Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:31][CH2:32][CH3:33])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18](C3C=CC(S(C)(=O)=O)=CC=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[F:42]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[C:1]([C:3]1([NH:6][C:7](=[O:34])[C@@H:8]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:39]=[CH:40][C:41]([F:42])=[C:36]([F:35])[CH:37]=3)=[CH:17][CH:16]=2)[C:11]([F:12])([F:14])[F:13])[CH2:31][CH2:32][CH3:33])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(F)c(F)c2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in similar manner to that described for N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-norvalinamide via Suzuki cross-coupling between 3,4-difluorophenylboronic acid and N2-[(1)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide in the presence of 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), dichloromethane complex.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:21]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:11]([CH:8]1[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]1)[CH2:12][CH2:13][CH2:14]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)CCCN2C1CCC2(CC1)OCCO2
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)CCCN2C1CCC2(CC1)OCCO2
Reaction time: 3.5 h
Yield: 91.9 %

Procedure:
A solution of compound 3 (0.19 g, 0.695 mmol) in dry DMF (3 mL) was treated with N-bromosuccinimide (0.124 g, 0.695 mmol) in DMF (2 mL) at 0° C. over a period of 10 minutes. The reaction was stirred at the same temperature for 3.5 h. The reaction was diluted with water (50 mL) and the product was extracted into ethyl acetate (2×20 mL). The combined ethyl acetate layer was washed with water (2×20 mL), brine (15 mL) and dried (Na2SO4). Solvent was evaporated and the crude mixture was purified by column chromatography on silica gel (ethyl acetate:hexanes, 1:9) to obtain compound 4 (0.225 g, 92%) as a syrup. 1H NMR (CDCl3) δ 7.16-7.05 (m, 2H), 6.60-6.52 (m, 1H), 3.96 (s, 4H), 3.64-3.55 (m, 1H), 3.20 (t, 2H, J=5.7 Hz), 2.69 (t, 2H, J=6.0 Hz), 1.91-1.54 (m, 10H); ESI-MS (m/z, %): 352, 354 (MH+, 100).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[CH3:12][C:7]1[CH:8]=[C:9]([S:16]([Cl:15])(=[O:18])=[O:17])[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([F:13])([F:14])[F:1]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1NC(=O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)C(F)(F)F
Temperature: 155 °C
Yield: 83.4 %

Procedure:
Synthesized according to general procedure 69. A mixture of 2,2,2-trifluoro-N-o-tolylacetamide (6.3 gm, 31 mmol) and chlorosulfonic acid (10.3 mL, 155 mmol) was heated at 155° C. for 15 min. After cooling to RT, the mixture was poured into ice water and extracted with EtOAc. The organic layer was concentrated and purified via silica gel chromatography using 0-25% EtOAc in hexanes gave 3-methyl-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (7.8 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.46 (dd, J=8.1, 1.8 Hz, 1H), 7.21 (dd, J=8.1, 2.9 Hz, 1H), 2.18 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18]([OH:20])=O)[CH3:2].[CH:21]([NH:24][NH:25][C:26]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[O:27])([CH3:23])[CH3:22].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH2:17][C:18]([N:24]([CH:21]([CH3:23])[CH3:22])[NH:25][C:26]([C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[O:27])=[O:20])=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[CH:14]=1
Reactant: CCc1ccccc1-c1cc(F)ccc1OCC(=O)O
Reactant: CC(C)NNC(=O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccsc1)C(C)C
Yield: 73.4 %

