Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:27]=[C:26]([CH3:28])[C:5]([C:6]([NH:8][CH2:9][CH2:10][C@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[CH2:15][CH2:14]2)[CH3:12])=[O:7])=[C:4]([CH3:29])[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>COCCOC.C(Cl)Cl.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:23]1[CH:24]=[CH:25][C:21]([CH2:20][NH:19][CH:16]2[CH2:17][CH2:18][N:13]([C@H:11]([CH3:12])[CH2:10][CH2:9][NH:8][C:6]([C:5]3[C:26]([CH3:28])=[CH:27][C:2]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[N:3][C:4]=3[CH3:29])=[O:7])[CH2:14][CH2:15]2)=[CH:22]1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cc(-c2cccnc2)nc(C)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To an argon-degassed solution of 6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (100 mg, 0.23 mmol) and 3-pyridine boronic acid (56 mg, 0.46 mmol) in DME/2 M Na2CO3 (5:2, 3.5 ml) was added Pd(PPh3)4 (15 mg, 0.013 mmol) and the reaction stirred at 90° C. overnight. The mixture was cooled, diluted with CH2Cl2 (25 ml) and saturated aqueous NaHCO3 (25 ml). The aqueous layer was extracted with CH2Cl2 (2×10 ml) and the combined organic extracts were dried (Na2SO4), concentrated and purified by column chromatography on silica gel (CH2Cl2MeOH/NH4OH, 96:4:0 then 88:10:2) to afford 4,6-dimethyl-[2,3′]bipyridinyl-5-carboxylic acid ((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide as a mixture of product and starting amine (˜25%).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([NH2:16])[CH:3]=1.[C:17](=S)=[S:18].C(O)C.[K+].[Br-]>O>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][C:5]2[N:15]=[C:17]([SH:18])[NH:16][C:4]=2[CH:3]=1
Reactant: S=C=S
Reactant: Nc1cc(F)c(N2CCC(O)CC2)cc1N
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OC1CCN(c2cc3nc(S)[nH]c3cc2F)CC1
Yield: 62.3 %

Procedure:
6-Fluoro-5-(4-hydroxypiperidin-1-yl)-2-mercapto-1H-benzimidazole (4.5 g, 62%) was prepared by a similar procedure to that described in preparation 1 (step 5) using the diamine (6.0 g, 0.027 mol) (obtained in step 2 above), carbon disulfide (3.9 g, 0.052 mol), ethanol (30 mL) and water (5 mL). mp 268-269° C.; IR (KBr) 3397, 3124, 1487 cm-1 ; 1H NMR (DMSO-d6) δd 1.45-1.56 (m, 2H, CH2), 1.60-1.87 (m, 2H, CH2), 2.24 (s, 1H, SH), 2.64-3.92 (m, 2H, NCH2), 3.11-3.17 (m, 2H, NCH2), 3.30-3.60 (m, 1H, CH), 4.30 (brs, 1H, OH), 6.70 (d, J=7.4 Hz, 1H), 7.00 (d, J=12.6 Hz, 1H), 12.00 (brs, 1H, NH); Mass (m/z) 267 (M+.).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:15]=[CH:14]3)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.CN(C=O)C>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:15]=[CH:14]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/c2ccc3c(=O)n(-c4ccccn4)ncc3c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccc(/C=C/c3ccc(O)cc3)cc2cnn1-c1ccccn1
Temperature: 180 °C
Yield: 55 %

Procedure:
Trans-6-[2-(4-methoxyphenyl)ethenyl]-2-(2-pyridyl)-1(2H)-phthalazinone (7 g) and pyridine hydrochloride were thoroughtly mixed and heated to 180° C. for 21/2 hours. The solution was cooled to about 120° C.; then DMF (30 ml) was added followed by water (80 ml). The mixture was cooled to 20° C., filtered and the precipitate was washed with isopropanol. The solid mass was recrystallized from DMF to give 3.7 g of the phenol, mp=272° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH2:19])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:20]1[N:21]([C:25]2[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:22]=[CH:23][CH:24]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:31]([C:26]2[C:25]([N:21]3[N:22]=[CH:23][CH:24]=[N:20]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:32])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C(O)c1ncccc1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl)c1ncccc1-n1nccn1

Procedure:
A solution of (1S,2S)-1-N-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 33; 100 mg, 0.32 mmol), 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 66 mg, 0.35 mmol), EDC (91 mg, 0.47 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (65 mg, 0.47 mmol) and triethylamine (0.132 ml, 0.95 mmol) in DCM (1 ml) was stirred at room temperature overnight. The reaction was partitioned between water (5 ml) and DCM (5 ml), filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=O.P(Cl)(Cl)(Cl)=O.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]=[C:31]4[CH2:32][CH2:33][CH2:34][N:30]4[CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: CN1CCCC1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCCC1=Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8 %

