Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH2:26])=[O:25].C(=O)(O)[O-].[Na+].NC1C(C#N)=C(C2CCCCO2)C(C#N)=C(SCC2N=C(C3C=CC(Cl)=CC=3)SC=2)N=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:18][CH2:20][C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([NH2:26])=[O:25])[C:5]([C:16]#[N:17])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:7]=1[C:8]#[N:9]
Reactant: NC(=O)c1cccc(CCl)c1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCCO1
Agent: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2cccc(C(N)=O)c2)c(C#N)c1C1CCCCO1

Procedure:
50 mg (0.14 mmol) of the compound from Example 31A, 36 mg (0.21 mmol) of 3-(chloromethyl)benzamide and 48 mg (0.58 mmol) of sodium bicarbonate in 2.0 ml of dry DMF are reacted analogously to the preparation of the compound of Example 14.
Reaction SMILES: [CH2:1]([C:4]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:18]2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].CN(C)P(N(C)C)(N(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:59][CH2:60][CH3:61]>C1COCC1>[CH2:1]([C:4]1[CH:29]=[C:28]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17]([CH2:59][CH2:60][CH3:61])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:18]2)=[CH:13][CH:12]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)OC(C(=O)OCC)CC2
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)OC(CCC)(C(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To a 2 ml THF solution of ethyl 7-(3-(2-propyl-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate (Example 1, Step B) (100 mg, 0.204 mmol) were added hexamethylphosphoramide (0.046 ml, 0.26 mmol) and sodium bis(trimethylsilyl)amide (1.0M THF solution) (0.265 ml, 0.265 mmol) upon cooling in a dry ice-acetone bath. After stirring at that temperature for 30min, to it was added iodopropane (0.06 ml, 6.2 mmol). The cooling bath was removed and the reaction mixture was gradually warmed to rt overnight. The solvent was removed under reduced pressure, diluted with AcOEt and water. The organic layer was separated. The aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 5% AcOEt/hexanes gave the title compound as a clear oil 33 mg (30%).
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]2[CH:19]=[CH:20][C:21]([C:23]3[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=3)=[CH:22][C:12]=2[N:11]=1.[NH2:31][NH2:32]>CCO>[NH2:29][C:26]1[N:25]=[CH:24][C:23]([C:21]2[CH:20]=[CH:19][C:13]3[N:14]([C:15]([CH3:17])([CH3:18])[CH3:16])[C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([NH:31][NH2:32])=[O:30])=[N:11][C:12]=3[CH:22]=2)=[CH:28][N:27]=1
Reactant: NN
Reactant: COC(=O)c1ccccc1-c1nc2cc(-c3cnc(N)nc3)ccc2n1C(C)(C)C
Solvent: CCO
Product: CC(C)(C)n1c(-c2ccccc2C(=O)NN)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 80 °C
Reaction time: 120 h
Yield: 51 %

Procedure:
To a vial is added 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-benzoic acid methyl ester (example 16) (85 mg, 0.212 mmol) in EtOH (5 mL), follow by the addition of hydrazine (35 wt % solution in water) (1 mL). The reaction mixture is stirred at 80° C. for 5 days. The reaction mixture is concentrated in vacuo. The residue is loaded to a silica gel column. The column is eluted with 0-10% 2M NH3 in MeOH/CH2Cl2. The product fractions are collected and is concentrated to afford 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-benzoic acid hydrazide (43 mg, 51%) as a off-white solid. LCMS (ESMS): m/z 402.57 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17](Cl)=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1.[F-:23].[K+].S1(CCCC1)(=O)=O>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17]([F:23])=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: [F-]
Reactant: COc1ccc(-c2nsc3cc(Cl)c([N+](=O)[O-])cc23)cc1C
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1ccc(-c2nsc3cc(F)c([N+](=O)[O-])cc23)cc1C
Temperature: 154 °C
Reaction time: 19 h
Yield: 30.1 %