Procedure:
A solution of (2′-ethyl-5-fluoro-biphenyl-2-yloxy)-acetic acid (100 mg, 0.36 mmol), and tiophene-3-carboxylic acid-N′-isopropyl hydrazide (32 mg, 0.1268 mmol) in DMF (5 mL), was treated with triethylamine (0.152 ml, 1.09 mmol), HOBT (59 mg, 0.44 mmol), and EDCI (84 mg, 0.44 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed with 1N NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (41 mg, 26%). MS m/e 441.30 (M+H+)
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:12][S:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][N:21]=1)[C:17]#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][S:13][C:14]1[CH:15]=[C:16]([C:17]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:18]=2)[CH:19]=[CH:20][N:21]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CSc1cc(C#N)ccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
Methyl thiosalicylate (0.76 g, 4.5 mmol) and 2-methylthioisonicotinonitrile (0.34 g, 2.3 mmol) were dissolved in toluene (2.0 ml). Triethylamine (0.70 ml, 5.0 mmol) was added thereto and the mixture was refluxed for 6 hrs. The reaction mixture was cooled at room temperature and the precipitated crystals were collected and recrystallized from ethanol to give the titled compound (0.11 g, 17%) as white crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].O=[C:14]([CH2:20][CH3:21])[CH2:15][C:16]([O:18][CH3:19])=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:20]([C:14]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[CH:2][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:21]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1oc(-c2ccc(OC)cc2)cc1C(=O)OC
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of 2-bromo-4′-methoxyacetophenone (13.7 g) and methyl 3-oxopentanoate (7.8 g) in toluene (100 mL) was added dropwise 1,8-azabicyclo[5.4.0]-7-undecene (9.1 mL) over 30 min or more under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 30 min under ice-cooling, and then at room temperature for 2 hr. The resulting precipitate was filtered, and washed with toluene. The obtained toluene solution was passed through silica gel, and the silica gel was washed with ethyl acetate-hexane (1:1). The collected solutions were concentrated under reduced pressure to remove ethyl acetate-hexane to give a toluene solution. To this toluene solution was added 4-toluenesulfonic acid monohydrate (2.3 g), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was washed with aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layers were collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 5% ethyl acetate/hexane) to give the title compound (9.2 g, 59%) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.[NH2:16][C:17]1[O:18][CH2:19][C@:20]2([N:37]=1)[C:33]1[CH:32]=[C:31]([OH:34])[C:30]([F:35])=[CH:29][C:28]=1[O:27][C:26]1[C:21]2=[CH:22][C:23](Br)=[CH:24][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:16][C:17]1[O:18][CH2:19][C@:20]2([N:37]=1)[C:33]1[CH:32]=[C:31]([OH:34])[C:30]([F:35])=[CH:29][C:28]=1[O:27][C:26]1[C:21]2=[CH:22][C:23]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)=[CH:24][CH:25]=1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1cc(F)c(O)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@]2(CO1)c1cc(C3=CCOCC3)ccc1Oc1cc(F)c(O)cc12
Temperature: 110 °C

Procedure:
A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (276 mg, 1.315 mmol), (S)-2-amino-7′-bromo-3′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (300 mg, 0.822 mmol), potassium phosphate (523 mg, 2.465 mmol) and Cl2Pdbis(di-tert-butyl(phenyl)phosphine) (15.28 mg, 0.025 mmol) in 3 ml of dioxane/water=2:1 was heated at 110° C. microwave for 30 min. The reaction mixture was purified by silica gel chromatography (DCM to DCM/MeOH=100:1 to 100:6) to give (R)-2-amino-7′-(3,6-dihydro-2H-pyran-4-yl)-3′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a white solid.
Reaction SMILES: [OH2:1].[OH-:2].[Li+].C(CCCC[CH2:10][CH2:11][CH2:12]/[C:13](=[N:20]\[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[O:34][C:35]=2[CH3:36])=[CH:25][CH:24]=1)/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.O.Cl>O1CCCC1.C(O)C>[CH3:36][C:35]1[O:34][C:33]([C:37]2[S:38][CH:39]=[CH:40][CH:41]=2)=[N:32][C:31]=1[CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:21]/[N:20]=[C:13](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[CH2:12][CH2:11][CH2:10][CH2:10][CH2:11][CH2:12][C:13]([OH:2])=[O:1])=[CH:24][CH:25]=1
Reactant: CCCCCCCCC/C(=N\OCc1ccc(OCc2nc(-c3cccs3)oc2C)cc1)c1ccccc1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 165.7 %

