Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[N:8]=[CH:7][C:6]=1[C:17]([O:19]CC)=[O:18])#[N:4]>C(O)C>[C:3]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=2)[N:8]=[CH:7][C:6]=1[C:17]([OH:19])=[O:18])#[N:4]
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Yield: 95.2 %

Procedure:
A hot solution of 8.2 g of potassium hydroxide in 155 ml of 3A ethanol was added to a hot solution of 18.7 g of 5-cyano-1-(4-bromophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 315 ml of 3A ethanol. The salt that precipitated out of solution was dissolved in 2 l. of hot water and acidified with hydrochloric acid. The solid was collected by filtration and dried to afford 16.24 g of 5-cyano-1-(4-bromophenyl)-1H-pyrazole-4-carboxylic acid. mp=209°-211° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:12]([C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>CO>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:30][CH3:29])=[CH:6][CH:7]=2)=[C:12]([C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:23][CH:24]=1
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)cn1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc(O)cn1

Procedure:
Following the same procedure as described in example 11, step D, 6-(1-(4-(2-chloroethoxy)phenyl)-1-(4-hydroxyphenyl)but-1-en-2-yl)pyridin-3-ol (0.22 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give the desired product (Z/E=1/1). 1H NMR (400 MHz, DMSO-d6) δ 9.31 (brs, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.92-6.97 (m, 2H), 6.81 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.55-6.69 (m, 4H), 6.45 (d, J=8.4 Hz, 1H), 4.06 (t, J=5.2 Hz, 1H), 3.93 (t, J=5.2 Hz, 1H), 2.93 (t, J=5.6 Hz, 1H), 2.85 (t, J=5.6 Hz, 1H), 2.46-2.50 (m, 2H), 2.40 (s, 1.5H), 2.35 (s, 1.5H), 0.83 (t, J=7.2 Hz, 3H); m/z=391[M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH:25]=[CH:26][N:14]2[C:13]1=[O:27].S(=O)(=O)(O)O.[CH:33]([OH:35])=[O:34]>C(OCC)(=O)C.CCCCCC.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH2:25][C@@H:26]([C:33]([OH:35])=[O:34])[N:14]2[C:13]1=[O:27]
Reactant: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)Cc2ccccc2C2CCC=CN12
Reactant: O=CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C(O)[C@@H]1CCCC2c3ccccc3CC(N3C(=O)c4ccccc4C3=O)C(=O)N21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine (S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine (67 mg, 0.19 imol) and sulfuric acid (2.0 mL, 95-98%) in a pressure vessel. Add 96% formic acid (400 μL) and quickly seal the vessel. After 18 hours, open the vessel cautiously and add ice-cold water (5 mL). Extract the reaction mixture repeatedly with chloroform. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2/1/0.01 ethyl acetate/hexane/acetic acid to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(C4CCNCC4)on3)ccc21
Reactant: O=CCCCCO
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(C4CCN(CCCCCO)CC4)on3)ccc21

Procedure:
The preparation was carried out as already described starting from 130 mg of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)isoxazol-5-yl]piperidine and 79 mg of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: Cl.Cl.[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([O:38][CH3:39])=[C:10]([CH:37]=1)[CH2:11][NH:12][C@@H:13]1[C@H:18]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]2[CH2:32][CH2:33][C@H:14]1[C@@H:15]([C:34](O)=[O:35])[CH2:16]2)([CH3:5])[CH3:4].Br.[NH2:41][C@H:42]([C:44]([NH2:46])=[O:45])[CH3:43].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:44]([CH:42]([NH:41][C:34]([C@@H:15]1[C@@H:14]2[CH2:33][CH2:32][N:17]([C@@H:18]([CH:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@H:13]2[NH:12][CH2:11][C:10]2[CH:37]=[C:6]([CH:3]([CH3:4])[CH3:5])[CH:7]=[CH:8][C:9]=2[O:38][CH3:39])[CH2:16]1)=[O:35])[CH3:43])(=[O:45])[NH2:46]
Reactant: COc1ccc(C(C)C)cc1CN[C@H]1[C@H]2CCN(C[C@@H]2C(=O)O)[C@H]1C(c1ccccc1)c1ccccc1
Reactant: C[C@H](N)C(N)=O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)C)cc1CN[C@H]1[C@H]2CCN(C[C@@H]2C(=O)NC(C)C(N)=O)[C@H]1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a mixture of (3R,4S ,5S ,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid dihydrochloride (300 mg, 0.5 mmol), alaninamide hydrobromide (100 mg, 0.6 mmol) and triethylamine (70 mg, 0.7 mmol) in DMF (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.8 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, then at room temperature for 14 hours. Water and NaHCO3 were added and the mixture was extracted with CH2Cl2. The combined extracts were dried, concentrated and purified by a column chromatography on silica-gel (CH2Cl2 /methanol=10:1) to give a title compound (220 mg, 0.39 mmol, 77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:26][C:27]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][N:29]2[C:28](=[O:33])[C:27]([CH3:26])([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:31][C:30]2=[O:32])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)NC(C)(c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2′-hydroxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.158 g, 0.44 mmol), 5-methyl-5-phenylhydantoin (0.102 g, 0.53 mmol), and triphenylphosphine (0.141 g, 0.53 mmol) in THF (3 mL) was added diisopropyl azodicarboxylate (0.1 mL, 0.53 mmol), and the reaction was stirred overnight at room temperature. Once no starting material was seen by analytical LCMS, the mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25](OCC)=[O:26].CC(C)([O-])C.[K+]>C(OCC)C>[OH:16][C:14]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:25](=[O:26])[C:24]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1
Reactant: CCOC(=O)Cc1ccccn1
Reactant: COC(=O)c1cccnc1Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=c1c(-c2ccccn2)c(O)c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Yield: 78.6 %

