Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].[Cl:14][CH2:15][Si:16]([CH2:19]Cl)([CH3:18])[CH3:17].C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[Cl:14][CH2:15][Si:16]([CH2:19][C@H:7]1[C:6]([O:12][CH3:13])=[N:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[C:9]([O:10][CH3:11])=[N:8]1)([CH3:18])[CH3:17]
Reactant: C[Si](C)(CCl)CCl
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[Si](C)(C)CCl
Temperature: 25 °C
Yield: 43.2 %

Procedure:
To a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (7.0 g, 38 mmol), bis(chloromethyl)dimethylsilane (6.0 g, 38 mmol) in THF (150 mL) was added n-butyl-lithium (20 mL, 50 mmol) at −65 to −75° C. dropwise. The mixture was allowed to gradually warm to RT overnight. An ammonium chloride solution at 0° C. was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (2% EtOAc in petroleum ether) to give the title intermediate (5 g, 44% yield) as a clear oil 1H NMR: (MeOD, 400 MHz) δ(ppm): 4.15 (m, 1H), 3.99 (m, 1H), 3.72 (m, 6H), 2.95 (m, 2H), 2.30 (m, 1H), 1.45 (m, 1H), 1.08 (m, 4H), 0.75 (m, 3H), 0.26 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][N:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>C1COCC1.[Pd](Cl)Cl.[Cu](I)I>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(Cl)nc1Cl

Procedure:
66.55 g of 2,4-dichloro-5-iodo-pyrimidine is stirred for three hous in 1.2 litres of absolute THF with 70 ml of triethylamine, 4.9 g of palladium chloride, 13.3 g of triphenylphosphine, 4 g of copper iodide and 39.3 ml of trimethylsilylacetylene at 40° C. After the reaction has ended the solvent is eliminated in vacuo and the dark red oil remaining is subjected to fractional distillation. The product is distilled over at 0.01 Torr and 100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:37][C:38]([O:40][CH3:41])=[O:39]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(Cl)cc2F)c1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
100 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (described later, produced in Intermediate Production Example 2) was dissolved in 1 ml of N,N-dimethylformamide, and to this was added 34 mg of anhydrous potassium carbonate, and 37 mg of methyl bromoacetate was added with stirring at room temperature, then, the mixtures was stirred for 1 hours at 60° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 110 mg of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [Compound 2-11 of the present invention].
Reaction SMILES: C([O:8][CH2:9][C@H:10]([NH:22][C:23](=[O:40])[C@@H:24]([NH:30][C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.Cl.[H][H]>CO.O1CCOCC1.[Pd]>[F:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH2:11][C@@H:10]([NH:22][C:23](=[O:40])[C@@H:24]([NH:30][C:31]1[O:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=1)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9][OH:8])[CH2:13][CH2:14]2
Reactant: [H][H]
Reactant: CC(C)(C)C[C@H](Nc1nc2ccccc2o1)C(=O)N[C@@H](COCc1ccccc1)CN1CCc2cc(F)ccc21
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)C[C@H](Nc1nc2ccccc2o1)C(=O)N[C@@H](CO)CN1CCc2cc(F)ccc21
Reaction time: 2 h
Yield: 58.5 %

Procedure:
The title compound of example 6 (34 mg, 70 μmol) was dissolved in MeOH (3 mL) and treated with 4 M HCl in dioxane (0.5 mL). The reaction was then treated with 10% Pd/C (7 mg) and the atmosphere was exchanged for hydrogen by sparging the solution with a needle and a balloon. After 2 h under a hydrogen balloon, the atmosphere was exchanged back to nitrogen and the catalyst was removed by filtration through celite. The solvent was removed and the residue was purified by preperative reverse phase HPLC to afford the title compound as a gum (18.6 mg, 47%); 1H NMR (CDCl3, 400 MHz) δ 0.97 (s, 9H), 1.69 (dd, 1H, J1=9.0, J2=14.5), 1.81 (dd, 1H, J1=3.4, J2=14.5), 2.71-2.90 (m, 2H), 3.04-3.16 (m, 1H), 3.19-3.31 (m, 2H), 3.40-3.50 (m, 1H), 3.66 (d, 1H, J=5.2), 4.13-4.21 (m, 1H), 4.38 (dd, 1H, J1=3.4, J2=9.0), 6.44-6.52 (m, 1H), 6.59-6.66 (m, 1H), 6.70-6.74 (m, 1H), 7.14 (dd, 1H, J1=J2=7.7), 7.23 (dd, 1H, J1J2=7.6), 7.30 (d, 1H, J=7.8), 7.33 (d, 1H, J=8.0); HPLC-MS calcd. for C25H31FN4O3 (M+H+) 455.2, found 455.5.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].CCN(C(C)C)C(C)C.[Br:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Br:21][CH2:22][C:23]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:24]
Reactant: O=C(Cl)CBr
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
3-Trifluoromethylaniline (1.6 g, 10 mmol) was dissolved in dichloromethane with DIEA (3.4 mL, 20 mmol), cooled to 0° C., and to this solution bromoacetyl chloride was added as a neat liquid (exothermic). After 1 hour the reaction mixture was washed with 1N HCl, dried and concentrated to a brown oil which was purified by column chromatography (10 to 40% EtOAc/hexanes) to give a light brown oil, 1.8 g, 6.4 mmol, 64% yield. 1H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 7.75 (s, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.35 (d, J=7.8 Hz, 3.96 (s, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](O)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20].P(Cl)(Cl)([Cl:23])=O>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([Cl:23])=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(O)c(C#N)cnc2cc1OCCCCl
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl

