Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:17]=3[CH:16]=[C:15]([F:31])[CH:14]=2)[CH:10]=[N:9]1)(C)(C)[CH3:2].[CH:33](OCC)=[O:34].[H-].[Na+].Cl>O.C(OCC)(=O)C.O1CCCC1>[F:31][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[N:9][N:8]([CH:7]([CH:33]=[O:34])[C:6]([O:5][CH2:1][CH3:2])=[O:32])[CH:12]=2)[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:17]=2[CH:16]=1
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)Cn1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C=O)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Temperature: 0 °C

Procedure:
To a mixture of tetrahydrofuran (80 ml) and an optically active form (10.1 g) of t-butyl[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate was added ethyl formate (4.13 ml), and the mixture was stirred at 0° C. To this mixture was added sodium hydride (60 w/w % mineral oil dispersion, 2.57 g). The reaction mixture was warmed to room temperature and stirred for 3 hr. The reaction mixture was ice-cooled, 1N hydrochloric acid was added and the mixture was stirred. Ethyl acetate and water were added thereto, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl acetate, and the extract was combined with the organic layer obtained earlier. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (13.2 g). The obtained residue was directly used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH:17]([N:20]=[C:21]=[S:22])([CH3:19])[CH3:18]>>[CH:17]([NH:20][C:21](=[S:22])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])([CH3:19])[CH3:18]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: CC(C)N=C=S
Product: CC(C)NC(=S)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Yield: 42.5 %

Procedure:
Following the example above and beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and isopropyl isothiocyanate (133 μL, 1.401 mmol), 15.6 mg (43%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.Cl.[CH2:13]([O:15][C:16](=[O:26])[CH2:17][C@@H:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:26])[CH2:17][C@@H:18]([NH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: CCOC(=O)C[C@@H](N)c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Nc1nc(C)ccc1[N+](=O)[O-])c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 104.2 %

Procedure:
To a solution of 2-chloro-3-nitro-6-picoline (200 mg, 1.16 mmol) in DMF (3 mL) were added (R)-3-amino-3-phenylpropanoic acid ethyl ester hydrochloride (319 mg, 1.39 mmol) and DIPEA (0.5 mL, 2.90 mmol). The reaction mixture was stirred at 70° C. for 12 hours. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated to afford 398 mg (100%) of the title compound as orange oil. The resulting residue was used for the next reaction without further purification. LCMS, M++1, m/z: 330.29.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][CH:36]([F:45])[N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[CH:39]=[N:38][N:37]([CH:36]([F:45])[F:35])[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: OB(O)c1cnn(C(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cnn(C(F)F)c2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 100 °C
Yield: 22.7 %

Procedure:
A mixture of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (500 mg, 0.998 mmol), 1-(difluoromethyl)-1H-pyrazol-4-ylboronic acid (808 mg, 4.99 mmol), bis(triphenylphosphine)palladium chloride (70.1 mg, 0.100 mmol) in dioxane (15 mL) and 2M saturated sodium carbonate (2 mL) were heated to 100° C. in a microwave for 30 min. The solution was concentrated and was purified by preparatory HPLC eluting with water (10 mM NH4HCO3) and ACN/water (80/20 v/v, 15-30% gradient, 10 mM NH4HCO3) to give the title compound as a white solid (132 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9 H), 1.52 (s, 9 H), 1.55-1.56 (m, 1 H), 2.46-2.47 (m, 1 H), 3.57-3.59 (m, 2 H), 3.81-3.84 (m, 3 H), 4.61-4.62 (m, 1 H), 4.78 (s, 2 H), 6.61 (d, J=6.35 Hz, 1 H), 7.15 (d, J=6.83 Hz, 1 H), 7.97 (s, 1 H), 8.54 (s, 1 H), 9.24 (s, 1 H). [M+H] calc'd for C26H33F3N6O6, 583; found, 583.
Reaction SMILES: C(N(CC)C(C1C=CC2N(C3CC4N(C)C(CC4)C3)C3C(OC=2C=1)=CC=CC=3)=O)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].[CH2:38]([N:40]([CH2:75][CH3:76])[C:41]([C:43]1[CH:44]=[CH:45][C:46]2[N:47]([CH:59]3[CH2:65][CH:64]4[N:66]([CH2:67]CC5C=CC=CC=5)[CH:61]([CH2:62][CH2:63]4)[CH2:60]3)[C:48]3[C:53]([O:54][C:55]=2[CH:56]=1)=[C:52]([O:57][CH3:58])[CH:51]=[CH:50][CH:49]=3)=[O:42])[CH3:39].C(#N)C>O>[CH2:75]([N:40]([CH2:38][CH3:39])[C:41]([C:43]1[CH:44]=[CH:45][C:46]2[N:47]([CH:59]3[CH2:60][CH:61]4[N:66]([CH3:67])[CH:64]([CH2:63][CH2:62]4)[CH2:65]3)[C:48]3[C:53]([O:54][C:55]=2[CH:56]=1)=[C:52]([O:57][CH3:58])[CH:51]=[CH:50][CH:49]=3)=[O:42])[CH3:76].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2CCc1ccccc1
Agent: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2C

