Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[C:4](=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([O:7][Si](C)(C)C)[CH:6]=1.C(O)(=O)C.O1CCCC1.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[C:3](=[O:30])[C:4](=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:5]([OH:7])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:6]=1
Reactant: CCCCCCCCC1(O[Si](C)(C)C)C=C(Cl)C(=O)C1=CCCCCCC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCC1(O)C=C(Cl)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 2 h
Yield: 97 %

Procedure:
31 g of the mixture of E- and Z-isomes of 2-chloro-5-(6-methoxycarbonylhexylidene)-4-octyl-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 2 was mixed with 3 ml of a 6:1:3 mixture of acetic acid, tetrahydrofuran and water, and the mixture was stirred for 2 hours. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ether. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was chromatographed on a silica gel column to give 25 mg (yield 97%) of a mixture of Z- and E-isomers of 2-chloro-4-hydroxy-5-(6-methoxxycarbonylhexylidene-4-octyl-2-cyclopentenone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[C:5]([F:15])[CH:4]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1C(=O)[N-]C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd+]>[F:15][C:5]1[CH:4]=[C:3]([CH2:2][C:18]2[CH:19]=[CH:20][S:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: OB(O)c1cccs1
Reactant: COC(=O)C(C)c1ccc(CBr)cc1F
Agent: Br[Pd+]
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)[N-]1
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(Cc2ccsc2)cc1F
Yield: 88.7 %

Procedure:
Compound 20 (0.88 g, 3.2 mmol) and 2-thiopheneboronic acid (0.87 g, 3.4 mmol) were dissolved in tetrahydrofuran (12 mL) and a 2 M-aqueous solution (4.2 mL) of sodium carbonate. To this solution, trans-bromo(N-succinimidyl)bis(triphenylphosphine)palladium(II) [trans-PdBr(N-Succ)(PPh3)2] (27.5 mg, 1.0 mol %) was added and treated in the same manner as in Example 11. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (20:1) solution followed by conventional hydrolysis with potassium hydroxide to give 0.75 g (85%) of compound (22b) of interest as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][O:25][CH3:26]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:22]([CH2:23][CH2:24][O:25][CH3:26])[CH2:21][CH2:20][O:19][CH3:18])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: COCCNCCOC
Product: COCCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
300 mg (1.12 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using 2-methoxy-N-(2-methoxyethyl)ethanamine to give after working up and purification 340 mg (79%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]2[CH:11]=1.[I:12]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]2[C:11]=1[I:12]
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc2nc(Cl)cn2c1
Solvent: CC#N
Product: Fc1ccc2nc(Cl)c(I)n2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound from Example 2 Step B (1.0 g, 5.86 mmol) in acetonitrile (29.3 mL) was added N-iodosuccinimide (1.583 g, 7.04 mmol). The resulting mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The resulting residue was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (10-30% ethyl acetate in hexanes) provided the title compound: LCMS m/z 296.70 [M+H]+, 298.65 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.03 (t, J=2.8 Hz, 1H), 7.56-7.51 (m, 1H), 7.22-7.18 (m, 1H).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:3]=[N:2]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]2[N:4]=[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:1]=[N:2]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cc1nnn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h
Yield: 78.4 %