Procedure:
Lithium hydroxide monohydrate (153 mg) was added to a solution of ethyl E-8-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctane (682 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.7 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoic acid (567 mg, yield 87%) as colorless crystals. m.p. 106-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17]C(=O)OC(C)(C)C)[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C.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.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH2:17])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1)=[O:47]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCC3)C1
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: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](N)C1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
A mixture of tert-butyl [(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (15 mg, 0.045 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (19 mg, 0.054 mmol), HATU (43 mg, 0.11 mmol) and DIPEA (24 μL, 0.14 mmol) in dry DMF (0.11 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give an intermediate, which was treated with TFA (0.070 mL, 0.90 mmol). The resulting reaction mixture was stirred at room temperature for 1 h then concentrated under reduced pressure. The residue was diluted with MeOH and neutralized with small amount of NH4OH. The mixture was filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 1.5% NH4OH) to give the title compound as a white powder (7.5 mg, 35%). LCMS calc. for C23H25F2N6OS (M+H)+: m/z=471.2. Found: 471.1. 1H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.61 (s, 2H), 7.57-7.45 (m, 1H), 7.36-7.17 (m, 2H), 3.12-2.96 (m, 3H), 2.91 (t, J=9.8 Hz, 1H), 2.88-2.70 (m, 4H), 2.66-2.55 (m, 1H), 2.07-1.99 (m, 2H), 1.86-1.56 (m, 3H), 1.18-1.01 (m, 1H) ppm.
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[O:15]([C:22]1[N:27]=[C:26]([CH2:28][SH:29])[CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([Si:3]([CH3:5])([CH3:4])[CH2:2][S:29][CH2:28][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:27]=2)=[CH:7][CH:8]=1)[CH3:14]
Reactant: SCc1cccc(Oc2ccccc2)n1
Reactant: CCOc1ccc([Si](C)(C)CCl)cc1
Product: CCOc1ccc([Si](C)(C)CSCc2cccc(Oc3ccccc3)n2)cc1
Yield: 82.4 %

Procedure:
In the manner described in Example 1, 1.8 grams (8.0 mmoles) of (chloromethyl)(4-ethoxyphenyl)dimethylsilane was reacted with 1.7 grams (8.0 mmoles) of 6-phenoxy-2-pyridine methanethiol giving 3.2 grams of a light orange oil. The product was purified on a Waters® Prep 500A liquid chromatograph (silica gel) eluting with 6 percent ethylacetate in hexane, to yield 2.7 grams of (4-ethoxyphenyl)dimethyl[(((6-phenoxy-2-pyridinyl)methyl)thio)methyl]silane as a clear oil. Analytical data for this product are shown in Table VI.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6].[OH-].[Na+].CN(C)[CH:22]=[CH:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)=O>C(O)(C)C>[N+:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:17]=[C:24]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][N:16]=2)[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Reactant: CN(C)C=CC(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cccc(Nc2nccc(-c3ccncc3)n2)c1

Procedure:
1.38 g (5.68 mmol) of 3-nitrophenyl-guanidine nitrate and 0.25 g (6.24 mmol) of sodium hydroxide are added to a solution of 1 g (5.68 mmol) of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one [U.S. Pat. No. 4,281,000] in 8 ml of isopropanol. The yellow suspension is heated at reflux for 20 hours and then cooled to 0°. After washing with 30 ml of isopropanol the filtration residue is made into a slurry in succession in 15 ml of ethanol and then in 15 ml of water and filtered each time. Drying under HV yields N-(3-nitrophenyl)-4-(4-pyridyl)-2-pyrimidine-amine; m.p. 282°-284°.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[O:37]([NH2:39])[CH3:38]>O1CCCC1.O>[CH3:38][O:37][NH:39][C:28]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:16][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:34]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(C2CCc3ccccc3N2)cc1
Reactant: CON
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CONC(=O)N1c2ccccc2CCC1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
A solution of 2-phenyl-1,2,3,4-tetrahydroquinoline (2.13 g, 10.2 mmol) and triethylamine (4.26 mL, 30.5 mmol) in tetrahydrofuran (30.0 mL) was added to a solution of triphosgene (3.20 g, 10.8 mmol) in tetrahydrofuran (38.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, treated with methoxylamine hydrochloride (1.70 g, 20.3 mmol) and triethylamine (4.26 mL, 30.5 mmol), and stirred at room temperature for an additional 19 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography (100% hexanes to 70% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (2.25 g, 78%) as a racemic mixture. LCMS calculated for C17H19N2O2 (M+H)+: m/z=283.1. found: 283.1.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[OH-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>C1COCC1.CCOC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCOC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
A solution of tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate (7.0 g) in THF (30 mL) was added to a suspension of 60% sodium hydroxide (2.3 g) in THF (40 mL) under ice-cooling. At the same temperature, a THF (30 mL) solution of ethyl bromoacetate (13 mL) was added to the mixture, and the mixture was stirred overnight. After water and EtOAc were added to the reaction mixture, extraction thereof was performed using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=99:1 to 70:30), whereby tert-butyl(3R)-3-(2-ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylate (6.6 g) was obtained as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22]Br)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:15][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:18])[CH3:17]
Reactant: COC(=O)c1cc(O)cc(C(C)(C)C)c1
Reactant: CC(=O)OCC(C)(C)CBr
Product: COC(=O)c1cc(OCC(C)(C)COC(C)=O)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 1.79 g) was reacted with 3-bromo-2,2-dimethylpropyl acetate, worked up and purified analogously to 02.85. 1.01 g of the title compound were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:12]1[C:17](=[O:18])[C:16]([CH:19]2OC(C)CC[O:20]2)=[C:15]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:14]=[N:13]1)([CH3:11])([CH3:10])[CH3:9].O>C(OCC)(=O)C>[C:8]([N:12]1[C:17](=[O:18])[C:16]([CH:19]=[O:20])=[C:15]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:14]=[N:13]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC1CCOC(c2c(NCc3ccncc3)cnn(C(C)(C)C)c2=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)n1ncc(NCc2ccncc2)c(C=O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 3 ml of a trifluoroacetic acid solution of 0.22 g of 2-tert-butyl-4-(4-methyl-1,3-dioxan-2-yl)-5-(4-pyridylmethylamino)pyridazin-3-(2H)-one obtained in Preparation Example 4 (2), 0.5 ml of deionized water was thoroughly dropwise added at room temperature. The mixture was stirred at room temperature for one hour. Then, 80 ml of ethyl acetate was added to the system, and the mixture was washed with a saturated sodium chloride aqueous solution. Then, the ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to column chromatography, and using an eluent (ethyl acetate:methanol=40:1), 0.15 g of the desired product (Compound No. 24) having a melting point of from 90° to 93° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:12][C:11]2[CH:13]=[CH:14][C:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:9][CH:10]=2)=[O:30])=[CH:32][CH:33]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Nc1ccc(-c2ncccc2Cl)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(-c3ncccc3Cl)cc2)cc1
Reaction time: 1 h

