Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=O)C.[F:27][C:28]([F:40])([F:39])[O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.[F-].[Cs+]>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.COCCOC.CO>[O:7]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:33]2[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:39])[F:40])=[CH:35][CH:34]=2)[CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cncc(-c3ccc(OC(F)(F)F)cc3)c2)SC[C@H]1O
Temperature: 110 °C
Yield: 68 %

Procedure:
0.5 g (1.11 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 0.275 g (1.33 mM) of 4-(trifluoromethoxy)phenylboronic acid, 0.373 g (2.45 mM) of cesium fluoride and 0.24 g of tetrakis(triphenylphosphine)palladium catalyst grafted onto polystyrene resin are mixed in 3.5 ml of DME and 5 ml of methanol. The reaction mixture is heated at 110° C. for 20 minutes by microwaves. It is filtered and then concentrated under reduced pressure. The crude product is purified by chromatography on a silica column (eluent: dichloromethane/methanol 90/10; v/v) to give the expected product in the form of a white solid with a yield of 68%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[Br:12]Br.Cl>[N+](C1C=CC=CC=1)([O-])=O.CCOCC>[Br:12][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[N:9][CH:8]=1
Reactant: Clc1cccc2ccncc12
Reactant: BrBr
Agent: Cl
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: Clc1cccc2c(Br)cncc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 8-chloroisoquinoline (1.0 g, 6.1 mmol) in nitrobenzene (20 mL) at 180° C. was added bromine (0.35 mL, 6.7 mmol) over 10 min. Heating and stirring were continued for 2 hours. The mixture was allowed to cool to about 80° C., then 2M HCl in Et2O (5 mL) was added, followed by Et2O (5 mL) and hexanes (60 mL). The resulting slurry was filtered, washed with hexane and dried. The collected solid was dissolved in water, then the solution was adjusted to pH 9 with Na2CO3 (aq). The solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 9.62 (s, 1H); 8.83 (s, 1H); 8.13 (t, J=5.0 Hz, 1H); 7.74 (d, J=5.0 Hz, 2H). LC6: 4.08 min, (M+H): 242.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22]([OH:24])=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22]([O:24][CH3:25])=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)alanine (100 g, 0.29 mol), potassium carbonate (82 g, 0.59 mol) and methyl iodide (42 g, 0.29 mol) in DMSO (1200 mL) was stirred at room temperature. After 12 hours, the reaction mixture was extracted with ethyl acetate, and the organics were separated and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give methyl 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)alaninate. MS ESI calc'd. for C17H25N2O6 [M+H]+ 353. found 353. 1H NMR (400 MHz, CDCl3) δ 7.36-7.33 (m, 5H), 5.09 (s, 2H), 4.34-4.30 (m, 1H), 3.74 (s, 2H), 3.59 (t, J=6.0 Hz, 2H), 2.62 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]2[NH:6][C:7](=[O:32])[C@H:8]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:9]([CH2:12][C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:35]([N:42]=[C:43]=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C>[CH2:35]([NH:42][C:43](=[O:44])[NH:1][C:2]1[CH:34]=[CH:33][C:5]2[NH:6][C:7](=[O:32])[C@H:8]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:9]([CH2:12][C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)NC(CC(=O)O)c1ccccc1)[C@@H](CCC(=O)O)C(=O)N2
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)CC[C@H]1C(=O)Nc2ccc(NC(=O)NCc3ccccc3)cc2C(=O)N1CC(=O)NC(CC(=O)O)c1ccccc1
Temperature: 45 °C

Procedure:
To a solution of 3-(R,S)-{2-[7-amino-3-(S)-(2-carboxy-ethyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid (0.15 mmol, 70 mg) in DMF (2.5 ml) was added benzylisocyanate (46 μl, 037 mmol). The mixture was shaken at 45° C. over night. Then the solution was evaporated and the crude product was purified by RP-HPLC to give 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(2-carboxy-ethyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid (14 mg): MS (ISN) 600 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1C=NNC=1.C(=O)CC.[CH:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])OCC.[N+]([O-])([O-])=O.[NH4+]>C(O)C>[CH2:19]([O:18][CH:11]([O:15][CH2:16][CH3:17])[CH2:1][CH3:2])[CH3:20]
Reactant: Cc1cn[nH]c1
Reactant: CCOC(OCC)OCC
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCC=O
Solvent: CCO
Product: CCOC(CC)OCC

