Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:12][C:13](=[NH:16])[O:14][CH3:15])([O:10][CH3:11])=[O:9].[CH:17]1([NH:23][S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1.C(Cl)Cl>[C:8]([N:12]([S:24](=[O:26])(=[O:25])[NH:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13](=[NH:16])[O:14][CH3:15])([O:10][CH3:11])=[O:9]
Reactant: COC(=N)NC(=O)OC
Reactant: O=S(=O)(Cl)NC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=N)N(C(=O)OC)S(=O)(=O)NC1CCCCC1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
Triethylamine (112 g) is added to a stirred solution of N-carbomethoxy-O-methylisourea (132.1 g) in anhydrous THF (900 ml). The solution is cooled to -70° C. under an N2 atmosphere and solution of cyclohexylsulfamoyl chloride (198 g) in anhydrous THF (400 ml) is added dropwise to the reaction mixture. The reaction mixture is warmed to RT filtered through Celite®, washed with anhydrous THF and evaporated to yield an oil which is taken up in methylene chloride, washed with 0.5N HCl and allowed to stand overnight. The organic layer is washed with 0.5N HCl, dried, filtered, washed with methylene chloride, evaporated and dried under high vacuum affording the desired product as an oil which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:17])=[N:12][CH2:11][CH2:10]2)=[O:5])[CH3:2]>[C].[Pd].CC1C=CC(C(C)C)=CC=1>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:17])=[N:12][CH:11]=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1ccc2c(c1)CCN=C2C
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: CCOC(=O)Nc1ccc2c(C)nccc2c1
Temperature: 195 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To 6-ethoxycarbonylamino-1-methyl-3,4-dihydroisoquinoline were added p-cymene (100 ml) and palladium-carbon (0.9 g), followed by heating under stirring at 195° C. in nitrogen atmosphere for 1 hour. After filtering off the catalyst, the reaction mixture was washed with ethanol and a part of the filtrate was evaporated. The residue was extracted with 1N hydrochloric acid, and then basified with potassium carbonate, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound (0.629 g, 69%, 2 steps) as pale yellow crystals.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(OCC)C>[O:4]=[C:1]([N:16]1[CH2:17][CH2:18][N:13]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][CH2:15]1)[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 13 %

Procedure:
A solution of acryloyl chloride (4.52 g, 0.05 mole) in 25 ml of ethyl ether was added to a cold solution of 1-benzylpiperazine (8.8 g, 0.05 mole) and triethylamine (30 ml, 0.20 mole) in 500 ml of ethyl ether. A white precipitate formed. The reaction mixture was stirred overnight, filtered and the precipitate washed well with ethyl ether. The solvent and triethylamine were removed and the product chromatrographed on silica, eluting with ethyl acetate/hexane [30:70(v/v)] to yield 1.5 g of the title compound. The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=O.CO.[H][H]>[Ni].[Pd].C(O)(=O)C>[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: [H][H]
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(O)cc1O
Temperature: 72.5 °C
Reaction time: 8 h

Procedure:
2,4-Dihydroxy acetophenone (76 g, 0.5 mole) was charged in a 1 liter autoclave reactor along with methanol (300 ml), acetic acid (5 ml), and Raney Nickel (15.2 g washed several times with water and water/methanol) and 750 mg of Pd/C. The pH of the system was 5.0. The autoclave was checked for leaks with nitrogen. The autoclave was pressurized to 500 psi with hydrogen and stirred at 70-75° C. up to 8 hrs. During this time 97% of the theoretical value for hydrogen was consumed. The reaction was vented and the contents were filtered through a milipore filter to give a yellow solution. Concentration of this solution in vacuo gave a solid. This solid was crystalized from 1,2-dichloroethane to give 4-ethyl resorcinol in 85% isolated yield. The unreacted 2,4-dihydroxy acetophenone was recovered (−13%) from the reaction mixture and was recycled. The structure of 4-ethyl resorcinol and 2,4-dihydroxy acetophenone were characterized by NMR (see FIG. 1), Gas Chromatography (see FIG. 2), IR (See FIG. 3) and Mass spectroscopy. The mass spectroscopy indicated that the mass was 138.
Reaction SMILES: [CH3:1][N:2]1[S:7](=[O:9])(=[O:8])[NH:6][C:5]([O:10][CH3:11])=[N:4][C:3]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:14].P(Cl)(Cl)(Cl)=O>>[Cl:14][C:3]1[N:2]([CH3:1])[S:7](=[O:9])(=[O:8])[N:6]=[C:5]([O:10][CH3:11])[N:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC1=NC(=O)N(C)S(=O)(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: COC1=NS(=O)(=O)N(C)C(Cl)=N1
Temperature: 110 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
215 parts of 6-methyl-3-methoxy-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide were introduced into a stirred mixture of 275 parts of phosphorous pentachloride in 1,480 parts of phosphorus oxychloride at room temperature, and the batch was heated to 110° C. in the course of 30 minutes. After 4 hours' stirring under reflux, the reaction mixture was concentrated under reduced pressure, giving 235 parts (99.6% of theory) of 5-chloro-6-methyl-3-methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide, of melting point 77°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[CH:11].C(N(CC)CC)C.C1COCC1>C(#N)C.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:11]#[C:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1cc(Cl)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cc(Cl)cc(C#Cc2ccccc2)n1

