Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.C=O.[C:24]([BH3-])#N.[Na+].C(#N)C>O.[OH-].[Na+].C(O)(=O)C>[CH3:24][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Nc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CNc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Reaction time: 8 h

Procedure:
To the mixture of 1.4 g of 2-(p-aminophenyl)-pyrazolo-[4,3-c]quinolin-3(5H)-one, 4.1 ml of 37% aqueous formaldehyde, 1.0 g of sodium cyanoborohydride and 20 ml of acetonitrile, 0.6 g of glacial acetic acid are added while stirring. Stirring is continued overnight at room temperature and the mixture diluted with water. The precipitate formed is dissolved in diluted sodium hydroxide, the aqueous solution washed with diethyl ether and its pH adjusted to 8.5 by addition of aqueous ammonium chloride. The precipitate formed is collected, washed with methanol, then with diethyl ether and dried to yield the 2-(p-methylaminophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one melting at 302°-304°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[C:12]([CH:17]=O)=[N:13][CH:14]=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][CH2:33][C:34]2[C:39]([CH3:40])=[CH:38][C:37]([Cl:41])=[CH:36][N:35]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([N:32]([CH2:33][C:34]2[C:39]([CH3:40])=[CH:38][C:37]([Cl:41])=[CH:36][N:35]=2)[CH2:17][C:12]2[C:11]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)([CH3:9])[CH3:10])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Reactant: Cc1cc(Cl)cnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reacting of 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde, 4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2 gave 4-((5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 1.22 (br, 2H), 1.44 (s, 9H), 1.59 (br, 2H), 1.60 (s, 6H), 2.27 (s, 3H), 2.47 (m, 3H), 3.34 (s, 2H), 3.65 (s, 2H), 4.03 (br, 2H), 6.87 (m, 4H), 7.18 (m, 1H), 7.36 (s, 1H), 7.82 (d, 1H, J=7.2 Hz), 8.21 (s, 1H), 8.48 (d, 1H, J=3.9 Hz). Deprotection with TFA using General Procedure F gave (5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-piperidine-4-yl-amine as a white solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)O)[O:5][CH2:6][CH3:7])[CH3:2].C(Cl)Cl.C(N(S(F)(F)[F:26])CC)C>O>[CH2:1]([O:3][P:4]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)[F:26])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(OCC)C(O)c1cccc(Br)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOP(OCC)C(F)c1cccc(Br)c1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
Into cold mixture of diethyl[(3-bromophenyl)(hydroxy)methyl]phosphonite (30 g) and CH2Cl2 (120 mL) was added diethylaminosulfur trifluoride (16.44 g, 101.53 mmol) and the mixture was stirred for 2 hours. The mixture was then poured into water and washed with NaHCO3 and brine. Purification by ISCO (hexane/EtOAc 1/1) gave diethyl[(3-bromophenyl)(fluoro)methyl]phosphonite (22.6 g); MS m/e (M+H)+ 325.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:9])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1cccc(C2CO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2cccc(Cl)c2)cc1
Temperature: 78 °C
Yield: 9.8 %

Procedure:
To a stirring solution of 2-(3-chlorophenyl)oxirane (6.20 g, 40.0 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (7.30 g, 60.0 mmol), 1M NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. for three hours. The reaction was allowed to cool to RT and then extracted with EtOAc (2×150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was adsorbed onto silica gel and chromatographed eluting with 25-40% EtOAc/hexanes. There are 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.08 g (10%) of the desired product as a colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.95 g (8%) of the regioisomer as a colorless oil, 44B. Some starting epoxide (2.85 g) was also recovered.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].ICC.[CH3:10][O:11][N:12]([CH3:26])[C:13]([C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:24][CH3:25])=[N:20][NH:21]2)=[CH:17][CH:16]=1)=[O:14].C(OCC)(=O)C>C1COCC1>[CH3:10][O:11][N:12]([CH3:26])[C:13]([C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:24][CH3:25])=[N:20][N:21]2[CH2:1][CH3:2])=[CH:17][CH:16]=1)=[O:14]
Reactant: CCc1n[nH]c2cc(C(=O)N(C)OC)ccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCc1nn(CC)c2cc(C(=O)N(C)OC)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.2 %

