Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](C1C=C(SC2N(C3C=CC=C(C(O)=O)C=3)N=NN=2)C2C(=CC=CC=2)C=1O)=[O:24])CCCCCCCCCCCCC.C(NN[C:55]1[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=1)=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:23]([NH:61][CH:58]1[CH2:57][CH2:56][CH2:55][CH2:60][CH2:59]1)([NH:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:16]1)=[O:24]
Reactant: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2cccc(C(=O)O)c2)c2ccccc2c1O
Reactant: Nc1ccc(NNC=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h
Yield: 55.5 %

Procedure:
13.9 g of 2-(2-tetradecyloxyphenyl)carbamoyl-4-[1-(3-carboxyphenyl)-5-tetrazolylthio]-1-naphthol and 3.0 g of 1-formyl-2-(4-aminophenyl)hydrazine were dissolved in 20 ml of DMF and to the solution was added dropwise with stirring 5 ml of a DMF solution containing 4.1 g of dicyclohexylcarbodiimide at 0° C. under nitrogen atmosphere. After the completion of the addition, the mixture was stirred for 2 hours and then further stirred at room temperature for 2 hours. Dicyclohexylurea formed was removed by filtration and the filtrate was poured into 1.5 liters of water. The crystals thus deposited were collected by filtration and dissolved in 50 ml of DMF. After treating with active carbon the DMF solution was poured into 400 ml of methanol and the crystals thus deposited were collected by filtration to obtain 9.2 g of the desired Compound (15). Yield: 55.5%. Melting Point: 173° to 180° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([O-:27])=[O:26])=[C:12]([CH2:15][N+:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22]C=O)[CH:17]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl>CO>[CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([O-:27])=[O:26])=[C:12]([CH2:15][N+:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccc(NC=O)c3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccc(N)c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
A mixture of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(3-formamido-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (4.4 g) and conc. hydrochloric acid (1.6 ml) in methanol was stirred for 4 hours at room temperature and evaporated to dryness. The residue was dissolved in water (100 ml) and subjected to column chromatography on a non ionic adsorption resin "Diaion HP 20" (160 ml). After the column was washed with water, the elution was carried out with 20% aqueous methanol. The fractions containing an object compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (2.3 g), mp 185° to 189° C. (dec.).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH2:23][NH2:24]>>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH2:23][NH:24][C:16]([C:14]1[O:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: NCc1cc(F)cc(F)c1
Reactant: CCc1cc(-c2ccc(C(=O)O)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)NCc3cc(F)cc(F)c3)o2)c(C)[nH]c1=O
Yield: 91 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-carboxylic acid and 3,5-difluoro-benzylamine to give the title compound (91% yield). LC/MS: RT 3.52 min; m/e 373 (M+H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].OC1C=CC=CN=1>CO>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: CN(C)CCN
Reactant: COC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Agent: Oc1ccccn1
Solvent: CO
Product: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A suspension of methyl 4-(4-biphenylylmethoxy)phenylacetate (2.00 g), N,N-dimethylethylenediamine (1.60 g), 2-hydroxypyridine (573 mg) in methanol (4.0 ml) was heated under reflux under nitrogen for 16 hr and cooled until the temperature of the reaction mixture reached to 60±2° C., to which methanol (8.0 ml) was added. The reaction mixture was heated under reflux for additional one hr and cooled to room temperature. The precipitate was collected by filtration and washed with methanol (4.0 ml to obtain the titled compound (2.18 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([O:9]CC)=O)[CH:3]=1.O.[OH-].[Li+].Cl.S(Cl)([Cl:18])=O>CO.C1COCC1.O.ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([Cl:18])=[O:9])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc(C)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)no1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 5-methylisoxazole-3-carboxylate (500 mg, 3.22 mmol) was suspended in MeOH-THF-H2O (20 mL, 1:1:1) and lithium hydroxide monohydrate (1.35 g, 32.2 mmol) was added. The reaction mixture was stirred for 16 h at room temperature, and acidified with 1N HCl. The crude product was extracted with ethyl acetate, and ethyl acetate layer was dried (Na2SO4) and solvent evaporated. The white solid thus obtained, was suspended in dichloromethane (30 mL) and treated with thionyl chloride (2.35 mL, 32.3 mmol) at reflux for 6 hr. The reaction mixture was evaporated, and the residue was dissolved in hexane-ethyl acetate mixture (100 mL, 6:4) and quickly filtered through a short silica plug. On evaporation of solvent, 5-methylisoxazole-3-carbonyl chloride was obtained as a colorless syrup (330 mg, 70%).
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([S:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:50][CH:49]=1>C(O)C>[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([S:54][C:55]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:33][CH:32]=[C:31]([N:30]([CH3:42])[CH3:29])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:50][CH:49]=1
Reactant: CCOC(=O)CSc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)Sc1ccc(Cl)cc1
Yield: 99.3 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (14.3 g), a 2M ethanolic solution of sodium ethylate (25 cc) and ethyl (4-chlorophenylthio)acetate (11.5 g) in ethanol (100 cc). Diethyl 5-(4-chlorophenylthio)-2-dimethylamino-2,4-hexadienedioate (19 g) is thereby obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:12][C:10]1[N:11]=[C:3]2[C:2]([NH:1][CH2:17][C:16]3[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:15]=3[CH3:14])=[CH:7][C:6]([F:8])=[CH:5][N:4]2[C:9]=1[CH3:13]
Reactant: Cc1cccc(C)c1C=O
Reactant: Cc1nc2c(N)cc(F)cn2c1C
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(C)c1CNc1cc(F)cn2c(C)c(C)nc12
Yield: 37.8 %

