Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:23]1(/[CH:29]=[CH:30]/B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(O)C.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:30](/[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1)=[CH:29]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COC(=O)c1ccc(Br)c2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2ccccc2)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of methyl 4-bromo-1-naphthoate, (Preparation 1, 5.4 g, 20.4 mmol) in ethanol (50 mL) and toluene (50 mL) was added Pd(dppf)2Cl2 (760 mg, 1.0 mmol), trans-2-phenylvinylboronic acid (3.3 g, 22.4 mmol) and sodium bicarbonate aqueous solution (40 mL of 2M solution). The mixture was heated to reflux for 3 hours. The mixture was cooled to room temperature and diluted with EtOAc (150 mL) and water (75 mL). The organic phase was separated, washed with brine (50 mL), dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel eluting from 10:90 EtOAc:heptane to 50:50 EtOAc:heptane to afford an oil which solidified upon standing (5.3 g, 90%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[C:49]([C:51]1([C:66]([O:68][CH2:69][CH3:70])=[O:67])[CH2:56][CH2:55][C:54](B2OC(C)(C)C(C)(C)O2)=[CH:53][CH2:52]1)#[N:50]>>[C:49]([C:51]1([C:66]([O:68][CH2:69][CH3:70])=[O:67])[CH2:56][CH2:55][C:54]([C:7]2[C:8]([CH3:46])([CH3:45])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:44])([C@@:13]4([CH3:43])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][S:38](=[O:41])(=[O:42])[CH2:39][CH2:40]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:53][CH2:52]1)#[N:50]
Reactant: CCOC(=O)C1(C#N)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C#N)(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 61 %

Procedure:
The title compound was prepared following the procedure described in general procedure Step 5, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and ethyl 1-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactants. The product was isolated as a mixture of diasteroisomers (solid, 61% yield). MS: m/e 748.6 (M+H)+, 2.99 min (method 4). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.35 (d, J=1.8 Hz, 1H), 5.28-5.23 (m, 1H), 4.73 (d, J=1.8 Hz, 1H), 4.61 (s, 1H), 4.29 (q, J=7.0 Hz, 2H), 3.13-3.01 (m, 8H), 2.80-2.46 (m, 9H), 2.33-2.15 (m, 2H), 2.08-0.82 (m, 22H), 1.70 (s, 3H), 1.34 (t, J=7.2 Hz, 3H), 1.07 (s, 3H), 0.97 (s, 3H), 1.03-0.92 (m, 6H), 0.86 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11]([CH:14]1[CH2:17][N:16]([C:18](=[O:38])/[CH:19]=[CH:20]/[C:21]2[CH:22]=[C:23]3[C:34](=[N:35][CH:36]=2)[NH:33][C:32](=[O:37])[C:25]2([CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:24]3)[CH2:15]1)(=O)[CH3:12]>CO>[CH3:31][N:28]1[CH2:29][CH2:30][C:25]2([CH2:24][C:23]3[C:34](=[N:35][CH:36]=[C:21](/[CH:20]=[CH:19]/[C:18](=[O:38])[N:16]4[CH2:15][CH:14](/[C:11](=[N:10]/[O:9][CH2:2][C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)/[CH3:12])[CH2:17]4)[CH:22]=3)[NH:33][C:32]2=[O:37])[CH2:26][CH2:27]1
Reactant: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CO
Product: C/C(=N\OCc1ccccc1)C1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Reaction time: 8 h

Procedure:
O-benzylhydroxylamine hydrochloride (13.5 mg, 0.08 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-1′-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (23.0 mg, 0.06 mmol) in methanol (1.5 mL) at room temperature. The reaction mixture was stirred overnight. After concentration to dryness, the residue was purified by chromatography on silica gel using dichloromethane/methanol (9:1) as eluent. The title product was obtained as a pink solid (9 mg, 31%).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:17][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[OH:1][C:2]1([CH3:17])[C:14]2[NH:13][C:12]3[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: C[Mg]Cl
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCCc2c1[nH]c1ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
1-Oxo-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (0.12 g, 0.57 mmol) was dissolved in anhydrous THF (5 mL), cooled to 0° C., and methyl magnesium chloride (0.12 g, 1.71 mmol, 3M in THF) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 3 h at room temperature then cooled to 0° C., saturated NH4Cl (10 mL) was added and then extracted with EtOAc (4×25 mL). The combined organic extracts were dried over Na2SO4 concentrated under reduced pressure to give the crude material which was purified by column chromatography [EtOAc-hexane (3:7) as eluant] to obtain the title compound (0.03 g, 23%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.4 (s, 1H), 7.9 (s, 1H), 7.42 (d, J=12.0 Hz, 1H), 7.39 (d, J=12.0 Hz, 1H), 5.0 (s, 1H), 2.64-2.61 (m, 2H), 2.0-1.7 (m, 4H), 1.4 (s, 3H). IR cm−1 2216 (CN).
