Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][CH:19]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:38][CH:39]([Cl:43])[C:40](Cl)=[O:41]>ClCCl>[Cl:38][CH:39]([Cl:43])[C:40]([N:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:15]=1)=[O:41]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylcarbamate (230 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane with triethylamine (120 μL, 0.82 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (120 mg, 0.82 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 95:5 hexanes:ethyl acetate to yield tert-butyl 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylcarbamate. 1H NMR (CDCl3): 7.99 (d, 1H), 7.82 (br s, 1H), 7.62 (m, 1H), 7.48-7.30 (m, 4H), 6.78 (s, 1H), 5.82 (s, 1H), 4.95 (m, 1H), 3.95 (m, 2H), 3.43 (m, 2H), 1.42 ppm (s, 9H).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3](N[C@@H](CC2C=C(OC)C(OC)=C(OC)C=2)C(O)=O)[CH:2]=1.[NH2:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)[C:33]([OH:35])=[O:34]>>[CH2:44]([O:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][C@H:32]([NH:31][C:27]2[CH:26]=[C:25]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:30]=[CH:29][CH:28]=2)[C:33]([OH:35])=[O:34])=[CH:38][CH:39]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)Nc1cccc(-c2ccccc2)c1

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using (S)-2-Amino-3-(4-benzyloxy-phenyl)-propionic acid (O-benzyl-L-tyrosine). Purification by MPLC (CH3CN/H2O/TFA) afforded the title compound; ES-MS: 424.3 [M+H]+; HPLC: single peak at tR=10.40 min (System 1).
Reaction SMILES: Br[CH:2]([C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O)[C:3]([O:5][CH3:6])=[O:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](=[S:24])[NH2:23])=[CH:20][CH:19]=1>CC#N>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:23]=[C:22]([C:21]3[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[S:24][C:2]=2[C:3]([O:5][CH3:6])=[O:4])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(N)=S)cc1
Reactant: COC(=O)C(Br)C(=O)c1ccc(F)cc1
Solvent: CC#N
Product: COC(=O)c1sc(-c2ccc(OC)cc2)nc1-c1ccc(F)cc1
Reaction time: 18 h
Yield: 22.2 %

Procedure:
To a stirring solution of methyl 2-bromo-3-(4-fluorophenyl)-3-oxopropanoate 78 (1 equiv, 1.15 g, 4.2 mmol) in MeCN at room temperature was added 4-methoxybenzo-thioamide 77 (1 equiv, 700 mg, 4.2 mmol) and the reaction mixture was stirred for 18 h. The solvent was evaporated and the residue purified by trituration with diethyl ether to afford methyl 4-(4-fluorophenyl)-2-(4-methoxyphenyl)thiazole-5-carboxylate 79 (320 mg, 22% yield). LRMS (ESI): (calc) 343.37 (found) 344.235 (MH+)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1.[N+]([C:21]([CH2:48][CH2:49][CH2:50][CH3:51])=[CH:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][C:24]=1[C:36]([N:38]1[CH2:47][CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])([O-])=O>>[C:30]([O:29][C:27]([C:26]1[CH:34]=[CH:35][C:23]([C:22]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:9][CH:8]=3)[C:21]=2[CH2:48][CH2:49][CH2:50][CH3:51])=[C:24]([C:36]([N:38]2[CH2:47][CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)=[O:37])[CH:25]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1ccc(CCO)cc1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(CCO)cc1
Yield: 17.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-(2-hydroxyethyl)phenyl)hydrazono)acetate (61 mg, 0.26 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (120 mg, 0.26 mmol) were converted to the title compound (29 mg, 17%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.10 (dd, J=8, 2 Hz, 1H), 8.05-8.03 (m, 1H), 7.44-6.82 (m, 9H), 5.02-4.98 (m, 1H), 4.48-4.38 (m, 1H), 4.32-4.26 (m, 2H), 4.15-3.98 (m, 1H), 3.89-3.88 (m, 2H), 3.58-3.38 (m, 1H), 2.96-2.92 (m, 2H), 2.88-2.50 (m, 4H), 1.61 (s, 9H), 1.29 (t, J=8 Hz, 1.5H), 1.21 (t, J=8 Hz, 1.5H), 1.13-0.95 (m, 4H), 0.62-0.57 (m, 3H); MS(ESI+) m/z 652.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Reactant: OB(O)c1ccccc1
Product: O=C(Nc1nc2ccc(-c3ccccc3)cn2n1)c1cccnc1
Yield: 55.5 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and phenylboronic acid (57 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gave the title compound as a beige powder (42 mg, 56%). HPLC, Rt: 2.26 min. (purity 98.7%).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:21][N:22]([CH3:37])[CH2:23][CH2:24][S:25]([N:28]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:29])(=[O:27])=[O:26]>>[CH3:21][N:22]([CH3:37])[CH2:23][CH2:24][S:25]([N:28]([C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:4](=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:35][CH:36]=1)[CH3:29])(=[O:27])=[O:26]
Reactant: CN(C)CCS(=O)(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Product: CN(C)CCS(=O)(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 39 from 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-[N-(2-dimethylamino-ethylsulphonyl)-N-methyl-amino]-aniline.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:14][C:15]#[N:16])[CH:7]=[C:8]([Cl:13])[C:9]=1[N:10]([CH3:12])[CH3:11].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20].O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:14]([C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])[C:15]#[N:16])[CH:7]=[C:8]([Cl:13])[C:9]=1[N:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CN(C)c1c(Cl)cc(CC#N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1c(Cl)cc(C(C#N)C(=O)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.41 g (35.3 mmol) of sodium hydride are initially charged in absolute THF (50 ml), and 4.05 g (17.6 mmol) of [3,5-dichloro-4-(dimethylamino)phenyl]acetonitrile in 20 ml of absolute THF are added dropwise at 0° C. The mixture is stirred at 0° C. for 20 minutes, and 5.02 g (35.3 mmol) of ethyl trifluoroacetate are then added dropwise at 0° C. The reaction mixture is warmed to room temperature and then carefully added to water. After washing with n-hexane, the aqueous phase is acidified with 1 N HCl. A colourless solid precipitates out and is, after filtration with suction and air-drying, used without further purification for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(Cl)(Cl)=O.[CH2:16](N(CC)CC)C>ClCCCl>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1ccc(Br)cc1C

