Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14]O)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:40])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][F:40])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCO)c1=O)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: ClCCl
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCF)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
50 mg (0.10 mmol) of 2-[3-(4-chlorophenyl)-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 396 are dissolved in 1.5 ml of dichloromethane and treated at −10° C. with 20.5 μl (0.155 mmol) of diethylaminosulphur trifluoride. This is warmed to RT within 1 hr. Next, the reaction solution is treated with 5 ml of water and extracted twice with 5 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 37 mg (73% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:28][CH3:29])=[CH:19][C:20]([CH3:27])=[C:21]([CH:26]=3)[C:22]([O:24]C)=O)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:30][NH2:31]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]([CH2:28][CH3:29])=[CH:19][C:20]([CH3:27])=[C:21]([CH:26]=3)[C:22]([NH:30][NH2:31])=[O:24])=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1cc(C)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: NN
Solvent: CCO
Product: CCc1cc(C)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate (compound 211.7, 500 mg, 1.28 mmol, 1.00 equiv) in ethanol (20 mL). Hydrazine (4 mL) was added to the reaction mixture. The resulting solution was stirred for 15 h at 80° C., then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield 400 mg (80%) of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazide as a light yellow solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11]1[S:15][C:14]2=[N:16][CH:17]=[C:18](I)[N:13]2[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>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.C(COC)OC>[CH2:3]([NH:10][C:11]1[S:15][C:14]2=[N:16][CH:17]=[C:18]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=3)[N:13]2[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Ic1cnc2sc(NCc3ccccc3)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COc1ccc(-c2cnc3sc(NCc4ccccc4)nn23)cc1OC
Temperature: 90 °C
Yield: 52.8 %

Procedure:
An aqueous solution of NaOH (1.00 ml) was added to a mixture of benzyl-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-amine (250.00 mg; 0.70 mmol; 1.00 eq.), 3,4-dimethoxyphenylboronic acid (191.59 mg; 1.05 mmol; 1.50 eq.), Pd(PPh3)4 and dimethoxyethane (5.00 ml) under N2. The resulting suspension was heated in the microwave at 90° C. for 30 minutes under N2. The reaction was filtered, washed with dimethoxyethane, water and dried at 40° C. for 18 h. 135.5 mg of the desired product were obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[C:11]([NH2:14])(=[O:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[C:7]([O:8][CH2:12][C:11]([NH2:14])=[O:13])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: CC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)COc1cccnc1Br
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 2-bromo-3-pyridinol (1.5 g, 8.49 mmol) in tetrahydrofuran (15 mL) at 0° C. is added 60% sodium hydride in mineral oil (509.44 mg, 12.74 mmol) and the mixture is stirred at that temperature for 30 min. Then acetamide, 2-chloro-(16.98 mmol) is added and the mixture is stirred at room temperature over the weekend. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is separated dried on magnesium sulfate and the solvent evaporated in vacuo to give the title compound in a 75% yield. The compound is used without any further purification. MS (m/z): 231 (M+1), 233 (M+3).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][C:7]1[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=1[O:9][CH2:10][CH:11]1[NH:15][CH2:14][CH2:13][S:12]1>ClCCCl>[Cl:1][CH2:2][C:3]([N:15]1[CH2:14][CH2:13][S:12][CH:11]1[CH2:10][O:9][C:8]1[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=1[OH:6])=[O:4]
Reactant: Oc1ccccc1OCC1NCCS1
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Product: O=C(CCl)N1CCSC1COc1ccccc1O
Temperature: -30 °C

Procedure:
Chloroacetylchloride (2.5 ml) is added to a stirred solution of 2-[(o-hydroxyphenoxy)methyl]thiazolidine (6 g) in 1,2-dichloroethane (80 ml) and triethilamine (4.3 ml) cooled at -30° C. After the usual work-up 3-αchloroacetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (5.7 g, from Et2O, m.p. 89°-91° C.) is obtained. A stirred solution of the latter compound in 1,2-dichloroethane (50 ml) is heated with solid potassium thioacetate (4 g). After 2 hours, the mixture is washed with water to give, after the usual work-up, 3-acetylthio-acetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (6.4 g, from EtOH) m.p. 97°-99° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[N:13]O)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CO.N.[H][H]>CCO.[Ni]>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([NH2:13])[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CC(=NO)c1ccc2ncccc2c1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCO
Product: CC(N)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 1-quinolin-6-yl-ethanone oxime (4.54 g, 24.4 mmol) in EtOH (50 mL) was added methanol solution of NH3 (7N, 12 mL, 80 mmol). A slurry of Raney Nickel (washed 3× with EtOH) about 2 g was added followed by a hydrogen-filled balloon. The reaction was stirred at ambient temperature for 16 hours under hydrogen-filled balloon. The reaction mixture was filtered over a pad of celite and the mother liquor was concentrated to give quantitative 1-quinolin-6-yl-ethylamine (4.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([F:12])=[CH:7]2.[Cl-].C([O:18][C:19](=[O:22])[CH2:20][Zn+])(C)(C)C.[OH-].[Na+].CO>O1CCOCC1>[F:12][C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:20][C:19]([OH:22])=[O:18]
Reactant: Fc1cnc2c(Br)cccc2c1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)Cc1cccc2cc(F)cnc12