Procedure:
The product from Example 41A (17.5 mg, 0.0855 mmol), DMAP (catalytic amount), and pyridine (21 μL, 0.26 mmol) were combined in CH2Cl2 (0.5 mL) and treated with 4-tert-butylbenzoyl chloride (33 μL, 0.17 mmol). After stirring for 1 hour, the mixture was diluted with saturated NaHCO3 (1 mL) and extracted with CH2Cl2 (3×1 mL). The organic layer was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (50% diethyl ether in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.59 (dd, 1H), 7.91 (br s, 1H), 7.83 (d, 2H), 7.81 (dd, 1H), 7.78 (d, 4H), 7.51 (d, 2H), 7.21 (dd, 1H), 1.36 (s, 9H); MS (m/z) 365.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:24]2[C:25]([F:37])=[C:26]([NH:30]C(=O)OCC=C)[CH:27]=[CH:28][CH:29]=2)[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC.O>ClCCl>[NH2:30][C:26]1[C:25]([F:37])=[C:24]([C:9]2[N:10]=[C:11]([C:13]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)NC(=O)OC(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution of 2-propen-1-yl (3-{5-(2-chloro-4-pyrimidinyl)-2-[1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-methylethyl]-1,3-thiazol-4-yl}-2-fluorophenyl)carbamate (1.28 g, 2.336 mmol). tri-n-butyltin hydride (0.624 mL, 2.336 mmol) in dichloromethane (DCM) (50 mL) was added tetrakis(triphenyl-phosphine)palladium(0) (0.135 g, 0.117 mmol) followed by water (0.2 mL). After 30 min, the reaction was concentrated. The residue was purified via chromatography on silica gel to obtain the title compound (0.81 g 74% yield). MS (ESI): 464.1 [M+H]+
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:6]([NH2:7])=[C:5]([Cl:11])[CH:4]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[Br:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:6]([NH:7][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[C:5]([Cl:11])[CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1c(Cl)cc(Br)cc1Cl
Temperature: 40 °C
Reaction time: 28 h
Yield: 96.6 %

Procedure:
12.0 g (50.0 mmol) of 4-bromo-2,6-dichloroaniline hydrochloride was dissolved in 50 mL of pyridine, 9.90 mL (80.0 mmol) of pivaloyl chloride and 0.61 g (5.0 mmol) of N,N-dimethylaminopyridine were added and the mixture was stirred at 40° C. for 28 hours. Thereafter, substantially the same manner as that in Reference Example (1) was repeated to give 15.7 g of 4-bromo-2,6-dichloro-N-pivaloylaniline (yield: 97%).