Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:10]2[N:6]([N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:9]=2)[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[CH:4]=1)[CH3:2].CO>C(O)(=O)C>[CH2:1]([C:3]1[C:10]2[N:6]([N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:9]=2)[N:5]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:28][N:29]=[N:30][N:31]=3)=[CH:19][CH:20]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cn(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)n2nc(C(C)C)nc12
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n2nc(C(C)C)nc12
Yield: 95.4 %

Procedure:
A mixture consisting of 2.38 g of 7-ethyl-2-isopropyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole, 90 ml of methanol and 10 ml of acetic acid was heated under reflux for 2 hours. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was subjected to silica gel column chromatography. Elution with methanol-chloroform (1:9, v/v) gave 1.43 g of 7-ethyl-2-isopropyl-5-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole in the form of colorless amorphous foamy material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O.C(C1C=CC(N)=CC=1)#N.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccn1
Agent: N#Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Picolinic acid chloride was prepared by refluxing a solution of picolinic acid (20.0 g, 162 mmol) and thionyl chloride (24.0 mL, 325 mmol) in chloroform (200 mL) overnight. After excess thionyl chloride and chloroform was removed in vacuo, some of the acid chloride (15.0 g, 106 mmol) was added to a solution of 4-cyanoaniline (10.0 g, 84.6 mmol) and triethylamine (30.0 mL, 215 mmol) in methylene chloride (250 mL) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 1 hour, poured into water (1 L), basified with 2.5N sodium hydroxide solution, and diluted with methylene chloride. The organic layer was dried over magnesium sulfate and concentrated to give a light brown solid (8.22 g, 36.9 mmol, 44%, mp 156°-159° C.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[N+:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28].CCOCC>C1(C)C=CC=CC=1.C(O)C.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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:27]([O-:29])=[O:28])[CH:35]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.25 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 3-nitrophenylboronic acid (0.21 g) in ethanol (1 ml). The mixture was heated under reflux for 1 hour, then left at room temperature overnight and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (20 g) eluted with dichloromethane:hexane (1:1). Combination and evaporation of suitable fractions followed by recrystallisation from ether/hexane gave the title compound as an pale yellow solid m.p. 212-4° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14]([CH2:22][C:23]#C)[CH2:15]2)=[N:6][CH:7]=1.BrCC[F:39]>>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14]([CH2:22][CH2:23][F:39])[CH2:15]2)=[N:6][CH:7]=1
Reactant: FCCBr
Reactant: C#CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(CCF)C2)ncc1Cl

Procedure:
2-{5-Chloro-2-[10-(2-fluoro-ethyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide was prepared from 2-[5-chloro-2-(10-prop-2-ynyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide and 1-bromo-2-fluoro-ethane in an analogous manner to Example 279. Product isolated as a yellow oil (22 mg, 66%). LCMS (m/e) 495 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.03 (s, 1H), 8.65 (d, 1H, J=8.4 Hz), 8.08 (s, 1H), 7.50-7.45 (m, 1H), 7.45-7.39 (m, 1H), 7.36 (d, 1H, J=2.2 Hz), 7.30-7.20 (m, 1H), 7.10-6.95 (m, 3H), 6.53 (bs, 1H), 4.52 (dt, 2H, J=5.1 and 47.7 Hz), 3.02 (d, 3H, J=4.8 Hz), 3.02-2.93 (m, 3H), 2.93-2.89 (m, 1H), 2.74 (dt, 2H, J=5.1 and 27.3 Hz), 2.43-2.31 (m, 2H), 2.27-2.18 (m, 2H), 1.67-1.57 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]2[CH2:9][C@H:4]([CH2:5][CH2:6][C@@H:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:3]1.[Li+].[OH-:18]>C1COCC1.O>[C:13]([O:12][C:10]([C@H:7]1[CH2:6][CH2:5][C@H:4]([OH:3])[CH2:9][C@@H:8]1[C:2]([OH:18])=[O:1])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H]2C[C@@H]1C(=O)O2
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](O)C[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl (1S,2S,5S)-7-oxo-6-oxabicyclo(3,2,1)octane-2-carboxylate was dissolved in THF-H2O. At 0° C., LiOH (3 eq.) was added and the resulting mixture was stirred at 0° C. for 2 hours. TLC showed starting material was consumed. The mixture was then acidified to pH of about 2. The product was extracted with EtOAc (×3). The combined extracts were washed with brine (×1); dried over MgSO4. After filtration, the filtrate was concentrated to give (1S,2S,5S)-2-(tert-butoxycarbonyl)-5-hydroxycyclohexanecarboxylic acid (quantitative).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.[Cl:19]N1C(=O)CCC1=O.O>C(#N)C>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:4]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1CNc2ccc(Cl)cc2C1
Reaction time: 6 h
Yield: 32.9 %