Procedure:
To a suspension of 4-bromo-2-methylbenzoic acid (10.0 g, 0.0465 mol) in 1,2-dichloroethane (60 mL) was added thionyl chloride (28 g, 0.23 mol) and the mixture heated to reflux for 1 hour. The mixture was concentrated to dryness and vacuum dried. The crude acid chloride was dissolved in methanol (100 mL) and the solution was treated with triethylamine (4.7 g, 0.046 mol). The mixture was heated to reflux for an hour and then concentrated to dryness. The crude ester was dissolved in EtOAc, washed consecutively with sat. sodium bicarbonate solution and water. The organic phase was dried and concentrated to obtain the title ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].S(Cl)([Cl:21])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:21])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(Br)ccc1C(=O)Cl
Temperature: 80 °C
Yield: 100 %

Procedure:
4-Bromo-2-methoxybenzoic acid (2.934 g, 12.70 mmol) was mixed with sodium carbonate (2.2 g, 26.51 mmol). Thionyl chloride (20 mL) was added and the reaction mixture was heated at 80° C. for 16 hours. After distilling off excess thionyl chloride, heptane was added and the solid was collected by filtration to give 4-bromo-2-methoxy-1-benzenecarbonyl chloride (3.16 g, 100%). 1H NMR (CDCl3) δ 3.94 (s, 3H), 7.16 (s, 1H), 7.20 (d, J=8.51 Hz, 1H), 7.95 (d, J=8.51 Hz, 1H).
Reaction SMILES: FC1C(O[C:9]([C:11]2[N:12]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)=[O:10])=C(F)C(F)=C(F)C=1F.S(=O)(=O)(O)O.[NH2:32][CH2:33][C:34]#[N:35].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:33]([CH2:34][NH:35][C:9]([C:11]1[N:12]([CH2:19][CH:20]2[CH2:21][CH2:22]2)[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)=[O:10])#[N:32]
Reactant: N#CCN
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc([N+](=O)[O-])cn1CC1CC1
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCNC(=O)c1cc([N+](=O)[O-])cn1CC1CC1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A mixture of compound 278 (3.6 g, 9.57 mmol), aminoacetonitrile bisulfate (2.94 g, 19.12 mmol) and N,N-diisopropylethyl-amine (3.5 ml) in DMF (60 ml) was stirred under Ar at 55° C. for 16 h. After evaporation of solvent, the residue was separated by chromatography on silica gel eluted by CHCl3-ethyl acetate (10:1) to give g of compound 279. MS (ESI) 247.12 (M−H+). H1-NMR (DMSO-d6) 9.16 (t, 1H), 8.26 ((d, 1H), 7.49 (d, 1H), 4.28 (d, 2H), 4.23 (d, 2H), 1.30–1.28 (m, 1H), 0.50–0.46 (m, 2H), 0.41−0.38 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Cl.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:20]1[NH:19][CH:23]=[CH:22][N:21]=1
Reactant: COC(=O)C(Cl)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
13 g (0.05 mole) diphenyl-chloroacetic acid methyl ester (b.p. 140°C/0.1 mm Hg, prepared from diphenyl-chloroacetic acid chloride and methanol according to Ber. 22, 1537) are heated with 10 g imidazole in 100 ml acetonitrile at boiling temperature for 18 hours. After distilling off the solvent in a vacuum, 50 ml of water are added and the mixture is extracted with methylene chloride. After drying over sodium sulphate, the solvent is distilled off in a vacuum and the residue recrystallized from a little ethyl acetate. The diphenyl-imidazolyl-acetic acid methyl ester is thus obtained in the form of colourless crystals of m.p. 155°C (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]1SCCCS1.[CH:17]1([CH:23]=[CH:24][C:25](OCC)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>[Ni]>[CH:17]1([CH:23]2[CH2:11][C:4]3[C:5](=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=3[O:2][CH3:1])[C:25](=[O:26])[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cccc(C2SCCCS2)c1OC
Reactant: CCOC(=O)C=CC1CCCCC1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1OC)CC(C1CCCCC1)CC2=O

