Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[N:11]1([CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: ClCCN1CCCC1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCN2CCCC2)CC1

Procedure:
1-(2-(1-Pyrrolidinyl)ethyl)-4-piperidone is prepared from 4-piperidone and 1-(2-chloroethyl)pyrrolidine essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37](C(O)=O)=[C:36]([O:44][CH3:45])[CH:35]=1>>[C:20]12([C:30]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][C@H:10]([CH2:9][NH:8][C:6](=[O:7])[C:37]4[CH:41]=[C:42]([Cl:43])[C:34]([NH2:33])=[CH:35][C:36]=4[O:44][CH3:45])[CH2:11]3)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCN)C1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCNC(=O)C23CC4CC(CC(C4)C2)C3)C1

Procedure:
4-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (1.20 g) as starting compound was reacted and treated in the same manner as in Example 1 using 1-adamantanecarbonyl chloride (0.98 g) and 4-amino-5-chloro-2-methoxybenzoic acid (0.85 g) to give N-((3R)-1-(4-(1-adamantanecarbonylamino)butyl)pyrrolidin-3-ylmethyl)-4-amino-5-chloro-2-methoxybenzamide.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[N:10]1([C:16]2[C:17]3[C:24]([C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=4)[C:28]#[N:29])=[CH:23][N:22]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C.O>[OH:3][N:2]=[C:28]([C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([C:24]2[C:17]3[C:16]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[N:21][CH:20]=[N:19][C:18]=3[N:22]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:23]=2)[CH:26]=1)[NH2:29]
Reactant: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C(N)=NO)c2)c2c(N3CCOCC3)ncnc21

Procedure:
Hydroxylamine hydrochloride (278 mg, 4.00 mmol) and sodium carbonate (318 mg, 3.00 mmol) were added to a stirred solution of 3-[4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (C34) (436 mg, 1.00 mmol) in ethanol (10 mL) and water (5 mL). The reaction mixture was heated at reflux for 2 hours, then concentrated in vacuo, poured into water (25 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated, affording the product as a white solid. Yield: 280 mg, 0.60 mmol, 60%. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.43 (s, 1H), 7.89 (br s, 1H), 7.72 (s, 1H), 7.64 (br d, J=7.8 Hz, 1H), 7.53 (br d, J=7.8 Hz, 1H), 7.46 (dd, J=7.6, 7.6 Hz, 1H), 5.89 (br s, ˜1.6H), 5.61 (s, 2H), 3.53-3.61 (m, 2H), 3.39-3.47 (m, 4H), 3.13-3.21 (m, 4H), 0.81-0.88 (m, 2H), −0.09 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.ClCCl.N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:20]([O:1][CH2:2][C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(CO)o1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-hydroxymethylfuran-2-carboxylic acid (5.90 g), dry dichloromethane (100 ml), pyridine (6.71 ml), 4-dimethyl-aminopyridine (507 mg), and acetic anhydride (4.21 ml) was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate and washed with 5M hydrochloric acid and brine (3 times), dried (MgSO4), and evaporated. The residue was re-evaporated twice from dry toluene to give the title acid as a solid (5.00 g); δH [(CD3)2CO) 2.05 (3 H, s), 5.11 (2 H, s), 6.62 (1 H, d, J 4 Hz), 7.17 (1 H, d, J 4 Hz) and 8.31 (1 H, br s).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+:6].[Cl:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(OCC)=O>>[Cl:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2][O-:4].[K+:6]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCl
Agent: [K+]
Solvent: CCOC=O
Product: CCOC(=O)C(Cl)=C[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a suspension of potassium tert-butoxide (5.2 g) in IPE (50 mL) were added ethyl 2-chloroacetate (5.6 g) and ethyl formate (3.4 g) under ice-cooling, and the mixture was stirred overnight at room temperature. The precipitate was collected by filtration, and dried to give the title compound (5.8 g). 1H NMR (300 MHz, DMSO-d6) δ 1.11 (3H, t, J=7.2 Hz), 3.92 (2H, q, J=7.2 Hz), 8.95 (1H, brs).
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1C=CN=C1)=O.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]([OH:23])=[O:22].[CH2:26]([O:28][C:29](NC=NO)=[O:30])[CH3:27]>O1CCOCC1>[NH2:8][C:1](=[N:3][O:22][C:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[C:14]([F:13])([F:24])[F:25])=[O:23])[C:29]([O:28][CH2:26][CH3:27])=[O:30]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)NC=NO
Reactant: O=C(O)c1cnccc1C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)C(N)=NOC(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
17.3 g of carbonyldiimidazole are initially charged in 200 ml of 1,4-dioxane and, a little at a time, admixed with 20 g of 4-trifluoromethyl-3-pyridinecarboxylic acid. The mixture is stirred at room temperature for 1 h and subsequently heated to 45° C. for 2 h. After cooling to 30° C., 14.5 g of ethoxycarbonylformamide oxime are added and the mixture is stirred at 45° C. for 3 h. The precipitated solid is filtered off with suction and the filtrate is concentrated to 50 ml and, together with the solid, added to 250 ml of ice-water. The solid is filtered off with suction and dried at 50° C. under reduced pressure. This gives 28.7 g of the product as a white solid of mp. 172-174° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH:3]=1.[NH4+].[Cl-].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[C:17]1([CH:15]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:12]=[C:11]([C:13]4[NH:27][N:26]=[N:25][N:14]=4)[CH:10]=[CH:9][N:8]=3)[N:5]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(c1ccccc1)c1cc(O)n(-c2cc(C#N)ccn2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccccc1)c1cc(O)n(-c2cc(-c3nnn[nH]3)ccn2)n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a suspension of 2-[5-hydroxy-3-(1-phenylethyl)pyrazol-1-yl]pyridine-4-carbonitrile (150 mg, 0.5 mmol), NH4Cl (278 mg, 5.2 mmol) in DMF (5 mL) was added NaN3 (338 mg, 5.2 mmol) at r.t. The reaction mixture was stirred at 110° C. for 2 h in a microwave oven. The reaction mixture was then filtered and purified by pre-HPLC to give the title compound (100 mg, 58%) as a brown solid. 1H NMR (400 MHz, CD3OD): δ 1.64 (3H, d, J=7.2 Hz), 4.07-4.12 (1H, m), 7.17-7.19 (1H, m), 7.20-7.35 (4H, m), 7.83 (1H, dd, J=1.2, 5.2 Hz), 8.43 (1H, d, J=5.2 Hz), 8.74 (1H, s). [M+H] Calc'd for C17H15N7O, 334. Found, 334.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[N+:14]([O-])[C:13]=2[C:19]([O:21][CH3:22])=[O:20])[N:4]=1.[CH3:23][N:24]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)C(Cl)=O.[I-].[Na+].C(N(C(C)C)CC)(C)C>O.C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[N:14][C:15]([N:24]([CH3:23])[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:16][CH:17]=2)[N:4]=1
Reactant: CN(C(=O)Cl)C1CCCCC1
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc[n+]1[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(N(C)C2CCCCC2)ccc1Oc1nc(OC)cc(OC)n1
Yield: 50 %

