Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(Cl)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(N3CCCC3)c(Cl)cc2N1

Procedure:
The title compound was prepared from (RS)-[4-chloro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-5-pyrrolidin-1-yl-phenyl]-carbamic acid tert.-butyl ester (Example M30) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (58 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:54]=[CH:53][C:8]([C:9]([O:24][CH2:25][C@H:26]2[O:30][C@@H:29]([N:31]3[CH:39]=[C:37]([CH3:38])[C:35](=[O:36])[NH:34][C:32]3=[O:33])[CH2:28][C@:27]2([CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)[OH:40])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13](OC)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.C1C[O:58][CH2:57]C1>>[CH3:57][O:58][C:13]1[CH:12]=[CH:11][C:10]([C:9]([O:24][CH2:25][C@H:26]2[O:30][C@@H:29]([N:31]3[CH:39]=[C:37]([CH3:38])[C:35](=[O:36])[NH:34][C:32]3=[O:33])[CH2:28][C@:27]32[CH2:41][O:40]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:53]=[CH:54][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)COS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]23CO3)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of NaH (60% in mineral oil, 0.18 g; 7.5 mmol) in anhydrous THF (18 ml) at 0° C. under argon was added dropwise a solution of 5′-O-(4,4′-dimethoxytrityl)-3′-p-toluensulfonyloxymethylthymidine (1.5 g; 2.06 mmol) in THF (10 ml). The resulting reaction mixture was stirred at room temperature for 2 h, cooled to 0° C., and quenched by addition of water. The mixture was diluted with EtOAc (250 ml), washed with water (2×200 ml), then with 10% NaHCO3 (2×200 ml), dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica (5% CH3OH in CH2Cl2) to yield 0.97 g (85%) of 5′-O-(4,4′-dimethoxytrityl)-3′-C,O-methylene thymidine as a foam.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[C:16]4[CH2:19][CH2:20][CH2:21][C@@H:22]5[CH2:27][C@@:26]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:25][CH2:24][C@@:23]5([C:33]#[N:34])[C:15]4=[CH:14][C:13]=3[CH:12]=[N:11]2)=[CH:6][CH:5]=1.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:36]([O:32][C@@:26]1([C:28]([F:31])([F:30])[F:29])[CH2:27][C@H:22]2[CH2:21][CH2:20][CH2:19][C:16]3[C:15](=[CH:14][C:13]4[CH:12]=[N:11][N:10]([C:7]5[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=5)[C:18]=4[CH:17]=3)[C@:23]2([C:33]#[N:34])[CH2:24][CH2:25]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: N#C[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60 wt % in oil, 103 mg, 2.57 mmol) in DMF (5 mL) was added a solution of (3R,4aR,12bS)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (32, R1=4-Fluorophenyl, R3=Trifluoromethyl) (760 mg, 1.71 mmol) in DMF (15 mL) at a dropwise rate. The reaction was stirred for about 10 min at rt, then (bromomethyl)benzene (0.26 mL, 2.14 mmol) was added. The mixture was stirred for about 1 h. Solvents were removed under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with water (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated onto silica gel (10 g). The crude product was purified on silica gel (40 g) using a gradient of 20-40% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to yield (3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (33, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rx=Benzyl) (890 mg, 97%) as a white solid; LC/MS, method 3, Rt=3.08 min, MS m/z 534 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=0.8 Hz, 1H), 8.12 (s, 1H), 7.86-7.78 (m, 2H), 7.71 (s, 1H), 7.48-7.29 (m, 7H), 4.80-4.66 (m, 2H), 3.41-3.31 (m, 1H), 3.13-3.01 (m, 1H), 2.74-2.62 (m, 1H), 2.61-2.51 (m, 1H), 2.29-2.22 (m, 1H), 2.18-1.93 (m, 4H), 1.89-1.70 (m, 3H), 1.42-1.27 (m, 1H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-:18].O.[CH2:20]([O:27][C:28]1[CH:51]=[C:50]([Cl:52])[C:31]([CH2:32][C@@H:33]2[CH2:37][CH2:36][N:35]([C@H:38]3[CH2:43][CH2:42][C@H:41](OS(C)(=O)=O)[CH2:40][CH2:39]3)[C:34]2=[O:49])=[C:30]([Cl:53])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:27][C:28]1[CH:51]=[C:50]([Cl:52])[C:31]([CH2:32][C@@H:33]2[CH2:37][CH2:36][N:35]([C@H:38]3[CH2:43][CH2:42][C@@H:41]([F:18])[CH2:40][CH2:39]3)[C:34]2=[O:49])=[C:30]([Cl:53])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Dissolve TBAF.3H2O (1.595 g, 1.30 mmol) in 10 ml of acetonitrile. Add water (0.18 ml, 9.91 mmol) and stir for 10 minutes. Add (R)-trans-Methanesulfonic acid 4-[3-(4-benzyloxy-2,6-dichloro-benzyl)-2-oxo-pyrrolidin-1-yl]-cyclohexyl ester (Preparation 14) (1.30 g, 2.48 mmol). Stir at 80° C. for 12 hours. Quench with saturated NaHCO3 and extract with ethyl acetate. Wash the extract with brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.230 g (21%) of the title compound: Mass spectrum (apci) m/z=450 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]#[N:4].[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:3]([CH:2]([NH:1]/[C:20](/[CH3:22])=[CH:19]/[C:18]([O:24][CH2:25][CH3:26])=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:4]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#CC(N)c1ccccc1Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(\C)NC(C#N)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Yield: 98.5 %