Procedure:
A stirred mixture of 8-amino-2,3-dimethyl-6-fluoroimidazo[1,2-a]pyridine (0.16 g, 0.89 mmol), zinc(II) chloride (0.14 g, 1.04 mmol) and 2,6-dimethylbenzaldehyd (0.14 g, 1.04 mmol) in methanol (50 ml) was treated with sodium cyanoborohydride (0.065 g, 1.04 mmol) and was refluxed for 7 h. The cooled reaction mixture was added to 0.5 M NaOH (20 ml) and the precipitated solids were filtered off and purified by column chromatography on silica gel, using methanol:methylene chloride (1:10) as eluent. Crystallization from petroleum ether gave 0.1 g (38%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=2)[CH2:4]1)[CH3:2].CCN(CC)CC.[CH3:22][C:23](OC(C)=O)=[O:24]>CO.[Pd]>[CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:12][C:23](=[O:24])[CH3:22])[CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1Cc2ccc(NC(C)=O)cc2C1
Temperature: 20 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
A solution of isoindole 245 (3.20 g, 16.7 mmol) in MeOH (100 mL) was stirred with Pd/C (5%, 300 mg) under H2 (60 psi) for 16 h. The solution was filtered through Celite, washed with MeOH (3×20 mL) and the solvent evaporated. The residue was dissolved in DCM (130 mL) and Et3N (13 mL, 93 mmol), Ac2O (13 mL, 138 mmol) was added dropwise and the solution stirred at 20° C. for 15 h. The mixture was partitioned between DCM and aqueous Na2CO3 solution. The organic solution was washed with water, dried and the solvent was evaporated to give acetamide 246 (3.00 g, 88%) as a dark oil: 1H NMR δ 7.45 (br s, 1H, H-4), 7.30 (br s, 1H, NH), 7.18 (br d, J=8.0 Hz, 1H, H-6), 7.12 (d, J=8.0 Hz, 1H, H-7), 3.90 (s, 2H, H-1), 3.87 (s, 2H, H-3), 2.76 (q, J=7.2 Hz, 2H, CH2), 2.15 (s, 3H, COCH3) 1.19 (t, J=7.2 Hz, 3H, CH3); HRMS (FAB+) calcd for C12H17N2O (MH+) m/z 203.1184, found 203.1188.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].[CH2:27]([NH2:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[NH:16][C:17](=[O:26])[C:18]1[CH2:25][CH2:24][CH2:23][CH2:22][C:19]=1[C:20]([NH:33][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:21]
Reactant: CC1CCC(Oc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)C1
Reactant: CCCCCCN
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCC(C)C3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide (1.26 g, 3.33 mmol), hexylamine (0.410 g, 4.05 mmol), triethylamine (0.380 g, 3.76 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-hexyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.29 g, 80.8% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.I[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21]=2[C:22]([NH:24][CH3:25])=[O:23])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21]=2[C:22]([NH:24][CH3:25])=[O:23])[CH:18]=1
Reactant: CNC(=O)c1c(-c2ccccc2)nn2cc(I)ccc12
Reactant: COc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CNC(=O)c1c(-c2ccccc2)nn2cc(-c3ccccc3OC)ccc12
Temperature: 150 °C
Yield: 39.9 %