Procedure:
A mixture of 3-(6-methoxy-m-tolyl)-6-chloro-5-nitro-1,2-benzisothiazole (7.30 g, 0.0218 mol), potassium fluoride (6.33 g, 0.109 mol) 18-crown-6 (2.31 g, 0.0872 mol) and sulfolane is stirred 19 hours at 154° C., cooled to room temperature, and poured into ice water. The resultant solid is filtered and chromatographed on silica gel with methylene chloride to afford a solid which is recrystallized from acetonitrile to afford a tan powder. The powder is recrystallized from ethyl acetate to give the title compound as a tan solid (2.09 g, 29.9%) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19].O[C:21]1[CH:22]=[CH:23][C:24]2[O:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][C:26](=[O:36])[C:25]=2[CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C([O-])(=O)C([O-])=O>O1CCCC1>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:21]3[CH:22]=[CH:23][C:24]4[O:29][C:28]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:27][C:26](=[O:36])[C:25]=4[CH:37]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19]
Reactant: Cn1c(N2CCN(CCO)CC2)cc(=O)n(C)c1=O
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])C(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCOc3ccc4oc(-c5ccccc5)cc(=O)c4c3)CC2)cc(=O)n(C)c1=O
Yield: 61.1 %

Procedure:
The same procedure as in Example 8-(2) was effected so as to react and treat 0.8 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazine-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 30), 1.19 g of 6-hydroxy-2-phenyl-4-oxo-4H-1-benzopyran (Compound 27), 40 ml of tetrahydrofuran containing 1.05 g of triphenylphosphine and 0.63 ml of diethyl azodicarboxylate, in order to obtain 0.89 g (yield 58%) of 1,3-dimethyl-6-(4-[2-(2-phenyl-4-oxo-4H-1-benzopyran-6-yl)oxyethyl]piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (the non-oxalate, of Compound 31).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH2:13][N:14]3C(OC(C)(C)C)=O)[CH2:11]2)=[N:7][CH:8]=1.Cl>CCOC(C)=O.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH2:13][NH:14]3)[CH2:11]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H](Oc3ccc(C(F)(F)F)cn3)[C@@H]1C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(O[C@@H]2C[C@@H]3CN[C@H]2C3)nc1
Reaction time: 2 h
Yield: 112.8 %

Procedure:
To the title compound of step A (622 mg, 1.74 mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (10 mL). After 2 h, the reaction was concentrated to give the title compound of step B (507 mg) which was used without further purification. MS (ESI) mass calcd. for C12H13F3N2O, 258.1. m/z found 259.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[CH3:14][C:15]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:24]=1)([CH3:18])[CH:16]=O>O1CCCC1>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:24]=[C:20]([NH:19][C:15]([CH3:18])([CH3:16])/[CH:14]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])[S:21][CH:22]=2)=[CH:32][CH:31]=1)#[N:30]
Reactant: CC(C)(C=O)Nc1nc(-c2ccc(C#N)cc2)cs1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/C(C)(C)Nc1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 0.75 h
Yield: 92.6 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.17 g, 4.5 mmol) in tetrahydrofuran (30 mL) was added trimethyl phosphonoacetate (0.75 mL, 5.2 mmol) dropwise and the mixture was stirred for 45 min. A solution of 4-{2-[(1,1-dimethyl-2-oxoethyl)amino]-1,3-thiazol-4-yl}benzonitrile (0.81 g, 3.0 mmol), prepared in step 1 of Example 83, in 5 mL of tetrahydrofuran was added and the mixture was stirred at 25° C. for 2 h. The reaction was quenched with saturated NH4Cl and diluted with ethyl acetate and washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (20% acetone/hexane) afforded methyl (2E)-4-{[4-(4-cyanophenyl)-1,3-thiazol-2-yl]amino}-4-methylpent-2-enoate (0.91 g, 93%) as a white solid. HRMS: calcd for C17H17N3O2S+H+, 328.11142; found (ESI, [M+H]+), 328.1135; Analytical HPLC: purity 100% at 210-370 nm, 9.9 min; 100% at 252 nm, 9.9 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].O.[NH2:25][NH2:26]>O1CCOCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:1][C:2]([NH:25][NH2:26])=[S:3])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: NN
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3ccc(NC(=S)NN)cc3)CC2)cc1
Yield: 89 %