Procedure:
To a stirred solution of 5.8 gm of methyl 2-phenylamino-3-pyridine carboxylate and 25 gm of ethyl 2-pyridylacetate there is added, portionwise, 5.7 gm of potassium tertiary butoxide under a nitrogen atmosphere. The system is heated to an internal temperature of 105° C. for 10 minutes. The reaction is cooled to room temperature, diluted with 100 ml of diethyl ether and the brown precipitate collected by filtration. The precipitate is washed with 200 ml water and the filtrate is acidified to pH 3-4 with a 15% HCl solution whereupon the product separates. The precipitate is filtered and dried to give 6.3 gm of crude 4-hydroxy-1-phenyl-3-(2-pyridyl)-1,8-naphthyridin-2(1H)one; recrystallization from pyridine yields the title product; m.p. 332°-333° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]Cl)=[CH:16][CH:15]=1>CN(C=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:21][CH2:22][CH2:23][N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][C:4]2=[O:12])=[CH:18][CH:19]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.72 g, 18 mmol) in DMF (15.0 mL) was added a solution of 1,3-dihydro-benzoimidazol-2-one (11) (2.6 g, 20.0 mmol, Aldrich) in DMF (10.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes and a solution of compound 2 (2.8 g, 10 mmol) in DMF (10.0 mL) was added. The resulting mixture was stirred at 60° C. for 4 hours. After this period, the mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL×3). The organic layer was dried with anhydrous Na2SO4 and concentrated to give a crude sample. The crude sample was purified by column chromatography using ethyl acetate/hexane gradient as an eluent to give the title compound 12. MS: m/z 379. 1H NMR (CDCl3): δ 9.41 (s, 1H), 7.10 (m, 8H), 6.92 (t, J=8 Hz, 4H), 3.93 (m, 3H), 2.07 (m, 2H), 1.73 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:4]2[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=3)[CH:7]=[CH:6][CH:5]=2)([CH2:19][F:20])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@](CF)(c2cccc(N)c2)C[C@@H](C(F)(F)F)O1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: NC1=N[C@](CF)(c2cccc(NC(=O)c3ccc(Cl)cn3)c2)C[C@@H](C(F)(F)F)O1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of (4S,6S)-4-(3-aminophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.080 g, 0.275 mmol) and 5-chloro-2-pyridinecarboxylic acid (0.048 g, 0.302 mmol) in THF/MeOH (3/1.2 mL) was stirred at room temperature and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.089 g, 0.302 mmol) was added. The reaction mixture was stirred for 30 min. The reaction was quenched with saturated NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, concentrated. The crude material was purified by column chromatographed on silica gel using 10-50% EtOAc/hexane to afford a white solid as N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)phenyl)-5-chloropicolinamide (0.075 g, 0.174 mmol, 63.4% yield). MS m/z=430.9 [M+H]+. Calculated for C18H15ClF4N4O2: 430.8
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)(=[O:23])=[O:22]>O1CCOCC1>[I:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:30][CH:27]4[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]4)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CS(=O)c1nccc(-n2nnc3c(I)cccc32)n1
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Temperature: 110 °C
Yield: 80.6 %