Procedure:
In the first step of the present synthesis of 4-MP, propionaldehyde is reacted with triethyl orthoformate in the presence of ethanol and ammonium nitrate to produce 1,1-diethoxypropane. In the second step, the 1,1-diethoxypropane produced in the first step is reacted neat (without a solvent) with a catalyst, which comprises an acid and an amine, to produce 1-ethoxy-1-propene (ethyl-1-propenyl ether). In the third step, this material is purified by washing and drying, without distillation. In the fourth step, the 1-ethoxy-1-propene from the third step is reacted with triethyl orthoformate in the presence of boron trifluoride-diethyl etherate to produce 1,1,3,3-tetraethoxy-2-methyl propane (“TEMP”). In the fifth step, the TEMP from the third step is reacted with hydrazine or a hydrazonium salt or hydrazine hydrate at elevated temperatures to produce 4-methylpyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[O:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[CH:17]=[C:18]([NH:22][C:8](=[O:10])[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(-c2nnco2)c1
Reactant: O=C(O)c1cc(Br)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2nnco2)c1)c1cc(Br)ccn1
Yield: 80.6 %

Procedure:
A solution of 4-bromopyridine-2-carboxylic acid (3.76 g, 18.6 mmol), 3-[1,3,4]oxadiazol-2-yl-phenylamine (3.0 g, 18.6 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (7.1 g, 18.7 mmol), and diisopropylethylamine (15 mL) in N,N-dimethylformamide was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was stirred with acetonitrile (40 mL) and water (40 mL). The solid thus obtained was isolated by filtration, washed with water (20 mL), acetonitrile (20 mL) and diethyl ether (40 mL), and dried under reduced ressure to give N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-4-bromopicolinamide as a white powder (5.2 g, 15.0 mmol, 81% yield).
Reaction SMILES: [Na].[CH2:2]([N:4]([CH2:26][CH2:27][CH2:28][CH3:29])[C:5]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[N:12]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[Cl:25])[N:13]=[C:14]([S:15][CH3:16])[C:6]=12)[CH3:3].[CH3:30][OH:31]>>[CH2:2]([N:4]([CH2:26][CH2:27][CH2:28][CH3:29])[C:5]1[N:10]=[C:9]([O:31][CH3:30])[N:8]=[C:7]2[N:12]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[Cl:25])[N:13]=[C:14]([S:15][CH3:16])[C:6]=12)[CH3:3]
Reactant: CO
Reactant: CCCCN(CC)c1nc(Cl)nc2c1c(SC)nn2-c1c(Cl)cc(Cl)cc1Cl
Agent: [Na]
Product: CCCCN(CC)c1nc(OC)nc2c1c(SC)nn2-c1c(Cl)cc(Cl)cc1Cl

Procedure:
To 1 ml of methanol was added sodium (25 mg) and the mixture was stirred until all the sodium was dissolved completely. The resulting solution was treated with ethyl-butyl-[6-chloro-3-methylsulfanyl-1-(2,4,6trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]amine (100 mg, 0.21 mmol) and heated at reflux for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give an oil residue. The oil residue was purified by silica gel column chromatography to give 73 mg of the title compound as a colorless oil. 1H NMR (CDCl3):0.96(t,3H), 1.35(t,3H), 1.42(m,2H), 1.71(m,2H), 2.63(s,3H), 3.74(dd,2H), 3.86(q,2H), 3.91(s,3H), 7.46(s,2H)ppm.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.CS[C:25]1[NH:29][C:28](=[O:30])[CH2:27][N:26]=1.[OH-].[Na+]>C(O)C>[O:30]=[C:28]1[NH:29][C:25]([NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:8]3)=[N:26][CH2:27]1
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reactant: CSC1=NCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN=C(NCc2cccc3cc(NS(=O)(=O)c4ccccc4)ccc23)N1