Procedure:
The title compound was prepared from 8-bromo-3-fluoroquinoline (568 mg, 2.51 mmol) and 0.5 M (2-Tert-butoxy-2-oxoethyl)zinc(II) chloride according to Protocol P, accept that the ester was converted to the acid using NaOH and MeOH in dioxane. Method [7] retention time 2.39 min by HPLC (M+=206).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH3:8].[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C)C=O.O>[C:12]([C:11](=[C:15]([OH:17])[CH3:16])[C:10]([O:9][CH2:7][CH3:8])=[O:14])#[N:13]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)=C(C)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcyanoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3×100 ml). Combined organic layer was washed with saturated sodium carbonate solution (3×100 ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3×100 ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:23][CH3:24])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]([F:22])[F:21])[CH:11]=3)=[CH:4][CH:3]=1.[CH2:25]([N:28]=[C:29]=[O:30])[CH2:26][CH3:27].C(N(CC)CC)C>ClCCCl>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH:20]([F:22])[F:21])=[CH:13][CH:14]=2)[N:9]([CH2:23][CH3:24])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]([NH:28][CH2:25][CH2:26][CH3:27])=[O:30])=[CH:3][CH:4]=1)#[N:18]
Reactant: CCCN=C=O
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC(F)F)cc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCNC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC(F)F)cc3n2CC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-(4-aminophenyl)-6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile (200 mg, 0.611 mmol) in 1,2-dichloroethane (2 mL) is treated with n-propylisocyanate (115 mL, 1.23 mmol) and triethylamine (170 mL, 1.22 mmol). The resulting solution is stirred at ambient temperature for 12 hours, and then concentrated. The residual material is separated by silica gel chromatography (1/2 ethyl acetate-hexane) to afford the title product as a solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[C:12]([C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27](OCC)=[O:28].[O-]CC.[Na+].Cl>C(O)C>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[C:12]([C:14]1[CH:22]=[C:21]2[C:17](/[C:18](=[CH:27]/[OH:28])/[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=O
Reactant: O=C1Cc2ccc(C(=O)c3cccc(NCc4ccccc4)c3)cc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cc(C(=O)c3cccc(NCc4ccccc4)c3)ccc2/C1=C/O
Temperature: 78 °C
Yield: 33.5 %

Procedure:
6-[3-(benzylamino)benzoyl]-1,3-dihydro-2H-indol-2-one (0.057 g, 0.167 mmol) and ethyl formate (0.040 mL, 0.500 mmol) were dissolved in anhydrous ethanol (1.67 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.310 mL, 0.833 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. The reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered yielding 6-(3-Benzylamino-benzoyl)-3-[1-hydroxy-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one as an orange solid (0.021 g, 0.056 mmol, 34%) which was carried on without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][CH:11]=2)=[NH:10])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)c1ccc(C#N)cc1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=N)c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 60 %

