Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].C([NH:10][C:11]1[C:12]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[C:13]([C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])(=O)C>CN1CCCC1=O.C(OCC)(=O)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:11]2[NH:10][C:25]([CH2:26][CH2:27][CH2:28][O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[CH:24][C:12]=2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])([O-:23])=[O:22]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(NC(C)=O)c1C#CCCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1c([N+](=O)[O-])ccc2[nH]c(CCCOC3CCCCO3)cc12
Temperature: 70 °C
Yield: 84.5 %

Procedure:
Potassium tert-butoxide (0.230 g) was added to a solution of methyl 3-acetylamino-6-nitro-2-[5-(tetrahydropyran-2-yloxy)-pent-1-ynyl]benzoate (Intermediate 23, 0.70 g) in anhydrous N-methyl-2-pyrrolidone (18 mL) and the reaction mixture was heated at 70° C. for 1 hour. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 5-nitro-2-[3-(tetrahydropyran-2-yloxy)-propyl]-1H-indole-4-carboxylate (0.530 g) as a dark orange gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.[F:35][C:36]1[C:46]([F:47])=[CH:45][C:44](I)=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39].C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[F:35][C:36]1[C:46]([F:47])=[CH:45][C:44]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])[C:12]3=[N:13][CH:14]=2)=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CN(C)C(=O)c1cc(I)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(F)c(F)c(C(=O)N(C)C)c3)cc12
Yield: 68 %

Procedure:
A mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (3.1 g, 6.43 mmol), 2,3-difluoro-5-iodo-N,N-dimethyl-benzamide (2 g, 6.43 mmol) and 1,1′-bis(diphenylphosphino)-ferrocenepalladium(II)-dichloride dichlormethane adduct (262 mg, 0.32 mmol) in acetonitrile (14 mL) and aqueous solution of sodium carbonate (2M, 6.5 mL) was irradiated in a Personal Chemistry Optimizer at 100° C. for 15 min. Sodium sulfate was added to the crude reaction mixture and the solids were filtered over Celite. The solids were washed with acetonitrile and the combined filtrate was concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded 1.23 g (4.37 mmol, 68%) of 2,3-difluoro-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J=2.5 Hz, 1H), 8.46 (d, J=2 Hz, 1H), 8.02 (ddd, J1=12 Hz, J2=10 Hz, J3=2.5 Hz, 1H), 7.67 (m, 1H), 7.61 (dd, J1=8 Hz, J2=1.5 Hz, 1H), 7.49 (m, 1H), 7.23 (d, J=8 Hz, 1H), 7.10 (td, J1=8 Hz, J2=1 Hz, 1H), 5.84 (s, 2H), 3.81 (s, 3H), 3.68 (t, J=8 Hz, 2H), 3.02 (s, 3H), 2.91 (s, 3H), 0.85 (t, J=8 Hz, 2H), −0.09 (s, 9H). MS: m/z 539 [MH+]
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[F:36][CH:37]([F:40])[CH2:38]Br>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:38][CH:37]([F:40])[F:36])[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: FC(F)CBr
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(C)N(CC(F)F)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=564.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2,2-difluoroethyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-])=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH2:19][CH3:20])[CH3:18])[CH:10]=1.N>Cl.CCO.C(OCC)(=O)C>[CH:17]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[O:8][C:7]1[C:6]([Cl:21])=[CH:5][C:4]([NH2:22])=[CH:3][C:2]=1[Cl:1])([CH2:19][CH3:20])[CH3:18]
Reactant: CCC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1OC
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(C)c1cc(Oc2c(Cl)cc(N)cc2Cl)ccc1OC
Yield: 100.5 %