Procedure:
A mixture of N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide, 2-methylsulfanyl-3,5-dihydro-imidazol-4-one (prepared by the method reported by Chen et al., WO9736859) and sodium hydroxide in ethanol is heated to reflux, then concentrated under reduced pressure, diluted with ethyl acetate, and washed with aqueous sodium carbonate. The organic phase is dried (magnesium sulfate) and concentrated under reduced pressure to give N-{5-[(5-Oxo-4,5-dihydro-1H-imidazol-2-ylamino)-methyl]-naphthalen-2-yl}-benzenesulfonamide. 5-[(5-Oxo-4,5-dihydro-1H-imidazol-2-ylamino)-methyl]-naphthalene-2-sulfonic acid phenylamide may be similarly prepared.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1C(Cc2ccccc2)CCCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1-Phenylmethyl-2-piperidinone (See: Yamaguchi M, Hirao 1 (1985) "A direct synthesis of [(tert-butoxycarbonyl)methylidene]-azacycloalkanes from N-alkyllactams" J. Org. Chem., 50, 1975-1977) (3.40 g, 18 mmol) was reacted with benzyl bromide (4.84 g, 28.3 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (2.73 g, 27 mmol) with butyllithium in hexanes (2.5 M, 10.3 mL, 25.7 mmol)) in THF (45 mL) and HMPA (2.7 mL, 15.5 mmol) as described above in the preparation of Example 7. After the addition of benzyl bromide, the reaction mixture was stirred for 2 h at -78° C., and then quenched with saturated NH4Cl (50 mL). The reaction mixture was extracted with ether (3×40 mL) and the combined ether extract washed with brine (40 mL) and dried over MgSO4. The solvent was removed in vacuo, and the residue (8.40 g) thus obtained, was chromatographed over silica gel (hexanes-CHCl3 -EtOAC, 15:4:1 and then 7:2:1) to give the product lactam (3.14 g, 63%) as a colorless solid: mp 94-95° C. (CH2Cl2 -hexanes).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([C@H:34]1[CH2:39][CH2:38][C@H:37]([C@H:40]2[CH2:45][CH2:44][C@H:43]([CH:46]=O)[CH2:42][CH2:41]2)[CH2:36][CH2:35]1)[CH2:31][CH:32]=[CH2:33]>C1COCC1>[CH3:2][O:3][CH:4]=[CH:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([C@H:37]2[CH2:36][CH2:35][C@H:34]([CH2:30][CH2:31][CH:32]=[CH2:33])[CH2:39][CH2:38]2)[CH2:45][CH2:44]1
Reactant: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=O)CC2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=COC)CC2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 66.4 g (193.7 mmol) of methoxymethyltriphenyl phosphonium chloride and 600 ml of THF was cooled to −50° C. under a gas stream of nitrogen. To the mixture, 20.1 g (179.1 mmol) of t-BuOK was added and stirred for 1 hour. To the mixture, a solution of 37.0 g (148.9 mmol) of trans-4-(trans-4-(3-_butenyl)cyclohexyl)cyclohexane carbaldehyde in 400 ml of THF was added dropwise with maintaining the temperature below −50° C. After dropwise addition, the reaction temperature was increased gradually to the room temperature, and stirring was carried out further for 5 hours. The solvent was distilled off under a decresed pressure, 250 ml of water was added and the mixture was extracted with 300 ml of toluene. The organic layer was washed with 200 ml of water for three times and dried with anhydrous magnesium sulphate. The solvent was distilled off under a decreased pressure, and the residue was subjected to silica gel column chromatography (eluent: a mixed solvent of toluene/heptane=3/7), to obtain 16.1 g of crude 1-(2-methoxyethenyl)-trans-4- (trans-4-(3-butenyl) cyclohexyl) cyclohexane.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH:14]([OH:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C.C([O-])(=O)C.[Na+].[H][H]>[Pd].CO.C(O)(=O)C>[OH:21][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][NH:12][C:6]1[C:5]2[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: OC(CNc1ccnc2cc(Cl)ccc12)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC(CNc1ccnc2ccccc12)c1ccccc1

Procedure:
A mixture of 7-chloro-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine (10 g), 0.8 g of palladium on powdered charcoal (10%), 5 ml of acetic acid, 7 g of sodium acetate.3H2O and 200 ml of methanol was hydrogenated at room temperature with shaking at 30-50 psi until completion of hydrogen uptake. The catalyst was filtered and the solvent evaporated. The oil residue was dissolved in 20 ml of water and the solution made alkaline (pH=10) with and NaOH solution. The crystalline compound was filtered and recrystallized from isopropanol. The yield was 7.5 g, mp 289°-290° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 73.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (36.2 mg, 0.0881 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with piperidine (0.035 mL, 0.35 mmol), acetic acid (0.101 mL, 1.76 mmol) and sodium triacetoxyborohydride (93 mg, 0.44 mmol), followed by purification by preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (31.2 mg, yield 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[N:11][N:10]=1.Cl[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=3)[CH2:21][CH2:22]2)=[O:15])=[N:11][N:10]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: O=C(NC1CCNCC1)c1nnc(Nc2ccccc2F)o1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)nc1
Yield: 11.7 %