Procedure:
To a solution of ethyl 5-tetrazolylacetate (1 g) (Lofquist et al. J. Amer. Chem. Soc. (1958), 80, 3908) in pyridine (6 mL) was added triphenylmethyl chloride (2.2 g) and the resulting solution allowed to stir for 3 h. The solvent was evaporated and the product crystallized from ether/hexane to give ethyl 3-triphenylmethyltetrazol-5-ylacetate as a white solid (2 g); TLC: Rf =0.5, ether:hexane (50:50).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[CH2:33]([NH:40][C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][O:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COC1CCCCO1)C(=O)O
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CO[C@@H]1CCCCO1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold solution (5° C.) of 10.00 g of Intermediate 2 in 150 mL of dichloromethane was added 5.89 g (0.036 mol) of 1,1′-carbonyldiimidazole. The mixture was allowed to warm to room temperature and stirred for 1.5 hours. Then, it was cooled to 5° C. and 4.37 g (0.041 mol) of benzylamine was added dropwise and the reaction was stirred at room temperature overnight. The organic phase was washed with 1 M HCl (2×80 mL), sodium bicarbonate solution (2×80 mL), water (80 mL), brine (80 mL) and dried over sodium sulfate. The solvent was evaporated under vacuum yielding 14.36 g as an oil. The oil was not purified and used directly in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][C@H:27]([OH:30])[CH2:28][OH:29]>>[OH:30][C@H:27]([CH2:28][OH:29])[CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: NC[C@H](O)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NC[C@H](O)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acid obtained in step B of Example 2-2-1 and (S)-3-amino-1,2-propanediol (produced by Wako Pure Chemical Industries) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: S(=O)(=O)(O)O.[N+]([C:9]1[CH:10]=C(S([O-])(=O)=O)C=C[CH:14]=1)([O-])=O.[Na+].[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([F:28])[CH:22]=1.N>O.OCC(CO)O>[Br:20][C:21]1[CH:27]=[C:26]2[C:24](=[C:23]([F:28])[CH:22]=1)[N:25]=[CH:10][CH:9]=[CH:14]2
Reactant: Nc1ccc(Br)cc1F
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: OCC(O)CO
Product: Fc1cc(Br)cc2cccnc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of concentrated sulphuric acid (63 ml, 820 mmol) in water (49.4 ml) was treated with sodium 3-nitro-benzenesulfonate (commercially available, for example, from Aldrich) (47.9 g, 213 mmol) and glycerol (commercially available, for example, from Fluka and/or Aldrich) (52 ml, 720 mmol) to give a thick grey suspension. This was heated to 110° C. (internal temperature was 85° C.). 4-Bromo-2-fluoroaniline (commercially available, for example, from Fluorochem and/or Aldrich) (38 g, 200 mmol) was added over 10 min in portions, during which the internal temperature rose to 95° C. The reaction was heated to 140° C. (internal temperature was 133° C.) and stirred overnight. The reaction mixture was cooled and then poured into water (1000 ml) and basified to pH 7 with aqueous ammonia (0.88 s.g, approximately 190 ml). The brown precipitate that formed was collected by filtration and partially dried. This solid (63 g) was loaded onto a column of silica (1500 ml) and eluted with EtOAc to give the title compound as a light brown solid (43.8 g, 97%). LCMS RT=2.87 min, ES+ve m/z 226/228 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]([N:17]=[C:18]=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:18]([NH:17][C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[S:19])[CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(Br)ccn1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)ccn1)c1ccccc1
Yield: 74.3 %

Procedure:
2.500 g (14.01 mmol) 4-bromopyridine-2-amine was dissolved in 20 mL acetone, and 1.92 mL (14.01 mmol) undiluted benzoyl isothiocyanate was added dropwise. The solution turned an orange color. The reaction mixture was then heated for 1 hr under reflux with stirring. Half of the added quantity of acetone was removed under vacuum, and the precipitated solid was filtered under vacuum and washed with diethyl ether. After drying of the crystallizate, 3.500 g (10.410 mmol, 74%) pure N-{[(4-bromopyridin-2-yl)amino]carbonothioyl}benzamide was obtained which was directly used for further reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)N(C)OC
Reactant: Brc1ccc2nc(-c3ccc(OCc4ccccc4)cc3)oc2c1
Product: CCCC(=O)c1ccc2nc(-c3ccc(OCc4ccccc4)cc3)oc2c1

Procedure:
The preparation is carried out analogously to Example 29a from 2-(4-benzyloxy-phenyl)-6-bromo-benzoxazole and N-methoxy-N-methyl-butyramide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.C[O:15][C:16](=O)[C:17]1[C:22]([I:23])=[C:21]([F:24])[CH:20]=[CH:19][C:18]=1[CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:24][C:21]1[C:22]([I:23])=[C:17]2[C:18]([CH2:25][N:9]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:5][CH:6]=3)[C:16]2=[O:15])=[CH:19][CH:20]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1c(CBr)ccc(F)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(ccc(F)c2I)CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
A mixture of 4-trifluoromethoxy-benzyl amine (0.763 mL, 5.0 mmol), 2-bromomethyl-5-fluoro-6-iodo-benzoic acid methyl ester (1.49 g, 4.0 mmol), and K2CO3 (0.828 g, 1 mmol) in toluene (7 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 6-fluoro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.717 g, 40%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.18 (s, 2H), 4.79 (s, 2H), 7.14-7.38 (m, 6H). GC-MS: m/z 451 (M)+, 366 (M−85)+.
Reaction SMILES: Cl[C:2]1[C:3]([F:15])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[NH:7][CH:8]1[CH2:10][CH2:9]1.[C:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(N(CC)CC)C>O>[C:16]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[C:6]([NH:7][CH:8]3[CH2:10][CH2:9]3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=2[F:15])[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCN(c2cc(NC3CC3)c([N+](=O)[O-])cc2F)CC1
Reaction time: 12 h
Yield: 93.3 %