Procedure:
A mixture of 3.5 g (12 mmol) of 7-(3-chloro-propoxy)-4-hydroxy-6-methoxy-quinoline-3-carbonitrile and 28 ml of phosphorous oxychloride was refluxed for 1.5 hr. Excess reagent was removed at reduced pressure. The residue was mixed with ice cold dilute sodium hydroxide and ethyl acetate. The mixture was extracted with a combination of ethyl acetate and tetrahydrofuran. The combined extracts were washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate, and filter through a short column of silica gel. Solvents were removed giving 3.2 g of the title compound as a pink solid that is used with additional purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([O-])=O>[Pd].CCO.C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=[N+]([O-])c1ccc2c(c1)Sc1ccccc1N2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)Sc1ccccc1N2
Yield: 97 %

Procedure:
Reduction of the nitro function of 3-nitro-10H-phenothiazine (J. Org. Chem. (1972) 37, 2691) is carried out in the presence of Pd/C in an EtOH/THF mixture under the conditions described for intermediate 2.2. A grey solid is obtained with a yield of 97%. Melting point: 150-156° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:31])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[O:24][C:25]([C:28](O)=[O:29])=[CH:26][CH:27]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:43]=[CH:44][CH:45]=[N:46]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:31])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[O:24][C:25]([C:28](=[O:29])[NH:46][CH:45]3[CH2:43][CH2:44]3)=[CH:26][CH:27]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)o1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)o1

Procedure:
In a similar procedure as described for the synthesis of Compound 5352 (Example 352), treatment of (S)-2-[4-(5-Carboxy-furan-2-yl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester with HATU (0.23 g, 0.6 mmol), DIEA (0.2 mL, 1.53 mmol), and cyclopropylamine (0.1 1 mL) furnished the desired product. 1HNMR (DMSO-d6) δ(ppm) 12.59-12.57 (d, 1H), 8.42-8.39 (m, 1H), 7.64-7.62 (d, 1H), 7.36-7.30 (m, 2H), 7.14-7.10 (m, 3H), 6.73-6.70 (m, 1H), 5.10-4.87 (m, 2H), 4.51-4.43 (m, 2H), 3.52-3.36 (m, 2H), 2.80-2.77, (m, 2H), 2.27-2.24 (m, 1H), 1.94-1.83 (m, 3H), 0.73-0.58 (m, 4H); MS: 481.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.[Br:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:25][CH:26]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCCBr)cc2)nc1-c1ccccc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (2.02 g), 1,2-dibromoethane (20 ml), potassium carbonate (1.68 g) and N,N-dimethylformamide (20 ml) was stirred at 90° C. for 24 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (1530 mg, yield 58%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[O:7]([C:14]([O:16][C@@H:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=O)C1C=CC=CC=1.C(OCC)(=O)C.[Cl-].[Na+]>CN(C)C=O>[CH3:1][NH:2][CH2:3][CH2:4][N:5]([C:14]([O:16][C@@H:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:7])[CH3:6]
Reactant: CNCCNC
Reactant: COC(=O)[C@H](Cc1ccccc1)OC(=O)Oc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNCCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OC
Yield: 97.9 %