Procedure:
To a solution of 1A (28.3 g, 114 mmol) in acetonitrile (240 mL) at RT was added dropwise a solution of N-chlorosuccinimide (15.22 g, 114 mmol) in acetonitrile (240 mL). After addition, the reaction mixture was stirred for 6 h, then water (500 mL) added. The mixture was extracted with EtOAc (2×500 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc/hexane 1:5 to give the title compound (10.6 g, 58% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][OH:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-t-butyldimethylsilyloxypyrrolidine (39.96 in dry pyridine (40 ml), acetic anhydride (40 ml) was added, and the resultant mixture was allowed to stand overnight. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium chloride solution, dilute hydrochloric acid, aqueous sodium chloride solution, aqueous sodium bicarbonate solution and aqueous sodium chloride solution in order and dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-1-benzyloxycarbonyl-2-acetoxymethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[I-:12].[Na+].[I-].O>C(O)CCC.[Cu]>[I:12][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Brc1ccc2ncccc2c1
Reactant: [I-]
Agent: [Cu]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: Ic1ccc2ncccc2c1
Temperature: 120 °C
Yield: 80 %

Procedure:
6-bromoquinoline (80.1 g, 0.385 mol) is dissolved in n-butanol (0.8 L). Copper catalyst CuI (3.7 g, 0.019 mol), a copper-ligand N,N′-dimethylethylenediamine (3.4 g, 0.0385 mol) and an iodide source NaI (115.5 g, 0.770 mol) are added and the mixture is heated in a heating jacket, under inert atmosphere to 120° C. After work-up (0.8 L water is added to the reaction mixture, the organic layer is separated off and evaporated) and purification (the crude evaporation residue was crystallized from 150 mL diisopropylether), 6-iodoquinoline was obtained in 80% yield.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:23][O:24][C:25]1[C:26](=[O:52])[C:27]([CH3:51])=[C:28]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[C:39]([CH:43]=2)[C:40](O)=[O:41])[C:29](=[O:33])[C:30]=1[O:31][CH3:32]>C(Cl)Cl>[CH3:23][O:24][C:25]1[C:26](=[O:52])[C:27]([CH3:51])=[C:28]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[C:39]([CH:43]=2)[C:40]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:41])[C:29](=[O:33])[C:30]=1[O:31][CH3:32]
Reactant: c1ccc2c(c1)CCCN2
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)N3CCCc4ccccc43)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
1,2,3,4-Tetrahydroquinoline (0.049 g, 0.367 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.105 g, 0.550 mmol) were added to a methylene chloride solution (10 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenoxybenzoic acid (0.075 g, 0.183 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.050 g, 0.0955 mmol, 52%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:12][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 66.9 %

Procedure:
3-Chloro-2-nitroaniline (5.00 g, 29.0 mmol) was dissolved in glacial acetic Acid (258 mL). N-Bromosuccinimide (5.06 g, 28.4 mmol) was added and the resulting mixture was refluxed for 1 hour. The reaction was cooled to room temperature and poured into water to give a precipitate that was filtered, rinsed with water and dried to constant weight to give the title compound (4.78 g, 67%). 1H NMR (400 MHz, CDCL3) δ ppm 7.46 (d, J=9.0, 1H), 6.64 (d, J=9.0, 1H), 4.74 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:9]=[CH:10][C:11]1C=C[CH:14]=[CH:13][CH:12]=1.C(C1C=CC=CC=1)=CC.C1CCCCC=1.C(C1CCCCC=1)=C>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:7]1[CH:8]2[CH:3]([CH:1]3[CH:12]([CH2:13][CH2:14]2)[CH2:11][CH2:10][CH2:9][CH2:2]3)[CH2:4][CH2:5][CH2:6]1
Reactant: C=Cc1ccccc1
Reactant: CCc1ccccc1
Agent: C=CC1=CCCCC1
Agent: CC=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1=CCCCC1
Solvent: c1ccccc1
Product: C1CCC2C(C1)CCC1CCCCC12

