Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:10])[CH2:5][CH2:6][CH2:7][NH:8][CH3:9].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.Cl>CS(C)=O.O>[CH3:3][N:4]([CH3:10])[CH2:5][CH2:6][CH2:7][N:8]([CH3:9])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNCCCN(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 65 °C

Procedure:
To a suspension of potassium hydroxide (1.4 g, 25 mmol) in dimethylsulfoxide (13 mL) is added N,N,N′-trimethyl-1,3-propanediamine (1.8 mL, 12 mmol). While stirring vigorously and while heating to 65° C., 4-fluoronitrobenzene (1.1 mL, 10 mmol) is added dropwise. After stirring at this temperature for 6 hours, the mixture is allowed to cool to room temperature. Water is added and the mixture is acidified to pH 1 with concentrated hydrochloric acid and then extracted 3× with chloroform (3×30 mL). The acidic phase is then basified to pH 11 with 2.5 M sodium hydroxide solution. The basic phase is extracted thrice with chloroform (3×30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an orange-red oil, which is purified by reverse phase high performance liquid chromatography to give N,N,N′-trimethyl-N′-(4-nitrophenyl)propane-1,3-diamine as its ditrifluoroacetate salt.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])C.[C:8]([O:11][CH2:12][C@H:13]1[C@H:17]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[O:16][CH2:15][O:14]1)(=[O:10])[CH3:9].C.[C:24](=O)([O-])O.[Na+]>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C.C(O)(=O)C>[C:5]([O:4][CH2:1][O:3][C@H:13]([C@@H:17]([O:16][C:15](=[O:14])[CH3:24])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:12][O:11][C:8](=[O:10])[CH3:9])(=[O:7])[CH3:6]
Reactant: CC(=O)OC[C@@H]1OCO[C@H]1COC(C)=O
Reactant: O=C([O-])O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCO[C@@H](COC(C)=O)[C@H](COC(C)=O)OC(C)=O

Procedure:
100.2 g of acetic anhydride was added to 61.0 g of (4S,5S)-4,5-bis(acetoxymethyl)-1,3-dioxolane obtained in Example 15. To this was added 11.8 g of glacial acetic acid to dissolve the mixture. 3.4 g of anhydrous zinc chloride was added while stirring. The zinc chloride was slowly dissolved to change the color of the mixture from yellow into charcoal. After the reaction overnight, the reaction mixture was charged into a separating funnel which contained 500 ml of ethyl acetate. To this was added saturated aqueous solution of sodium hydrogen carbonate to neutralize. After washing with water and drying, the product was concentrated by evaporator. Acetic anhydride not decomposed was removed by a chemical pump to obtain 91.9 g (yield: 87.7%) of an yellow oil of the title compound.
Reaction SMILES: [C:1]([CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)=[O:17])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29](N)[CH3:30].[C:32]([O-:35])(=[O:34])C.[Na+].Cl.[O:38]([NH2:40])[CH3:39]>C(O)C.O>[C:30]([OH:29])(=[O:8])[C:32]([OH:35])=[O:34].[C:2]1([C:1](=[N:40][O:38][CH3:39])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]4)=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: CON
Reactant: O=C1CCc2cc(C(=O)N3CCN(CC(=O)c4ccccc4)CC3)ccc2N1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Product: O=C(O)C(=O)O