Procedure:
A mixture of potassium tert-butoxide (0.144 g, 1.28 mmol) and iodoethane (0.20 g, 1.28 mmol) in THF (1 mL) was added to a solution of 3-ethyl-1H-indazole-6-carboxylic acid methoxy-methyl-amide (0.20 g, 0.86 mmol) in THF (3 mL) and the resulting mixture stirred at room temperature for 16 hours. Ethyl acetate (30 mL) was then added and the product was extracted with 0.5 N HCl (10 mL). The aqueous layer was then re-extracted with ethyl acetate (30 mL). The organics were combined, dried, filtered and concentrated to afford 250 mg of 1,3-diethyl-1H-indazole-6-carboxylic acid methoxy-methyl-amide that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH:8]=[CH2:9])[N:5]=[C:4]([CH3:10])[C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[Na+]>O1CCCC1.O.CO>[Cl:1][C:2]1[N:6]([CH2:7][CH:8]=[CH2:9])[N:5]=[C:4]([CH3:10])[C:3]=1[C:11]([OH:13])=[O:12]
Reactant: C=CCn1nc(C)c(C(=O)OCC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCn1nc(C)c(C(=O)O)c1Cl
Temperature: 65 °C
Yield: 94.1 %

Procedure:
To a solution of 5.0 g (0.0249 mole) of ethyl 5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole-4-carboxylate (XVI) in 40 mL of tetrahydrofuran-water-methanol (3:1:1) was added 5 mL of 10 M sodium hydroxide solution. The mixture was heated at 65° C. for 4 hours and then concentrated to a smaller volume under reduced pressure. The pH was adjusted to 1-2 by the addition of hydrochloric acid. The product was collected by filtration, washed with water and dried to yield 4.7 g of 5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole-4-carboxylic acid (XVII) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[I:13]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(O)c(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Methyl 3-chloro-4-hydroxybenzoate (12.31 g) was dissolved in dichloromethane (100 mL) and methanol (12 mL), and N-iodosuccinimide (15.59 g) and trifluoromethanesulfonic acid (2 mL) were added to the solution, and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the obtained residue was'washed with water (100 mL) to obtain the title compound (20.52 g) as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.Cl.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C:24]1([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO.C(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH2:8][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[C:24]([CH3:30])([CH3:29])[CH2:25]1
Reactant: CN1CCNCC1(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CN2CCN(C)C(C)(C)C2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
A solution of (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate (267 mg, 1 mmol) and 1,2,2-trimethylpiperazine dihydrochloride (402 mg, 2 mmol) in THF (5 mL) was stirred at room temperature for 1 h and treated with sodium triacetoxyborohydride (848 mg, 4 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous solution of NaHCO3 (15 mL) and extracted with EtOAc (3×25 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (MeOH/CH2Cl2 0 to 10%) provided (S)-tert-butyl 1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamate as a white solid (186 mg, 49% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[C-:17]1([CH2:22][C:23]([OH:25])=O)[CH:21]=[CH:20][CH:19]=[CH:18]1.[CH-:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1.[Fe+2:31]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:23](=[O:25])[CH2:22][C-:17]1[CH:18]=[CH:19][CH:20]=[CH:21]1)[CH2:9][CH2:8]2.[CH-:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1.[Fe+2:31]
Reactant: O=C(O)C[c-]1cccc1
Reactant: CCCNC1CCc2cccc(OC)c2C1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCN(C(=O)C[c-]1cccc1)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A4-4 when using 360 mg (1.6 mmol) N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and 240 mg (0.99 mmol) ferrocenylacetic acid (A3-7: W=OH, Cy=ferrocenyl). Flash chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate 10/1 gave the crude product N-(8-methoxytetralin-2-yl)-N-propyl-2-ferrocenylacetamide.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:19]=[CH:18][O:17][C:16]=1[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.NCC1C=C([Si](CC)(CC)CC)OC=1>CN(C)C=O>[C:27]1([NH:33][C:34]([O:1][CH:2]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1ccoc1[Si](CC)(CC)CC
Agent: CC[Si](CC)(CC)c1cc(CN)co1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(OC(=O)Nc1ccccc1)c1ccoc1[Si](CC)(CC)CC