Procedure:
N4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-N6-(1-methyl-pyrrolidin-2-ylidene)-quinazoline-4,6-diamine is prepared by reacting N4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine and 1-methyl-pyrrolidin-2-one. Phosphorous oxychloride (0.047 g, 0.30 mmol) is added to a stirred solution of 1-methyl-pyrrolidin-2-one (0.63 g, 0.63 mmol) in methylene chloride (3 ml) at −78° C. under N2 (Bullock et al WO0220526). After 10 minutes, the reaction mixture is warmed to room temperature and stirred for 1 hour. N4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine (0.100 g, 0.253 mmol) is added followed by Et3N (0.031 g, 0.30 mmol). After 16 hours, the reaction mixture is quenched with saturated aqueous Na2CO3, the layers separated and the aqueous layer extracted with methylene chloride. The combined organic extracts are dried (Na2SO4), concentrated and purified on a silica gel column (10:2:1 EtOAc:hexanes:MeOH with 0.3% NH4OH solution) to yield 0.010 g (8%) N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-N6-(1-methyl-pyrrolidin-2-ylidene)-quinazoline-4,6-diamine. MS APCI (+) m/z 476, 478 (M+1, Cl pattern) detected; 1H NMR (400 MHz, MeOH d) δ 8.42 (s, 1H), 7.89 (s, 2H), 7.77 (d, 1H), 7.58 (m, 2H), 7.33 (m, 3H), 7.18 (d, 1H), 7.04 (t, 1H), 5.20 (s, 2H), 3.60 (t, 2H), 2.61 (t, 2H), 2.03 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([NH:9][C@H:10]([C:12]([CH:14]([SH:27])[C@@H:15]([CH3:26])[C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])=[O:13])[CH3:11])=[O:8].[Na+].[I-:29]>CC#N>[I:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([NH:9][C@H:10]([C:12]([CH:14]([SH:27])[C@@H:15]([CH3:26])[C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])=[O:13])[CH3:11])=[O:8]
Reactant: [I-]
Reactant: C[C@H](NC(=O)OCCCCCl)C(=O)C(S)[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Solvent: CC#N
Product: C[C@H](NC(=O)OCCCCI)C(=O)C(S)[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 100.4 %

