Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=12.[O-:23]Cl=O.[Na+].Cl>O.CC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([OH:23])=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C=O)cnc32)cc1
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C(=O)O)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a stirred solution of NaH2PO4.2H2O (513 mg, 3.3 mmol) in water (3 ml), was added a solution of 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 1.50 mmol) in acetone (6 ml) at 0° C. A solution of NaClO2 (541 mg, 5.98 mmol) in water (3 ml) was added to the reaction mixture at 0° C. and the reaction mixture was warmed to room temperature spontaneously. After 2 hours, 1N HCl solution was added to reach pH=5. The produced solid was filtered and dried with nitrogen gas flow. The title product (440 mg, 84% yield) was used next reaction without further purification. MS m/z: 351 [M+1].
Reaction SMILES: C(Cl)Cl.Cl[Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[OH:12][CH2:13][CH2:14]/[C:15](=[CH:25]\[S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].N1C=CN=C1>O>[Si:5]([O:12][CH2:13][CH2:14]/[C:15](=[CH:25]\[S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: O=C(Nc1ccccc1)/C(=C/Sc1ccccc1)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
2 ml of methylene chloride solution including 0.79 g of chloro t-butyl dimethylsilane was dropped into 6 ml of methylene chloride solution including 1.20 g of (E)-4-hydroxy-N-phenyl-2-(phenylthiomethylene)butanamide and 0.63 g of imidazole at room temperature. The resulting solution was stirred at room temperature for 2 hours and added with water, then filtered using ethyl acetate. The organic layer was washed with water 3 times, then washed with brine, and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.63 g of the title compound.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].Cl.[F:16][C:17]([F:33])([F:32])[C:18]1[CH:31]=[CH:30][C:21]([CH2:22][NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25])=[CH:20][CH:19]=1>C(O)C>[ClH:14].[NH2:29][C:27]1[NH:26][C:24]([NH:23][CH2:22][C:21]2[CH:30]=[CH:31][C:18]([C:17]([F:16])([F:32])[F:33])=[CH:19][CH:20]=2)=[N:25][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:28]=1
Reactant: N=C(N)NC(=N)NCc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCC1N=C(N)NC(NCc2ccc(C(F)(F)F)cc2)=N1

Procedure:
100 ml of ethanol, 5.6 ml (25.4 mmol) of 1-dodecanal and 0.7 ml of concentrated hydrochloric acid were added to 5.0 g (16.9 mmol) of N1-(4-trifluoromethylbenzyl)-biguanide hydrochloride, and the mixture was refluxed for 26 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)). An aqueous acetonitrile solution was added to the eluate to obtain 2.4 g of colorless crystals having a melting point of 144 to 149° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH:9]([C:11]1([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:9][C:11]2([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:2][CH2:3]1
Reactant: COC(=O)C1(C=O)CCCC1
Reactant: OCC1CCNCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(CO)CC2)CCCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using piperidin-4-ylmethanol and methyl 1-formylcyclopentanecarboxylate (Synthesis, 1997, 32) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O>ClCCl>[Br:21][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=3)[C:19]3[C:14]([C:13]=2[CH:12]=1)=[CH:15][CH:16]=[CH:17][CH:18]=3
Reactant: Cc1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1ccc(-n2c3ccccc3c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 9-p-tolyl-9H-carbazole (0.82 g, 3.2 mmol) in dichloromethane (DCM)(30 mL) was added N-bromosuccinimide (NBS) at about 0° C. The whole was stirred at about 0° C. to about room temperature (RT) overnight. The resulting solution was purified by flash column (silica gel, hexanes to hexanes/dichloromethane 8:1). After removal of solvent, a white solid (Compound 13) was obtained (1.0 gram, in 93% yield).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>>[ClH:3].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:25][C:17]1[CH:18]=[CH:19][C:20]2[NH:21][C:22]3[N:23]=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=4)[CH2:14][CH2:15][C:16]=1[CH:24]=2)[N:6]=[CH:5][C:4]=3[Cl:3])=[O:31]
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)c1ccccc1Cl
Yield: 24 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and 2-chlorobenzoyl chloride as the starting materials in 24% yield. LCMS for C25H20Cl2N5O (M+H)+: m/z=476.2.
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.[N-:7]=[N+:8]=[N-:9].[Na+].[NH4+].[Cl-]>CO.O>[N:7]([C@@H:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[OH:6])=[N+:8]=[N-:9]
Reactant: C1CC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=N[C@@H]1CCC[C@H]1O
Yield: 92.5 %