Procedure:
To a microwave vial equipped with a magnetic stir bar was charged 2-methoxyphenylboronic acid (12.09 mg, 0.080 mmol), 6-iodo-N-methyl-2-phenylpyrazolo[1,5-a]pyridine-3-carboxamide (15 mg, 0.040 mmol), sodium carbonate (7.38 mg, 0.070 mmol), palladium(II) acetate (0.893 mg, 3.98 μmol) and dimethylfomamide (1.0 mL). This mixture was placed under an argon atmosphere and heated at 150° C. for 10 minutes. The title compound (5.7 mg, 36%) was isolated by reverse phase HPLC: Start % B=30 to Final % B=80, Gradient time=10 minutes, Flow Rate=35 mL/minute, Wavelength=220 nm, Solvent A=10% methanol, 90% water with 0.1% TFA; Solvent B=90% methanol, 10% water with 0.1% TFA, Column=Phenomenex-Luna 30×50 mm S10, Product peak at 7.6 minutes. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.85 (d, J=4.88 Hz, 3H) 3.86 (s, 3H) 7.03 (d, J=7.93 Hz, 1H) 7.08 (t, J=7.02 Hz, 1H) 7.39 (m, 2H) 7.54 (m, 3H) 7.63 (dd, J=9.16, 1.53 Hz, 1H) 7.69 (m, 1H) 8.36 (dd, J=9.16, 0.61 Hz, 1H) 8.76 (m, 1H). LCMS: 2.0 minutes, M+1=358.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]([CH3:44])[CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]([CH3:43])[CH3:44])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (233 mg, 0.75 mmol) and 3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K39) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (240 mg, 56%).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].[K].I[CH2:13][CH2:14]I>C(O)(C)C>[CH2:5]([S:10][C:14]1[CH:13]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3])[CH2:6][S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3]
Reactant: ICCI
Reactant: Nc1ccccc1S
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1ccccc1SCCSc1ccccc1N
Yield: 58.6 %

Procedure:
A 4-necked, 1-L flask was fitted with a reflux condenser, nitrogen line, mechanical stirrer (PTFE bearing and paddle), thermocouple, pressure-equilibrated dropping funnel, and a mantle. The flask was charged with 300 mL of isopropyl alcohol followed by 42.0 g of potassium hydroxide. The mixture was stirred under nitrogen at ca. 300 rpm until the KOH was partially dissolved. 88.86 g of 2-aminothiophenol was then added over 1.25 r. This was accompanied by an exotherm and the formation of a suspension of the potassium salt. 99.71 g of 1,2-diiodoethane suspended in 200 mL isopropanol at 50° C. was then added over ca. 0.25 hr. The resultant suspension was heated at 80° C. for 8.9 h. The reaction mixture was filtered hot through Whatman GF/A paper. The filter cake was washed with 100 mL isopropanol. The weight of the filter cake was 95.25 g. The filtrate crystallized while cooling overnight to room temperature. The crystals were isolated by suction filtration through Whatman #1 paper. The yellow crystals were dried on a rotary evaporator (1 torr final vacuum, 90° C. water bath) to afford 57.32 g (58.5%) of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[CH:15]=1)=[O:28]
Reactant: O=C(O)/C=C/c1c(F)cccc1Cl
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2c(F)cccc2Cl)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-6-fluoro-phenyl)-acrylic acid. LC-MS-conditions 01: tR=0.91 min; [M+H]+=364.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][Si](C(C)(C)C)(C)C)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(Cl)Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)c2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1cc(Br)c2[nH]ccc2c1
Reaction time: 1 h

Procedure:
Combine 7-bromo-5-(tert-butyldimethylsilanyloxy)-1H-indole and methylene chloride and treat with tetrabutyl ammonium fluoride (1.0 eq.) at 0° C. After the mixture is stirred for about 1 hour, pour into ethyl acetate, wash with brine, dry the organic layer over Na2SO4 and concentrate. Purify to give 7-bromo-5-hydroxy-1H-indole.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([O:37][CH3:38])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)=[O:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]([N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([O:37][CH3:38])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)=[O:12]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)C(=O)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)C(=O)CCN)COc1ccccc1-3