Procedure:
1-[(4-chlorobutoxycarbonyl)-L-alanyl-(2S)-3-mercapto-2-methyl-1-oxopropyl]-L-proline (3.15 g, 0.0078 Mol) was dissolved in CH3CN (100 ml) and NaI (11.7 g, 0.078 Mol) was added to the solution. The mixture was refluxed for 7 h, then concentrated and diluted with CH2Cl2. The solid formed was filtered off and the organic phase was washed with H2O (3×50 ml), dried over sodium sulphate and evaporated under reduced pressure affording 1-[(4-iodobutoxycarbonyl)-L-alanyl-(2S)-3-mercapto-2-methyl-1-oxopropyl]-L-proline (4.03 g) as a foam that was used without further purification.
Reaction SMILES: [C:1]([N:5]1[CH2:38][CH2:37][CH2:36][CH2:35][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([C@@H:20]5[O:24][C:23]([CH3:26])([CH3:25])[O:22][C@H:21]5[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:16]([O:32][CH3:33])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:39])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:45]1[S:46][CH:47]=[CH:48][CH:49]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:5]1[CH2:38][CH2:37][CH2:36][CH2:35][C:8]2[C:9]([C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C@@H:20]5[O:24][C:23]([CH3:26])([CH3:25])[O:22][C@H:21]5[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:16]([O:32][CH3:33])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:39])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c3c(c(Br)c1-2)CCCCN(C(C)(C)C)C3=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c3c(c(-c4cccs4)c1-2)CCCCN(C(C)(C)C)C3=O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 750 mg of 21e, 550 mg of 2-(tributylstannyl)-thiophene and 28 mg of tetrakis(triphenylphosphine)palladium(0) in 14 ml of degassed toluene was heated under N2 atmosphere for 16 hr at 110° C. The reaction mixture was cooled, 15 ml of sat. aq. KF was added, and stirring prolonged for 2 hr. The reaction was filtered through Celite, and the product was extracted with ethyl acetate. The organic layer was washed, dried and concentrated and the product purified by chromatography over silicagel (using a gradient of heptane-ethylacetate as eluent). This provided 630 mg of 21f; LC-MS-ESI: [M+1] 607.26. NMR (CDCl3) δ 7.35, 7.08, and 6.93 (3×m, 3, thienyl-H), 6.67 and 7.30 (2×s, 2, Ar—H) 5.35 (d 1, CHO), 3.95 (d, 1, CHO), 3.75 (s, 3, OCH3), 0.20 (m, 2, ethyl ester), 1.28 (t, 3, ethyl ester), 4.60, and 3.80 (2×bm, 2, CH2), 3.55 and 4.15 (2×br.m, 2, CH2), 2.92 and 3.13 (2×b.m, 2, CH2) 1.6-2.0 (bm, 4, 2×CH2), 1.32 and 1.50 (2×s, 6, dimethylketal), 1.57 (s, 9, tertC4H9).
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+].O>CO>[N+:17]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:5]2[C:6](=[O:9])[CH2:7][CH2:8][C@H:4]2[C:3]([OH:20])=[O:2])=[CH:16][CH:15]=1)([O-:19])=[O:18]
Reactant: COC(=O)[C@@H]1CCC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-N-(4-Nitrobenzyl)pyroglutamic acid methyl ester (0.365 g, 1.31 mmol) was dissolved in 10 ml MeOH, cooled to 0° C., and 1N NaOH (5.2 ml, 5.2 mmol) was added. The reaction was stirred at room temperature for 1 h. Water (50 ml) was added and the aqueous was washed with 2×50 ml EtOAc. The aqueous was acidified with 1N HCl and extracted with 3×40 ml EtOAc. The organic layers were dried (MgSO4), filtered, and concentrated to give the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([N:18]=[C:19]=[S:20])[CH:17]=1)=[CH:5]2.[C:23]([O:27][C:28](=[O:37])[C@H:29]([CH2:31][O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH2:30])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:37])[C@@H:29]([NH:30][C:19]([NH:18][C:16]1[CH:17]=[C:12]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=3)[CH:13]=[CH:14][C:15]=1[O:21][CH3:22])=[S:20])[CH2:31][O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N=C=S
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
The product from Example 35, Step A, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenyl isothiocyanate (0.316 g, 1.0 mmol) was reacted with serine tert-butylether tert-butylester (0.226 g, 1.0 mmol) according to the procedure for Example 23, Step B to give the product after filtration through silica gel using hexanes/ethyl acetate, 1/1, v/v as eluant (0.377 g in 2 portions), mp 111-114° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][CH2:47][CH2:48][S:49]([NH2:52])(=[O:51])=[O:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][CH2:47][CH2:48][S:49]([NH2:52])(=[O:50])=[O:51])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(N)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 3-piperazin-1-yl-propane-1-sulfonic acid amide dihydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C36H47N6O4SCl2 [(M+H)+] 729.2751, observed 729.2754.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]1[C:16]([Cl:17])=[N:15][C:13](Cl)=[N:12][C:10]=1[Cl:11]>C1COCC1>[Cl:11][C:10]1[N:9]=[C:16]([Cl:17])[N:15]=[C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenylmagnesium bromide (97.6 ml of a 1.0 M solution in THF, 97.6 mmol, 1.0 equiv) was added dropwise to a THF (8 mL) solution of cyanuric chloride (18.0 g, 97.6 mmol, 1.0 equiv) at 0° C. The reaction mixture was stirred at room temperature for 1 h and was poured onto ice and stirred for 30 min. The product was extracted with ethyl acetate, and the combined organic layers were washed with (sat.) sodium chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 16 g the title compound. The crude product was carried forward without purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[C:10]2/[C:11](=O)[CH2:12][CH2:13][C:14]3[C:19]/2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.[NH2:24][NH2:25]>C(O)(=O)C.C(O)C>[CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([C:9]2[NH:24][N:25]=[C:11]3[C:10]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NN
Reactant: CS(=O)(=O)c1ccc(/C=C2/C(=O)CCc3ccccc32)cc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2[nH]nc3c2-c2ccccc2CC3)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one (50 mg, 0.16 mmol), hydrazine hydrate (0.0155 ml, 0.32 mmol) were added into ethanol (5.0 ml) and 1-2 drops of acetic acid was added properly. Then, the solution was stirred and refluxed for 48 hours and cooled to room temperature. Afterward, the resulting solution was concentrated under reduced pressure, diluted by adding dichloromethane (10 ml), and then washed with water and the saturated brine. The residue was purified through silica gel column chromatography (eluent: ethylacetate/n-hexane=1/1, v/v). As a result, 35 mg of the present compound (productive yield 68%) was obtained as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.[NH4+:31].[OH-:32]>CCO.O>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:32])=[C:24]([F:30])[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: [NH4+]
Reactant: [OH-]
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Solvent: CCO
Solvent: O
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (183) (164 mg, 0.404 mmol) in 3 mL EtOH was added 1 mL 50% NH4OH in water. The resulting mixture was stirred at 55° C. for 2 hr, concentrated in vacuo, dried under vacuum, and used as it is for the next step.
Reaction SMILES: [ClH:1].[CH2:2]1[O:10][C:9]2[CH:8]=[CH:7][C:6]([CH:11]([OH:14])[CH2:12][NH2:13])=[CH:5][C:4]=2[O:3]1.[CH3:15][C:16]([CH3:18])=O.[H][H]>[Ni].C(O)C>[ClH:1].[CH2:2]1[O:10][C:9]2[CH:8]=[CH:7][C:6]([CH:11]([OH:14])[CH2:12][NH:13][CH:16]([CH3:18])[CH3:15])=[CH:5][C:4]=2[O:3]1
Reactant: CC(C)=O
Reactant: [H][H]
Reactant: NCC(O)c1ccc2c(c1)OCO2
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: CC(C)NCC(O)c1ccc2c(c1)OCO2