Procedure:
--0.63 g of substrate and 0.1 g charcoal was irradiated for 25 minutes. The reaction gave gases (20.6%) and liquids (11.3%). The products included benzene, toluene, ethylbenzene, styrene, 2-propenylbenzene, cyclohexene, and vinylcyclohexene.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)(=O)C>[C:20]([C:19]1[C:13]2[CH:14]=[C:15]([CH3:17])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Yield: 16.6 %

Procedure:
A solution of 1.0 g of 5-benzyloxy-4-t-butyl-2-formylbenzofuran in a mixed solvent of 50 ml of ethyl acetate and 2 ml of acetic acid was vigorously stirred with 1.0 g of 10% palladium on carbon for 20 hours in a hydrogen atmosphere. After the palladium on carbon was filtered out, the filtrate was concentrated and the concentrate was purified by silica gel column chromatography (in n-hexane containing 20% ethyl acetate) to give 0.11 g of 4-t-butyl-5-hydroxy-2-methylbenzofuran as a white crystal (yield 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([NH2:13])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:13][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[O:12][N:11]=1)=[O:18]
Reactant: Nc1cc(-c2ccc(Cl)cc2)on1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(-c2ccc(Cl)cc2)on1)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
5-(4-Chlorophenyl)-3-aminoisoxazole (25 grams) was placed in a 500 ml. 3-necked flask under an atmosphere of nitrogen. Following the addition of 150 ml. of toluene, the reaction mixture was stirred continuously and treated in rapid fashion (15 minutes), with 2,6-dichlorobenzoylchloride (60 grams). The mixture was then heated to reflux for 18 hours and allowed to gradually cool to room temperature. When the reaction mixture was further cooled to approximately 0° C. the final product precipitated. The product was filtered and recrystallized from acetone to yield 28 grams, m.p. 228°-229° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH2:24][CH2:25]OS(C)(=O)=O)[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=2[CH2:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.[CH2:31]([NH2:34])[CH:32]=[CH2:33]>C(O)CC>[CH2:31]([N:34]1[CH2:25][CH2:24][C:8]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=3[CH2:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:6]1)[CH:32]=[CH2:33]
Reactant: COc1cccc2c1Cc1ccccc1C2(CCOS(C)(=O)=O)CCOS(C)(=O)=O
Reactant: C=CCN
Solvent: CCCO
Product: C=CCN1CCC2(CC1)c1ccccc1Cc1c(OC)cccc12

Procedure:
A mixture of 9,9-di(2-methanesulphonyloxyethyl)-4-methoxy-9,10-dihydroanthracene (1.5 g.) and allylamine (7.0 g.) in n-propanol (30 ml.) is heated under reflux for 18 hours. The solvent is evaporated and 2N sodium hydroxide (20 ml.) is added; the suspension is extracted with ether and the ether layer washed with water, and extracted with 2N hydrochloric acid. The acid extract is washed with ether, basified with 15N ammonia solution, and the precipitated product is extracted into ether, the ether is washed with water and with brine, dried (MgSO4) and evaporated to give 1'-allyl-4-methoxy-9,10-dihydroanthracene-9-spiro-4'-piperidine as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]#[N:20])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:34]=[N+:35]=[N-:36])(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]1[NH:36][N:35]=[N:34][N:20]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1