Procedure:
A mixture of 4,6-dichloropyridin-2-amine (2.0 g, 12.3 mmol), ethynylbenzene (2.51 g, 24.5 mmol), copper(I) iodide (234 mg, 1.23 mmol), Dichlorobis(triphenylphosphine)-palladium(II) (1.0 g, 1.23 mmol) and triethylamine (4.3 ml, 31 mmol) is stirred under argon atmosphere in ACN (20 ml) with THF (10 ml) for 6 h at 90° C. The mixture is diluted with water and extracted with EtOAc. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product purified by NP chromatography. Yield: 1.2 g (43%). HPLC-MS: M+H=229; tR=1.96 min (*Method—2).
Reaction SMILES: CC1C([N+]([O-])=O)=C(C=CC=1)C(OCC=C)=O.[CH3:17][C:18]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[C:19]=1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>>[NH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:18]([CH3:17])[C:19]=1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]
Reactant: C=CCOC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: C=CCOC(=O)c1cccc(C)c1[N+](=O)[O-]
Product: C=CCOC(=O)c1c(C)cccc1N

Procedure:
The above nitro compound was reduced by the method described in example 6, for the reduction of allyl 2-methyl-6-nitrobenzoate, to give allyl 2-amino-6-methylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.B.C1COCC1.Cl>O1CCCC1>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
Step A To the solution of 4-chloro-2,5-difluorobenzoic acid (Oakwood) (6.08 g, 31 mmol) in anhydrous tetrahydrofuran (75 mL) at 0° C. was added a solution of BH3.THF (1 M, 62 mL, 62 mmol). The reaction mixture was stirred at room temperature for 18 h. Aqueous HCl solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give (4-chloro-2,5-difluoro-phenyl)-methanol as a colorless oil (5.5 g, 98%).
Reaction SMILES: [N+](C1C=CC(C(O[CH:11]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH:15]([CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:14]([CH2:34][O:35][C:36](=[O:46])[C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)[CH2:13][O:12]2)=O)=CC=1)([O-])=O.[F:49][C:50]([F:65])([F:64])[C:51]1[CH:52]=[C:53]([C@H:61]([OH:63])[CH3:62])[CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[N+:43]([C:40]1[CH:41]=[CH:42][C:37]([C:36]([O:35][CH2:34][C@@H:14]2[C@@H:15]([CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[C@@H:11]([O:63][C@@H:61]([C:53]3[CH:52]=[C:51]([C:50]([F:64])([F:65])[F:49])[CH:56]=[C:55]([C:57]([F:58])([F:59])[F:60])[CH:54]=3)[CH3:62])[O:12][CH2:13]2)=[O:46])=[CH:38][CH:39]=1)([O-:45])=[O:44]
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc(F)ccc1C1C(OC(=O)c2ccc([N+](=O)[O-])cc2)OCC(COC(=O)c2ccc([N+](=O)[O-])cc2)C1COCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@H](COC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1COCc1ccccc1
Temperature: -25 °C

Procedure:
The intermediate from step F (6.17 g, 9.36 mmol) was combined with (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (2.53 g, 9.83 mmol) and dissolved in 100 mL DCM. The vessel was cooled to −25° C. followed by the addition boron trifluoride etherate (0.23 mL, 1.87 mmol). The reaction vessel was maintained at −25° C. for 1 hr. The reaction was quenched by the addition of a saturated solution of NaHCO3 and the mixture was allowed to warm to ambient temperature. The aqueous mixture was extracted several times with EtOAc and washed with brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude residue was purified on silica gel and eluted with tBuOMe/hexanes=10 to 14%. The first component collected off the column was the desired diastereomer. (M+Na)+772
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6]C(=O)[O:8][C:9](=O)[C:4]=2[CH:3]=1.[CH3:14][NH2:15]>C(O)C>[NH2:6][C:5]1[CH:12]=[CH:13][C:2]([OH:1])=[CH:3][C:4]=1[C:9]([NH:15][CH3:14])=[O:8]
Reactant: CN
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Solvent: CCO
Product: CNC(=O)c1cc(O)ccc1N
Reaction time: 72 h
Yield: 60.2 %