Procedure:
A solution of 5-[(2-fluorophenyl)amino]-N-piperidin-4-yl-1,3,4-oxadiazole-2-carboxamide (Intermediate 101) (100 mg, 0.33 mmol) and methyl 6-chloronicotinate (56 mg, 0.33 mmol) in dry DMF (3 mL) was heated in the microwave at 120° C. for 1 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to give the title compound (17 mg, 12%) as a solid; 1H NMR δ 1.66-1.53 (m, 2H), 1.92-1.82 (m, 2H), 3.12-2.99 (m, 2H), 3.80 (s, 3H), 4.16-4.04 (m, 1H), 4.54-4.42 (m, 2H), 6.92 (d, 1H), 7.18-7.10 (m, 1H), 7.33-7.21 (m, 2H), 7.97-7.92 (m, 1H), 8.04-7.98 (m, 1H), 8.65 (d, 1H), 9.03 (d, 1H), 10.62 (s, 1H); MS m/e MH+ 441.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.C[Si]([C:31]#[CH:32])(C)C>C(N(CC)CC)C.O.[Cu]I.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>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:31]#[CH:32])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: C#Cc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A solution of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (50 mg, 0.11 mmol) in triethylamine (2 mL) containing CuI (2.1 mg, 0.011 mmol) was degassed with bubbling nitrogen for 10 min. Pd(PPh3)4 (13 mg, 0.011 mmol) was added followed by trimethylsilylacetylene (5 equiv). The reaction vessel was sealed and heated in the microwave at 130° C. for 30 min. The cooled mixture was diluted with water and extracted with ethylacetate. The combined organics were concentrated and the residue dissolved in 2 mL methanol. The solution was treated with potassium carbonate (100 mg) and the suspension stirred for 2 hr at room temperature. The reaction mixture was concentrated, diluted with water and extracted with ethylacetate. The combined organics were concentrated and the residue purified by reverse phase HPLC to give 133. MS: (ESI+) 394.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]([OH:21])=[C:6]([CH:8](O)[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=2[OH:19])[CH:7]=1.S(Cl)([Cl:27])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]([OH:21])=[C:6]([CH:8]([Cl:27])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=2[OH:19])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(O)c2cc(Cl)cc([N+](=O)[O-])c2O)c1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cc(C(Cl)c2cc(Cl)cc([N+](=O)[O-])c2O)c1O

Procedure:
A mixture of bis(5-chloro-2-hydroxy-3-nitrophenyl)methyl alcohol (4.5 g) and thionyl chloride (50 ml) was heated under reflux for 3 hr. Dimethylformamide (0.1 g) was added to the reaction mixture and the mixture was heated under reflux for a further hour. Excess thionyl chloride was then removed by distillation under reduced pressure and the remaining red oil was crystallised from ethanol to give 4 g of bis(5-chloro-2-hydroxy-3-nitrophenyl)methyl chloride, m.p. 180° C.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:16][CH:17]=2)=[N:9][CH:10]=1.[CH2:24]([O:26][C:27]1[C:31]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][NH:29][N:28]=1)[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27]1[C:31]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][N:29]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:16][CH:17]=3)=[CH:7][CH:6]=2)[N:28]=1)[CH3:25]
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of 5-chloromethyl-2-(2-phenyl-4-thiazolylmethoxy)pyridine (475 mg), ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (657 mg, yield: 89%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCC.C([Li])CCC.[CH:32]12[CH2:37][CH:36]1[CH2:35][CH:34]([OH:38])[CH2:33]2.[CH:39]12C[CH:43]1[CH2:42][CH2:41][CH:40]2[OH:45]>CCCCCC.C1C=CC=CC=1>[O:45]1[CH2:39][CH2:43][CH2:42][CH2:41][CH:40]1[O:38][CH:34]1[CH2:35][CH:36]2[CH:32]([CH2:37]2)[CH2:33]1
Reactant: OC1CCC2CC12
Reactant: OC1CC2CC2C1
Agent: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C1CCC(OC2CC3CC3C2)OC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of hexyltriphenylphosphonium bromide (102 g.) and benzene (1200 ml.) is stirred under nitrogen during addition of a solution of butyl lithium in hexane (146 ml. of a 15% solution- w/v). The resulting mixture is stirred 30 min. Then a solution of the mixture (27 g.) of products obtained according to Preparation 4 in 300 ml. of benzene is added dropwise with stirring during 30 min. The mixture is heated and stirred at 70°C. for 2.5 hrs., and then is cooled to 25°C. The resulting precipitate is collected by filtration and washed with benzene. The filtrate and benzene wash are combined, washed with water, and dried to give 58 g. of a mixture of the tetrahydropyranyl ethers of endo-6-(cis- and trans-1-heptenyl)bicyclo[3.1.0]hexan-3-ol and endo-6-(cis- and trans-1-heptenyl)bicyclo[3.1.0]hexan-2-ol.