Procedure:
To a solution of Stannous chloride dihydrate (194.6 g, 0.86 mol) in concentrated HCl (80.0 mL) was added to 3,5-dichloro-4-(4′-methoxy-3-sec-butyl-phenoxy)nitrobenzene (80 g, 0.21 mol) in EtOH (400 mL). The reaction mixture was refluxed for about 2 h. The resulting mixture was brought at 20-30° C. and diluted with ethyl acetate. The mixture was made alkaline with ammonia solution. Resulting solid was filtered through cellite. The organic phase was washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give 4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine (71.8 g; 98% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:13]([C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17](OC)=O)=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C>[O:14]=[C:13]1[C:15]2[C:16](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][N:12]1[CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COC(=O)c1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2Cc3ccccc3C2=O)C1
Reaction time: 5.5 h
Yield: 87.3 %

Procedure:
To a solution of 1-Boc-3-aminoazetidine 1a (1.0 g, 5.8 mmol) and methyl 2-formylbenzoate 2a (0.95 g, 5.8 mmol) in 1,2-dichloroethane (30 mL) and acetic acid (1.5 mL) was added Na(OAc)3BH (1.29 g, 6.08 mmol) at room temperature. The reaction was stirred for 5.5 h. It was quenched with aq. NaHCO3, and the resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 40% EtOAc/heptane) gave compound 2b (1.46 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21]CS([O-])(=O)=O)=[CH:15][CH:14]=1.C1OCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:21][CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)([O-])CCCCc1ccc(Cl)cc1
Reactant: [O-]CCCN1CCCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(CCCOCCCN2CCCCC2)cc1

Procedure:
Sodium 3-piperidinopropanolate (20 mmol), 7 mmol of 3-(4-chlorophenyl)propylmesylate, and 0.5 mmol of 15-crown-5 in 30 ml of dry toluene were refluxed for 4 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel (eluent: methylene chloride/methanol (90/10)). After removing the solvent under reduced pressure the residue was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10].[NH2:25][OH:26].[OH-].[K+].CO>C1COCC1>[OH:26][NH:25][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: NO
Reactant: COC(=O)CCCCCS(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCCCCS(=O)c1ccc(-c2ccc(Cl)cc2)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of the 6-(4′-chloro-biphenyl-4sulfinyl)-hexanoic acid methyl ester (400 mg, 1.1 mmol) in distilled THF (10 mL) containing 50% aqueous hydroxylamine (0.65 mL, 9.9 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1.9 mL, 1M, 1.9 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (10 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×20 mL) and the combined extracts were washed with brine (40 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (315 mg, 79%) as a white powder, mp 108-110° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[C:19]([N+:29]([O-:31])=[O:30])=[C:18]([F:32])[CH:17]=2)[CH2:11][S@@:10](=[O:33])[CH2:9]1)(C)(C)C>C(Cl)Cl.CO.C(O)(C)=O.O>[NH2:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:25])[F:26])[C:19]([N+:29]([O-:31])=[O:30])=[C:18]([F:32])[CH:17]=2)[CH2:11][S@@:10](=[O:33])[CH2:9]1
Reactant: C[C@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NC(=O)OC(C)(C)C)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C[C@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](N)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as described for example 1g, starting from {(1R,3R,4S,5S)-5-[3-fluoro-4-nitro-5-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzyl]-4-hydroxy-1-oxo-tetrahydro-thiopyran-3-yl}-carbamic acid tert-butyl ester and was obtained as a light yellow foam: TLC (CH2Cl2-MeOH-AcOH-H2O 180:20:2:1) Rf=0.10; HPLC RtA=1.50 min; ESIMS [M+H]+=415; 1H NMR (600 MHz, DMSO-d6): δ 8.09 (s, 3H), 7.29 (s, 1H), 7.14 (d, 1H), 6.02 (s broad, 1H), 5.48 (m, 1H), 3.56 (m, 1H), 3.30 (t, 1H), 3.16 (m, 2H), 2.89 (d, 1H), 2.76 (t, 1H), 2.72 (dd, 1H), 2.5-2.6 (m, 2H), 1.46 (d, 3H).
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH:20]=[C:19]([CH2:22][OH:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+]>ClCCl>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][C:19]2([CH2:22][OH:23])[CH:20]([CH2:1]2)[CH2:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)CC1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ICI
Product: CC(C)(C)OC(=O)N1CCC2(CO)CC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice-cooling, 15.3 ml of diethylzinc and 6.7 g of diiodomethane were added to 130 ml of dichloromethane. After further adding a solution of 1.07 g of 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-methanol in dichloromethane (20 ml), the resulting mixture was stirred at room temperature overnight. Then the reaction mixture was poured into saturated ammonium chloride, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 90 mg of the title compound as a colorless oily substance.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:34][OH:35])(=[O:15])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>ClCCl>[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])=[CH:23][CH:22]=[CH:21][C:20]=2[CH:34]=[O:35])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)c1cnc2c(CO)cccc2c1Nc1ccccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Oxalyl chloride (18.22 g, 0.144 mol) in dichloromethane (180 ml, dried over molecular sieves) was cooled to -70° C., and a solution of dimethylsulphoxide (13.08 g, 0.168 ml) in dry dichloromethane (20 ml) added dropwise under nitrogen with stirring, keeping the temperature below -60° C. After 30 minutes, a solution of 3-butyryl-4-(2-methylphenylamino)-8-hydroxymethylquinoline (40 g, 0.12 mol) in dry dichloromethane (700 ml was added dropwise below -60° C. After a further 30 minutes, triethylamine (102 ml) was added dropwise, and the mixture allowed to warm to room temperature, washed with water and dried (Na2SO4). The filtered solution was evaporated to a yellow oil, which crystallized on trituration with ether to give the title compound (33.02 g), m.p. 142°-4°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[OH:4].[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(O)(=O)C.[Na]>ClCCCl>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:1][CH2:2][CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: NCC(O)c1ccccn1
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NCC(O)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
2-Amino-1-pyridin-2-yl-ethanol (0.700 g, 5.07 mmol) and N-boc-piperidone (1.20 g, 5.90 mmol) was dissolved in 5 mL of 1,2-dichloroethane. Glacial acetic acid (0.40 mL, 7.0 mmol) was added followed by sodium tricaetoxyborohydride (2.00 g, 8.97 mmol). This mixture was stirred at room temperature under argon for 16 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel 12 g, eluted with dichloromethane, MeOH and ammonium hydroxide 100 to 95:4.9:0.1) to give 4-(2-hydroxy-2-pyridin-2-yl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester as a brown oil (1.46 g, 90%).
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)[N:11]=1)(=[O:5])=[O:4])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:1]([S:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)[N:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)Nc1nc(CCc2ccc(CC(=O)OC)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1nc(CCc2ccc(CC(=O)O)cc2)cs1
Temperature: 0 °C
Yield: 99.2 %