Reaction SMILES: [C@@H:1]1(N2C=CC(N)=NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O.[C@@H:18]1([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]1O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)C1.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>>[C@@H:18]1([N:27]2[CH:34]=[C:33]([CH3:1])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[CH2:19]1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
Referring now to the drawing, FIG. 1 shows barley malt sprouts being fed to a dry mill 11, where they are ground to finer than 60 mesh, and normally 100 to 200 mesh (U.S. standard series mesh size). The ground sprouts in line 12 are admixed with an aqueous medium containing low levels of an activator (e.g., a metallic salt), and optionally, with recycled filtered liquor from line 17 to form a dispersion or mixture. Hydrolytic enzymes (e.g., pectinase, cellulase, hemicellulase, glucanase, etc.) may be added as processing aids to reduce the viscosity of the dispersion of barley malt sprouts, thereby allowing easier recovery of any thymidine in line 14. The resulting dispersion is heated and held at about 40° to 60° C. within kettle 15. The dispersion within kettle 15 is gently stirred continuously during the incubation period. The product which comprises crude liquor is then filtered in filter 16, and, as discussed above, some of the filtered liquor may be recycled or returned to feed line 12 by recycle line 17. Large molecular weight impurities are removed by filter 16 which can be either an ultrafiltration unit or a precipitator (e.g., to perform selective precipitation). The filtered liquor is sent to a solvent extraction unit or a unit containing an adsorption/desorption material on a suitable support in 18. A by-product of the solvent extraction process is removed from unit 18 by means of line 20. The resultant solvent extraction product from the filtered liquor yields thymidine and normally also contains other nucleosides, including cytidine, uridine, deoxy-guanosine and guanosine. The solvent extraction product on purified liquor is then sent via line 21 to a liquid chromatographic separator 22 to fractionate the nucleosides to obtain liquid thymidine. The liquid thymidine is then sent via line 23 to an evaporator 24 to concentrate the liquid thymidine. Evaporated liquid from the concentrated thymidine is removed from evaporator 24 via line 25. The concentrated thymidine is fed via line 26 to a crystallization unit 27. The crystalline thymidine is fed via line 28 to a dryer 29 and subsequently to packaging.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1>[Ru].CO>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]([OH:12])[CH2:10][CH3:11])[CH2:5][CH2:4]1
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: [Ru]
Solvent: CO
Product: CCC(O)C1CCC(OC)CC1

Procedure:
A mixture of 100 g of p-methoxypropiophenone, 250 ml of methanol and 5 g of a 5% strength ruthenium/active carbon catalyst was hydrogenated at 120° C. and under 150 bar until absorption of hydrogen was virtually complete. The catalyst was removed, the solvent was distilled off under 1013 mbar and the residue was then fractionated. 92 g of a colorless liquid having a boiling point of 73°-75° C. 0.01 mbar and a fine woody note were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]([NH2:19])=[S:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[S:18][CH:21]=[C:22]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:19]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)Nc1cc(OCc2ccccc2)c(Br)cn1
Reactant: O=C(CBr)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Brc1cnc(Nc2nc(CCc3ccccc3)cs2)cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A flask was charged with 1-(4-(benzyloxy)-5-bromopyridin-2-yl)thiourea (2.34 g, 6.92 mmol), 1-bromo-4-phenylbutan-2-one (1.65 g, 7.26 mmol), and triethylamine (1.93 ml, 13.8 mmol). Ethanol (100 mL) was added and the reaction was stirred at 75° C. for 8 hours. The reaction was cooled and filtered, and the collected solids were washed with water to give the desired product (2.54 g, 77.9% yield) as a white solid.