Procedure:
18.1 g. of 1-(3,4-methylenedioxyphenyl)-2-aminoethanol hydrochloride are dissolved in 20 ml. of acetone and 300 ml. of ethanol. To the resulting solution are added 10 g. of extended Raney nickel and the mixture is heated and stirred at 70° C. in an atmosphere of hydrogen in an autoclave. After the absorption of hydrogen is complete, the catalyst is filtered off and the filtrate is concentrated to dryness. Upon recrystallization of the crude crystalline residue from isopropyl alcohol, 14.4 g. of 1-(3,4-methylenedioxyphenyl)-2-isopropylaminoethanol hydrochloride are obtained as white needles.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br.Br[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl.O>[N:15]1([CH2:14][CH2:13][NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrCCN1CCCCC1
Reactant: Nc1n[nH]c2ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(NCCN3CCCCC3)n[nH]c2c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 55.9 %

Procedure:
4.0 g of 3-aminoindazole prepared by the method described in C. E. KWARTLER et. al., J. Am. Chem. Soc., 65, 1804 (1943), 8.18 g of 1-(2-bromoethyl)piperidine hydrobromide obtained from Referential Example 1, 8.28 g of anhydrous potassium carbonate and 80 ml of dried N,N-dimethylformamide were mixed and stirred for 24 hours at 80° C. After the reaction mixture was condensed under reduced pressure, 100 ml of chloroform and 50 ml of water were added to the condensed residue. Then the chloroform layer was separated, dried with anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue thus obtained was subjected to alumina-column chromatography (alumina: 200 g) using chloroform as the solvent to give 4.09 g of 3-(2-piperidinoethylamino)indazole in a yield of 56%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]phenylamine (60 mg, 0.26 mmol) obtained in Example 2 was dissolved in THF (1.5 mL) and the solution was added with triethylamine (71 μL, mmol) and p-fluorobenzoylchloride (45 μL, 0.38 mmol), followed by stirring at room temperature for 30 minutes. Further, the reaction mixture was added with potassium carbonate and stirred for a while. Then, the solid precipitated by adding water to the mixture was collected by filtration and the solid was triturated in ethanol to obtain Compound 3 (57 mg, 62%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1(C)OC(=O)CC(=O)[O:5]1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](Cl)=[O:24].[CH3:26][C:27]([OH:36])([CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:28]=[CH2:29]>O1CCCC1.O>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](=[O:24])[CH2:3][C:4]([O:36][C:27]([CH3:26])([CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:28]=[CH2:29])=[O:5]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.26 g, 0.057 mol, 95%) is charged to a 250 mL three-necked round-bottomed flask fitted with a magnetic stirrer, ice bath, addition funnel, internal thermometer and argon inlet. The contents of the reaction vessel are slurried with 50 mL of tetrahydrofuran (THF) and subsequently cooled to 0° C. 2,2-dimethyl-1,3-dioxan-4,6-dione (Meldrum's acid) (3.78 g, 0.026 mol) is dissolved in 20 mL of THF and the solution is subsequently added over 15 min. The evolution of gas indicates the reaction is ensuing. After 30 min, 2-naphthoyl chloride (5.00 g, 0.026 mol) which is dissolved in 30 mL of THF is added over 15 min. The mixture is allowed to warm to room temperature and stirred for 72 h. A solution of 3,7-dimethyl-1,6-octadien-3-ol (linalool) (4.05 g, 0.026 mol) dissolved in 30 mL of THF is added over 30 min. The mixture is heated to reflux for 18 h. The cooled mixture is poured into 100 mL of water and extracted with ether (50 mL) three times. The organic layers are washed with saturated NaHCO3 solution, water, dried over MgSO4, filtered, concentrated by rotary evaporation and purified by flash chromatography to yield 3,7-dimethyl-1,6-octadien-3-yl 3-(β-naphthyl)-3-oxo-propionate.