Procedure:
2-(2',3'-Dimethoxyphenyl)-1,3-dithiane, from Step 1 of Example 1, Method B, and ethyl 3-cyclohexylpropenoate, from Step 1 of this Example, were condensed as described in Step 2 of Example 1, Method B. The adduct was treated with Raney nickel and sodium hydroxide to give the corresponding acid. The acid was cyclized with polyphosphoric acid as described in Step 6 of Example 1, Method A, to give 3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-one. This ketone was treated with trimethylsilylcyanide in the presence of aluminum chloride and reduced with lithium aluminum hydride as described in Step 1 of Example 2 to give 1-aminomethyl-5,6-dimethoxy-1-hydroxy-3-cyclohexyl-1,2,3,4-tetrahydronaphthalene. The hydroxy group was eliminated by treatment with anhydrous hydrogen chloride in isopropyl alcohol as described in Step 2 of Example 2 to give 1-aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalene hydrochloride, m.p. 178°-179° C.; 1H NMR (d6 -DMSO) δ: 1.0-1.4 (m, 7H), 1.5-1.9 (m, 6H), 2.0-2.2 (m, 1H), 2.5 (dd, 1H), 2.7 (dd, 1H), 3.6 (s, 3H), 3.81 (s, 3H), 5.8 (d, 1H), 6.6 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.Cl.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:1][C:3]3[CH:18]=[CH:17][C:6]([O:7][C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=4)=[CH:5][CH:4]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2)nc1
Reaction time: 23 h
Yield: 21.4 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.299 g, 1.23 mmol), 1-(4-fluoro-phenyl)-piperizine, bis hydrochloride salt (0.314 g, 1.24 mmol), triethylamine (0.36 mL, 2.58 mmol) in methanol (12 mL) and stir. After 23 h, add sodium borohydride (0.108 g, 2.85 mmol). After 1 d, concentrate and purify the residue by silica gel chromatography (25:1→4:1 methylene chloride:methanol) to provide 0.107 g (21%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C23H24FN4O2 407.1883, found 407.1883; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.4; 8.8 Hz), 7.52-7.47 (m, 2H), 7.20-7.15 (m, 2H), 7.05 (d, 1H, J=7.8 Hz), 7.01 (d, 1H, J=6.3 Hz), 3.66 (s, 2H), 3.21-3.16 (m, 4H), 2.74-2.68 (m, 4H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:12](Cl)(=O)CC.N>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH2:5][CH3:12]
Reactant: COC(=O)CC(C)=O
Reactant: CCC(=O)Cl
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCC(=O)CC(=O)OC
Yield: 89.9 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 106.5 g (1.15 mol) of propionyl chloride. The pH in the subsequent reaction with ammonia was adjusted to 9.1. This gave 117 g (GC purity 79.0%) of methyl propionylacetate (yield 71.0%).
Reaction SMILES: [CH2:1]([N:3]([C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][N:32]=1)=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:33][N:32]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)cn1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cn1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 46.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(5-hydroxypyridine-2-carbonyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-piperidin-1-ylethanone (16 mg) according to an analogous synthetic method to Example 404 described below and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[CH:12]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[CH:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
Benzenesulfonyl chloride (1b) (98.7 g) was added dropwise into a solution of 7-azaindole (1a) (60.0 g) and triethylamine (56.6 g) in DCM (500 mL) at 0° C. The mixture was warmed to rt and stirred for 2 days to produce a white crystalline product. The white crystals were filtered off and the solution was washed with a saturated aqueous NaHCO3 solution and brine, then dried over MgSO4 and concentrated. The residue was recrystallized in ethyl acetate (200 mL) to provide N-phenylsulfonyl-7-azaindole (1c) (121.31 g, 94%) as white crystals. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=4.8 Hz, 1H), 8.18 (d, J=8.0 Hz, 2H), 7.85 (d, J=8.0 Hz, 1H), 7.73 (d, J=4.8 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.48 (t, J=7.6 HZ, 2H), 7.15 (dd, J=8.0 Hz, 4.8 Hz, 1H), 6.58 (d, J=4.8 Hz, 1H).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:34][C@@:32]3([CH3:33])[C@@H:28]([CH2:29][CH2:30][C@@H:31]3[OH:35])[C@H:27]3[C@H:18]2[C:19]2[CH:20]=[CH:21][C:22]([OH:36])=[CH:23][C:24]=2[CH2:25][CH2:26]3)=[CH:13][CH:12]=1>CC(CC)=O.C(OCC)(=O)C>[I:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:34][C@@:32]3([CH3:33])[C@@H:28]([CH2:29][CH2:30][C@@H:31]3[OH:35])[C@H:27]3[C@H:18]2[C:19]2[CH:20]=[CH:21][C:22]([OH:36])=[CH:23][C:24]=2[CH2:25][CH2:26]3)=[CH:13][CH:12]=1
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCCCl)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: C[C@]12C[C@H](c3ccc(OCCCCCCI)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 24 h