Reaction SMILES: [C:1]([NH:7][NH2:8])([C:3]([NH:5][NH2:6])=[O:4])=[O:2].[C:9](Cl)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12]>CC(N(C)C)=O>[C:9]([N:5]([C:3](=[O:4])[C:1]([NH:7][NH2:8])=[O:2])[NH:6][C:9](=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12])(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12]
Reactant: NNC(=O)C(=O)NN
Reactant: O=C(Cl)c1ccccc1O
Solvent: CC(=O)N(C)C
Product: NNC(=O)C(=O)N(NC(=O)c1ccccc1O)C(=O)c1ccccc1O
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
35.4 g of oxalic acid bis-hydrazide are suspended in 1000 ml of dimethyl acetamide, the suspension is briefly heated to 100° C and cooled to room temperature, and 93.5 g of salicylic acid chloride are slowly added in such a way that the reaction temperature does not exceed 40° C. After a further 15 minutes' stirring a largely homogeneous, yellowish solution has been obtained. After filtering off the undissolved constituents, the solution is mixed with 1.2 liters of ice water, whereupon the reaction product precipitates. The substance is filtered off, washed with water and purified by again precipitating it from dimethyl acetamide solution by means of water. After isolation and intensive drying at 130° C in vacuo, N,N'-bis-(salicyloyl)-oxalic acid dihydrazide (Stabiliser No. 2) is obtained as a white powder of melting point>320° C (decomposition).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[I:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]([NH:14][NH:13][C:11](=[O:12])[C:10]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:8]([I:7])[CH:9]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(C(=O)NN)cc1I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NNC(=O)C2CC2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of cyclopropanecarbonyl chloride (1.81 mL, 20.0 mmol) in dichloromethane (20 mL) was added dropwise to a stirred solution of 3-iodo-4-methylbenzohydrazide (preparation 55b, 5.00 g, 18.1 mmol) and triethylamine (2.78 mL, 20.0 mmol) in dichloromethane (80 mL) at 0° C. After 2 hours stirring at ambient temperature, the mixture was concentrated in vacuo and water was added to the residue. The resultant precipitate was filtered and was washed with water and diethyl ether to give the title compound (4.75 g, 76%) as a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:10]=[C:8]([OH:9])[C:7]([OH:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.O.[C:16]1(C)C=CC=CC=1>CS(C)=O.CN1CCCC1=O.C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]2[O:11][CH2:16][O:9][C:8]=2[CH:10]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(O)c1O
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)cc2c1OCO2
Temperature: 130 °C
Yield: 70.3 %

Procedure:
Under N2 8.0 g of NaOH (powdered) is dissolved in 80 ml of DMSO, or, alternatively, in N-methylpyrrolidone (NMP) at 80° C. In about 15 min a solution of 20.0 g of 5-chloro-3-nitro-catechol in 20 ml DMSO (NMP) and 100 ml CH2Cl2 is added at 80° C. The reaction mixture is heated at 130° C. for 8-30 hours while stirring. After cooling down to room temp., successively 200 ml water and 400 ml toluene are added. Stirring for 5 min., separation of the layers, and extraction of the water layer with 100 ml toluene yields a combined organic phase, which is washed twice with 50 ml satd. aqueous NaCl solution, with 50 ml water and twice with 100 ml satd. aqueous NaCl solution. After evaporation of the solvent (100 mbar, 40° C.), the desired product is obtained in a yield of 70.3%; purity 84%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][C:28](=[O:39])OC2C=CC([N+]([O-])=O)=CC=2)([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.Cl.[F:41][C:42]1([F:48])[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][C:28]([NH:47][CH:44]2[CH2:45][CH2:46][C:42]([F:48])([F:41])[CH2:43]2)=[O:39])([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCC(F)(F)C1
Agent: Cl
Solvent: ClCCl
Product: O=C(NC1CCC(F)(F)C1)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a crude solution of (S)-4-nitrophenyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylcarbamate in DCM (1 mL) (29 mg, 0.053 mmol) was added 3,3-difluorocyclopentanamine hydrochloride (17 mg, 0.106 mmol). The reaction mixture was stirred at room temperature for 2 h and the solution turned yellow. The solution was diluted with CH2Cl2 (1 mL) and washed with 1N NaOH (3×1 mL), dried over Na2SO4, and concentrated. The yellow residue was purified by flash chromatography (4 g SiO2, 0-40% EtOAc/hexane) to furnish 1-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(3,3-difluorocyclopentyl)urea as a white solid (13 mg, 45%). LCMS: 4.06 min [M+1] 542.2 (4 min gradient, MeOH/H2O 0.1% NH4OAc) LC/MS: [M+H]=542.2 1H NMR (CDCl3, 400 MHz): 8.26 (m, 1H), 7.67 (dd, J=2 Hz, J=4 Hz, 1H), 7.52 (br, 1H), 7.38 (m, 1H), 7.22 (m, 1H), 7.18-7.08 (m, 5H), 6.57 (m, 2H), 4.50 (d, J=8 Hz, 1H), 4.46 (dd, J=4 Hz, J=8 Hz, 1H), 4.25 (m, 1H), 3.55 (d, J=12 Hz, 1H), 2.65-1.54 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH:8]([OH:10])[CH3:9])[N:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl.O>[CH3:9][CH:8]([O:10][C:30](=[O:32])[CH3:31])[CH2:7][N:6]1[C:2]([CH3:1])=[CH:3][C:4]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc([N+](=O)[O-])nn1CC(C)O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC(C)Cn1nc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.5 %