Procedure:
2 Grams of 6-[4-(benzoylmethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril, 0.53 g of methoxylamine and 0.78 g of sodium acetate were dissolved in 10 ml of ethanol and 5 ml of water, then the solution was refluxed for 4 hours with stirring. Further, 0.53 g of methoxylamine hydrochloride and 0.78 g of sodium acetate were added to the reaction mixture, and refluxed for 2 hours with stirring. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. Thus obtained residue was extracted with chloroform, and the extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=50:1) then the desired compound was converted into an oxalate by adding with oxalic acid in acetone, and recrystallized from ethanol-water to yield 2.6 g of 6-[4-(2-phenyl-2-methoxyiminoethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril oxalate. White powdery substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Si:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[S:33][C:32]=2[CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Br:1][C:2]1[CH:3]=[C:4]([Si:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:38]3[CH:39]=[CH:40][C:34]4[S:33][C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:36]=5[C:35]=4[CH:37]=3)[CH:22]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc2sc3ccccc3c2c1
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-c3ccc4sc5ccccc5c4c3)c2)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture solution of bis(3-bromophenyl)diphenylsilane (10.84 g, 21.92 mmol), dibenzo[b,d]thiophen-2-yl boronic acid (2.000 g, 8.77 mmol), Pd(PPh3)4 (0.101 g, 0.088 mmol) and K2CO3 (2.424 g, 17.54 mmol) in toluene (200 mL) and water (50 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated and evaporated to dryness. The residue was purified by column chromatography on silica gel with hexane:DCM (9:1, v/v) as eluent to yield (3-bromophenyl)(3-(dibenzo[b,d]thiophen-2-yl)phenyl)diphenylsilane (3.16 g, 60% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][C:3]=1[CH2:14][CH2:15][CH2:16][C:17]#[N:18].CO.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.C(OCC)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH:4]=1)#[CH:9]
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(CCCC#N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: C#Cc1ccc(F)c(CCCC#N)c1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2-Fluoro-5-trimethylsilanylethynyl-phenyl)-butyronitrile (0.27 g, 1.04 mmol), in dry methylene chloride (2.5 mL) and methanol (2.5 mL) was added cesium carbonate (0.41 g, 1.2 mmol) and stirred for 2 h under a nitrogen atmosphere. The mixture was diluted with diethyl ether (15 mL), and partitioned between diethyl ether and H2O (10 mL), and the aqueous layer was extracted with diethyl ether (10 mL), washed with brine and dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (5-10% ethyl acetate/petroleum ether) gave the title compound as a brown semi solid (0.154 g, 79%), identified by NMR and mass spectral analyses. MS (EI+): 187 (M+).
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[C:6](Cl)[C:5]=1[OH:13])([O-])=O.ClC1C(C)=CC(O)=CC=1.[S:23](=O)(=[O:26])([OH:25])[OH:24]>>[S:23]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[OH:13])([OH:26])(=[O:25])=[O:24]
Reactant: Cc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl
Reactant: O=S(=O)(O)O
Agent: Cc1cc(O)ccc1Cl
Product: Cc1cc(O)c(S(=O)(=O)O)cc1Cl

