Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine trans-(4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (16.0 g, 0.064 mol), immidazol (13.9 g, 0.10 mol), and anhydrous THF (300 mL), add tert-butyldimethylsilyl chloride (14.5 g, 0.10 mol) and stir at room temperature for 18 hours. Wash the reaction mixture with water (250 mL), saturated aqueous NaHCO3 (250 mL) and dry the organic layer over anhydrous Na2SO4. Remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 30% EtOAc in hexane) to obtain trans-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-carbamic acid benzyl ester as clear oil (23.0 g, 98%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]([CH3:16])([CH3:15])[C:11](OC)=[O:12].[F:17][C:18]([S:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)([F:20])[F:19]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:16][C:10]1([CH3:15])[NH:9][C:29](=[O:30])[N:28]([C:25]2[CH:24]=[CH:23][C:22]([S:21][C:18]([F:20])([F:17])[F:19])=[CH:27][CH:26]=2)[C:11]1=[O:12]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)cc2)C1=O
Temperature: 20 °C
Yield: 95.6 %

Procedure:
5.12 ml of triethylamine and 2.8 g of methyl α-aminoisobutyrate hydrochloride are added to a solution of 4 g of 4-trifluoromethylsulfanylphenyl isocyanate in 40 ml of toluene, under an inert atmosphere of argon at a temperature in the region of 20° C. The mixture thus obtained is refluxed for 24 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure and the residue obtained is taken up in ethyl ether and filtered. 5.3 g of 5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione are thus obtained, the characteristics of which product are as follows:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][CH3:11].[Cl:12][CH2:13][CH2:14][CH2:15][OH:16].[H-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:12][CH2:13][CH2:14][CH2:15][O:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][CH3:11]
Reactant: COc1cc(F)ccc1CCl
Reactant: OCCCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1COCCCCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To an ice-cold solution of 0.36 g (2.06 mmol) of 1-chloromethyl-4-fluoro-2-methoxy-benzene and 0.195 g (4.12 mmol) of 1-chloro-3-propanol in 3 ml of dry N,N-dimethyl-formamide were added 92.5 mg (3.09 mmol) of sodium hydride (80% dispersion in refined oil) in 3 portions at one hour intervals. After complete addition the stirring was continued for 2 hours at room temperature, then 2 ml of an saturated aqueous sodium hydrogencarbonate solution were added and the reaction mixture evaporated under reduced pressure. Subsequently, the residue was treated with a mixture of dichloromethane and water, the organic phase was separated and dried over sodium sulfate. Finally, the solvent was evaporated under reduced pressure and the crude product was purified by chromatography on silica gel with a 1:1 mixture of hexane and dichloromethane as the eluent. There were obtained 0.29 g (60% of theory) of 1-(3-chloro-propoxymethyl)-4-fluoro-2-methoxy-benzene as a colorless liquid; MS: 232 (M)+.
