Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:26]([O:29][CH2:30]Br)(=[O:28])[CH3:27]>CN(C=O)C>[C:26]([O:29][CH2:30][O:18][C:17]([C:9]1[NH:10][C:11]2[C:16]([C:8]=1[NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])(=[O:28])[CH3:27]
Reactant: CC(=O)OCBr
Reactant: O=C(O)c1[nH]c2ccccc2c1Nc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Stir at 50° C. for 10 min. a mixture of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid (1.27 g, 5 mmol) in DMF (25 mL), and add Cs2CO3 (1.63 g, 5 mmol). After 10 min. add bromomethyl acetate (0.95 g, 6.21 mmol) and one minute thereafter quench into aqueous NH4Cl solution. Extract with EtOAc and wash the extract with aqueous NaHCO3 solution. Dry the extract (MgSO4), filter and concentrate under vacuum to give a solid. Triturate the solid with EtOAc and obtain the title compound as a solid: MS 326(M+H).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[CH2:34]([OH:37])[C:35]#[CH:36]>>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:36]#[C:35][CH2:34][OH:37])[CH:3]=1
Reactant: C#CCO
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCO)c(OCc1ccccc1)c2=O
Yield: 84.4 %

Procedure:
Reaction of intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.563 g, 1.00 mmol) with propargyl alcohol (0.18 ml, 3.2 mmol) using the conditions described for intermediate 178 gave 0.415 g (85% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.39 (2H, d, J=6.6 Hz, CH2), 4.68 (2H, d, J=6.0 Hz, CH2), 5.29 (2H, s, OCH2), 6.99 (1H, m, aromatic), 7.13 (1H,dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.22 (1H,dd, J=5.6 Hz and J=8.6 Hz, aromatic), 7.33–7.37 (3H, m, aromatics), 7.44–7.47 (2H, m, aromatics), 7.68 (1H, broad t, NH). HRMS (ESI+) calculated for C27H27FN3O5 [M+H+]: 492.1935. found: 492.1939.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[C:22](O)=[O:23]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([C:21]2[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:19]([O:18][CH3:17])[CH:20]=2)[OH:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: COc1cc(OC)cc(C(=O)O)c1
Product: COc1cc(OC)cc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)c1

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 3,5-dimethoxybenzoic acid
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([O:15][C:16](OC1CC(=O)NC1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[C:16]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: OCCNCCO
Reactant: O=C1CC(OC(=O)OCc2ccccc2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N(CCO)CCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a 0° C. solution of diethanolamine (1.9 ml, 20 mmol) in 50 ml of THF was added benzyloxycarbonyloxysuccinimide (5.0 g, 20 mmol) followed by the slow addition of a solution of sodium carbonate (3.2 g, 30 mmol) in 50 ml of water. The reaction was stirred at 0° C. for 2 hours, diluted with 50 ml of water, and the majority of the THF was removed under vacuum. The reaction mixture was extracted with ethyl acetate (2×75 ml), washed with brine and dried over sodium sulfate. The solvent was concentrated and the residue was purified by SiO2 chromatography (250 g SiO2, 8% MeOH/methylene chloride) to give N-Cbz-diethanolamine (4.25 g) as a clear oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15].[CH:16]([C:18]([CH2:20][CH3:21])=[O:19])=[CH2:17].C[O-].[Na+]>CO.CCOC(C)=O>[OH:1][CH2:2][CH2:3][C:4]1([CH2:17][CH2:16][C:18](=[O:19])[CH2:20][CH3:21])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15]
Reactant: C=CC(=O)CC
Reactant: COc1ccc2c(c1)CC(CCO)C2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(=O)CCC1(CCO)Cc2cc(OC)ccc2C1=O
Temperature: 60 °C
Yield: 93 %