Procedure:
According to the present invention there is provided a process for preparing 2-nitro-4,6-dichloro-5-methylphenol comprising sulphonation of 4-chloro-5-methyl-phenol with concentrated sulphuric acid at elevated temperature to form 2-sulpho-4-chloro-5-methylphenol, thereafter diluting the reaction mixture with water to a sulphuric acid content of 20 to 30%, chlorinating the resulting 2-sulpho-4-chloro-5-methylphenol with chlorine at elevated temperature and normal or elevated pressure to form 2-sulpho-4,6-dichloro-5-methylphenol and reacting the 2-sulpho-4,6-dichloro-5-methylphenol with nitric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C1C[O:24]CC1>O.C(O)(=O)C.OO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([OH:24])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=c1c2cc(B(O)O)ccc2ccc2ncc(Cl)cc12
Agent: OO
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2cc(O)ccc2ccc2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)boronic acid (1.00 g, 3.5 mmol) was dissolved in a 0° C. solution of 25 mL of THF, 25 mL of water, 0.5 mL of acetic acid and 0.5 mL of 30% (w/w) hydrogen peroxide. The solution was stirred and allowed to warm to ambient temperature. After 6 h, the reaction mixture was partially concentrated and dissolved in 500 mL ethyl acetate. The organic layer was washed with water (2×100 mL), dried with magnesium sulfate, filtered, and concentrated to afford solids. The solids were dissolved in 20 mL dichloromethane and 60 mL hexanes and stirred as solids crystallized from the solution. After 2 hours, the crystalline solids were filtered and dried to afford the title compound. 1H NMR (600 MHz, DMSO-D6) δ 10.50 (s, 1H); 8.93 (s, 1H); 8.45 (s, 1H); 7.68 (d, 1H); 7.58 (d, 1H); 7.39 (d, 1H); 7.23 (d, 1H); 7.12 (d, 1H). LRMS (APCI) calculated for C14H9ClNO2 [M+H]+, 258.0; found 258.1.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[F:13][C:14]([F:25])([F:24])[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[CH:35]([NH:37][C:38]1[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH2:48])[CH:44]=3)[N:39]=1)[CH2:34][CH2:33]2>>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[CH:35]([NH:37][C:38]1[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH:48][C:1]([NH:23][CH:20]4[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][C:14]([F:13])([F:24])[F:25])[CH2:22][CH2:21]4)=[O:2])[CH:44]=3)[N:39]=1)[CH2:34][CH2:33]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCN(CCC(F)(F)F)CC1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(CCC(F)(F)F)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(3,3,3-trifluoro-propyl)-piperidin-4-ylamine and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=528.8 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[NH2:9][CH2:10][CH2:11][OH:12]>C(Cl)Cl>[CH3:7][C:3]([C:4]1[O:5][CH2:11][CH2:10][N:9]=1)([CH3:8])[CH2:2][Cl:1].[OH:12][CH2:11][CH2:10][NH:9][C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1]
Reactant: NCCO
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)NCCO
Product: CC(C)(CCl)C1=NCCO1

Procedure:
2-(1,1-dimethyl-2-chloroethyl)-2-oxazoline was prepared as follows. Initially, N-(2-hydroxyethyl)-3-chloropivalamide was prepared by adding dropwise, at room temperature, a solution of 3-chloropivaloyl chloride (1.0 eq., 22.4 g, 0.14 mol) in CH2Cl2(100 mL) to a stirred mixture of 2-aminoethanol (2.0 eq., 17.6 g, 0.29 mol) in CH2Cl2(300 mL) over a period of one (1) hour. This mixture was allowed to auto-reflux for twenty (20) minutes and was then stirred for an additional forty (40) minutes. The whitish-yellow precipitate that formed was gravity filtered, and the resulting yellow solution was concentrated under vacuum. The resulting viscous yellow oil (23 g, 89% yield) was pure N-(2-hydroxyethyl)-3-chloropivalamide, as evidenced by 1H NMR (CDCl3): δ1.31 (s, 6H, CH3, CH3), 3.44 (q, 2H, CH2—NH), 3.61 (s, 2H, CH2—Cl), 3.73 (t, 2H, CH2—OH), 6.3 (br s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C([Li])CCC.Br[CH2:22][CH2:23][CH2:24][Cl:25]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:22][CH2:23][CH2:24][Cl:25])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Nc1ccccc1S2
Reactant: ClCCCBr
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: ClCCCN1c2ccccc2Sc2ccc(Br)cc21

Procedure:
A solution of 2-bromophenothiazine (41.72 g., 0.05 mole) in 200 ml. of dry toluene was added to a stirred solution of 9.6 g. (0.15 mole) of n-butyllithium in 100 ml. of dry toluene. The stirred solution was warmed for about 2.0 hours at 45°-50° C. and then 31.5 g. (0.20 mole) of bromopropylchloride in 50 ml. of dry toluene was added. The mixture was refluxed for 15 hours. The cooled reaction mixture was washed with water, dried over sodium sulfate and the dried solution concentrated at reduced pressure. The residual oil was distilled to give the product, 2-bromo-10-(3-chloropropyl)phenothiazine.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11](=[O:16])[CH:12](Br)[CH2:13]Br)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C)(C)C.O>[C:1]1([N:7]2[C:12](=[CH2:13])[C:11](=[O:16])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(=O)C(Br)CBr)Nc1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: C=C1C(=O)NC(=O)N1c1ccccc1

