Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1>CN(C)C=O.O>[CH3:16][O:15][C:4]1[CH:3]=[C:2]([NH:35][CH2:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(NCc2ccc(OC)cc2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of methyl 4-fluoro-2-methoxy-5-nitrobenzoate (40 g, 174.55 mmol) in N,N-dimethylformamide (1000 mL) was added DIEA (45.2 g, 349.74 mmol). Then (4-methoxyphenyl)methanamine (31.1 g, 226.71 mmol) was added dropwise with stirring for 1 hour at 25° C. The reaction mixture was diluted with water (2 L). The solids were collected by filtration to afford methyl 2-methoxy-4-(4-methoxybenzylamino)-5-nitrobenzoate as a yellow solid (44 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[CH:5]=[C:4]([CH3:16])[CH:3]=1.[ClH:17]>>[ClH:17].[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: COC(=O)CCCCc1cc(C)cc(N)n1
Agent: Cl
Product: Cc1cc(N)nc(CCCCC(=O)O)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 5-(6-amino-4-methyl-2-pyridinyl)pentanoate (119 mg, 0.536 mmol) in 10 mL of 2.0 N hydrochloric acid was refluxed for 3 h. After cooling to room temperature, the reaction was extracted with 2×10 mL of dichloromethane and the aqueous phase was concentrated in vacuo to give 134 mg of 5-(6-amino-4-methyl-2-pyridinyl)pentanoic acid hydrochloride as a pink solid.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)[C:9]2=[N:21]S(C(C)(C)C)=O.Cl>O1CCOCC1>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12]([CH2:11][C:10]3([CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]3)[C:9]2=[NH:21])=[CH:13][CH:14]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Agent: Cl
Solvent: C1COCCO1
Product: N=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.3 %

Procedure:
To N-(5′-(3-fluoropropoxy)-4-hydroxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 32, 275 mg, 0.70 mmol) in dioxane (1 mL) under an atmosphere of nitrogen was added HCl (4 M in 1,4-dioxane, 1.74 mL, 6.95 mmol). The mixture was stirred at r.t. for 2 h and was then concentrated. DCM (1-2 mL) and Et2O was added and a solid was formed. The solid was filtered off and washed with diethylether. The solid was dissolved in DCM. Sat. aq. NaHCO3 was added and mixture was poured in to a phase separator. The organic phase was collected and concentrated to give 6′-(3-fluoropropoxy)-1′-imino-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-ol (227 mg). The obtained imine was mixed with 2-oxopropanethioamide (Intermediate 1, 239 mg, 2.32 mmol) in dry MeOH (4 mL) and the resulting orange solution was heated at 60° C. under an atmosphere of nitrogen overnight. The mixture was allowed to cool to r.t., and concentrated. The residue was purified by flash column chromatography using a gradient of 0-100% EtOAc in heptane, providing 104 mg (36% yield) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.04-1.21 (m, 4 H) 1.41-1.48 (m, 2 H) 1.66-1.73 (m, 2 H) 2.02 (t, 1 H) 2.07 (quin, 1 H) 2.26 (s, 3 H) 2.93 (d, 1 H) 3.01 (d, 1 H) 3.22-3.29 (m, 1 H) 3.97 (tq, 2 H) 4.52 (t, 1 H) 4.55 (d, 1 H) 4.62 (t, 1 H) 6.32 (d, 1 H) 6.89 (dd, 1 H) 7.26 (d, 1 H) 12.28 (s, 1 H); MS (ES+) m/z 377.07 [M+H]+.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.C(O[C:17](=[O:33])[C:18](=[CH:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>CCCCCC>[CH2:22]([O:21][C:19]([C:18]1[C:17](=[O:33])[C:31]2[C:26](=[N:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(=CNc1cccc(C)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Temperature: 250 °C
Yield: 70.3 %