Procedure:
A solution of 2-(2-hydroxyethyl)-5-methoxy-1-indanone (105 mg, 0.51 mmol) in methanol (2.0 mL) at room temperature was treated with ethyl vinyl ketone (EVK, 0.102 mL) and 0.5M sodium methoxide in methanol (0.204 mL, 0.1 mmol). The mixture was stirred in a capped flask and heated in an oil bath at 60° C. for 8 hours. After cooling, the reaction mixture was diluted with EtOAc (25 mL), washed with 0.2N HCl (15 mL), water (15 mL), and brine (15 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford 2-(2-hydroxyethyl)-5-methoxy-2-(3-oxopentyl)-1-indanone (138 mg, 93% yield) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][OH:17])=[N:8]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([OH:24])=[O:23].[H-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][O:17][CH2:21][C:22]([OH:24])=[O:23])=[N:8]2)=[CH:18][CH:19]=1
Reactant: O=C(O)CBr
Reactant: OCc1nn(Cc2ccc(F)cc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COCc1nn(Cc2ccc(F)cc2)c2ccccc12
Temperature: 0 °C
Yield: 57.8 %

Procedure:
A suspension containing [1-(4-fluorobenzyl)-1H-indazol-3-yl]methanol (6 g; 0.022 mol), bromoacetic acid (4 g; 0.03 mol) and 50% NaH (3 g; 0.066 mol) in THF (170 ml) was stirred at reflux for 72 hours. The reaction was then stopped by diluting with a suspension with water and ice (300 ml) and washing the aqueous phase with diethyl ether (3×150 ml). The aqueous phase was acidified with concentrated HCl. The solid thus formed was filtered off and purified by crystallization from isopropanol. 4 g of {[1-(4-fluorobenzyl)-1H-indazol-3-yl]methoxy}acetic acid were thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)=O)[CH3:2].[CH:16]1([O:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[CH2:1]([O:3][C:4](=[O:15])/[C:5](=[N:22]/[O:21][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)/[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:2]
Reactant: NOC1CCCC1
Reactant: CCOC(=O)C(=O)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: CCOC(=O)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
(3,4-Dichloro-phenyl)-oxo-acetic acid ethyl ester (1.08 g, 4.37 mmol) was stirred in ethanol (9.7 mL) and warmed in a 70° C. oil bath. O-Cyclopentyl-hydroxylamine (prepared as in Example 1, 722 mg, 5.25 mmol) was added. After 2 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 33% methylene chloride/hexanes) afforded (E)-cyclopentyloxyimino-(3,4-dichloro-phenyl)-acetic acid ethyl ester (371 mg, 26%) as a clear, colorless oil: H1-NMR (400 MHz, CDCl3) δ=1.37 (3H, t, J=7.1 Hz), 1.63 (4H, m), 1.85 (4H, m), 4.36 (2H, q, J=7.1 Hz), 4.94 (1H, m), 7.26 (1H, dd, J=8.3 Hz, J=1.9 Hz), 7.46 (1H, d, J=8.3 Hz), 7.54 (1H, d, J=1.9 Hz).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([O:21][C:22]([N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C:30]([OH:32])=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[CH2:14]([O:21][C:22]([N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C:30]([Cl:35])=[O:32])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: Cc1ccccc1
Product: O=C(Cl)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
50 g (0.113 mol) of the previously obtained dicyclohexylamine salt of N-benzyloxycarbonyl-(L)-pyroglutamic acid are mixed to a paste with 1 liter of toluene, 110 ml of thionyl chloride are run in dropwise and the temperature is then raised to 60° C. for 2 hours. The mixture is cooled and filtered, the filtrate is evaporated and the residue is taken up several times with benzene. The acid chloride finally crystallizes from petroleum ether with a practically quantitative yield. Melting point=65°-70° C. (literature=71/72° C.).
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:4]=2[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>>[Cl:14][C:12]1[CH:11]=[CH:10][C:5]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)=[N:3][C:4]=2[CH:13]=1
Reactant: CC(C)n1c(Cl)nc2cc(Cl)ccc21
Reactant: CN1CCNCC1
Agent: Cl
Product: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)ccc21
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 46.9 %

Procedure:
A mixture of 2,5-dichloro-1-isopropylbenzimidazole (7 g) and N-methylpiperazine (10 g) was stirred at 140° C. for 3.5 hours. After cooling, 2N hydrochloric acid was added to the mixture and the mixture was washed with ethyl acetate. The 2N hydrochloric acid layer was made basic with an aqueous 2N sodiumhydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to give 5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)benzimidazole (4.2 g). A part of the obtained product was recrystallized from acetonitrile, which showed the following physical properties:
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)CC1.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([O:23][CH3:1])=[O:22])[CH2:18]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.7 %