Procedure:
20.0 g of the N-phenyl-N'-(2,3-dibromopropionyl)-urea prepared in accordance with Example 1(b) are suspended in 200 ml of tert.-butanol, 23 g of potassium tert.-butylate (90%) are introduced into the resulting suspension and the mixture is heated under reflux for 1 hour. The solvent is then distilled off under normal pressure and the residue is heated in vacuo for 20 minutes to 120° C. The white crystalline powder obtained is dissolved in 400 ml of water at 60° C. and the solution is filtered and adjusted to pH 1 with dilute hydrochloric acid. The precipitated imidazolidine derivative is filtered off, washed and dried. Yield: 9.0g m.p: 168° - 170° C. (from methanol)
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])=[O:17]
Reactant: NCC(=O)CCC(=O)O
Reactant: Cc1ccccc1CO
Agent: Cl
Product: Cc1ccccc1COC(=O)CCC(=O)CN
Reaction time: 96 h

Procedure:
From 2-methylbenzyl alcohol (5.0 g; 41 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 4 days at 100° C. The yield was 0.72 g (44%). Mp 107-109° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:40])[CH3:39])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: NS(=O)(=O)c1cnn2c(Nc3cccc(Cl)c3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: CC(=O)O
Product: CC(=O)NS(=O)(=O)c1cnn2c(Nc3cccc(Cl)c3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 61.2 %

Procedure:
Using 7-(2,3-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.089 mmol) obtained in step 5 and acetic acid (0.025 mL, 0.444 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.033 g, 61%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[S:14][C:13]([NH2:15])=[N:12][CH:11]=2)=[CH:5][CH:4]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][C:24](O)=[O:25])[CH:17]=1.CCN(CC)CC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[S:14][C:13]([NH:15][C:24](=[O:25])[CH2:23][CH2:22][C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)=[N:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: COc1ccc(Sc2cnc(N)s2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cnc(NC(=O)CCc3cccnc3)s2)cc1
Yield: 74.8 %

Procedure:
A solution of 5-(4-methoxy-phenylsulfanyl)-thiazol-2-ylamine (70b, 3.0 g, 12.6 mmol), 3-pyridin-3-yl-propionic acid (2.30 g, 15.1 mmol), NEt3 (6.10 ml, 44.1 mmol), EDC (4.80 g, 25.2 mmol) and HOBt (3.40 g, 25.2 mmol) in DMF (150 mL) was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s), and concentrated under reduced pressure to give N-[5-(4-methoxy-phenylsulfanyl)-thiazol-2-yl]-3-pyridin-3-yl-propionamide (70, 3.50 g) in 75% yield: 1H NMR (500 MHz, DMSO) δ 8.45 (d, 1H), 8.39 (m, 1H), 7.64 (m, 2H), 7.29 (m, 3H), 6.92 (t, 2H), 3.73 (t, 3H), 2.90 (t, 2H), 2.77 (t, 2H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]#[C:27][Si](C)(C)C)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]#[CH:27])[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC#C[Si](C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#CCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
In THF (7.8 ml)/methanol (7.8 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-trimethylsilyl-2-propynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.78 g). To the solution was added 2N potassium hydroxide (7.8 ml), and the mixture was stirred at room temperature for 16 hours. pH was adjusted to approximate 4 with 6N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was washed with hexane/ethyl acetate (=8/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-propynyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.52 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH:12]1([CH:18]=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH:18]([OH:19])[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]#[N:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=CC1CCCCC1
Reactant: COc1ccc(CC#N)cc1
Product: COc1ccc(C(C#N)C(O)C2CCCCC2)cc1
Yield: 68 %