Procedure:
The title compound was prepared from 4-methylsulfonylbenzonitrile (5.43 g, 30 mmol) and 4-isopropylaniline (4.05 g, 30 mmol) by following the procedure described in preparation 1 (5.66 g, yield 60%, purity 88% by HPLC). 1H-NMR (CDCl3):δ 1.25-1.27 (d, 6H), 2.9-2.95 (m, 1H), 3.07 (s, 3H), 4.92 (bs, 2H, D2O exchangeable), 6.90-6.92 (d, 2H), 7.23-7.26 (d, 2H), 8.01-8.03 (d, 2H), 8.08-8.1 (d, 2H). MS m/z:317.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[O:19]1[CH2:24][CH2:23]OCC1>[Ni]>[CH2:12]([NH:11][C:4]1[N:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[N:8]=[CH:17][C:18]([C:13]1[CH:12]=[CH:23][C:24]([OH:19])=[CH:15][CH:14]=1)=[N:1]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1COCCO1
Reactant: Nc1nc(NCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Product: Oc1ccc(-c2cnc3ccc(NCc4ccccc4)nc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
2-Amino-6-benzylamino-3-nitropyridine (25 g, 0.10 mol) was hydrogenated under 5.5 bar of H2 in the presence of 10 g of Raney-Ni in 400 mL of dioxane at 60 C. After 2 hours the reaction mixture was cooled to room temperature, filtrated and 4-hydroxy phenylglyoxal was added and stirred for 2 hours under an argon atmosphere. The suspension was then diluted with water, the solid was collected by filtration, washed with water, recrystallized from 2-propanol, and dried at 50 C. in vacuo to give 6-benzylamino-3-(4-hydroxyphenyl)-5-azaquinoxaline (8 g, 24.4%, m.p. 271-273 C.).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[N:26][NH:25][C:24]4=[O:28])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl[CH2:30][C:31](=[O:33])[CH3:32]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[N:26][N:25]([CH2:30][C:31](=[O:33])[CH3:32])[C:24]4=[O:28])=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[CH:7][CH:6]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(CC(C)=O)c4=O)cc3)CC2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 1.6 %

Procedure:
Reaction under N2 atmosphere. NaH 60% (0.12 mol) was added to 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.1 mol) in DMF, and stirred for 30 minutes at 50° C. A solution of 1-chloro-2-propanone (0.1 mol) in DMF was added dropwise and the resulting reaction mixture was stirred overnight at 50° C. The reaction mixture was cooled, poured out into ice-water and the resulting precipitate was filtered off, washed with water, and dried. This fraction was recrystallized from CH2Cl2/CH3OH. The precipitate was filtered off and the filtrate was evaporated. The residue was crystallized from methanol, filtered off and dried. The residue was combined with the crystallized compound, recrystallized from CH2Cl2/CH3OH, filtered off and dried, yielding 0.65 g of 2,4dihydro-4-[4-[4-(4-methoxy-phenyl)-1-piperazinyl]phenyl]-2-(2-oxopropyl)-3H-1,2,4-triazol-3-one (interm. 20).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C([Sn]([N:53]=[N+:54]=[N-:55])(CCCCCCCC)CCCCCCCC)CCCCCCC.C1(C)C=CC=CC=1>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:55][N:54]=[N:53][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCCCCCC[Sn](CCCCCCCC)(CCCCCCCC)N=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
A mixture of 5 g of 2-butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole, 30.2 g of trioctyltin azide (tri-n-octyltin azide), 25 ml of toluene and 1 ml of dimethylformamide was stirred for 24 hours at 115° C. in nitrogen streams. The reaction mixture was, after cooling, concentrated, and there were added 40 ml of ethanol and a solution of 5.2 g of sodium nitrite in 19 ml of water, whose pH was adjusted at 3.4 with conc. hydrochloric acid. The resultant mixture was subjected to extraction with methylene chloride, and the extract was concentrated under reduced pressure. To the concentrate was added hexane, then resulting crystalline precipitates were collected by filtration. The crystals were washed with hexane, then dried to afford 5.27 g (yield 94.7%) of 2-butyl-4-chloro-5-(hydroxymethyl)-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole. The NMR spectrum of the product was in good agreement with that described in J. Med. Chem., 1991, 34, 2525.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13](N)[C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)[CH2:3]1.N1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[C:27]([F:35])[CH:26]=1>C(Cl)Cl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([C:13]2[N:14]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:32])=[O:33])=[C:27]([F:35])[CH:26]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1S(=O)(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Yield: 38.8 %