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:25][O:24][C:8]2([CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:9]2)[O:7]1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][OH:60].[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:25]1[CH2:6][O:7][C:8]2([CH2:13][CH2:12][CH:11]([CH3:14])[C:10]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][OH:60])([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:9]2)[O:24]1
Reactant: CC1CCC2(CC1S(=O)(=O)c1ccccc1)OCCO2
Reactant: OCCCCCCCCCCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CC1CCC2(CC1(CCCCCCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyl lithium (1.8 ml) was added dropwise to a 5 ml THF solution of 560 mg of 1,1-(ethylenedioxy)-4-methyl-3-(phenylsulfonyl)-cyclohexane and 4 mg of triphenylmethane under an argon gas stream at −78° C. The resulting mixture was stirred for 10 minutes and then reacted at room temperature for one hour. HMPT (1 ml) was added and the resulting mixture was cooled to −78° C. again, followed by the dropwise addition of a 2 ml THF solution of 205 mg of 14-bromo-1-tetradecanol. After reaction at −20° C. for 2 hours, the reaction mixture was poured into a saturated solution of ammonium chloride. The resulting mixture was extracted with ether. The organic layer was washed with water and saturated saline, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 1,1-(ethylenedioxy)-3-(14-hydroxytetradecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexane was obtained in the form of a colorless oil (yield: 98%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)(O)[CH3:10].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[CH2:10]
Reactant: CC(O)(c1ccco1)c1cccc(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=C(c1ccco1)c1cccc(Cl)c1Cl
Temperature: 0 °C

Procedure:
(±) 1-(2,3-Dichlorophenyl)-1-(2-furyl)ethanol (92 g.) was heated on a steam bath in pyridine (250 ml.) containing p-toluenesulphonyl chloride (69 g.) for 1 hour. The solution was poured into ice water (1 liter) and extracted with diethyl ether (5 × 500 ml.). The combined ethereal extracts were washed with water (2 × 500 ml.), dried over sodium sulphate, filtered and evaporated to give a dark oil, which was distilled to give 1-(2,3-dichlorophenyl)-1-(2-furyl)ethylene as a pale yellow liquid (46 g.), b.p. 140°-180° C./20 mm.Hg.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:46][CH3:47])=[C:39]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:40]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([O:46][CH3:47])=[C:39]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:40]=4)[N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Nc1cc(N)ccc1OC
Reactant: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccc3)c2)n1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)n2)ccc1OC
Temperature: 100 °C

Procedure:
To a slurry of (1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)-amine (Example 3, Step 3) (90 mg, 0.267 mmol) in IpOH (3 ml) was added DIEA (0.070 mL, 0.401 mmol) and N-(5-amino-2-methoxyphenyl)acrylamide (Step 2) (56.5 mg, 0.294 mmol). The mix was heated at 100° C. for 18 h. The solution was then cooled to RT. A precipitate fell out of solution, was filtered off and dried under reduced pressure to give N-{5-[4-(1-benzyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-2-methoxyphenyl}-acrylamide: MS m/z=493[M+H]+. Calc'd for C27H24N8O2: 492.20.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH:15]=[CH:14][CH2:13]1.ClC1C=CC=C(C(OO)=[O:25])C=1.S(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:1]([NH:8][C:9](=[O:10])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]1[CH:15]2[CH:14]1[CH2:13][NH:12][CH2:16]2
Reactant: C1=CCNC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)NCc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C1NCC2OC12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 15.00 g (74 mmol) sample of the 3-pyrroline benzyl carbamate from Step 1a was dissolved in 200 mL of methylene chloride and cooled to 0° C. A 46.3 g (267 mmol) sample of m-chloroperbenzoic acid was dissolved in 500 mL of methylene chloride and added dropwise with stirring over a period of 1 hours. The flask was then equipped with a condenser and the temperature was increased to 45° C. for 18 hours. The solution was cooled to room temperature, 2 g of sodium bisulfite was added, the solution was stirred for 30 min then poured into 1 L of 1M NaOH. and washed in a separatory funnel. The methylene chloride was then washed with 2×500 mL portions of potassium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was filtered and removed by evaporation under vacuum. to afford 14.26 g of 3,4-epoxypyrrolidine benzyl carbamate, MS (DCl) M/Z 220 (M+H), 237 (M+NH4); NMR (CDCl3) d 3.39 (ddd, 2H, J=6.0, 1.5, 13.5 Hz), 3.87 (dd, 2H, J=12, 15 Hz), 5.12 (d, 2, J=3 Hz), 7.35 (m, 5H).