Procedure:
A solution of diphenyl ether was heated to 250° C. and the product of Example 1a (2.50 g, 9.0 mmol) was added in several small portions over a period of about 5 min then heated at 250° C. for 30 min. After cooling to room temperature diluted with hexane. The resulting solid was filtered and was dried under vacuum giving the title compound as a tan solid (1.47 g, 71%).
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[CH2:11][CH2:10][C@@H:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C@H:8]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:7]1)[CH2:3][CH2:4][CH3:5].[CH2:33](N1CCC(C2C=CC(N(C)C)=CC=2)C(CO)C1)CCC.[H-].[Na+].FC1C=CC(C(F)(F)F)=CC=1>CN(C=O)C>[ClH:1].[CH3:19][N:18]([CH3:20])[C:15]1[CH:16]=[CH:17][C:12]([C@@H:9]2[CH2:10][CH2:11][N:6]([CH2:2][CH:3]([CH3:33])[CH2:4][CH3:5])[CH2:7][C@H:8]2[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=2)=[CH:13][CH:14]=1
Reactant: CCCCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1
Reactant: CCCCN1CCC(c2ccc(N(C)C)cc2)C(CO)C1
Agent: Cl
Agent: Fc1ccc(C(F)(F)F)cc1
Agent: [H-]
Solvent: CN(C)C=O
Product: CCC(C)CN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1

Procedure:
Was prepared as described for compound (11) from the 1-(2-methylbutyl) analogue of compound (12) (2 g), NaH (0.32 g) and 4-fluorobenzotrifluoride (2.16 g) in DMF (100 ml). 3 g crude product was purified on a silica gel column identified as compound (13) by MS and 1H NMR. M.p. 237.2°-237.6° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO.[OH-].[Na+]>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCn1cc(-c2ccccc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCn1cc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A mixture of ethyl 4-(4-phenyl-1H-pyrazol-1-yl)butanoate (273 mg, 1.06 mmole) in methanol (5 ml) and 1N NaOH (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was adjusted to be acidic (pH=3-4) with 6 N HCl with an ice bath and then extracted with EtOAc (3×). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated to give the desired product (190 mg, 78%). LCMS calculated for C13H15N2O2 (M+H): 231.1; found: 231.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([F:25])=[CH:20][N:19]=1.O>CO>[C:11]([C:9]([NH:8][C:6]1[C:5]([O:15][CH3:16])=[CH:4][CH:3]=[C:2]([NH:1][C:20]2[C:21]([F:25])=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)[N:7]=1)=[O:10])([CH3:13])([CH3:12])[CH3:14]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)nc1NC(=O)C(C)(C)C
Solvent: CO
Solvent: O
Product: COc1ccc(Nc2nc(Cl)ncc2F)nc1NC(=O)C(C)(C)C

Procedure:
A homogeneous mixture of 6-amino-2-(tert-butylcarbonyl)amino-3-methoxypyridine (35) (1.5 g, 6.72 mmol) and 2,4-dichloro-5-fluoropyrimidine (53) (1.68 g, 10 mmol) in methanol:water (20 mL, each) was stirred at 60° C. for 48 hours. The reaction mixture upon dilution with water (100 mL) gave a solid, which was isolated by filtration to obtain N4-[2-(tert-butylcarbonyl)amino-3-methoxypyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine. LCMS: purity: 89%; MS (m/z): 354 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.OO.S([O-])([O-])=[O:16].[Na+].[Na+]>C1COCC1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:16]
Reactant: O=S([O-])[O-]
Reactant: COc1cccc(B(O)O)c1F
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(O)c1F
Temperature: 25 °C

Procedure:
To a solution of 2-fluoro-3-methoxyphenylboronic acid (30.4 g) in THF (300 mL) was added dropwise aqueous hydrogen peroxide (100 mL, 30% wt in water), and the mixture was heated with reflux for 1 hr. The reaction mixture was allowed to be cooled to room temperature, saturated aqueous sodium sulfite was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by combi flash (petroleum ether/ethyl acetate) to give the title compound (24.8 g).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:38]([NH:40][CH2:41][C:42]([NH:44][C@H:45]([C:56]([N:58]1[CH2:65][CH2:64][CH2:63][C@H:59]1[C:60]([NH2:62])=[O:61])=[O:57])[C@@H:46]([CH3:55])[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:43])=[O:39])[CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:26])=[O:22])[C@@H:11]([CH3:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:73]([C:95]([O:97][C:98]([CH3:101])([CH3:100])[CH3:99])=[O:96])[C@H:74]([C:85]([O:87]N1C(=O)CCC1=O)=O)[C@@H:75]([CH3:84])[O:76][CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[NH:73]([C:95]([O:97][C:98]([CH3:99])([CH3:100])[CH3:101])=[O:96])[C@H:74]([C:85]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:38]([NH:40][CH2:41][C:42]([NH:44][C@H:45]([C:56]([N:58]1[CH2:65][CH2:64][CH2:63][C@H:59]1[C:60]([NH2:62])=[O:61])=[O:57])[C@@H:46]([CH3:55])[O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:43])=[O:39])[CH2:29][O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])=[O:22])[C@@H:11]([CH3:20])[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:87])[C@@H:75]([CH3:84])[O:76][CH2:77][C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Yield: 93.6 %