Procedure:
To a solution of methyl [4-(2-{2-[(ethylsulfonyl)amino]-1,3-thiazol-4-yl}ethyl)phenyl]acetate (1.74 g, 4.72 mmol) in dioxane (17.4 ml) was added at 0° C. 1M aqueous sodium hydroxide solution (11.8 ml, 11.8 mmol), and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and water (20 ml) was added. After cooling to 0° C., 1M hydrochloric acid (16 ml) was added dropwise with stirring. After stirring at 0° C. for 30 mins, the precipitate was collected by filtration, washed with water and dried under reduced pressure to give [4-(2-{2-[(ethylsulfonyl)amino]-1,3-thiazol-4-yl}ethyl)phenyl]acetic acid (1.66 g, yield 99%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([O:10]C(=O)C)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CO.C1COCC1.C([O-])(=O)C.[Na+]>CCOCC>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Oc1ccc(C2CC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(C2CC2)cc1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of acetic acid 4-cyclopropyl-phenyl ester (16.1 g, 0.0914 mol) in mixed solvent (40 mL, MeOH: THF=1:1) was added sodium acetate (19.4 g, 0.183 mol). The reaction mixture was stirred two hours. Solvent was evaporated under reduced pressure to provide a crude mixture, to which was then added Et2O. The solid was filtered and the filtrate was concentrated to afford the title compound as a yellow oil (12.1 g, 99%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH2:3][CH2:2]1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>>[CH3:26][N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:11][C:10]=23)=[O:18])[CH2:21][CH2:22]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1cccc2oc(N3CCOCC3)nc12
Product: CN1CCC(NC(=O)c2cccc3oc(N4CCOCC4)nc23)CC1