Procedure:
Using an adaptation of Procedure 16, and substituting the TFA salt of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 4e for TFA salt of 6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 6e, the title compound 6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 8e was obtained as a TFA salt and as a mixture of endo and exo isomers after reverse phase chromatography (eluent gradient: acetonitrile in water containing 0.1% TFA). MS m/z (MH+) 422.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=S)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27].C(Cl)CCl>CC#N>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[NH:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:9][C:10]=3[N:15]=2)=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Oc2ccncc2)cc1N
Solvent: CC#N
Solvent: ClCCCl
Product: FC(F)(F)c1cc(Nc2nc3cc(Oc4ccncc4)ccc3[nH]2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(pyridin-4-yloxy)-benzene-1,2-diamine (0.273 g, 1.36 mmol) in 20 mL CH3CN was added 1-chloro-4-isothiocyanato-2-trifluoromethyl-benzene (prepared similarly to the procedure described in Preparation III, 0.322 g, 1.36 mmol). The reaction was stirred 18 h at RT. The reaction was diluted with 25 mL CH3CN, and then EDC (0.39 g, 2.03 mmol) was added. The reaction was heated at 80° C. for 2.5 h. The reaction was cooled to RT and concentrated in vacuo. The crude mix was dissolved into EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a hexane-EtOAc gradient. The partially pure compound was triturated with CH2Cl2 to yield the title compound. MS (MH+)=405.1; Calc'd 404.78 for C19H12ClF3N4O.
Reaction SMILES: [C:1]([CH2:3][CH:4]([P:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:11])[O:8][CH2:9][CH3:10])[CH2:5][CH3:6])#[N:2].N>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH:4]([P:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:11])[O:8][CH2:9][CH3:10])[CH2:5][CH3:6]
Reactant: CCOC(OCC)P(=O)(OCC)C(CC)CC#N
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(CC)CCN

Procedure:
73.4 g (0.264 mol) of ethyl P-(4-cyanobut-3-yl)-P-(diethoxymethyl)-phosphinate in 770 ml of dry ethanol are treated with 126 g of an 8% solution of ammonia in ethanol. Subsequently, 15 g of Raney-nickel and the resulting mixture is hydrogenated at 45° under atmospheric pressure. The catalyst is then filtered of and the filtrate is concentrated under reduced pressure. The crude product is distilled in vacuo to yield the ethyl P-(5-aminopent-3-yl)-P-(diethoxymethyl)-phosphinate (b.p.: 100°/0.01 Torr).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5]Cl.[CH2:13]([NH:16][C:17](=[S:20])[NH:18][NH2:19])[CH2:14][CH3:15]>CO>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]1[CH2:5][S:20][C:17]([NH:16][CH2:13][CH2:14][CH3:15])=[N:18][N:19]=1
Reactant: CCCNC(=S)NN
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: CO
Product: CCCNC1=NN=C(c2ccc(Cl)cc2Cl)CS1
Product: Cl
Yield: 126 %

Procedure:
6.70 g (0.03 mole) of 2,4-dichlorophenacyl chloride and 3.99 g (0.03 mole) of 4-n-propyl-thiosemicarbazide are reacted in 150 ml of methanol under the conditions of Example 2. The concentrated product is crystallized and then recrystallized from methanol/ethyl acetate, to produce 6.4 g of 5-(2,4-dichlorophenyl)-N-propyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 184°-185° C. The product is then dried at 65° C. under high vacuum.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14]1)([CH3:12])[CH3:11])(C(C)(C)C)(C)C.N1C=CC=CC=1.F>C(#N)C>[OH:8][CH2:9][C:10]([N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1ccc(=O)n(C(C)(C)CO[Si](C)(C)C(C)(C)C)c1
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(=O)n(C(C)(C)CO)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of tert-butyl 1-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridin-3-ylcarbamate (800 mg, 2017 μmol) in ACN (10 mL) was added hydrogen fluoride pyridine (484 μl, 24206 μmol). The reaction mixture was stirred for 1 h and quenched with dry silica. The solvent was removed under reduced pressure and the product purified on silica (40 g) eluting with 0-5% MeOH/CH2Cl2. MS (ESI pos. ion) m/z (MH+): 283. Calc'd exact mass for C14H22N2O4: 282.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[H][H]>C(O)C.[Pd]>[N:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:7][CH:2]=1
Reactant: [H][H]
Reactant: Clc1nccc(N2CCN(Cc3ccccc3)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: c1cc(N2CCNCC2)ncn1