Procedure:
By using 21.00 g of Boc-Asn-Thr(Bzl)-Gly-Ser(Bzl)-Gly-Thr(Bzl)-Pro-NH2 and 9.37 g of Boc-Thr(Bzl)-OSu, and the same procedure as in Reference Example 18 was repeated to obtain 23.4 g (yield: 93.6%) of the above-mentioned objective product. Melting point: 110-113° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH:21]=[O:22])[CH:8]=[C:7]([Cl:23])[CH:6]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH2:21][OH:22])[CH:8]=[C:7]([Cl:23])[CH:6]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1cc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2CO)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To [3-chloro-5-(2-formyl-4-nitro-phenoxy)-phenyl]acetic acid methyl ester (3.7 g, 10.6 mmol) in MeOH (30 mL) was added sodium borohydride (0.52 g, 13.8 mmol), and the reaction was stirred at room temperature for 20 minutes. After work-up with EtOAc and H2O, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2[CH2:9][N:10]([CH:13]([C:15]3[CH:16]=[N:17][C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[C:19]([CH3:21])[CH:20]=3)[CH3:14])[C:11](=[O:12])[C:7]=2[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>C1COCC1.CCOC(C)=O>[CH3:35][O:36][CH2:37][C:38]([NH:2][C:3]1[C:8]2[CH2:9][N:10]([CH:13]([C:15]3[CH:16]=[N:17][C:18]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[C:19]([CH3:21])[CH:20]=3)[CH3:14])[C:11](=[O:12])[C:7]=2[CH:6]=[CH:5][N:4]=1)=[O:39]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3N)C2=O)cnc1OCC(F)(F)F
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC(=O)Nc1nccc2c1CN(C(C)c1cnc(OCC(F)(F)F)c(C)c1)C2=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 38.8 %

Procedure:
To a solution of 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (20 mg, 0.050 mmol, Example-17, single enantiomer) and triethylamine (0.069 mL, 0.50 mmol) in THF (1.0 mL) is added 2-methoxyacetyl chloride (27 mg, 0.25 mmol) at rt. The reaction mixture is stirred for 21 hours at rt and diluted with EtOAc. The organic phase is washed with water and dried over sodium sulfate. After filtration, the filtrate and volatiles are removed. The residue is filtered through a short column of NH-gel eluting with EtOAc and the filtrate is concentrated in vacuo. The residue is purified by preparative LC-MS to give 8.5 mg (39% yield) of the title compound.
Reaction SMILES: OC1C=CC(C2C3C=C(N(C)C)C=CC=3S(=O)(=O)CCC2)=CC=1.[O:24]=[S:25](=[O:37])([CH3:36])[O:26][CH2:27][CH2:28][CH2:29][CH2:30]OS(=O)(C)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[S:25]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:37])(=[O:24])[CH3:36]
Reactant: CS(=O)(=O)OCCCCOS(C)(=O)=O
Agent: CN(C)c1ccc2c(c1)C(c1ccc(O)cc1)CCCS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOS(C)(=O)=O
Yield: 61.6 %

Procedure:
A mixture of 1.00 g (2.18 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone was stirred at reflux overnight. The mixture was concentrated in vacuo and the crude was dissolved in 30 mL of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through silica gel column, and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butyl mesylate intermediate as a white solid: 1H NMR (CDCl3) δ 0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:11][CH2:12][O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([OH:24])=[O:23])[CH2:17]2)[CH:7]=[CH:8][CH:9]=1>[Pd].CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([OH:24])=[O:23])[CH2:17]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C(=CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2C)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc(C(CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2C)c1
Yield: 14.9 %