Procedure:
Following general procedure GP-C1, a mixture of 2-morpholinobenzoxazole-4-carboxylic acid and 4-amino-1-methylpiperidine were coupled to provide N-(1-methylpiperidin-4-yl)-2-morpholinobenzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:23]([CH3:30])[CH2:24][O:25]C(C)(C)C)[CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)=[O:4].C(OCC)(=O)C.O>C(O)=O.[Cl-].[Na+].O>[CH3:31][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:23]([CH3:30])[CH2:24][OH:25])[CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(C)(C)C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)CO)c1
Yield: 101.1 %

Procedure:
A solution of methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(2S)-1-[(2-methylpropan-2-yl)oxy]propan-2-yl]oxy-benzoate (170 g, 0.39 mol) in formic acid (850 mL) was heated to 90° C. for 3 hours. Ethyl acetate (1700 mL), water (1700 mL) and saturated aqueous brine (850 mL) was added and the aqueous layer separated and extracted with ethyl acetate (850 mL) and the combined organic layers were washed with saturated aqueous brine (850 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved with ethyl acetate (1500 mL), water (1500 mL) and methanol (150 mL). Sodium carbonate (170 g) was added and the biphasic solution heated to reflux for 2 hours. The aqueous layer was separated and the organic layer washed with water (1700 mL). The combined aqueous phases were extracted with ethyl acetate (850 mL) and the combined organic layers dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 100% ethyl acetate to obtain a the title compound (148 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:16][C:15]([C:26]#[N:27])=[N:14]1.[F:28][C:29]([F:33])([F:32])[S:30]Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[C:16]([S:30][C:29]([F:33])([F:32])[F:28])[C:15]([C:26]#[N:27])=[N:14]1
Reactant: N#Cc1cc(NCc2ccncc2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: FC(F)(F)SCl
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2ccncc2)c1SC(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
In 10 ml of dichloromethane was suspended 0.5 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-(4-pyridylmethylamino)pyrazole obtained in Example 1 above, and 0.2 g of trifluoromethylsulfenyl chloride in 10 ml of dichloromethane was added thereto dropwise at −20° C. The mixture was taken out of the cooling bath. After stirring for 3 hours, ice-water was added to the mixture to extract. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography to yield 0.4 g of compound No. 1 shown in Table 1 below. The NMR data of the compound were as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](I)[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5].O1CCCCC1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1.Cl>>[ClH:1].[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[NH:19][N:18]=[CH:22][CH:21]=2)[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)cc(I)cc1Cl
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: Cl
Product: N#Cc1c(Cl)cc(-c2ccn[nH]2)cc1Cl

Procedure:
The title compound was prepared from 2,6-dichloro-4-iodobenzonitrile (1.09 g, 3.66 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (1.32 g, 4.76 mmol) as described in Example 34 (a) and (b) until the isolation of the hydrochloride. Yield 0.824 g. 1H NMR (400 MHz; d6-DMSO): δ 7.07 (d, 1H), 7.88 (d, 1H), 8.14 (s, 2H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH2:67][CH2:68][NH:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:66][CH2:67][CH2:68][NH:69][C:70](=[O:76])[O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 4)((70 mg, 0.164 mmol) and HATU (74.9 mg, 0.197 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.086 mL, 0.492 mmol). After 5 min, tert-butyl (2-aminoethyl)carbamate (52.6 mg, 0.328 mmol) was added and the mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 (×3), then brine, dried over MgSO4 and concentrated in vacuo to give tert-butyl (2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzamido)ethyl)carbamate as a brown foam which was further purified by MDAP (HpH). to give tert-butyl (2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzamido)ethyl)carbamate (65 mg, 0.114 mmol, 69.6% yield) as a white solid. LCMS (HpH, 2 min), Rt=1.00 min, MH+=569.