Procedure:
A mixture of 4-iodo-1-(2-methanesulfinyl-pyrimidin-4-yl)-1H-benzotriazole (700 mg) and 1-methanesulfonyl-piperidin-4-ylamine (642 mg) in 1,4-dioxane (20 mL) was stirred under argon, then heated at 110° C. for 4.5 h. The reaction mixture was then cooled, and the solvent removed in vacuo to provide a solid. The solid was chromatographed on silica using 0-100% EtOAc/hexanes to provide [4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl]-(1-methanesulfonyl-piperidin-4-yl)-amine (731 mg).
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]Cl>ClC1C=CC=CC=1>[Cl:18][C:9]12[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15](=[O:17])[O:16][C:1]2([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCCC1C(=O)c1ccccc1
Reactant: ClCl
Solvent: Clc1ccccc1
Product: O=C1OC(O)(c2ccccc2)C2(Cl)CCCCC12
Temperature: 59 °C
Yield: 35 %

Procedure:
23.2 g (0.1 mol) of 2-benzoyl-cyclohexanecarboxylic acid and 100 ml of chorobenzene are heated to 55° C. while stirring. Chlorine gas is then slowly introduced into the suspension over two hours while maintaining the temperature at 58-60° C. When no more starting material is detected by thin layer chromatography (TLC) analysis, the slightly yellowish solution is purged with nitrogen during one hour and subsequently cooled to room temperature. The solvent is then distilled off in vacuum to give a yellowish oil which according to TLC analysis consists of two main products. These products are isolated via preparative column chromatography on silica gel, using white spirit/ethyl acetate 1:4 as the eluant. The first fraction isolated is obtained as white solid with a melting point of 89-92° C. and is identified by 1H-NMR and elemental analysis as 3a-chloro-3-hydroxy-3-phenyl-hexahydro-isobenzofuran-1-one 9.3 g (35% yield). The second fraction is obtained as viscous yellowish oil, which is identified by 1H-NMR and elemental analysis as 3,3a-dichloro-3-phenyl-hexahydro-isobenzofuran-1-one (6.7 g, 25% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.C=O.[CH3:18]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]3[CH2:15][CH2:14][N:13]([CH3:18])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(=O)O
Reactant: Fc1ccc2nnc([C@@H]3CCNC3)n2c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CC[C@@H](c2nnc3ccc(F)cn23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 90c (225 mg, 1.09 mmol), formaldehyde (37% in water, 0.885 mL, 10.9 mmol) and AcOH (0.0625 mL, 1.09 mmol) in DCM (20 mL) and MeOH (1 mL) was added NaBH(OAc)3 (462 mg, 2.18 mmol) (CARE: gas evolution) and the pale yellow solution stirred at RT for 16 h. The solution was concentrated to 2 mL volume, then was applied to an SCX-2 cartridge and was washed with MeOH (25 mL). The product was eluted with 2M NH3 in MeOH (25 mL); concentration in vacuo left the title compound as a pale brown viscous oil (228 mg, 95%). LCMS (Method 3): Rt 0.44 min, m/z 221 [MH+].
Reaction SMILES: O1[C:6]2[CH:5]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:3](=[O:21])[C:2]1=2.[ClH:22].C(=O)([O-])O.[Na+]>CC(C)=O>[Cl:22][C:2]1[C:3](=[O:21])[C:4](=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:5]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:6]=1
Reactant: CCCCC1C(=CCCCCCC(=O)OC)C(=O)C2=C1O2
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCC1C=C(Cl)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 0.83 h
Yield: 9 %

Procedure:
300 mg (1.02 mmol) of 2,3-epoxy-4-butyl-5-(6-methoxycarbonylhexylidene)cyclopentenone was dissolved in 3 ml of acetone. 0.5 ml of concentrated hydrochloric acid was added to the solution and the mixture was stirred for 50 minutes. A saturated aqueous solution of sodium hydrogen carbonate was added thereto and was extracted with hexane. The organic layer was washed with a saturated saline solution, dried over sodium sulfate anhydride, filtrated, and subjected to column chromatography on silica gel (silica gel, 20 g; eluent, cyclohexane:ethyl acetate=10:1) to obtain 28 mg (yield 9%) of a less polar isomer (Z-form) of 2-chloro-4-butyl-5-(6-methoxycarbonyl-hexylidene)-2-cyclopentenone and 183 mg (yield 57%) of its more polar isomer (E-form).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:14])[C:5]([NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2OCC)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:36][C@H:37]1[O:41][C@@H:40]([C@H:42]([NH2:45])[CH2:43][CH3:44])[CH2:39][CH2:38]1.CCN(CC)CC>CC#N>[Cl:1][C:2]1[C:7]([S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[C:6]([OH:14])[C:5]([NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2[NH:45][C@@H:42]([C@H:40]2[CH2:39][CH2:38][C@@H:37]([CH3:36])[O:41]2)[CH2:43][CH3:44])=[CH:4][CH:3]=1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)C)c2O)c(=O)c1=O
Reactant: CC[C@@H](N)[C@H]1CC[C@@H](C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)C)c2O)c(=O)c1=O)[C@H]1CC[C@@H](C)O1