Procedure:
To a solution of DCC (5.96 g, 28.95 mmol) in DCM (20 ml) was added dropwise a mixture of 3-oxocyclobutanecarboxylic acid (3.0 g, 26.31 mmol), MeOH (1.68 g, 52.62 mmol) and DMAP (2.57 g, 21.05 mmol) in DCM (30 ml). The reaction mixture was stirred at RT overnight. The mixture was filtrated. The filtrate was washed with 0.5 M HCl solution (50 ml). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by SGC (PE: EA=5:1) to obtain the title compound (4.0 g). 1H N.R (500 MHz, CDCl3): δ 3.77 (s, 3H), 3.42-3.26 (m, 5H) ppm.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@@:24]([CH2:27][OH:28])([CH3:26])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Si:42](Cl)([CH3:45])([CH3:44])[CH3:43].O>ClCCl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@:24]([CH3:26])([CH2:27][O:28][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(CO)N2
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(CO[Si](C)(C)C)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
To a solution of (2S,5S,7R)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-7-(4-fluoro-2-methylphenyl)-2-(hydroxymethyl)-N,2-dimethyl-1,8-diazaspiro[4.5]decane-8-carboxamide (Example 19, 80 mg, 0.136 mmol) in dichloromethane (DCM) (2 ml), TEA (0.021 ml, 0.149 mmol) was added and the reaction mixture was stirred at 0° C. for 5 min. TMS-Cl (0.026 ml, 0.204 mmol) was added dropwise and mixture was stirred at the same temperature overnight. Water (2 ml) was added and two phases were separated. The organic layer was dried and evaporated in vacuo affording the title compound (88 mg) that was used in the next step without further purifications.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][CH3:14])[CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:25](O)[CH3:26]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][CH3:14])[CH2:9][C:10]([O:12][CH2:25][CH3:26])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CNC(CC(=O)O)c1cccc(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CC(NC)c1cccc(O)c1

Procedure:
3-(3-Hydroxyphenyl)-3-methylaminopropionic acid (24.1 g) obtained from Example 7a was dissolved in ethanol (200 ml), and concentrated sulfuric acid (10 ml) was added dropwise to the solution. The resulting mixture was heated under reflux for 8 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution and the solvent was removed under reduced pressure. The residual aqueous solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired compound which was used in next step reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.CO>CN(C=O)C>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[CH:32]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cccnc4)cc3)[nH]2)c1
Yield: 18.2 %

Procedure:
4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 2 mL of anhydrous DMF in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (203.4 mg, 0.62 mmol) was added, followed by 3-bromopyridine (74.0 mg, 0.468 mmol). The vial was capped and microwaved at 250° C. for 30 min. Then ca. 1 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a yellow solid (22.4 mg).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1.Cl.C(OCC)(=O)C>C1COCC1>[OH:15][C:9]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=CCCC1
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.96 g (10 mmol) of 2-cyclohexen-1-one in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 10 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.61 g of the desired product (yield 94%).
Reaction SMILES: [F:1][C:2]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([F:26])[C:3]=1[NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:13]=1)[C:9]#[N:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[C:9]([C:8]1[CH:7]=[C:6]([CH2:5][NH:4][C:3]2[C:2]([F:1])=[C:24]([CH:23]=[CH:22][C:21]=2[F:26])[O:25][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:11]=1)#[N:10]
Reactant: N#Cc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(C#N)cc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of 3-[(2,6-Difluoro-3-hydroxy-anilino)methyl]-5-(3-fluorophenyl)benzonitrile (280 mg, 0.8 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (550 mg, 4 mmol, 5 eq). The solution was stirred at room temperature for 30 min, then ethyl bromoacetate (200 mg, 1.2 mmol, 1.5 eq) was added dropwise. The reaction was stirred overnight, then water was added and the aqueous phase extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 15:1) to give the title compound as colorless oil (300 mg, 86%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43](=[O:47])[NH:42][CH:41]=[CH:40]2.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][CH2:55][N:56]([CH2:61][C:62]2[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=2)[CH2:57][CH2:58][CH2:59]O)[CH:49]=1.C(OC(=O)C)C.[ClH:74]>C(OCC)(=O)C.O1CCCC1>[ClH:74].[ClH:74].[ClH:74].[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][CH2:55][N:56]([CH2:61][C:62]2[CH:63]=[CH:64][N:65]=[CH:66][CH:67]=2)[CH2:57][CH2:58][CH2:59][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[C:43](=[O:47])[NH:42][CH:41]=[CH:40]3)[CH:49]=1
Reactant: O=c1[nH]ccc2cc(O)ccc12
Reactant: OCCCN(CCc1cccnc1)Cc1ccncc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]ccc2cc(OCCCN(CCc3cccnc3)Cc3ccncc3)ccc12
Reaction time: 8 h