Procedure:
To a soln of cyclopenteneoxide (2.0 g, 23.8 mmol) in CH3OH and H2O (40 mL) (4/1, v/v), were added NaN3 (7.73 g, 119 mmol) and NH4Cl (3.17 g, 59.2 mmol). The resulting mixture was heated to solvent reflux for 18 h then cooled to 23°. The mixture was concentrated and the residue was diluted with EtOAc, washed with H2O, the organic layer was dried over Na2SO4, concentrated to give the desired product (2.8 g, 93%). 1H NMR (CDCl3): δ 4.10 (m, 1H), 3.72 (m, 1H), 2.10 (m, 2H), 1.72-1.60 (m, 4H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:2]=1.[CH3:12]C1C=CC(C(O)=O)=CC=1.[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-:29])=[O:28])=[CH:25][CH:24]=1>CO>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:6]=1.[C:27]([O:29][CH3:12])(=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([C:22]([O:33][CH3:34])=[O:32])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: COC(=O)c1ccc(C)cc1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)OC)cc1

Procedure:
A process for the production of terephthalic acid from p-xylene and methanol by way of dimethyl terephthalate obtained by oxidation, in the liquid phase with atmospheric oxygen in the presence of dissolved heavy metal compounds as the catalyst, of a mixture of p-xylene and a fraction containing predominantly methyl p-toluate, which fraction is recycled into the oxidation, to obtain an oxidation product containing primarily p-toluic acid and monomethyl terephthalate at a temperature of 140-170° C. and under a pressure of 4-8 bar; by esterification of the oxidation product in a reactor with liquid and subsequently vaporized methanol brought to an elevated pressure, at a temperature of 220-280° C. and under a pressure of 20-25 bar to obtain a raw ester containing primarily methyl p-toluate and dimethyl terephthalate; by withdrawing the raw ester fraction and a methanol-containing vapor fraction from the esterification reactor; by distillatory separation of the raw ester into a methyl p-toluate fraction and a fraction rich in terephthalic aldehyde methyl ester, which fractions are recycled into the oxidation, a raw dimethyl terephthalate fraction, and a residual fraction; by hydrolysis of the raw dimethyl terephthalate fraction with water, obtaining the thus-formed terephthalic acid and separation of a methanol-water mixture, characterized in that the methanol-containing vapor fraction and the methanol-water mixture are separated by rectification under elevated pressure and elevated temperature into a methanol-rich head fraction and an aqueous sump phase, the methanol formed at the head of the rectification stage is withdrawn in vapor phase under elevated pressure, and esterification of the oxidation product is conducted with the methanol-containing vapor brought by compression to esterification pressure and esterification temperature.
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8]1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>[Zn].C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][C:7]1([OH:6])[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8]1)[CH3:32]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Zinc dust (1.05 g, 16 mmol, 1.6 eq.) in a flask was heated with a heat gun two times. Dry THF (10 mL) and chlorotrimethylsilane (0.405 mL, 3.2 mmol, 0.32 eq.) were added to this flask. The suspension was stirred for 15 min at room temp., heated to reflux, and then removed from the heat. (S)-di-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylate (2.85 g, 10 mmol, 1 eq.) and ethyl 2-bromoacetate (1.77 mL, 16 mmol, 1.6 eq.) were combined with dry THF (10 mL), and added slowly to the Zinc suspension at a rate that at which a gentle reflux was observed. The reaction was refluxed for 2 hrs and monitored by TLC. Upon completion, the reaction was concentrated. Chromatography using hexanes and ethyl acetate gave 2.64 g (7.3 mmol) of (2S)-di-tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (A1) as a 4:1 (2S,4S:2S,4R) mixture of the diastereomers. 1H NMR (300 MHz, DMSO) 4.97 (m, 1H), 4.14-4.01 (m, 3H), 3.48-3.33 (m, 2H), 2.56 (m, 2H), 2.35-2.19 (m, 1H), 2.03 (dd, 1H), 1.40-1.35 (m, 18H), 1.18 (t, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:24])[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1.FC(F)(F)C(O)=O.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)Cl>[CH3:12][C:13]1([CH3:24])[C:22](=[O:9])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1