Procedure:
150 mg of sodium iodide is added to a solution of 310 mg of the product obtained in Stage C in 6 cm3 of methylethylketone and agitation is carried out for 24 hours under reflux. 100 mg of sodium iodide is added, followed by agitation for 2 hours under reflux and for 16 hours while leaving the temperature to return to ambient, taking up in ethyl acetate, washing, drying and evaporating to dryness under reduced pressure. 470 mg of expected product is collected which is used as it is for the following stage.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([N:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH2:5][CH2:4][S:3]1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: N=C1SCCN1Cc1ccncc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])N=C1SCCN1Cc1ccncc1
Reaction time: 0.5 h

Procedure:
5.8 g of 2-imino-3-(4-pyridylmethyl)thiazolidine was added to 20 ml of conc. sulfuric acid at -5°~0° C. 6 ml of fuming nitric acid was then added dropwise to the solution at the same temperature. After stirring for 30 minutes at 0°~5° C., the reaction mixture was poured onto crushed ice. Twice extract with dichloromethan followed by treating in the usual way yielded 1.4 g of desired 2-nitroimino-3-(4-pyridylmethyl)thiazolidine.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][O:28][CH2:29][CH:30]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]>C1COCC1.[OH-].[Pd+2].[OH-]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][O:28][CH2:29][CH:30]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)[OH:11]
Reactant: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2s1

Procedure:
To a round bottomed flask was added benzo[d]thiazol-2-yl(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone (0.6000 g, 1.448 mmol) in THF (4.83 mL). Palladium hydroxide (0.051 g, 0.072 mmol) was added. The round bottomed flask was flushed with N2(g) followed by vacuum repeating the process three times. A balloon of H2(g) was then added to the reaction. Reaction was filtered through celite. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in ACN/H2O, gradient 50% to 100% over 15 min to provide benzo[d]thiazol-2-yl(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanol. MS (ESI, pos. ion) m/z: 416.9 (M+1). IC50 (uM) +++.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1>>[Cl:25][C:19]1[N:18]=[C:17]2[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: COc1ccc(C(=O)O)cc1OC
Product: COc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc1OC
Yield: 49.9 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 3,4-dimethoxybenzoic acid (14.6 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g), and heating for 17 hours under reflux. The product obtained, after precipitation of the reaction mixture in water (1000 cc) and drying, is purified by recrystallization in acetonitrile (250 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-3,4-dimethoxybenzamide (8.5 g), m.p. 196° C., is thereby obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:4]2[CH2:5][CH2:6][CH:2]([CH3:1])[CH2:3]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCC(O)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(C)C2)cc1
Yield: 92.5 %

Procedure:
3-Methylcyclopentanol (5.0 g, 49.9 mmol) was reacted with p-toluenesulfonyl chloride in pyridine (50 ml) in the same procedure as in Reference Example 7 to obtain 3-methylcyclopentyl p-toluenesulfonate (11.7 g, 46.2 mmol, 92.5% yield).