Procedure:
A mixture of Example 85a (1.063 g, 4.74 mmol), ethyl acetoacetate (0.602 mL, 4.74 mmol), and p-toluenesulfonic acid (0.05 g, 0.263 mmol) in toluene (10 mL) was heated at 80° C. for 4 hours. The reaction mixture was cooled to 0° C. and added to cold saturated NaHCO3. The mixture was extracted with ethyl acetate (2×). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.57 g, 98% yield) which was used without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:23][CH2:24][O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:23][CH2:24][O:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCOCCc1ccccc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCOCCOc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
10 g of 4-benzyloxyphenol in 120 ml of dimethylformamide were treated with 2.4 g of a 50% sodium hydride dispersion in mineral oil and the mixture was stirred for 5 minutes. 12.2 g of 2-(2-phenylethoxy)ethyl methanesulfonate [prepared as described in Example 1(a)] were added and the mixture was heated at 60° C. for 0.5 hour with stirring. The mixture was evaporated to dryness and the residue was partitioned between 2N sodium hydroxide and ethyl acetate. The organic phase was separated, washed well with water, dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from methylcyclohexane to give 16.1 g (93%) of 1-benzyloxy-4-(2-phenethyloxyethoxy)benzene of melting point 46°-49° C.
Reaction SMILES: C(O[C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:15])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 260 °C
Yield: 74.2 %

Procedure:
31.7 g (147 mmol) of 2-Ethoxymethylene-malonic acid diethyl ester and 13.7 g (147 mmol) of aniline were stirred neat at 110° C. for 1 h, then 300 mL of diphenyl ether was added and the temperature of the oil bath was raised to 260° C. for 2 h. The solution was then cooled down to rt, diluted with 600 mL of hexanes and filtered. The solids were washed with 200 mL of hexanes and dried to yield 23.7 g of the product as a light brown powder. LC-MSD, m/z for C12H11NO3 [M+H]+=218.2, HPLC retention time: 2.5 min.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[H-].[Na+].CN(C)C=O.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:1]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:11])[O:3][C:2]2=[O:12])=[CH:24][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)oc(=O)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2H-3,1-benzoxazine-2,4(1H)-dione (18.7 g), sodium hydride (an oily, about 66%, 4.8 g) and N,N-dimethylformamide (70 ml) was added dropwise 4-methoxybenzyl chloride (17.6 ml), stirred at room temperature for 1 night. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and a saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the target compound (26.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14][Mg]Br.C(OCC)(=O)C.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([OH:13])[CH3:14])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: C[Mg]Br
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cc(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (4.1 mmol) of 5-bromo-3-formyl-2-hydroxy-benzoic acid was dissolved in 100 mL of anhydrous THF under nitrogen. The solution was cooled in an ice-bath and 13.6 ml of a 3 M solution of methyl magnesium bromide was added. The mixture was stirred for 16 h, slowly warming to room temperature. The resulting solution was distributed between ethyl acetate and dilute aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and evaporated to afford 1.09 g of 5-bromo-2-hydroxy-3-(1-hydroxy-ethyl)-benzoic acid as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.76 (d, 1H), 7.72 (d, 1H), 4.98 (q, 1H), 1.30 (d, 3H), MS: m/z 258.9+261.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[N:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: NCCN1CCCC1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Agent: Cl