Procedure:
Triphenyl phosphine (51 mg) and di-tert-butyl azodicarboxylate (45 mg) were added to a tetrahydrofuran (THF) solution (1.5 ml) of 6-hydroxy-2H-isoquinolin-1-one (29 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol (40 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.06 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and was dried to produce the title compound (31.4 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[CH:26][C:7]2[CH:8]3[CH2:14][CH2:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[C:16]=4[F:25])=[CH:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:28])[CH3:2].C(OC1C=CC2C3CC=C(C4C=CC(OCC)=C(F)C=4F)CC3OC=2C=1F)C>C(OCC)(=O)C.C(O)C.[Ni]>[CH2:1]([O:3][C:4]1[CH:27]=[CH:26][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[C:16]=4[F:25])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:28])[CH3:2]
Reactant: CCOc1ccc(C2=CC3Oc4c(ccc(OCC)c4F)C3CC2)c(F)c1F
Agent: [Ni]
Agent: CCOc1ccc(C2=CCC3c4ccc(OCC)c(F)c4OC3C2)c(F)c1F
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1ccc(C2CCC3c4ccc(OCC)c(F)c4OC3C2)c(F)c1F
Reaction time: 18 h

Procedure:
7.4 g (about 19.0 mmol) of a mixture of (±)-(4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,2,4a,9b-tetrahydrodibenzofuran and (±)-(4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,4,4a,9b-tetrahydrodibenzofuran in 160 ml of ethyl acetate/ethanol mixture (3:1) are hydrogenated at 80° C. in the presence of 3.70 g of Raney nickel and 1.50 g of ion exchanger (weakly H-acidic) under hydrogen pressure (4.4 bar). After 18 h, the catalyst is filtered off, and the filtrate is concentrated to dryness. The crude product is recrystallised successively from isopropanol, n-heptane and ethanol, giving (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 126° C.).
Reaction SMILES: C(O)C.[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]#[N:20])=[N:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[OH:22][NH3+:23].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([NH:23][OH:22])=[NH:20])=[N:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [NH3+]O
Reactant: N#CCc1ccc(OCc2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(Cc1ccc(OCc2ccccc2)cn1)NO
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
To an ethanol (30 mL) solution of (5-benzyloxy-pyridin-2-yl)-acetonitrile (1.77 g, 7.89 mmol) described in Manufacturing Example 127-1-4 were added hydroxylammonium chloride (848 mg, 11.8 mmol) and potassium carbonate (2.18 g, 15.8 mmol), which was stirred for 11 hours and 20 minutes at 70° C. The mixture was then stirred for another 5 hours and 45 minutes under reflux. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (550 mg, 27%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH2:13]>CO.O>[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH:13][C:2]1[N:7]=[C:6]([NH:13][C:12]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:11]=2[CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Solvent: O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(F)c(Nc2cc([N+](=O)[O-])ccc2C)n1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (33 mg, 0.2 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 2-Methyl-5-nitroaniline (122 mg, 0.8 mmol) was added and the mixture was refluxed for 2 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 8.31 (d, 1H, J=2.3 Hz), 8.20 (d, 1H, J=2.3 Hz), 8.06 (d, 1H, J=3.5 Hz), 7.91 (dd, 1H, J=2.3, 8.2 Hz), 7.65 (dd, 1H, J=2.9, 8.8 Hz), 7.41 (m, 1H), 7.28 (d, 1H, J=8.2 Hz), 2.28 (s, 3H), 2.24 (s, 3H); LCMS purity: 87.4%; MS (m/e): 399.20 (M+, 100).