Procedure:
The acid prepared in Example 27 (2.0 g, 4.5 mmol) was dissolved into methanol (50 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (65% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a solid residue which was recrystallised from a mixture of acetone and ethyl acetate to give 0.30 g (23%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:9][C:8]1[CH:11]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:13][CH3:14])=[CH:6][C:7]=1[CH3:12]
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: COc1cc(C)c(C=C2C(=O)Nc3ccc(Br)cc32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C([O:3][C:4]([NH:6][C:7]1[C:8](=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[C:9]([OH:11])=[O:10])=O)C.S(Cl)(Cl)=O>O1CCOCC1>[Cl:16][C:15]1[C:7]2[NH:6][C:4](=[O:3])[O:10][C:9](=[O:11])[C:8]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)Nc1c(Cl)cccc1C(=O)O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: O=c1[nH]c2c(Cl)cccc2c(=O)o1

Procedure:
468 gm of N-ethoxycarbonyl-3-chloro-anthranilic acid (m.p. 111°-114° C) were refluxed in 1500 ml of dioxane with 420 ml of thionyl chloride for 3 hours while stirring. Thereafter, the reaction solution was evaporated in vacuo until crystallization started, and then cooled. The precipitate was collected by suction filtration and washed with ether. 8-Chloro-2H-3,1-benzoxazine-2,4(1H)-dione, m.p. 225°-230° C, was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[C:5]([CH3:23])=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:40])([F:39])([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:39])([F:40])([F:36])([F:37])[F:38])[CH:34]=1)[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[C:7]=1[OH:8])=[O:30])#[N:25]
Reactant: Cc1ccc(N)c(O)c1-n1ccn2nc(-c3cccnc3)cc12
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)c(O)c1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the process described in Example 155, 37 mg (0.109 mmol) of the compound of Example 82A and 28 mg (0.104 mmol) of the compound of Example 23A were reacted to give 9 mg (15% of theory) of the title compound. Here, preparative HPLC purification was carried out according to Method 37.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 4 h
Yield: 70.1 %

Procedure:
A mixture of 3.7 g of N-(tert-butoxycarbonyl)piperazine, 2.5 g of bromodiphenylmethane, 6.9 g of potassium carbonate and 20 ml of hexamethylphosphoramide was stirred at 40° to 50° C. for 4 hours. After cooling, water was added and the reaction mixture was extracted with diethyl ether. The exact was washed and dried, and the solvent was removed under reduced pressure. Hexane was added to the precipitated crystals and the crystals were collected by filtration to give 2.5 g of 4-(tert-butoxycarbonyl)-1-diphenylmethylpiperazine (melting point: 129°-131° C.).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[C:3]#[CH:4].I[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(O)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccccn3)c21

Procedure:
Using Method C above, 3-hydroxy-3-(2-pyridinyl)-1-propyne (133 mg, 1 mmol) (from Example 36 above) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (147 mg, 0.4 mmol) using (Starting Material 2) (Ph3P)2PdCl2 (40 mg) (Aldrich) and CuI (20 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 19 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(2-pyridinyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 84 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:1][C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:22][CH:21]=1)#[N:30]
Reactant: CCOC(=O)c1cnn(C)c1N
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of ethyl 5-amino-1-methylpyrazole-4-carboxylate (1.6 9 g) (P. Schmidt et al. Helv. Chim. Acta., 1959, 42, 349) in tetrahydrofuran (30 ml) was added at 0° C. sodium hydride (about 60% in oil, 0.48 g). The mixture was stirred for one hour at room temperature. To the reaction mixture was added portionwise at 0° C. 4-bromomethyl-2'-cyanobiphenyl (3.27 g). The mixture was stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, which was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled under reduced pressure to give crude crystals. Recrystallization from ethyl acetate-isopropyl ether afforded the title compound as colorless crystals (2.47 g, 69%), m.p. 107°-108° C.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:48])[C@@H:35]([NH2:47])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:47][C@@H:35]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=4)[C:34]([OH:33])=[O:48])=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@@H](Cc4ccc(C(F)(F)F)cc4)C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 94.8 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-3-(4-trifluoromethyl-phenyl)-propionic acid methyl ester HCl (38.4 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 70.4 mg of the title compound as a white solid.