Procedure:
To N,N'-dimethylethylenediamine (7.93 g) in N,N-dimethylformamide (27 ml) was dropwise added methyl 2(S)-phenoxycarbonyloxy-3-phenylpropionate (9.0 g) in N,N-dimethylformamide (9 ml) under cooling at -5°-10° C. over 30 minutes. After the dropwise addition, the mixture was stirred at said temperature for 60 minutes and poured into a mixture of ethyl acetate and 20% aqueous sodium chloride for partition. The water layer was re-extracted with ethyl acetate, the organic layer was combined, and 5% hydrochloric acid was added thereto for partition. The water layer was washed with ethyl acetate, added with methylene chloride, and adjusted to pH 9.0 with an aqueous solution of 24% sodium hydroxide. The organic layer was separated, washed with 20% aqueous sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 8.64 g of methyl 2(S)-[N-(2-methylaminoethyl)-N-methylaminocarbonyloxy]-3-phenylpropionate (yield 97.9%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:23]([O:25][CH3:26])=[O:24])=[N:9][C:10]([C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][NH:20]4)=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37](=O)[O:38]C1C=CC([N+]([O-])=O)=CC=1>CC#N>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]([N:20]1[C:21]2[C:16](=[CH:15][CH:14]=[C:13]([C:10]3[N:9]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:11]=3)[CH:22]=2)[CH2:17][CH2:18][CH2:19]1)=[O:38]
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1-c1ccccc1
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-phenyl-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (29H) (17 mg, 0.049 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (15.5 mg, 0.049 mmol) in anhydrous CH3CN (0.8 mL) was heated to reflux for 6 hours, cooled to rt, concentrated under reduced pressure, and the crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 72:28-55:45, to provide the desired product methyl 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinate (29I): 1H NMR (300 MHz, CDCl3) δ 8.23 (1H, d), 8.13 (1H, d), 7.85-7.76 (3H, m), 7.66 (1H, d), 7.48-7.35 (4H, m), 7.34-7.28 (2H, m), 6.89 (1H, d), 3.98 (2H, t), 3.71 (3H, s), 2.85 (2H, t), 2.09 (2H, m).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:7]=O)[CH:2]=[CH2:3].C1COCC1.[Br-].[N+:23]([C:26]1[CH:51]=[CH:50][C:29]([CH2:30][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:14]([N:12]([CH3:13])[C:11]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:30][C:29]2[CH:50]=[CH:51][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3])[CH:15]=[CH2:16]
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCc1cc(C=O)ccc1N(C)CC=C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCc1cc(C=Cc2ccc([N+](=O)[O-])cc2)ccc1N(C)CC=C
Reaction time: 2 h

Procedure:
A mixture of 3-allyl-4-(N-allyl-N-methylamino)benzaldehyde (10.25 g, 0.05 mol), THF (100'ml), p-nitrobenzyl triphenylphosphonium bromide (27.4 g, 0.55 mol) and water (50 ml) is mixed at room temperature while 2M sodium carbonate solution (50 ml) is added over 5 minutes. The mixture is stirred mechanically for 2 hours. The mixture is diluted With water (300 ml) and extracted two times with ether (250 ml portions). The extracts are washed with water and brine, dried over magnesium sulfate and concentrated. The mixture is diluted with toluene (100 ml) and hexane (200 ml) and the triphenyl phosphine oxide filtered off. The filtrate is concentrated and chromatographed on silica with hexane-ethyl acetate to give pure N,2-diallyl-N-methyl-4-[2-(4-nitrophenyl)ethenyl]aniline.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:11])[NH:4][CH:3]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:11])[N:4]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccnc2[nH]cc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ccnc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 71 %

Procedure:
3-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (2.32 g) was dissolved in anhydrous THF and cooled to 0° C., the NaH (60%, 1.2 g) was added slowly and the mixture stirred at 0° C. for 40 min. The benzenesulfonyl chloride was added, and the mixture was allowed to warm to room temperature and stirred at room temperature for 3 h. The reaction mixture was quenched with H2O, and extracted with EtOAc. The organic layer was dried over Na2SO4. Ater the solvent evaporated under reduced pressure, the residue was purified with chromatography on silica gel to give 3-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine: (2.63 g), yield: 71%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[C:13]([Br:34])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Yield: 64.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (99 mg, 0.22 mmol) and N-bromosuccinimide (43 mg, 0.24 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 76 mg of the title compound as a yellow solid. MS: (−) m/z 531.23, 533.18 (M−1, 79/81Br).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:8]([F:10])([F:9])[C:7]([F:12])([F:11])[C:6]=1Cl)([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl-].[Ca+2].[Cl-]>[C].[Pd].CCOCC>[CH:1]([O:4][CH:5]1[CH2:6][C:7]([F:11])([F:12])[C:8]1([F:9])[F:10])([CH3:3])[CH3:2]
Reactant: CC(C)OC1=C(Cl)C(F)(F)C1(F)F
Agent: [Pd]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)OC1CC(F)(F)C1(F)F