Product: COc1ccc2c(c1)CCn1c-2cc(NCCN2CCCC2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6, 1-a]isoquinolin-4-one (4) and 2-pyrrolidin-1-yl-ethylamine as in Example 1 d, followed by treatment with HCl. 1H-NMR (400 MHz, dB-DMSO) δ 7.64 (d, 1H), 7.59 (br, 1H), 7.00-6.92 (2H), 6.18 (s, 1H), 3.92 (t, 2H), 3.82 (s, 3H), 3.46 (m, 2H), 2.91 (t, 2H), 2.90-2.50 (6H) and 1.76 (4H); MS (ESI) (M+H)+ 341.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1Cl.FC1C=CC(C=O)=C([C:23]([F:26])([F:25])[F:24])C=1>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[C:23]([F:26])([F:25])[F:24]
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Product: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
The titled compound is prepared analogously to 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene by replacing 2-chloro-4-fluorobenzaldehyde (step 90a) with 4-fluoro-2-trifluoromethylbenzaldehyde.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:13]=1)[CH:11]=O>CO.[Pt]>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:13]=1)[CH2:11][NH:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CC(C)c1ccc(Cl)cc1C=O
Reactant: NC1CC1
Agent: [Pt]
Solvent: CO
Product: CC(C)c1ccc(Cl)cc1CNC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Cyclopropylamine (3.26 g, 0.057 mol) was added to a solution of 5-chloro-2-isopropylbenzaldehyde (II) (10 g, 0.054 mol, 99.3 GC % by area) in methanol (100 ml) and the mixture was stirred at room temperature for 1 hour. Platinum on activated carbon (0.2 g, 5% Pt, dry) was subsequently added, the reaction vessel was flushed with nitrogen and pressurized to 6 bar with hydrogen at a maximum of 25° C. for 8 hours. The contents of the autoclave were filtered through Celite, washed with methanol and the solvent was distilled off under reduced pressure. N-(5-Chloro-2-isopropylbenzyl)cyclopropanamine (9.8 g, 96.8 GC-% by area, 78.0% of theory) was obtained as a light-yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2[O:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[O:11])[N:3]=[CH:2]1.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2[O:8][CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[OH:11])[N:3]=[CH:2]1
Reactant: O=C(COc1ccccc1-c1c[nH]cn1)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(COc1ccccc1-c1c[nH]cn1)c1cccc(Br)c1
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a solution of 2-(2-(1H-imidazol-4-yl)phenoxy)-1-(3-bromophenyl)ethanone (0.025 g, 0.0699 mmol) in MeOH (2 mL) at room temperature, was added NaBH4 (0.349 mmol) and the resulting suspension was stirred for 1.5 h. The reaction was quenched by adding 1N HCl followed by basification with saturated Na2CO3 solution. The product was extracted with EtOAc (3×10 mL), organic extract was dried (Na2SO4) and concentrated under reduced pressure to afford yellow solid. The crude was subjected to column chromatography to afford the final product. Yield 84%. 1H NMR: 3.48 (s, 1H), 4.08 (t, 1H, J=9.39 Hz), 4.40 (dd, 1H, J=3.06, 6.69 Hz), 5.18 (dd, 1H, J=3.48, 5.85 Hz), 6.97 (d, 1H, J=7.59 Hz), 7.04 (d, 1H, J=7.59 Hz), 7.19-7.28 (m, 3H), 7.40 (d, 1H, J=8.73 Hz), 7.46 (d, 1H, J=7.80 Hz), 7.55-7.59 (m, 2H), 7.66 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([OH:20])[CH:22]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1OC
Reactant: Nc1cccc(O)c1
Product: COc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with 3-hydroxyaniline gave N4-(3,4-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.77 (d, 1H, J=3.3 Hz), 7.15 (d, 1H, J=2.4 Hz), 7.05 (dd, 1H, J=2.4 and 8.4 Hz), 7.00-6.90 (m, 4H), 6.80 (d, 1H, J=8.1 Hz), 6.40 (m, 1H), 4.05 (q, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.20 (t, 3H); 19F NMR (CD3OD): −47223; LCMS: ret. time: 17.94 min.; purity: 99%; MS (m/e): 357 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[CH3:24])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[Cl:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[CH3:24]
Reactant: CC(c1cnc(OCC(C)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Reactant: O=COc1ccccc1
Product: CC(c1cnc(OCC(C)(F)F)c(Cl)c1)N1Cc2c(ccnc2C(=O)Oc2ccccc2)C1=O
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (230 mg, pale brown solid) from 4-chloro-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.62 mmol, Intermediate-80, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[N:15]=[C:14](O)[CH:13]=[C:12]([CH3:17])[N:11]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:14]1[CH:13]=[C:12]([CH3:17])[N:11]=[C:10](/[CH:9]=[CH:8]/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:15]=1
Reactant: Cc1cc(O)nc(/C=C/c2cccc(Cl)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(/C=C/c2cccc(Cl)c2)n1