Procedure:
A solution of methyl(7R)-7-[[N-(tert-butoxycarbonyl)-β-alanyl](methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.15 M) in DCM was treated with TFA (10 eq.) and the resulting mixture was stirred for 4h at RT before removing all volatiles in vacuo. The residue was partitioned between EtOAc and sat aq NaHCO3 and the layers separated. The combined organics were washed with brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The product was used directly in the next step without further purification. (ES+) m/z 490 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([O:24][CH3:25])=[O:23])[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([O:24][CH3:25])=[O:23])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(Nc2ccc(F)cc2)CCNCC1

Procedure:
A mixture of 53 parts of methyl 4-[(4-fluorophenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylate and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 15% of methanol, previously saturated with gaseous ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on scratching in hexane. The product is filtered off and dried, yielding methyl 4-[(4-fluorophenyl)amino]-4-piperidinecarboxylate; mp. 83.7° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: COc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c(OC)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2,4-dimethoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 366.0 (M+H)+, retention time 1.37 minutes.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[NH2:21][C:22]1[CH:23]=[C:24]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[O:34][C:27]1([CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[CH:26]=[CH:25]2.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:39][O:38][C:37]1[CH:36]=[C:35]2[C:24]([CH:25]=[CH:26][C:27]3([O:34]2)[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)=[CH:23][C:22]=1[NH:21][C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1
Reactant: COc1cc2c(cc1N)C=CC1(CCN(C)CC1)O2
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4OC)n3n1)C=CC1(CCN(C)CC1)O2
Yield: 9.9 %

Procedure:
A slurry of 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (78.0 mg, 0.271 mmol), 6-Amino-7-methoxy-1′-methyl-spiro[chromene-2,4′-piperidin]-4-((3H)-one (151 mg, 0.546 mmol)) and N,N-Diisopropylethylamine (0.150 mL, 0.861 mmol) in 1-Methoxy-2-propanol (0.300 mL, 3.07 mmol) was irradiated in a CEM microwave (200° C., 60 min). Purification by prep HPLC afforded 7-methoxy-6-{[7-(2-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl]amino}-1′-methylspiro[chromene-2,4′-piperidin]-4-((3H)-one trifluoroacetic acid salt (13 mg; Yield=7.8%). 1H-NMR (DMSO-d6): 9.41 (br s, 1H), 8.93 (s, 1H), 8.16 (s, 1H), 7.82 (m, 2H), 7.39 (m, 1H), 7.18 (d, 1H, J=8.3 Hz), 7.07 (m, 1H), 6.99 (d, 1H, J=4.2 Hz), 6.94 (d, 1H, J=4.2 Hz), 6.79 (s, 1H), 3.93 (s, 3H), 3.79 (s, 3H), 3.34 (m, 2H), 3.20 (m, 2H), 2.84 (s, 3H), 2.82 (s, 2H), 2.17 (m, 2H), 1.87 (m, 2H). LCMS (HPLC): m/z=550 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([CH3:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[CH3:24])=[O:5])C.[OH-].[Na+]>CS(C)=O.O>[CH3:24][C:7]1[N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9](=[O:17])[C:10]2[C:15]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16]
Reactant: CCOC(=O)c1c(C)n(-c2ccccc2)c(=O)c2c(C)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc2c(C(=O)O)c(C)n(-c3ccccc3)c(=O)c12
Yield: 41.2 %

Procedure:
A solution of 3,8-dimethyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl ester (200 mg, 0.62 mmol) in DMSO (3 ml) and aqueous 1N NaOH (2 ml, 2 mmol) was heated under microwave irradiation at +120° C. for 20 min and diluted with water (30 ml). Uncharged impurities were extracted with diethyl ether (30 ml) and the aqueous solution was poured into ice (50 g) with aqueous 2M HCl (10 ml). The obtained precipitate was filtered, washed with water and dried in vacuo to give 75 mg of yellow solid. Yield 41%. LC-MS (m/z) 293.9 (MH+); tR=1.09. 1H NMR (500 MHz, DMSO-d6): 1.95 (s, 3H), 2.74 (s, 3H), 7.3 (d, 1H), 7.32 (d, 2H), 7.48 (two overlapping m, 2H), 7.55 (t, 2H), 7.62 (t, 1H), 13.42 (b, 1H).