Reactant: CC1(C)C=Cc2cc(F)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2ccc(F)cc2CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40.6 g (0.2 mol) of m-chloroperbenzoic acid are added, while stirring at from 15° to 20°, to a solution of 17.8 g (0.1 mol) of 2,2-dimethyl-6-fluoro-2H-chromene in 300 ml of trichloromethane. 17.1 g (0.15 mol) of trifluoroacetic acid are added rapidly to the resulting suspension at room temperature. The reaction mixture is then stirred at room temperature for 2 hours and then an aqueous solution of sodium sulfite/sodium hydrogen carbonate (1:1) is added thereto. The organic phase is separated off, washed in succession with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The resulting residue is subjected to bulb tube distillation under a high vacuum at 160°. The distillate is dissolved in diethyl ether and the solution is washed in succession with sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and again concentrated by evaporation in vacuo. The resulting oily residue is chromatographed on 500 g of silica gel (0.040- 0.063 mm) with toluene as eluant, yielding 7.76 g (40% of the theoretical yield) of 2,2-dimethyl-6-fluoro-3-oxo-chroman in the form of a light-yellow oil.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:28]=1[N:36]=[C:37]=[O:38])([CH3:26])[CH3:25]>>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:37]([NH:36][C:28]2[C:27]([CH:24]([CH3:25])[CH3:26])=[CH:32][CH:31]=[CH:30][C:29]=2[CH:33]([CH3:35])[CH3:34])=[O:38])=[CH:5][CH:6]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1ccc(NCc2ccc(-c3ccccc3)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(-c3ccccc3)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 52.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-biphenylylmethyl)(4-isopropylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.88 g) as starting materials, N-(4-biphenylylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (0.88 g) was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:21][NH2:22])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[CH:18][CH:17]=1
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)(6-chloro-pyridin-3-yl)-amine and hydrazine monohydrate.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:21][CH:22]=2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(Cl)cc2)CC1
Reactant: ON=C1CCCCCC1
Product: Clc1ccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=1[Cl:11].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C(N(CC)CC)C.Cl[Pd-2](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.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(I)ccc1Cl
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#C[Si](C)(C)C)ccc1Cl
Yield: 98.1 %

Procedure:
A mixture of 2-chloro-5-iodo-benzoic acid methyl ester (3.5 g, 12 mmol), dichlorobis(triphenylphosphino)palladium(II) (0.04 g, 0.06 mmol), triphenylphosphine (0.06 g, 0.24 mmol), copper iodide (0.05 g, 0.24 mmol), (trimethylsilyl)acetylene (1.9 g, 19.2 mmol) in triethylamine (40 mL) was heated at reflux for 12 h. The mixture was concentrated in vacuo, diluted with ethyl acetate (150 mL) and washed sequentially with 10% aqueous citric acid, water, and brine. The organic solution was dried, filtered and concentrated in vacuo to afford the title compound (3.14 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br.O>C1COCC1>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:25]
Reactant: COC(=O)c1ccccc1CBr
Reactant: O=C(O)Cc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1CSc1ccc(CC(=O)O)cc1
Reaction time: 0.5 h
Yield: 12 %