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/[N:21](C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[F:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:33]([C:29]5[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=5)[N:21]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Product: O=c1ccn(-c2ccc3c(c2)OC(F)(F)O3)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=413.2 (M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[Br:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:34](=[O:35])[CH2:33][Br:32])[C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)CBr
Reactant: c1ccc(Oc2ccccc2NCc2cccc3c2OCO3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)N(Cc1cccc2c1OCO2)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of N-(benzo[1,3]dioxol-4-ylmethyl)-N-(2-phenyloxy-phenyl)amine (0.18 g, 0.58 mmol) dissolved in DCM (4 mL) was added triethylamine (0.24 g, 2.32 mmol, 0.32 mL). The reaction was cooled to 0° C. and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) was added. The mixture was stirred at room temperature for 2 h. LC-MS indicated starting material and product (1:1). Further triethylamine (0.24 g, 2.32 mmol, 0.32 mL) and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) were added and stirred at room temperature for 2 h. The solvents were removed in vacuo, the residue quenched with water (10 mL), extracted with DCM (2×20 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with DCM (A) and MeOH (B) (1% B, 80 g, 2 CV, 60 mL/min). The impure product was further purified by silica gel chromatography eluting with DCM (A) and EtOAc (B) (1-5% B, 80 g, 4.5 CV, 60 mL/min) to afford 120 mg (47%) of N-(benzo[1,3]dioxol-4-ylmethyl)-2-Bromo-N-(2-phenyloxy-phenyl)acetamide as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:31])[CH:25]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]3)[CH2:19][CH2:18]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH:32]1[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33]1>C(#N)C>[CH3:31][N:24]([CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:4]2[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][S:8][C:6]=3[N:7]=[C:2]([N:32]3[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33]3)[N:3]=2)[CH2:18][CH2:19]1)[CH:25]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]1
Reactant: CN1CCC(N(C)CC2CCN(c3nc(Cl)nc4scc(-c5ccccc5)c34)CC2)C1
Reactant: NC(=O)C1CCNC1
Solvent: CC#N
Product: CN1CCC(N(C)CC2CCN(c3nc(N4CCC(C(N)=O)C4)nc4scc(-c5ccccc5)c34)CC2)C1
Temperature: 140 °C

Procedure:
N—[[1-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]-N,1-dimethyl-pyrrolidin-3-amine (100 mg, 0.219 mmol) and pyrrolidine-3-carboxamide (300 mg, 2.63 mmol) were stirred in dry acetonitrile (1.5 ml) and heated in a microwave at 140° C. for 0.5 h. The solvent was evaporated and the crude residue purified by flash column chromatography (0 to 5% 7.0M NH3/MeOH in dichloromethane) to give 1-[4-[4-[[methyl-(1-methylpyrrolidin-3-yl)amino]methyl]-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]pyrrolidine-3-carboxamide as an off white solid (25 mg, 21%). m/z (M+H)+534.3, RT=2.69 min.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[CH3:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1)=[O:14].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C=O)C>[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:18][CH:17]=1)(=[O:14])[CH3:12]
Reactant: CC(=O)Nc1ccc(I)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C#CC2(O)CN3CCC2CC3)cc1
Temperature: 65 °C