Procedure:
A mixture of 47.8 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 100 parts of hydrazine hydrate and 400 parts of 1,4-dioxane is stirred and refluxed for 1 hour. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off, washed with water and with methanol and dried, yielding 46 parts (89%) of N-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarbothioamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCCC1[O:20][NH:21][C:22](/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([C:36]2[CH:47]=[CH:46][C:39]([CH2:40]OS(C)(=O)=O)=[CH:38][CH:37]=2)=[O:35])=[CH:28][CH:27]=1)=[O:23]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]3[CH:30]=[CH:31][C:26](/[CH:25]=[CH:24]/[C:22]([NH:21][OH:20])=[O:23])=[CH:27][CH:28]=3)=[CH:47][CH:46]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCc1ccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CN3CCN(Cc4ccccc4)CC3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
1-Benzyl-piperazine (40 mg, 0.22 mmol) was added to a stirred mixture of methanesulfonic acid 4-((E)-3-{4-[(E)-2-(tetrahydro-pyran-2-yloxycarbamoyl)-vinyl]-phenyl}-acryloyl)-benzyl ester (prepared as described in Preparation 5, 90 mg, 0.185 mmol) and TEA (0.052 ml, 0.37 mmol) in DMF (2 ml). The resulting solution was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with hot AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was triturated with di-isopropylether/DCM, filtered and the resulting powder was suspended in DCM and treated with HCl/Et2O for 1 h. The solid was filtered and washed with DCM to give 28.1 mg of (E)-3-(4-{(E)-3-[4-(4-benzyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy-acrylamide as its bis-hydrochloride salt.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:3]1.Br[C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:22]2[S:26][C:25]([NH2:27])=[N:24][N:23]=2)[CH2:3]1
Reactant: CC1CCCN(Cc2cccc(OCCCCN)c2)C1
Reactant: Nc1nnc(Br)s1
Product: CC1CCCN(Cc2cccc(OCCCCNc3nnc(N)s3)c2)C1
Yield: 54 %

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 4-[3-[(3-methylpiperidin-1-yl) methyl]phenoxy]-butanamine and 5-bromo-1,3,4-thiadiazole2-amine. Yield: 54% of theoretical: melting point: 123°-124° C.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C([O-])(=O)C.[Na+].[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1>O.C(O)C>[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:3][OH:2])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(Cc2ccccc2)=NO)cc1
Yield: 70.9 %

Procedure:
Hydroxylammonium chloride (4.19 g, 60.2 mmol) and sodium acetate (7.42 g, 90.4 mmol) are dissolved in 20 ml of water. To this solution 9.72 g (40.1 mmol) of 1-(4-methylsulfanyl-phenyl)-2-phenyl-ethanone in 60 ml of ethanol are added. The reaction mixture is heated to reflux for 18.5 hr. The reaction mixture was concentrated by rotary evaporation and poured into water. The resulting white solid is filterd and washed with water. After drying under reduced pressure, recrystallization from hexane-CH2Cl2 affords 7.32 g of a white solid (71%). 1H NMR (CDCl3), δ[ppm]: d 2.45 (s, 3H), 4.20 (s, 2H), 7.16-7.20 (m, 3H), 7.24-7.27 (m, 4H), 7.54 (d, 2H), 9.03 (s, 1H).
Reaction SMILES: C[C:2]1[C:3](C)=[C:4]([C:16]#[C:17]CO)[CH:5]=[CH:6][C:7]=1[C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:8]([C:7]1[CH:2]=[CH:3][C:4]([C:16]#[CH:17])=[CH:5][CH:6]=1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(C#CCO)ccc(C(=O)c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 120 °C
Yield: 76.2 %