Procedure:
A solution of 7.4 g (0.0256 mol) of 1-(2-chloro-4-pyrimidinyl)-4-(phenylmethyl)piperazine in 100 ml of ethanol was hydrogenated in the presence of 2 g of 10% palladium/charcoal for 4 hours at 40° C. under 5 bar of hydrogen pressure. The crude product obtained after conventional working up was purified by column chromatography over silica gel (30-60 μm) using FM1/cyclohexane 9/1 (v/v) as eluant. Colourless crystals, Rf=0.3 (FM1/cyclohexane 9/1 (v/v)); Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC). Yield: 1.7 g (40.7% of theory).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][N:10]2[CH2:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[N:3]=1.[C:17](=[O:20])([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>C(#N)C>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:2]2[N:7]=[C:6]([NH:30][CH2:29][C:28]3[CH:31]=[CH:32][C:25]([O:20][CH3:17])=[CH:26][CH:27]=3)[N:5]=[C:4]([NH:9][N:10]3[CH2:14][C:13](=[O:15])[NH:12][C:11]3=[O:16])[N:3]=2)=[CH:27][CH:26]=1
Reactant: O=C1CN(Nc2nc(Cl)nc(Cl)n2)C(=O)N1
Reactant: COc1ccc(CN)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNc2nc(NCc3ccc(OC)cc3)nc(NN3CC(=O)NC3=O)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.1 %

Procedure:
To a stirred suspension of 1-(4,6-dichloro-[1,3,5]-triazin-2-yl-amino)-imidazolidine-2,4-dione (770 mg, 2.93 mmol) and potassium carbonate (2.42 g, 17.6 mmol) in acetonitrile (20 mL) at room temperature was added 4-methoxybenzylamine (0.96 mL, 7.32 mmol). The reaction mixture was stirred for 24 h at room temperature under an atmosphere of nitrogen and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and the ethyl acetate was dried (MgSO4) and evaporated to give the crude product which was purified by flash chromatography on silica using CH2Cl2/MeOH (50:1→10:1) as eluent. The pure product was isolated as a colourless solid (587 mg, 43%). 1H NMR (d6 DMSO): δ=3.67 (s, 6H); 3.96 and 4.05 (2s, total 2H); 4.20 and 4.32 (2s, total 4H); 6.80 (bs, 4H); 7.13-7.39 (m, 6H); 8.67, 8.85 and 8.99 (2s, total 1H); 11.0 (bs, 1H). Mass spectrum (ES+) 465 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:30][C:25]1[CH:24]=[C:23]([NH:22][C:11](=[O:13])[CH2:10][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:14])[CH:28]=[CH:27][C:26]=1[OH:29]
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Reactant: Nc1ccc(O)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
3-(4-Fluorophenylamino)-3-oxopropanoic acid (197 mg, 1.00 mmol) was dissolved in 4 mL of dimethylformamide. Triethylamine (140 μL, 1.00 mmol) was added and the solution was cooled to 0° C. 4-Amino-2-fluorophenol (127 mg, 1.00 mmol, Aldrich) was added followed BOP reagent (442 mg, 1.00 mmol). The reaction was allowed to warm to room temperature and was then stirred at room temperature for 3 h. The reaction mixture was concentrated to remove methylene chloride and water was added to precipitate the product. Filtration and trituration with water gave the title compound (211 mg, 69%) as a white solid. 1H NMR (CD3OD) δ 7.61 (m, 2H), 7.51 (dd, 1H, J=13, 2.5 Hz), 7.08 (m, 3H), 6.88 (t, 1H, J=9.4 Hz), 3.51 (s, 2H); MS(ESI+) m/z 307.4 (M+H)+.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5](OC)=[O:6])=[CH2:3].[C:12]1([C@H:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:6]=[C:5]1[N:20]([C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:19])[CH2:3][C@@H:2]([C:1]([O:10][CH3:11])=[O:9])[CH2:4]1.[O:6]=[C:5]1[N:20]([C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:19])[CH2:3][C@H:2]([C:1]([O:10][CH3:11])=[O:9])[CH2:4]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Product: COC(=O)[C@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reaction time: 18 h
Yield: 48 %
Yield: 36 %