Temperature: 130 °C
Yield: 70.9 %

Procedure:
0.246 g (1 mmol) of (E)-2-[2-(3-chloro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol were treated with 1.83 ml (20 mmol) of POCl3 and subsequently heated at 130° C. for 4.5 hours. The mixture was cooled to RT, concentrated in vacuo and the residue was partitioned between EtOAc, water and saturated KHCO3. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo. The residue was applied to a short silica gel column with CH2Cl2/hexane (3:2) as eluent. Combination of the purified fractions and concentration in vacuo gave 188 mg (71%) of the desired (E)-4-chloro-2-[2-(3-chloro-phenyl)-vinyl]-6-methyl-pyrimidine as a white solid. EI mass spectrum, m/e: 264 (M calculated for C13H10Cl2N2: 264)
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([C:12]([O:14]CC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.[Cl:23][C:24]1[CH:30]=[C:29]([S:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])(=[O:33])=[O:32])[CH:28]=[CH:27][C:25]=1[NH2:26]>C1(C)C(C)=CC=CC=1>[Cl:23][C:24]1[CH:30]=[C:29]([S:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])(=[O:32])=[O:33])[CH:28]=[CH:27][C:25]=1[NH:26][C:12](=[O:14])[CH:6]([N:5]1[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]2[C:1]1=[O:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)N1C(=O)c2ccccc2C1=O
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(N)c(Cl)c1
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(NC(=O)C(C(=O)OCC)N2C(=O)c3ccccc3C2=O)c(Cl)c1

Procedure:
Diethyl 2-phthalimidomalonate (obtained from Aldrich Chemical Company Limited) (9.8 g, 32.0 mmol) and 2-chloro-4-dodecylsulphonylaniline (11.5 g, 32.0 mmol) were added to xylene (250 ml) and refluxed under a Dean and Stark trap for 96 hr. The distillate was periodically removed and the main bulk of solvent replenished as necessary. Removal of the xylene solvent under reduced pressure afforded a light brown oil which was purified by column chromatography using a 4:1 mixture of 60-80° C. petroleum ether:ethyl acetate and silica gel. The product, coupler (C13), was obtained as a white solid which was slurried with a little petroleum ether, filtered and dried in air, 13.6 g, 67%.
Reaction SMILES: Cl[C:2]1[C:8]([F:9])=[CH:7][C:6]([F:10])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[H][H]>[C].[Pd].O>[F:9][C:8]1[CH:2]=[C:3]([CH:5]=[C:6]([F:10])[CH:7]=1)[NH2:4]
Reactant: Nc1cc(F)cc(F)c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cc(F)cc(F)c1
Temperature: 50 °C
Yield: 92 %

Procedure:
Into a 500 ml SUS autoclave, 45.4 g (purity: 98%, 0.272 mol) of 2-chloro-3,5-difluoroaniline, 1.84 g of 5% palladium-carbon, 30.2 g (0.299 mol) of triethylamine and 45.4 g of water were introduced, and hydrogen gas was sealed in. Then, the mixture was reacted under a hydrogen gas pressure of 15 kg/cm2 at a temperature of 100° C. for 4 hours. Then, the reaction solution was cooled to 50° C. Then, palladium-carbon was filtered off, and 50 g of a 25% sodium hydroxide aqueous solution was added. The mixture was stirred and left to stand still. Then, the oil layer was separated. Then, this oil layer was distilled to recover 28.5 g of triethylamine, and then 32.3 g (purity: 99%, yield: 91.0%) of 3,5-difluoroaniline was obtained.
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)[CH2:2]CCC.[F-].O.O.O.[C:22]1([CH3:29])[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1.O>CS(C)=O>[CH2:26]([C:27]1[CH2:22][CH:29]=1)[CH2:25][CH2:24][CH2:23][CH2:28][CH3:2]
Reactant: Cc1ccccc1C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCC1=CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In situ, 0.586 g (2.0 mmol) of (trans)-1-hexyl-1-(methane sulfonyloxy)-2-(trimethylsilyl)cyclopropane of Preparation Example 9 was dissolved in 2.0 ml of DMSO, 0.94 g of Bu4NF.3H2O was added thereto and the resulting mixture was vigorously stirred at room temperature for one hour. 8.0 ml of xylene and 5.0 ml of water were added to the reaction solution and vigorously stirred for 5 minutes and stood. When the mixture was separated into a xylene layer (upper layer) and an aqueous layer (lower layer), only the xylene layer was collected and the aqueous layer was discarded. 1.0 g of sodium dodecylbenzenesulfonate and 1.0 g of tristyrenylphenykethoxy)12ethanol were added to the xylene layer, stirred for 5 minutes, 2.0 L of water was added thereto and the resulting mixture was slowly stirred such that it was homogeneously mixed. As a result, a 1.0 mM 1-hexylcyclopropene formulation was prepared. This solution was diluted to 1 to 100 times prior to use, as necessary.