Procedure:
1.85 g (7 mmol) of dimethylhydroxymethyl-4-benzoylphenylacetylene and 294 mg (7.35 mmol) of NaOH (KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 50 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 35 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 0.5 hour. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate, followed by distilling off of the solvent under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=10/1) using silica gel to give 4-benzoylphenylethyne as a pale brown solid (1.1 g, yield: 76%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14].S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:9][CH2:10][C:11]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:13](=[O:14])[CH:12]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(CCl)c2ccc(O)cc2o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Resorcinol (275 g) was dissolved in acetic acid (560 mL) at 50° C. to prepare a solution. Separately, ethyl 4-chloroacetoacetate (205 g) was dissolved in acetic acid (187 ml), and concentrated sulfuric acid (100 mL) was added at 8° C. The solution was added at 8° C. to the resorcinol solution prepared in advance, and the mixture was stirred at 25° C. for 1 hr and at 60° C. for 3 hr. Warm water (3.24 L) was added at 40° C., and the mixture was stirred at 25° C. for 2 hr. The precipitated solid was collected by filtration. The solid was washed with water and air-dried to give the title compound (255 g) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:56][C:57]1[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=1[NH2:59]>CN(C=O)C>[Cl:56][C:57]1[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=1[NH:59][C:10](=[O:12])[C:9]1[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:22])=[N:7][CH:8]=1
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Reactant: Nc1ccccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccccc2Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To an ice-cold solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol, 1.0 eq) in DMF (2.0 mL) was added HBTU (91 mg, 0.24 mmol, 1.50 eq) followed by DIPEA (62 mg, 0.48 mmol, 3.0 eq) and finally 2-chloroaniline (24 mg, 0.19 mmol, 1.20 eq). The resulting reaction mixture was stirred overnight at room temperature. The reaction mass was then poured onto ice-cold water followed by extraction with EtOAc (3×20 mL). The organics were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (60-120 M, 1-2.5% MeOH-DCM) to obtain Compound 9 (10 mg, 15%). NMR (300 MHz, DMSO-d6): δ 10.17 (br s, 1H), 10.08 (br s, 1H), 9.12 (s, 1H), 8.67 (s, 1H), 7.87 (m, 1H), 7.56 (m, 1H), 7.24-7.40 (m, 8H), 7.15 (m, 1H), 3.14 (m, 2H), 1.06 (t, J=7.20 Hz, 3H). [M+H]+ m/z=410.15.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH:17]1[NH:16][C:2]1[C:3]2[C:10]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Clc1ncnc2scc(-c3cccs3)c12
Product: c1csc(-c2csc3ncnc(NC4Cc5ccccc5C4)c23)c1
Yield: 100 %

Procedure:
Using 4-chloro-5-(2-thienyl)thieno[2,3-d]pyrimidine (50 mg, 0.20 mmol) and 2-aminoindan (110 mg, 0.80 mmol), a similar procedure to Production Example 190 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (70 mg, 0.20 mmol) having the following physical properties:
Reaction SMILES: O[C:2]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[F:15])([CH3:6])[C:3](=[O:5])[CH3:4].OS(O)(=O)=O>>[F:15][C:8]1[C:9]([F:14])=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[C:2](=[CH2:6])[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)C(C)(O)c1c(F)ccc(F)c1F
Agent: O=S(=O)(O)O
Product: C=C(C(C)=O)c1c(F)ccc(F)c1F
Temperature: 0 °C
Yield: 97.4 %