Procedure:
6-[(3R,5S)-3,5-Dimethyl-1-piperazinyl]-3-(methyloxy)-2-pyridinamine (D7, Method D) (2.25 mmol) was dissolved in DCM (5 mL) and pyridine (5 mL) and then cooled to 0° C. 4-Bromo-2-fluoro benzenesulfonyl chloride (0.738 g, 2.706 mmol), dissolved in DCM (5 mL) was then added dropwise and the reaction then allowed to warm to rt overnight. The reaction was then evaporated to a minimum and redissolved in DCM (100 mL) and washed with water (2×75 mL), saturated sodium hydrogen carbonate (3×75 mL) and brine (75 mL). The organic layer was dried (MgSO4) and evaporated to give a brown oil which was triturated with methanol and dried at 50° C. under high vac to give the title compound as a pale brown powder (D18) (0.400 g). MS (ES+) m/e 473/475 [M+H]+.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.C([Li])CCC.C1(O[C:36]#[N:37])C=CC=CC=1.[OH-].[Na+]>O1CCCC1.CCCCCC>[CH2:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]#[C:2][C:36]#[N:37])=[CH:5][CH:6]=2)[CH2:13][CH2:14]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: N#COc1ccccc1
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C=C(Br)Br)cc2)CC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C#CC#N)cc2)CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A solution of 1.55 g of β,β-dibromo-p-[2-(trans-4-pentylcyclohexyl)ethyl]styrene in 35 ml of absolute tetrahydrofuran was placed at about -45° C. in a sulphonation flask under argon gasification and treated within 5 minutes with 8.8 ml of a 1.2N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at the same temperature for a further 90 minutes, then cooled to -78° C. and treated with 0.79 ml of phenyl cyanate. The mixture was subsequently stirred at -78° C. for a further 3 hours, then poured into 50 ml of 1N sodium hydroxide and extracted three times with 50 ml of diethyl ether/petroleum ether (1:1) each time. The organic phases were washed with 50 ml of 1N sodium hydroxide and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (1.17 g) on silica gel with hexane followed by 3% ethyl acetate/petroleum ether gave 740 mg (69%) of p-[2-(trans-4-pentylcyclohexyl)ethyl]phenylpropiolonitrile as colourless crystals (purity 97.3%) which were recrystallized further from methanol; m.p. (C-N) 36.7° C., cl.p. (N-I) 105.5° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][CH3:7])([CH3:4])[CH3:3].C([Li])CCC.[Si:13]([O:20][CH:21]1[CH2:25][C:24](=[O:26])[CH:23]=[CH:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>O1CCCC1.CCCCCC>[Si:13]([O:20][CH:21]1[CH2:25][C:24]([OH:26])([CH2:7][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:23]=[CH:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1C=CC(O)(CC#C[Si](C)(C)C)C1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution mixture of 6.5 g of trimethylsilyl-1-propyne and 50 ml of tetrahydrofuran was added under nitrogen stream and at -30° C. 17.4 ml of 1.56 M hexane solution of n-butyllithium and the resulting mixture was stirred at the same temperature for 1 hour. Then, a solution mixture of 10 g of (RS)-4-oxo-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether and 100 ml of tetrahydrofuran was added by drops to the reaction solution obtained above, and the resulting mixture was stirred for further one hour. The reaction liquid thus obtained was after-treated and purified in the same manner as in (2) of the intermediate preparation example 1 to obtain 8.9 g of (1RS,4RS)-4-hydroxy-4-(3-trimethylsilyl-2-propynyl)-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 59%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][OH:23])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC(CC(=O)Nc1ccc(Cl)cc1)c1ccc(Cl)c(Cl)c1
Yield: 89.8 %

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-(4-chlorophenyl)benzenepropanamide (3.5 g) in CH2Cl2 (60 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (1.19 g), and methanesulfonyl chloride (1.35 g). After two hours the reaction mixture was washed with water (3×50 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[S-:13][C:14]#[N:15].[Na+].BrBr.O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([S:13][C:14]#[N:15])=[CH:11][N:12]=1
Reactant: c1ccc(Nc2nccs2)nc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CSc1cnc(Nc2ccccn2)s1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a suspension of N-(pyridin-2-yl)thiazol-2-amine (4.26 g, 24 mmol) and sodium thiocyanate (3.9 g, 48 mmol, 2 eq) in methanol (100 mL) at 0° C., was slowly added bromine (1.23 mL, 24 mmol, 1 eq) over 2 min, then the temperature was raised to 23° C. and the mixture was stirred for 3 h. The resulting suspension was added to stirring cold water (400 mL) and the resulting precipitate was collected by filtration and vacuum dried (4.5 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.00-7.08 (1 H, m), 7.11 (1 H, d, J=8.34 Hz), 7.74-7.84 (1 H, m), 7.89 (1 H, s), 8.39 (1 H, d, J=5.05 Hz), 11.93 (1 H, s). LC/MS (M+H)+: 235.