Procedure:
To 40 g of 10% strength palladium-carbon under nitrogen a solution of 274 g (1.26 mol) of 2-chloro-3,3,4,4-tetrafluorocyclobutenyl isopropyl ether, 252 g (2.50 mol) of triethylamine, and 1200 ml of ether dried over calcium chloride is added, and the mixture is hydrogenated in a 3 l VA autoclave at 100° C. until the pressure is constant (about 5 hours). The solid is filtered off with suction and washed well with ether, and the filtrate is washed with dilute hydrochloric acid. After drying, the organic phase is distilled.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 95.8 %

Procedure:
20.0 g (92.73 mmol) of (L)-phenylalanine methyl ester hydrochloride was suspended in 93 ml of toluene, and 15.82 g (92.73 mmols) of benzyl chloroformate was added thereto. 130 ml of an aqueous solution of 1 M sodium carbonate was dropwise added thereto, while keeping it at 7° C. or lower, and stirred for 3 hours. After this was subjected to phase separation, the resulting organic layer was washed with 60 ml of 0.1 N hydrochloric acid and 60 ml of a saturated aqueous solution of sodium hydrogen carbonate, and then dried with anhydrous sodium sulfate. This was filtered and concentrated to obtain 28.75 g (96.8 wt. %, 88.81 mmol) of the above-entitled compound. The yield was 95.8%.
Reaction SMILES: C[C@@H](CCC)CCCO[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[CH:9][CH:8]=1.[CH3:19][C@@H:20]([CH2:36][CH2:37][CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>>[CH2:11]([C:10]1[CH:9]=[CH:8][C:7]([O:32][C:31](=[O:33])[C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:19])[CH2:36][CH2:37][CH3:38])=[CH:35][CH:34]=2)=[CH:15][CH:14]=1)[CH2:14][CH2:15][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCC[C@H](C)CCCOc1ccc(C(=O)O)cc1
Reactant: CCC[C@H](C)CCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCc1ccc(OC(=O)c2ccc(OCCCCC[C@@H](C)CCC)cc2)cc1

Procedure:
The procedure of Example 8 was followed except that the (S)-4-(4'-methylheptyloxy)benzoic acid was replaced by (S)-4-(6'-methylnonyloxy)benzoic acid to thereby give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]3[C:14]4[C:19]([C:20]([C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[C:30]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)=[CH:29][CH:28]=5)=[C:21]5[C:26]=3[CH:25]=[CH:24][CH:23]=[CH:22]5)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>CN1CCCC1=O>[C:37]1([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([C:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]([C:9]4[CH:10]=[C:11]5[C:6]([CH:5]=[CH:4][C:3]([OH:2])=[CH:12]5)=[CH:7][CH:8]=4)=[C:14]4[C:19]=3[CH:18]=[CH:17][CH:16]=[CH:15]4)=[CH:28][CH:29]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccc2ccc(-c3c4ccccc4c(-c4ccc(-c5ccccc5)c5ccccc45)c4ccccc34)cc2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Oc1ccc2ccc(-c3c4ccccc4c(-c4ccc(-c5ccccc5)c5ccccc45)c4ccccc34)cc2c1
Temperature: 200 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Under the nitrogen atmosphere, 9-(7-methoxynaphthalen-2-yl)-10-(4-phenylnaphthalen-1-yl)anthracene (16.0 g) as the twentieth intermediate compound, pyridine hydrochloride (17.3 g) and N-methylpyrrolidone (30 ml) were added to a flask and stirred for 8 hours at 200° C. Once the heating is completed, the mixture was cooled to 100° C. or lower. Liquid separation was performed by adding water and toluene. The solvent was distilled off under reduced pressure and the resulting solid was purified by silica gel column chromatography (solvent: toluene) to give 7-(10-(4-phenylnaphthalen-1-yl)anthracen-9-yl)naphthalen-2-ol (15.5 g) as a twenty-first intermediate compound. The scheme is shown in the following “Reaction 33”.