Procedure:
4-Mercaptophenylacetic acid (995 mg, 5.915 mmol) in THF (15 ml) was cooled in an ice-bath and sodium hydride (55-65%, 520 mg, ˜13 mmol) was added. The mixture was stirred for 30 minutes and then 2-bromomethyl-benzoic acid methyl ester (1.49 g, 6.507 mmol) in THF (5 ml) was added. The resulting mixture was stirred overnight and the temperature was allowed going up to room temperature. Water was dropped in and the mixture was stirred for ca. 20 minutes. It was then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜3, and then extracted with ethyl acetate. The organic extracts were combined, dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 20 g/70 ml) using DCM, then MeOH/DCM (1:99) as eluant gave 224 mg desired product, yield 65%.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[CH2:9]([NH2:12])[CH2:10][NH2:11]>C(O)C>[CH2:6]([O:5][C:1]([NH:11][CH2:10][CH2:9][NH2:12])=[O:8])[CH3:7]
Reactant: NCCN
Reactant: CCOC(=O)OCC
Solvent: CCO
Product: CCOC(=O)NCCN

Procedure:
15 g (0.13 mol) of diethyl carbonate are heated in an oil bath at 90° C., for five hours, with 10 g (0.17 mol) of ethylenediamine under reflux. The ethyl alcohol formed during the reacton is then removed using a rotary evaporator. The product is removed from the residue by distillation in a Kugelrohr distillation apparatus.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[S:28][CH:29]=[C:30]([C:32](O)=[O:33])[N:31]=2)[CH2:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:32]([C:30]3[N:31]=[C:27]([CH2:26][N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)[S:28][CH:29]=3)=[O:33])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: O=C(O)c1csc(CN2CCOCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1csc(CN2CCOCC2)n1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.3 g, 1.07 mmol), 2-(morpholinomethyl)-thiazole-4-carboxylic acid (0.29 g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) and EDCI (0.31 g, 1.61 mmol) in 10 mL DMF as solvent using the method of Example 34(d). Yield 0.27 g. 1H NMR (400 MHz; d6-DMSO): 1.13 (d, 3H), 3.61 (m, 4H), 3.84 (d, 2H), 4.39 (m, 3H), 6.78 (dd, 1H), 7.84 (dd, 1H), 7.90 (d, 1H), 8.06 (dd, 1H), 8.15 (s, 1H), 8.45 (d, 1H).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:9][CH3:10])[CH3:7].[O:28]=[C:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1.[Cl-].[NH4+]>O1CCCC1>[CH2:6]([C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:29]2([OH:28])[CH2:34][CH2:33][S:32][CH2:31][CH2:30]2)=[C:13]([CH3:19])[CH:12]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: O=C1CCSCC1
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCSCC2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
n-Butyllithium (2.71 M solution in hexane, 2.8 mL, 7.6 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 1 g, 3.4 mmol) in tetrahydrofuran (17 mL) in a nitrogen atmosphere at 0° C. Then, a solution of 4-oxothiane (0.4 g, 3.4 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture, which was further stirred at 0° C. for 30 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound (1.04 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:14])[CH:13]=[N:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: Nc1ccccc1Cl
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1ccccc1Cl

Procedure:
98% 2-chloroaniline (195 g; 1.5 mol) and 98% dimethylformamide dimethyl acetal (228.2 g; 1.8 mol) were dissolved in toluene (300 g), and the solution was heated under reflux for 4 h. During this time, the internal temperature fell from 96 to 77° C. Thereafter, 15 g of distillate were removed, and the internal temperature rose again during this time to 84° C. Finally, the reaction solution was concentrated on a rotary evaporator at 90° C. and 5 mbar and the resulting brown oil (270.5 g) was fractionated by means of column distillation. The main fraction distilled over at 120° C. and 1.4 mbar and comprised the product in a purity of >99% (determined using area percentages of the GC spectrum).