Procedure:
Reaction of p-methoxyphenylacetonitrile and cyclohexane-carboxaldehyde on a 20 mmol scale according to the procedure in Example 1, and two successive recrystallizations from chloroform/hexane gave 3.51 g of the desired anti-aldol product (68%), mp: 112.0-113.2° C. NMR (1H, 13C), IR, and Mass spectra were consistent with the assigned structure. Analysis: Calcd for C16H21NO2 : C, 74.10; H, 8.16; N, 5.40. Found: C, 74.25; H, 8.15; N, 5.39.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([N:11]3[CH2:19][CH2:18][CH:14]([C:15](O)=O)CC3)[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH2:22]([N:24](CC)CC)[CH3:23].C(Cl)(=O)[O:30]CC(C)C.N>O1CCCC1.CN(C)C=O>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:19](=[O:30])[CH:18]3[CH2:14][CH2:15][NH:24][CH2:22][CH2:23]3)[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)COC(=O)Cl
Reactant: CCN(CC)CC
Reactant: O=C(O)C1CCN(c2nc3ccc([N+](=O)[O-])cc3s2)CC1
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc([N+](=O)[O-])cc2s1)C1CCNCC1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
90 g of the N-(6-nitrobenzothiazol-2-yl)isonipecotic acid obtained in the Preparation Example 11 was suspended in 500 ml of tetrahydrofuran and 1,000 ml of dimethylformamide. 100 ml of triethylamine was added to the suspension and 45 ml of isobutyl chlorocarbonate was added dropwise to the suspension under cooling to -20° C. After stirring for 20 min, 100 ml of concentrated aqueous ammonia was added to the mixture at -40° C. and stirred for 20 min. The reaction mixture was poured into ice/water and the formed precipitates were recovered by filtration, washed with water and then with ether, and dried to give 75 g of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH2:11][C:12](=O)[CH3:13].[C:15](O)(=O)C.[CH:19]([NH2:21])=[NH:20]>C(O)CCC>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:15][N:21]=[CH:19][N:20]=1
Reactant: CC(=O)CCC1=C(C)CCCC1(C)C
Reactant: CC(=O)O
Reactant: N=CN
Solvent: CCCCO
Product: CC1=C(CCc2ccncn2)C(C)(C)CCC1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A 100 mL reaction flask is charged with 4-(2,6,6-trimethyl-cyclohex-1-enyl)-butan-2-one (10 g, 0.05 mol, commercially available at IFF), formamidine acetate (26 g, 0.3 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 4-[2-(2,6,6-trimethyl-cyclohex-1-enyl)-ethyl]-pyrimidine (˜10 g) is obtained.
Reaction SMILES: [C:1]([C:3]12[CH2:11][CH:8]3[CH2:9][CH:10]1[CH:6]([CH:7]3[OH:12])[O:5][C:4]2=[O:13])#[N:2].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].O>O1CCCC1.C1(C=CC(O)=CC=1)O>[C:1]([C:3]12[CH2:11][CH:8]3[CH2:9][CH:10]1[CH:6]([CH:7]3[O:12][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[O:5][C:4]2=[O:13])#[N:2]
Reactant: C=C(C)C(=O)Cl
Reactant: N#CC12CC3CC1C(OC2=O)C3O
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3(C#N)C2
Temperature: 5 °C

Procedure:
In 252 g of tetrahydrofuran (THF) was dissolved 23 g (in terms of 0.127 mol) of the above-prepared compound represented by Formula (2a) (crude product). The solution was combined with 16.9 g of triethylamine and 0.2 g of hydroquinone and was further combined with 18.3 g of methacryloyl chloride (3a) added dropwise while cooling the mixture to 5° C. The reaction mixture was combined with 300 ml of water and was extracted with ethyl acetate. The organic layer was sequentially washed with an aqueous sodium hydrogen carbonate solution and water, was concentrated, the concentrate was crystallized from diisopropyl ether and thereby yielded 14 g of 1-cyano-5-methacryloyloxy-3-oxatricyclo[4.2.1.04,8]nonan-2-one represented by Formula (1a).