Procedure:
A mixture of methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate (10 g), tri-n-butyltin azide [prepared according to the method in Rec. Trav. Chim. Pavs-Bas, 1963, 81, 286; 12 g] and THF (60 ml) was stirred and heated to reflux for 40 hours. The mixture was evaporated. The resultant brown oil was triturated in diethyl ether which had been saturated with hydrogen chloride gas. The precipitate was isolated and washed with diethyl ether. There was thus obtained methyl (2S)-2-benzyloxycarbonyl-amino-4-(tetrazol-5-yl)butyrate (2.23 g, 32%);
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14]([OH:16])=O)=[CH:3]1.[CH:17]([N:20]([CH:23]([CH3:25])C)CC)([CH3:19])C.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1CCCC1>CN(C)C=O.C(OCC)(=O)C.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14]([N:20]2[CH2:17][CH2:19][CH2:25][CH2:23]2)=[O:16])=[CH:3]1
Reactant: Cn1cc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: Cn1cc(C(=O)N2CCCC2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
400 mg of 1-methyl-6-nitro-1H-indole-3-carboxylic acid are dissolved in 4 ml dimethylformamide, combined with 774 μl N,N-diisopropyl-N-ethyl-amine as well as 583 mg O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TBTU) and stirred for 45 minutes at ambient temperature. 225 μl of pyrrolidine are added and the mixture is stirred for 5 hours at ambient temperature. Then it is divided between water and ethyl acetate, the organic phase is washed with saturated sodium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo.
Reaction SMILES: O[CH:2]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].CCN(CC)CC.CC(C)=O.[C:37]([OH:40])(=[S:39])[CH3:38]>C1(C)C=CC=CC=1>[C:37]([S:39][CH:2]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:40])[CH3:38]
Reactant: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)OC)cc1
Reactant: CC(O)=S
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(OCC(CC#CCCCC(=O)OC)SC(C)=O)cc1

Procedure:
In a dry flask equipped with a condenser was placed 4 g of methyl 8-hydroxy-9-(4-pentylphenoxy)-5-nonynoate, the product of Example 8, 1.69 ml of Et3N, 20 ml of toluene and 20 ml of acetone. To the mixture was added 3.43 g of N-methyl-2-fluoropyridimium tosylate stirring at RT for 1 hr. A solution of 0.87 ml of thioacetic acid and 1.69 ml of Et3N in 5 ml of toluene was added. The resulting solution was refluxed for 2 hr. Solvent was removed and the residue was dissolved in Et2O and then was washed with NaHCO3 solution and dried over MgSO4. The crude product, after solvent removal, was purified on a Waters Prep 500 HPLC (EtOAc-hexane 1:16) to obtain the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:21]=1[CH2:22][N:23]=[C:24]=[O:25]>C(Cl)(Cl)Cl>[CH3:18][O:19][C:20]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:21]=1[CH2:22][NH:23][C:24]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:10])[CH:7]([CH3:9])[CH3:8])=[O:25]
Reactant: COc1ccc(CN=C=O)c(OC)c1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)NCc1ccc(OC)cc1OC)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a solution of L-valine methyl ester hydrochloride (2.6 g) and triethylamine (1.6 g) in chloroform (30 mL) was added 2,4-dimethoxybenzyl isocyanate (3.0 g), and the mixture was stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford methyl N-[(2,4-dimethoxybenzyl)carbamoyl]-L-valinate (4.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:10][C:11](=[O:21])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[N:8][CH:9]=1)=[O:4].[CH2:22](OC(C)C(O)=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH:10][C:11](=[O:21])[CH:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:22])[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cncn1NC(=O)COCc1ccccc1
Reactant: CC(OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cncn1NC(=O)C(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of compound 2 (4.2 g, 29.7 mmol), 2-Benzyloxy-propionic acid (5.5 g, 29.7 mmol) and DIEA (10 mL) in a mixture of DMF (1 mL) and THF (50 mL) in ice-water bath was added HATU (13.5 g, 35.7 mmol). The resulting mixture was then stirred at ambient temperature overnight. Water (100 mL) was added. The mixture was extracted with ethyl acetate (300 mL×2). The combined organic phases were concentrated to give a crude residue, which was purified by chromatography on silica gel column (eluted with PE/EtOAc=1:1 to 1:3) to afford compound 9 (8.2 g, 91% yield) as brown oil. LC-MS: m/z 304 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([OH:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([OH:21])[CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[(3S)-3-hydroxypiperidin-1-yl]quinolin-7-yl}ethanone (18 mg, 0.059 mmol) and ammonium acetate (45.5 mg, 0.591 mmol) in methanol (0.33 mL) and acetonitrile (0.34 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (7.42 mg, 0.118 mmol). The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude amine was used directly in the next step. LCMS calculated for C16H21ClN3O (M+H)+: m/z=306.1; Found: 306.1.