Procedure:
A solution of 6-hydroxy-1H-benzo[d][1,3]oxazine-2,4-dione (500 mg, 2.79 mmol) in ethanol (20 mL) was cooled to 0° C. and methylamine solution (33% in ethanol, 2.92 mL, 27.9 mmol) added and the reaction stirred for 3 days. The solvent was removed under reduced pressure and the product purified by silica chromatography, eluent 5% methanol in dichloromethane to yield 2-amino-5-hydroxy-N-methylbenzamide (280 mg, 1.68 mmol).
Reaction SMILES: II.Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[C:13]1[N:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1>C1COCC1.[Cl-].[NH4+].[Zn].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>[CH3:9][C:8]([O:7][C:5](=[O:6])[CH2:4][C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(C#N)cn1
Temperature: 110 °C
Yield: 43.1 %

Procedure:
0.715 g (10 mmol) of zinc, a few flakes of iodine and 0.845 ml (5.4 mmol) of t-butyl bromoacetate in 10 ml of THF are introduced into a microwave reactor. The mixture is heated by microwaves for 5 min at 110° C. and then filtered and added to a solution of 0.5 g (2.7 mmol) of 6-bromo-3-pyridinecarbonitrile in 15 ml of THF. 316 mg of tetrakis(triphenylphosphine)palladium are added and the reaction mixture is heated by microwaves at 120° C. for 5 min, with stirring, and then cooled, diluted with ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel using a methylcyclohexane/ethyl acetate mixture (9/1; v/v) as the eluent to give 254 mg of the expected product in the form of a yellow solid (yield=43%).
Reaction SMILES: [CH2:1]([Sn:5]([N:14]=[N+:15]=[N-:16])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:17]([CH2:19][C:20]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])([OH:27])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)#[N:18]>>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:20]([OH:27])([CH2:19][C:17]1[N:16]=[N:15][N:14]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[N:18]=1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Product: CCCC[Sn](CCCC)(CCCC)n1nnc(CC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)n1
Yield: 73.2 %