Procedure:
5-Chloro-N-cyclopropyl-4-fluoro-2-nitroaniline (3.5 g, 15.2 mmol) is heated with N-acetylpiperazine (3.89 g, 30.4 mmol) and triethylamine (2.3 g 22.8 mmol) while stirring vigorously and held at 60° for 12 hours. The mass obtained is dissolved in water (200 ml) and extracted with ethyl acetate. The organic phase is washed with 10 percent sodium chloride solution and then dried over magnesium sulfate. After distillation of the solvent the residue is recrystallized from ethanol. There are obtained 4.57 g (93%) of 1-acetyl-4-[5-(cyclopropylamino)-2-fluoro-4-nitrophenyl]piperazine with a m.p. of 142°-143°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:23]1([N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[O:15])[CH2:17][CH2:18]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCN(C3CCC3)CC2)CC1
Reaction time: 0.08 h

Procedure:
1-(1-tert-Butoxycarbonyl-piperidine-4-carbonyl)-[1,4]-diazepane (2.0 g)(D8, Step 2) was dissolved in DCM (50 ml) and cyclobutanone (0.96 ml) added and the mixture stirred for 5 min. Sodium triacetoxyborohydride (2.7 g) was then added and the reaction stirred at rt for 1.5 h. The reaction mixture was then washed with saturated potassium carbonate solution (50 ml), sodium hydrogen carbonate solution (3×50 ml) and brine (50 ml). The organic layer was dried (MgSO4) and evaporated to give the subtitled compound as a white solid (1.67 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[C:6]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:5][CH:4]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][NH:18][C:6]1[C:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:4][CH:5]=1)[CH3:23]
Reactant: CCS(=O)(=O)Cl
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)CCNc1ccc(CNS(=O)(=O)CC)c2sc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of 2.5 g of 4-(aminomethyl)-l-[[2-(diethylamino) ethyl]amino]-thioxanthen-9-one (prepared by the method described in Example 4) in 30 mL of pyridine was cooled in an ice bath for 15 min and 0.95 g of ethanesulfonyl chloride in 5 mL of pyridine was added rapidly dropwise and the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into 75 mL of water containing 0.75 g of NaOH, extracted into chloroform, the organic layer was washed with water (2x) and brine, and dried over sodium sulfate. The mixture was concentrated in vacuo and the residue was stirred in ether and dried (40° C./0.1 mm) to afford 1.7 g of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]ethane-sulfonamide, m.p. 105° C. (dec.). The sulfonamide was dissolved in methanol and treated with methanesulfonic acid in methanol to afford 1.61 g (42%) of the methanesulfonate salt, m.p. 135° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].[Br:15]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:15][CH2:11][C:10]([C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:13][CH3:14])[CH:4]=1)=[O:12]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)cc(OC)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C(=O)CBr)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanone (0.895 g, 3.45 mmol) in anhydrous CH2Cl2 (5 mL) under a drying tube was added a freshly made solution of Br2 in CH2Cl2 (1.95 M, 1.9 mL, 3.7 mmol) dropwise. The reaction was stirred at room temperature for 30 min then neutralized with a solution of saturated aqueous NaHCO3. The mixture was diluted with CH2Cl2 and the layers were separated. The organics were washed with saturated aqueous NaHCO3 and brine then dried over MgSO4/Na2SO4 and concentrated in vacuo. The crude product was adsorbed onto silica gel (2.9 g) as a CH2Cl2 solution. Purification by chromatography (0-20% EtOAc-hexanes) gave 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone as a white solid (0.737 g, 63% yield). Large-scale synthesis of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone was performed without chromatographic purification of the bromide.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1/[CH:10]=[CH:11]/[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1.C(OCC)(=O)C>[Br:20][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1/[CH:10]=[CH:11]/[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(/C=C/C(=O)OC(C)(C)C)c(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(/C=C/C(=O)OC(C)(C)C)c(CBr)c1
Reaction time: 2.5 h
Yield: 93.9 %