Procedure:
A solution of 1-(5-Methyl-3-Nitro-Pyrazol-1-Yl)-Propan-2-ol (440 Mg, 2.5 Mmol) in methylene chloride at 25° C. was treated with triethylamine (1.1 mL, 7.7 mmol), catalytic dimethylaminopyridine and acetic anhydride (0.29 mL, 3.0 mmol). The reaction was stirred at 25° C. for 1.5 h. At this time, the reaction was poured into water and was extracted into methylene chloride. The organics were concentrated in vacuo to afford acetic acid 1-methyl-2-(5-methyl-3-nitro-pyrazol-1-yl)-ethyl ester (440 mg, 75%) as a white solid which was used without further purification; ES+-HRMS m/e calcd for C9H13N3O4 [M+Na+] 250.0798, found 250.0798.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH:30](O)=[O:31]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH:30]=[O:31])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: O=CO
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C=O)C3)cc1

Procedure:
Compound dx was prepared according to the procedure described in Example 213 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with formic acid. LC-MS: m/z=+425 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl[CH2:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][CH2:23][OH:24]
Reactant: OCCCCl
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: OCCCN1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
1.5 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, 0.74 g of 3-chloropropanol, 2.32 g of potassium carbonate and 0.10 g of sodium iodide were added to 30 ml of ethanol, and the mixture was heated under reflux for 20 hours. At the end of this time, the reaction mixture was filtered, and then The solvent was removed from the filtrate by distillation under reduced pressure. The residue was then subjected to column chromatography through silica gel, and the desired compound was obtained as crystals from the fractions eluted with 5% by volume ethanol in chloroform; it was then recrystallized from ethyl acetate, to afford 1.28 g (69% yield) of the title compound, melting at 127°-128° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=1.O.O.[OH-].[Li+].[Cl-].[NH4+]>CO>[CH3:1][O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
Methyl 5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-carboxylate (264 mg, 0.57 mmol) synthesized in Example (129e) was dissolved in methanol (20 mL), and water (3 mL) and lithium hydroxide monohydrate (71 mg, 1.70 mmol) were added, followed by stirring at 50° C. for 1 hour under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, followed by extraction twice with methylene chloride (40 mL), washing with saturated brine, and drying over sodium sulfate. The solvent was distilled off under reduced pressure, and vacuum drying was carried out to afford the desired compound (256 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:6](=[C:19](OCC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:29])(=O)C.[N:30]1([CH2:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH:41]/[C:19](=[C:6]3\[C:5](=[O:29])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=4)/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:42][CH:43]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3)ccc21)c1ccccc1
Product: O=C1Nc2cc(-c3ccccc3)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH:7]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=1)=O.[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:7]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=1)=[CH2:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1ccc(NC(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (3.82 g, 10.69 mmol) in THF (20 mL) at 0° C. under nitrogen was added potassium tert-butoxide (1.20 g, 10.69 mmol) and the reaction mixture was stirred at 0° C. for 15 min, then warmed to RT and stirred for a further 45 min. The suspension was cooled to 0° C. and a solution of tert-butyl 4-formylnaphthalen-1-ylcarbamate (30) (1.16 g, 4.28 mmol) in THF (10 mL) was added dropwise. The reaction mixture was warmed to RT and stirred for 2 hr. Saturated aqueous NH4Cl solution (30 mL) was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 0-10% ethyl acetate in isohexane, gradient elution) to afford the title compound (31) as a white solid (0.831 g, 72%): m/z 268 (m-H)− (ES−)