Procedure:
To a solution of dimethyl itaconate (25 g, 158 mmol) in methanol (150 ml) was added (R)-1-phenylethylamine (20 ml, 158 mmol) at room temperature. The resulting mixture was stirred for 18 hours and concentrated. The residue was dissolved in toluene (100 ml) and p-toluenesulfonic acid (3.0 g, 16 mmol) was added at room temperature. The mixture was refluxed for 16 hours and concentrated. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1 to 1/3) to afford methyl (3S)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate as a white solid (14.0 g, 56.5 mmol, 36%) and methyl (3R)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate as a yellow oil (18.7 g, 75.5 mmol, 48%). Each stereochemistry was determined by the data based on the literature (J. Med. Chem. 1990, 33, 71-77).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)n[nH]c3c1)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCNCC5)cc4)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 19.1 %

Procedure:
To a solution of tert-butyl 4-(4-(6-((1R,2S)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)-1H-indazol-3-yl)phenyl)piperidine-1-carboxylate (102 mg, 0.181 mmol) in CH2Cl2 (5 mL) was added TFA (0.4 mL, 5.4 mmol). The resulting reaction mixture was stirred at rt for 2.5 h. The crude reaction mixture was concentrated under reduced pressure to dryness, and purified by preparative HPLC to give the title compound as a yellow solid (20 mg, 72%). 1H NMR (400 MHz, MeOD) δ 7.89 (d, J=8.2 Hz, 3H), 7.47 (s, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.01 (d, J=8.6 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 5.60 (d, J=2.3 Hz, 1H), 3.56-3.50 (m, 2H), 3.39-3.32 (m, 1H), 3.25 (s, 3H), 3.17 (t, J=11.9 Hz, 2H), 3.02-2.92 (m, 1H), 2.25-2.22 (m, 1H), 2.19-2.01 (m, 3H), 2.02-1.91 (m, 2H); MS ESI 465.3 [M+H]+, calcd for [C29H28N4O2+H]+465.22.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:14])=[CH:8]2)=[O:4].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:10][C:9]=2[CH3:14])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c(C)c(Cc3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
A methylene chloride (15 ml) solution of 5-(methoxycarbonyl)-2-methylindole (0.567 g) and 4-benzyloxybenzaldehyde (0.700 g) is dropwise added to a methylene chloride (15 ml) solution of trifluoroacetic acid (0.513 g) and triethylsilane (1.047 g) in an ice-water bath, over a period of 15 minutes. This is stirred for 30 minutes in the ice-water bath, and an aqueous solution of 2 M sodium hydroxide is added thereto to stop the reaction. The organic layer is washed with a saturated saline solution, dried and concentrated. The resulting residue is purified through silica gel column chromatography (eluent:ethyl acetate/hexane=3/7) to obtain 3-(4-benzyloxybenzyl)-5-(methoxycarbonyl)-2-methylindole (62) (0.510 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:8]1[C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: Cc1cccc2c1NC(=O)CO2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cccc2c1N(CCCCl)C(=O)CO2
Yield: 48.1 %

Procedure:
5-Methyl-4H-benzo[1,4]oxazin-3-one (81MF941a) (1.514 g, 9.28 mmol), Cs2CO3 (4.53 g, 13.9 mmol) and 3-chloro-1-iodopropane (2.09 g, 10.21 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF941b) (1.07 g, 48%). 1H NMR (CDCl3) d 6.99-6.87 (m, 3H), 4.42 (s, 2H), 4.17 (t, J=7.2 Hz, 2 H), 3.45 (t, J=6.4 Hz, 2H), 2,41 (s, 3H), 2.04-1.97 (m, 2H); 13C NMR (CDCl3) d 168.3, 149.9, 129.1, 128.7, 126.9, 125.1, 115.0, 69.4, 42.2, 42.1, 30.6, 20.9.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26]([OH:28])=O)=[O:19])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:1][C:2]1[C:3]([NH:17][C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])=[O:19])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: C1CCNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 70 °C
Reaction time: 60 h
Yield: 52.8 %

Procedure:
A mixture of 5-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (138 mg, 363 μmol), pyrrolidine (240 μl, 2.9 mmol), propylphosphonic anhydride (50% in ethyl acetate, 534 μl, 907 μmol) and diisopropylethylamine (190 μl, 1.09 mmol) in tetrahydrofuran (10 ml) was stirred for 2.5 days at 70° C. The solvent was evaporated; the residue was triturated with saturated aqueous sodium hydrogencarbonate solution and the precipitated solid was filtered off and dried in vacuo. The material was applied on silica and purified by flash chromatography over a 20 g silica column using heptane/EtOAc 10-100% as eluent, affording N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (83 mg, 52.8%) as white solid. Mp. 250-251° C. MS: m/z=434.4 (M+H+).