Procedure:
To a solution of 2.32 g of tert-butyl (2E)-3-[2-(hydroxymethyl)-4-methylphenyl]acrylate in 46 ml of THF were added 4.64 g of carbon tetrabromide and 3.67 g of triphenylphosphine under ice-cooling, followed by stirring at the same temperature for 2.5 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.73 g of tert-butyl (2E)-3-[2-(bromomethyl)-4-methylphenyl]acrylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].[H][H]>O.Cl.CO.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOC(=O)CC1CCCCN1

Procedure:
Platinum(IV) oxide (15 mg) was added to a mixture of 2-(2-pyridyl)acetic acid ethyl ester (1.652 g) in water (1.25 mL) and concentrated hydrochloric acid (1.25 mL) in methanol (15 mL), and the resultant mixture was stirred in a hydrogen atmosphere at room temperature for 15 hours. The catalyst was filtered off. The solvent was evaporated under reduced pressure, and ethanol was added to the residue, and then the solvent of the mixture was evaporated again under reduced pressure. To the residue, a small amount of water, diethyl ether (about 100 mL), and an excessive amount of potassium carbonate were added, and the resultant mixture was stirred, followed by filtration. The solvent of the filtrate was evaporated under reduced pressure, to thereby give the title compound as an oily product (1.322 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[C:33]([NH:40][CH2:41][C:42](O)=[O:43])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[C:36]([O:35][C:33]([NH:40][CH2:41][C:42]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)=[O:43])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OC(=O)CNC(=O)OC(C)(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 30.2 mg, 0.070 mmol) and Boc-glycine (15.1 mg, 0.086 mmol) were dissolved in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (31.4 μL, 0.18 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (35.4 mg, 0.093 mmol) were added thereto, and then the mixture was stirred at room temperature overnight. Ethyl acetate (10 mL) was added to the reaction mixture, then the mixture was washed with water (10 mL) and saturated brine (10 mL) successively. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (35.3 mg) as a colorless amorphous product. (Yield 86%)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Cl:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[CH:34][N:33]=1>CC#N>[Cl:31][C:32]1[N:37]=[C:36]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=2)[CH:35]=[CH:34][N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: Clc1ccnc(Cl)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Yield: 35.7 %

Procedure:
To a degassed solution of tert-butyl 4-hydroxynaphthalen-1-ylcarbamate (13.3 g, 51.3 mmol) and DBU (12.6 mL, 51.3 mmol) in MeCN (80 mL) under nitrogen was added 2,4-dichloropyrimidine (7.65 g, 51.3 mmol) in acetonitrile (19 mL) and the reaction mixture was heated to reflux for 4 hr. The solvent was evaporated in vacuo and the residue was taken up into DCM (100 mL) and was washed with water (2×100 mL) and brine (100 mL), then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 330 g, EtOAc in isohexane, 0-50%, gradient elution) to afford the title compound as a pale pink solid (6.80 g, 34%); Rt 2.50 min (Method 2); m/z 372/374 (M+H)+, (ES+)+.
Reaction SMILES: S([O-])(=O)(=O)C.Cl.[CH2:7]([NH:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(=O)C.[Na+]>>[NH:15]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:14]1
Reactant: NNCc1ccccc1
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)[O-]
Agent: Cl
Product: c1ccc2[nH]ncc2c1
Temperature: 25 °C

Procedure:
The mesylate (1.0 equivalent) is combined with the HCl salt of the benzyl hydrazine (1.5 equivalent) and sodium acetate (3.0 equivalent) in xylenes (6 vol). The mixture is heated to reflux in a Dean-Stark apparatus until completion. The reaction is cooled to room temperature, poured into 1 N HCl and extracted with toluene. The combined organic extracts are dried over sodium sulfate and concentrated to afford the crude indazole which is purified by flash chromatography.