Procedure:
A paste of tri-n-butyltin azide (2.45 g) and 1-cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (2.0 g) was heated at 160° C. for three hours. A further quantity of tri-n-butyltin azide (0.2 g) was added and the heating continued for a further hour to complete the reaction. The resulting viscous oil was triturated with ethyl acetate and the product collected and dried under vacuum to give 2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(2-tribut-1-ylstannyltetrazol-5-yl)propan-2-ol as a crystalline solid (3.1 g, 73%) m/e 628.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]=1.[I:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C[O-].[Na+].[BH4-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH2:19][C:18]3[CH:21]=[CH:22][C:15]([I:14])=[CH:16][CH:17]=3)=[C:5]2[C:4](=[O:13])[N:3]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: NCC1=C2C(=O)N=C(N)N=C2N=C1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC1=NC(=O)C2=C(CNCc3ccc(I)cc3)C=NC2=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
In 40 ml of dry methanol were suspended 126 mg of 2-amino-5-aminomethylpyrrolo[2,3-d]pyrimidin-4-one (dihydrochloride) and 116 mg of p-iodobenzaldehyde. After addition of 1 N methanolic sodium methoxide, the mixture was stirred at room temperature for 30 min. To this mixture was added 76 mg of sodium borohydride and the reaction was conducted at room temperature for 15 min. The reaction was then terminated by addition of 500 mg silica gel. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography to give 121 mg of the desired compound.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[CH2:40]([N:42](CC)[CH2:43]C)C.CN(C)C(Cl)=O>C(Cl)Cl>[CH3:40][N:42]([CH3:43])[C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: CCN(CC)CC
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To a solution of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (250 mg, 0.52 mmol) in DCM (4.5 mL) was added TFA (0.5 mL). The reaction mixture stirred at RT for 1 h, then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH, and concentrated in vacuo. The resultant residue was dissolved in DCM (6 mL) and triethylamine (0.48 mL, 3.28 mmol) was added. The reaction mixture was cooled to 0° C. then a solution of dimethylcarbamoyl chloride (57 μL, 0.615 mmol) in DCM (0.5 mL) was added. The reaction mixture was stirred at RT for 1 h, then partitioned between water and DCM. The organic layer was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a colourless oil (55 mg, 24%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:17]2[N:18]=[CH:19][N:20]=[CH:21][C:16]=2[C:15](I)=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23]1([C:29](=[N:36][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:48]=2)[C:42](N(OC)C)=[O:43])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Si:1]([O:8][CH2:9][C:10]([N:13]1[C:17]2[N:18]=[CH:19][N:20]=[CH:21][C:16]=2[C:15]([C:42]([C:41]2[CH:40]=[N:39][CH:38]=[C:37]([N:36]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:48]=2)=[O:43])=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncnc21
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 24 using 7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 15) and 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (see Preparation 23) to afford the title compound as a colourless gum in 56% yield, 1.49 g.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[CH:10]=[O:11].[Cl:12][C:13]1[CH:14]=[C:15]([SH:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[C:15]([S:20][C:2]2[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=2[CH:10]=[O:11])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: CCn1nc(C)c(C=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C)c(C=O)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
A mixture of 9.2 g of 5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde, 14.3 g of 3,5-dichlorothiophenol and 11.8 g of potassium carbonate in 40 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 100° C. for 18 hours. Water (200 ml) was added and the mixture was extracted three times with 100 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/petroleum ether (bp 40–60° C.) for the elution to give 12.2 g of 5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde as an orange solid. Mass spectrum (ES) m/z 356 [M+CH3CH+H]+.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH:34]2[CH2:41][CH2:40][CH2:39][CH:38]([OH:42])[CH2:37][CH2:36][CH2:35]2)=[CH:28][CH:27]=1>ClCCl.CCOCC>[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH:34]2[CH2:41][CH2:40][CH2:39][C:38](=[O:42])[CH2:37][CH2:36][CH2:35]2)=[CH:28][CH:27]=1
Reactant: COCOc1ccc(CCC2CCCC(O)CCC2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COCOc1ccc(CCC2CCCC(=O)CCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
1.65 g of pyridinium dichromate was dissolved in 30 ml of dichloromethane. To the solution was added 0.40 g of 5-[2-(4-methoxymethoxyphenyl)ethyl]-1-cyclooctanol prepared in Reference Example 2. The reaction solution was stirred at room temperature for two hours. To the reaction solution was added another 2.5 g of pyridinium dichromate. The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with 50 ml of ether and purified on Florisil column eluted with ether, to afford 0.37 g of the titled compound as colorless liquid.
Reaction SMILES: [C:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:15][CH:16]([CH3:20])[C:17](Cl)=[O:18].[Al+3].[Cl-].[Cl-].[Cl-]>>[C:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([C:17](=[O:18])[CH:16]([Cl:15])[CH3:20])=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(=O)N1CCCCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCCCc2cc(C(=O)C(C)Cl)ccc21

Procedure:
Analogously to Example 1, 5-(2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)-6-methyl-3,6-dihydro-1,3,4-thiadiazin-2-one ("E"), m.p. 142°, is obtained from 7-(2-chloropropionyl)-2,3,4,5-tetrahydro-1H-1-benzazepin [obtainable by reaction of 1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-chloropropionyl chloride/AlCl3 to give 1-acetyl-2,3,4,5-tetrahydro-7-(2-chloropropionyl)-1H-1-benzazepine (in addition, the 8-(2-chloropropionyl) isomer is obtained, which can be separated chromatographically) and subsequent removal of the acetyl group with HCl].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:37])[C@@H:23]([NH2:36])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)(=[O:17])[CH3:16].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:37])[C@@H:23]([NH:36][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:14][CH:13]=1)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=1)(=[O:17])[CH3:16]
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCC2CC2)cc1
Reaction time: 0.08 h
Yield: 36.6 %

Procedure:
4-(Cyclopropylmethoxy)benzoic acid (1.52 g, 7.90 mmol) prepared in Example 18 (18a) was added to a DMF (53 mL) solution of 2-({(2S)-2-amino-3-[4-(trifluoromethoxy)phenyl]propanoyl}amino)ethyl acetate (2.64 g, 7.90 mmol). To the mixture was added diethyl cyanophosphate (1.54 mL, 9.78 mmol) under ice-cooling with stirring, and then triethylamine (1.32 mL, 9.78 mmol) was dropwise added thereto over 5 minutes. The resulting mixture was stirred at room temperature for 2.5 hours, and to this reaction solution was added ethyl acetate (380 mL). The resulting mixture was washed with water (380 mL, three times) and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was washed with ethyl acetate and dried to give 1.47 g of the title compound. The ethyl acetate used for the washing was also concentrated, and the resulting residue was washed with methanol to give 0.82 g of the title compound. These compound fractions were combined to give 2.29 g of the title compound (white powder, yield: 57%).