Yield: 31.7 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (302 mg), 4-iodoacetanilide (522 mg), bis(triphenylphosphine)-palladium (II) chloride (70 mg), copper (I) iodide (35 mg), triethylamine (2 ml) and DMF (4 ml) was heated at 65° C. under an atmosphere of argon for 4 hours. The reaction mixture was cooled then poured into 5% sodium carbonate solution (10 ml) and the resulting mixture extracted with ethyl acetate (3×5 ml). The organic extracts were combined, dried (MgSO4) and evaporated to give a solid residue. This residue was purified by flash column chromatography using a mixture of 10% methanol in dichloromethane containing 1% 0.880 ammonia as eluent to give 3-[2-(4-acetamidophenyl)ethynyl]-3-hydroxyquinuclidine (180 mg), m.p. 198° to 205° C. (with decomposition); microanalysis, found: C, 67.9; H, 7.0; N, 9.5%; C17H20N2O2.H2O requires: C, 67.55; H, 7.28; N, 9.27%; NMR (DMSO-d6): 1.3-1.45(1H, m), 1.56-1.7(1H, m), 1.8-2.0(3H, m), 2.06(3H, s), 2.7-2.8(4H, t), 2.85-2.92(1H, d), 3.1-3.17(1H, d), 5.65(1H, s), 7.3-7.35(2H, d), 7.55-7.6(2H, d) and 10.1(1H, br); m/Z 285 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:22](=[O:25])[CH:23]=[CH2:24])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
Dissolve 3-nitro-5-(trifluoromethyl)aniline (150 mg, 0.73 mmol), triethylamine (220 mg, 2.18 mmol) in DCM (8 mL), cool to 0° C. at ice bath, add slowly acryloyl chloride (198 mg, 2.18 mmol). After addition, stir the reaction at room temperature for 2 hrs. Pour the mixture into water (30 mL), extract with EtOAc (10 mL×3), combine the organic layers; wash with brine (50 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product (190 mg) which is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15](OC)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:15][OH:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(CO)C2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To an ice cooled solution of the product of Step II (9.75 g, 28.7 mmol) in THF (200 mL) under nitrogen, LAH (2.18 g, 57.4 mmol) was added portionwise. Mixture was allowed to react at room temperature for 20 minutes. Reaction was cooled to 0° C., and H2O (1.6 mL) and 2N NaOH (7 mL) were carefully added. The mixture was stirred for 1 h and filtered through a pad of silica gel and Celite. Solvent was removed under reduced pressure to afford the title compound (96%) as a white solid. MS m/z 313.2 (M++1)
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Li]CCCC.CN(OC)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>O1CCCC1>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:18]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: CON(C)C(=O)c1ccncc1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2ccncc2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A solution of veratrole (8.04 g, 58.2 mmol) in tetrahydrofuran (50 mL) is treated with BuLi (26 mL, 2.5 M in hexane, 65 mmol) at −70° C. After the addition is complete, the reaction mixture is permitted to warm to room temperature and stirred for 2 hours. The mixture is re-cooled to −70° C. and treated with a solution of N-methyl-N-methoxyisonicotinamide (19) (9.15 g, 55.1 mmol) in tetrahydrofuran (30 mL). The resulting slurry is permitted to slowly warm to room temperature over an hour period. When the reaction mixture reaches 0° C. it becomes homogeneous. After 3 hours at room temperature, the reaction is quenched with 10% AcOH (aqueous, 100 mL). After stirring for 45 minutes, the tetrahydrofuran is removed at reduced pressure and the residue is diluted with toluene (150 mL). After neutralization with NHCO3, the phases are separated and the organic phase is submitted to a normal workup to provide an oil. Kugelrohr distillation provides the title compound (12) as a dark oil (12.77 g, 95% yield); b.p. 130-150° C./0.05 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8]O)[NH:4][N:3]=1.P(Br)(Br)[Br:11]>C(Cl)Cl>[Br:11][CH2:8][CH2:7][C:5]1[NH:4][N:3]=[C:2]([NH2:1])[CH:6]=1
Reactant: Nc1cc(CCO)[nH]n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Nc1cc(CCBr)[nH]n1
Temperature: -10 °C
Yield: 47.9 %

Procedure:
To a solution of 2-(3-amino-1H-pyrazol-5-yl)ethanol (13 g, 102.2 mmol) in DCM (200 mL) was added PBr3 (83 g, 306.7 mmol). The reaction mixture was heated under reflux for 3 h and then cooled to −10° C. and carefully quenched with aq satd Na2CO3 (200 mL). The resulting mixture was extracted with DCM (3×200 mL), and the Na2CO3 (200 mL). The resulting mixture was extracted with DCM (3×200 mL) combined organic layers were washed with brine, dried over anhydrous Na2SO4, and then concentrated in vacuo to give 5-(2-bromoethyl)-1H-pyrazol-3-amine (9.3 g, 48%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3([CH2:18][CH2:19][CH3:20])[C:13]([C:14]=2[C:15]=1[Cl:16])=[CH:12][C:11](=[O:17])[CH2:10][CH2:9]3.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]#[N:31]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:21][CH2:29][C:30]#[N:31])=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3([CH2:18][CH2:19][CH3:20])[C:13]([C:14]=2[C:15]=1[Cl:16])=[CH:12][C:11](=[O:17])[CH2:10][CH2:9]3
Reactant: N#CCCl
Reactant: CCCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC#N)c(Cl)c1Cl)CC2
Temperature: 65 °C

Procedure:
A stirred mixture of 3,4-dichloro-6,7,8,8a,9,10-hexahydro-2-hydroxy-6-oxo-8a-propylphenanthrene (0.4 g, 1.22 mmole), potassium carbonate (0.2 g, 1.45 mmole) and chloroacetonitrile (160 μl, 1.78 mmole) in dimethylformamide (7 ml) is heated at 65° C. for 2 hours, poured into ice water, extracted with ether, washed with water, brine, dried over MgSO4 and evaporated in vacuo. Trituration of the residual oil with butyl chloride give 2-[(3,4-dichloro-6,7,8,8a,9,10-hexahydro-6-oxo-8a-propyl-2-phenanthrenyl)oxy]acetonitrile which is removed by filtration, and dried.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=3)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.C([Sn](C(C)(C)C)(C(C)(C)C)[C:35]1[O:36][CH:37]=[CH:38][N:39]=1)(C)(C)C.C(#N)C>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[CH3:27])[C:20]([C:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)[N:7]=2)[CH:10]=1)=[O:29]
Reactant: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C
Reactant: CC(C)(C)[Sn](c1ncco1)(C(C)(C)C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(-c4ncco4)n3)c3ccccc3c2=O)cc1C

Procedure:
90 mg (0.2 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 143 mg (0.40 mmol) of 2-tri-t-butylstannyloxazole, 23 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 2 mL of anhydrous tetrahydrofuran. The resultant mixture was stirred at 75° C. for 18 h. The reaction solution was quenched by pouring into a container having 20 mL of water. The crude product precipitated out of solution and was isolated by filtration. The crude product was purified by flash chromatography to yield 16 mg of 4nn as a colorless solid: LC-MSD, m/z for C27H21N3O3, [M+H]+=436.5, [M+2H]+=437.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.136 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.35 (d, 6H), 5.62 (s, 2H), 7.06 (d, 1H), 7.19 (d, 1H), 7.35-7.44 (m, 3H), 7.54-7.62 (m, 2H), 7.66 (s, 1H), 7.78 (t, 1H), 7.84 (d, 1H), 8.08 (d, 1H), 8.34 (s, 1H), 8.48 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:15][C:14]([CH3:16])=[CH:13][C:5]=2[NH:6][C:7]=1[C:8]([O:10]CC)=[O:9])#[N:2].O.[OH-].[Li+]>O1CCCC1.C(O)C.O>[C:1]([C:3]1[C:4]2[S:15][C:14]([CH3:16])=[CH:13][C:5]=2[NH:6][C:7]=1[C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCOC(=O)c1[nH]c2cc(C)sc2c1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1cc2[nH]c(C(=O)O)c(C#N)c2s1
Temperature: 50 °C
Reaction time: 35 h
Yield: 104.7 %

Procedure:
To a mixed solution of ethyl 6-cyano-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.64 g) in tetrahydrofuran (8.0 mL), ethanol (4.0 mL) and water (6.0 mL) was added lithium hydroxide monohydrate (1.14 g), and the mixture was stirred at 50° C. for 35 hours. The reaction solution was concentrated under reduced pressure. To the residue was added 2 mol/L hydrochloric acid (18 mL) and water. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure at 50° C. to give the title compound (0.59 g).