1.867 mmol), lithium hydroxide monohydrate (394 mg, 9.391 mmol), ethanol (8 mL) and water (24 mL) was placed in an oil bath preheated to 90° C. and the resulting solution was heated for 28 min. The reaction solution was diluted with water (20 mL), saturated with sodium chloride, acidified with aqueous 2N HCl and extracted with 4/1 ethyl acetate/THF (4×100 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 4-Methyl-2-{2-[1-(tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carboxylic acid (0.54 g, 72.2%) as a yellow solid. MS m/e 401.4 (M+H+).