Procedure:
The hydroxy ketone 30 (7.69 g, 35.2 mmol) and 95% H2SO4 (26.2 mL, 492.8 mmol) were pumped at 2.3 and 9.2 mL/min respectively into the flow reactor. The temperature on mixing was controlled at 22-25° C. by placing the reactor in a water bath (21° C.). The effluent was quenched into a a mixture of cold water (106 g) and heptane/IPAc (1:1, 92 mL) in a jacketed reactor cooled at 0° C.; the internal temperature of the quench solution was ˜7° C. during the reaction. The layers in the quench reactor were separated and the organic layer was washed with 10% NaH2PO4/Na2HPO4 (1:1, 50 mL). The pH of the final wash was 5-6. Solka flock (3.85 g, 50 wt %) was added to the organic solution. The resulting slurry was concentrated and solvent-switched to heptanes at 25-30° C. The mixture was filtered, rinsed with heptanes (50 mL×1). The combined filtrates were concentrated under vacuum to give 31 as an light yellow oil (6.86 g, 90 wt %, 87% yield), which solidified in a freezer. 1H NMR (CDCl3, 400 MHz): δ 7.13 (m, 1H), 6.86 (m, 1H), 6.60 (s, 1H), 6.15 (s, 1H), 2.46 (s, 3H); 19F NMR (CDCl3, 376.6 MHz): δ −117.7 (dd, J=15.0, 1.4 Hz), −135.4 (dd, J=21.4, 1.4 Hz), −42.7 (dd, J=21.4, 15.0 Hz); 13C NMR (CDCl3, 100 MHz): δ 196.3, 155.3 (ddd, J=245, 5.1, 2.9 Hz), 147.9 (ddd, J=250, 14.5, 7.8 Hz), 147.0 (ddd, J=245, 13.4, 3.7 Hz), 137.5 (d, J=1.3 Hz), 131.7, 116.6 (ddd, J=19.9, 9.7, 1.2 Hz), 116.2 (dd, J=22.6, 16.5 Hz), 110.6 (ddd, J=24.8, 6.5, 4.1 Hz), 25.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]([CH:14]2[S:18][CH2:17][CH2:16][S:15]2)([CH3:13])[CH3:12])=[CH:7][C:4]=1[CH:5]=O.[NH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][CH2:5][C:4]2[CH:7]=[C:8]([C:11]([CH:14]3[S:18][CH2:17][CH2:16][S:15]3)([CH3:13])[CH3:12])[CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[C@@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1ccc(C(C)(C)C2SCCS2)cc1C=O
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C2SCCS2)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 81 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14](O)[CH2:15][CH:16]=[CH2:17].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH2:14]([C:4]1[C:5]([CH3:13])=[C:6]([O:11][CH3:12])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1])[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCC(O)c1c(C)c(OC)c(C)c(C)c1OC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCc1c(C)c(OC)c(C)c(C)c1OC
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Crude 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)but-3-en-1-ol (9.8 g) in 10 mL CH2Cl2 was added slowly, dropwise to a rapidly stirred, biphasic solution of TFA (10.5 mL, 153 mmol, 5 equiv.) and Et3SiH (6.3 mL, 1.3 equiv). The exothermic reaction was cooled in a room temperature water bath until addition was complete and the reaction stirred for and additional 2 h at room temperature. The brown solution was concentrated via rotovap, azeotroped 3×50 mL MeOH and 3×50 mL heptane and remainder taken up into 100 mL 5% EtOAc/heptane. The organic layer was washed 1×100 mL water, 1×50 mL saturated aqueous NaCl, filtered to remove particulates and dried over Na2SO4. Flash chromatography yielded 5.08 g of 1-(but-3-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene as a pale yellow oil which solidified upon standing to an off white wax. 1H NMR (400 MHz, CDCl3) δ=5.93 (m, 1H), 5.08 (m, 1H), 4.99 (m, 1H), 3.68 (s, 3H), 3.65 (s, 3H), 2.70 (m, 2H), 2.24 (m, 5H), 2.18 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2)c2ccc(F)cc2n1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(F)ccc2c1NCCC(=O)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy-6-fluoro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (10 mL). Add trifluoracetic acid (3 mL) and stir for 4 hours at room temperture. Dilute with ethyl acetate (50 mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dry over magnesium sulfate, filter and concentrate in vacuo to yield 3-[(phenacyl)methylamino]-2-carbethoxy-6-fluoroindole.