Procedure:
3-(1-Hydroxytridecyl)-2-triethylsilylfuran is reacted with phenyl isocyanate and copper (2) chloride in dimethylformamide to give 3-(1-phenylcarbamoyloxytridecyl)-2-triethylsilylfuran. Oxidizing the latter intermediate with singlet oxygen and thereafter reduction with sodium borohydride gives 3-(1-phenylcarbamoyloxytridecyl)-2(5H)-furanone. Substituting phenyl isocyanate with diethyl chlorophosphate, gives 3-(1-diethylphosphonooxytridecyl)-2(5H)-furanone. Substituting phenyl isocyanate with ethyl chloroformate, gives 3-(1-ethoxycarbonyloxytridecyl)-2(5H)-furanone. Substituting phenyl isocyanate with methoxyethyl chloromethyl ether, gives 3-[1-(2-methoxy)ethoxymethoxy]tridecyl-2(5H)-furanone.
Reaction SMILES: C(C1C=CC=CC=1)C.N([O:11][C:12](C)(C)[CH3:13])=O.ON1C(=O)C2=CC=CC=C2C1=O.C(=NO)(C1C=CC=CC=1)C.[N+](C(C1C=CC=CC=1)C)([O-])=O.[C:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=[O:51])[CH3:50]>C(O)(=O)C>[C:12]([O:51][CH:49]([CH3:50])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=[O:11])[CH3:13]
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)(C)ON=O
Agent: CC(=NO)c1ccccc1
Agent: CC(c1ccccc1)[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Solvent: CCc1ccccc1
Product: CC(=O)OC(C)c1ccccc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Ethylbenzene (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that acetophenone oxime, (1-nitroethyl)benzene, acetophenone, and α-methylbenzyl acetate were formed in yields of 47%, 4%, 17%, and 14%, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][CH:7]=3)[N:1]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: COc1ccc(C(N)=O)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-4-methoxy-benzamide (1.00 g, 6.01 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.28 g, 6.59 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was stirred at 115° C. for 16 hours, and cooled to room temperature. Solvent was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 hour, filtered, and dried under vacuum, to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.20 g (58%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)#[CH:19]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:19]=[CH:18]/[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=1)[C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Product: Cc1ccc2c(c1)c1c(n2/C=C/c2cccc(C(F)(F)F)c2)CC2CCCC1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (1132 mg, 5.0 mmol; Example 118A) and 1-ethynyl-3-(trifluoromethyl)benzene (1701 mg, 10.0 mmol; Aldrich) was performed according to the procedure described in Example 20 to afford the title compound as the major isomeric product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.34-1.54 (m, 2H), 1.67-1.80 (m, 2H), 1.89-2.07 (m, 2H), 2.42 (s, 3H), 2.84 (d, J=17 Hz, 1H), 3.34-3.45 (m, 1H), 3.68 (t, J=5 Hz, 1H), 4.41 (t, J=3 Hz, 1H), 6.91 (d, J=15 Hz, 1H), 7.06 (dd, J=8, 1 Hz, 1H), 7.22 (s, 1H), 7.46-7.57 (m, 2H), 7.65 (d, J=8 Hz, 1H), 7.72-7.84 (m, 3H); MS (DCI/NH3) m/z 397 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1>C1COCC1>[F:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH:60][C:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]2)=[O:17])[CH3:59])=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trans-4-(tert-Butoxycabonylamino)cyclohexanecarboxylic acid (10.2 g, 42 mmol), HATU (24 g, 63 mmol) and N,N-diisopropylethylamine (22 ml, 126 mmol) were dissolved in THF (350 ml). The reaction mixture was stirred for 30 min at room temperature, then (R)-1-(4-Fluoro-phenyl)-ethylamine 6.3 ml, 46 mmol) was added. The reaction was stirred overnight at room temperature. LCMS indicated that the reaction was complete, and it was concentrated in vacuo. The concentrate was taken up in 1M NaOH (500 ml) and EtOAc (100 ml) and was stirred for 1 hr. The precipitate that formed was collected by filtration and washed with 1M NaOH:EtOAc (4:1) and dried to give the title compound as a white solid (14.8 g, 97%). LCMS [M+H]=365.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13]2[CH:17]=[CH:16][C:15]([CH3:18])=[N:14]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13]2[CH:17]=[CH:16][C:15]([CH3:18])=[N:14]2)[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(-n2ccc(C)n2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(-n2ccc(C)n2)ccc1C(=O)O