Procedure:
To a stirred solution of 253 mg of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N,N-dimethyl-benzenesulfonamide in 5 ml of dry MeCN are added 362 mg of (R)-1-((2R,5R)-5-methyl-tetrahydrofuran-2-yl)-propylamine p-toluenesulfonate salt followed by 94 μl of Et3N at rt under an inert atmosphere of nitrogen. A reaction mixture obtained is heated at reflux for 45 minutes and solvent is evaporatedA residue obtained is purified by flash chromatography on silica eluting with 30-40% EtOAc in iso-hexane. The title compound is obtained. MH+ 472.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[C:22]=1[CH3:29])=[O:17])C>>[CH:10]([S:9][C:5]1[N:4]=[C:3]([CH2:2][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH:19]3[CH2:20][CH:18]3[C:16]([OH:17])=[O:15])=[C:22]([CH3:29])[C:23]=2[CH3:28])[CH:8]=[CH:7][CH:6]=1)([CH3:12])[CH3:11]
Reactant: CC(C)Sc1cccc(CCl)n1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(C)c1C
Product: Cc1c(OCc2cccc(SC(C)C)n2)ccc(C2CC2C(=O)O)c1C
Yield: 83.1 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.030 g, 0.149 mmol) obtained in Step C of Preparation Example 16 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.046 g, 83%).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([N:25]3[CH:29]=[N:28][N:27]=[N:26]3)[CH:22]=[C:21]([C:30](O)=[O:31])[CH:20]=2)=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.[CH3:50][C@H:51]([NH2:59])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(Cl)Cl>[CH3:50][CH:51]([NH:59][C:30]([C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH:24]=[C:23]([N:25]2[CH:29]=[N:28][N:27]=[N:26]2)[CH:22]=1)=[O:31])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1
Reactant: C[C@H](N)CN1CCOCC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3cnnn3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NC(C)CN3CCOCC3)cc(-n3cnnn3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
EDCI (54.0 mg, 0.282 mmol) was added in one portion at 0° C. to a solution of 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid (60.0 mg, 0.214 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.000 mmol) in CH2Cl2 (3 mL). After the reaction stirred at 0° C. for 1 hour, (S)-1-Methyl-2-morpholin-4-yl-ethylamine (50.0 mg, 0.230 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to afford 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)-amide as a white solid (70 mg, 81%). MS (M+H)=407.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH2:8]O)[CH:7]=1.[Br-:20].[C:21]1([PH+:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[Br-:20].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH:7]=1)[CH2:8][P+:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(CCc2ccc(F)cc2CO)cc1
Agent: [Br-]
Solvent: CC#N
Product: COc1ccc(CCc2ccc(F)cc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 5.95 g (22.86 mmol) of {5-fluoro-2-[2-(4-methoxyphenyl)ethyl]phenyl}methanol in 130 ml of acetonitrile is mixed with 7.45 g (21.71 mmol) of triphenylphosphonium bromide and heated under reflux for 3 hours. The reaction solution is then concentrated to dryness, and the resulting oil is triturated in diethyl ether. The product crystallizes as a white solid during this. After filtration, the solid is dried in a drying oven at 50° C. overnight. 11.5 g (77% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH2:18][C@H:17]1[CH:20]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1CNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 4-chloro-aniline (0.57 g, 4.5 mmol) in methanol (18 ml) were added acetic acid (2 ml), (S)-2-formyl-azetidine-1-carboxylic acid tert.butyl ester (1.74 g, 9.4 mmol) and after 15 min stirring sodium cyanoborohydride (0.57 g, 9.0 mmol). The resulting suspension was stirred for 2 hours at room temperature. Aqueous sodium bicarbonate solution (20 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=9:1) to yield a colourless oil (0.99 g, 74%); MS (ISP): 297.1 ((M+H)+.); 241.3 ((M−C(CH3)3+H)+.).