Procedure:
A solution of 2-methoxy-4-(3-methyl-pyrazol-1-yl)-benzoic acid methyl ester (0.5 g) from Example 105 in tetrahydrofuran (2.5 ml) was treated with 1 N lithium hydroxide (2.13 ml) at room temperature. After 14 hours the solvent was removed in vacuo and the title compound precipitated by the addition at 0° C. of 1N hydrochloric acid. After drying under vacuum 0.42 g of the title compound was obtained as a solid. MS, m/z: 232 (M)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][C:28]([C:30]([NH2:32])=[O:31])=[CH:27][C:26]=3[CH:33]=2)[CH2:18][CH2:17]1)#[N:2].Cl.CC(C)=[O:37]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:37])[CH:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][C:28]([C:30]([NH2:32])=[O:31])=[CH:27][C:26]=3[CH:33]=2)[CH2:20][CH2:21]1)#[N:2]
Reactant: CC(C)=O
Reactant: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1
Agent: Cl
Solvent: CS(C)=O
Product: N#Cc1ccc2c(c1)C(CCCCN1CCN(c3ccc4oc(C(N)=O)cc4c3)CC1)C(=O)N2
Temperature: 25 °C

Procedure:
4.78 g (10 mmol) of 5-{4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl}benzo-furan-2-carboxamide are dissolved in 28.4 ml of hot DMSO. After cooling to room temperature, 66.4 ml of conc. HCl are added dropwise with stirring. The batch temperature is held at 24° C. by cooling by means of an ice bath. When the addition of HCl is complete, the batch is stirred at room temperature for 10 h. The crystal slurry is subsequently stirred with 50 ml of acetone, filtered off with suction and rinsed with acetone, isopropanol and diethyl ether. The resultant crystals were dried in air.
Reaction SMILES: I.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[F:15][C:16]1[C:29]([N:30]=[C:31]=[S:32])=[CH:28][C:19]2[N:20]([CH2:25][CH2:26][CH3:27])[C:21](=[O:24])[CH2:22][O:23][C:18]=2[CH:17]=1.CCCCCCC>C(Cl)Cl>[F:15][C:16]1[C:29]([NH:30][C:31]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]2)=[S:32])=[CH:28][C:19]2[N:20]([CH2:25][CH2:26][CH3:27])[C:21](=[O:24])[CH2:22][O:23][C:18]=2[CH:17]=1
Reactant: C1CCNNC1
Reactant: CCCN1C(=O)COc2cc(F)c(N=C=S)cc21
Agent: I
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCCN1C(=O)COc2cc(F)c(NC(=S)N3CCCCN3)cc21
Temperature: -25 °C
Reaction time: 2.5 h
Yield: 70.8 %

Procedure:
To a stirred, cold (-20° C.) solution of 11.3 g (0.0529 mole) of perhydropyridazine hydroiodide in 200 mL of methylene chloride was added 16.1 g (0.159 mole) of triethylamine. While maintaining a reaction temperature of -25° C., a solution of 12.8 g (0.0481 mole) of (7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl)isothio-cyanate in methylene chloride was added. After complete addition, the reaction mixture was stirred at -20° C. for 2.5 hours. The solvent was removed from the mixture by evaporation under reduced pressure leaving a residue. This residue was partitioned between ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving an oily solid residue. This oily solid was dissolved in methylene chloride to which was added n-heptane, causing a precipitate to form. The precipitate was collected by filtration and was dried to yield 12.0 g of N-(7-fluoro-4-propyl-2H- 1,4-benzoxazin-3(4H)-on-6yl)aminothiocar-bonylperhydropyridazine.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br>>[Br:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: BrCc1ccccc1Br
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccccc2Br)cc1

Procedure:
Analogously to Method D, 0.953 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy) propoxy]phenyl}piperidine-1-carboxylate and 0.510 g of 2-bromobenzylbromide are reacted. The title compound is obtained as a beige oil. Rf=0.31 (1:2 EtOAc-heptane); Rt=6.46.
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[O:3].[C:12]([C:15]1[C:16](=[O:26])[O:17][C:18]([OH:25])=[C:19]([C:22](=O)[CH3:23])[C:20]=1[OH:21])(=[O:14])[CH3:13]>CO>[C:12]([C:15]1[C:16](=[O:26])[O:17][C:18](=[O:25])[C:19](=[C:22]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([NH:1][C:2]([NH2:4])=[O:3])=[CH:6][CH:7]=2)[CH3:23])[C:20]=1[OH:21])(=[O:14])[CH3:13]
Reactant: NC(=O)Nc1ccc(N)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(NC(N)=O)cc2)C(=O)OC1=O

Procedure:
A solution of 1.5 g. (0.01 m.) of p-ureidoaniline in 50 ml. of methanol is added to a solution of 2.1 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy 2H-pyran-2-one in 150 ml. of methanol. A solid is formed immediately and the mixture is refluxed for 12 hours. The filtered solid is recrystallized to give 5-acetyl-4-hydroxy-3-[1-(p-ureidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 250°-253° C.