Procedure:
11.0 g (36 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate N-oxide, 9.5 g (54 mmol) of N-methyl-N-cyclohexylcarbamoyl chloride, 10.5 g (70 mmol) of sodium iodide and 9.0 g (70 mmol) of diisopropylethylamine were added to 150 ml of acetonitrile and reacted at a temperature of from 60° to 70° C. for one hour. Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate, dried and concentrated. The obtained oily product was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the desired product.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:14]=1[CH2:15]Br)(=[O:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:14]=1[CH2:15][N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:1])(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(C(C)(C)C)cc1CBr
Reactant: CNC1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1CN(C)C1CCCCC1

Procedure:
24 gm of N-methyl-cyclohexylamine were added to 23 gm of 2-acetylamino-5-tert.butyl-benzylbromide in 1.6 liters of carbon tetrachloride, and the mixture was refluxed for 1 hour. After cooling, the precipitated N-methyl-cyclohexylamine hydrobromide was filtered off, the filtrate was evaporated, and the crude product was purified chromatographically on silicagel with ethyl acetate. The corresponding fractions were combined and evaporated, and the 2-acetylamino-5-tert.butyl-N-cyclohexyl-N-methyl-benzylamine thus obtained was recrystallized from petroleumether, whereupon it had a melting point of 111°-112.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:27]1(C)C=CC=C[CH:28]=1>C(O)C>[CH2:27]([O:14][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:28]
Reactant: Cc1ccccc1
Reactant: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
243 g of 2(S)-benzyloxycarbonylamino-3-cyclohexylpropionic acid (manufacture: Helvetica Chimica Acta 57. 2131(1974)) are placed in 600 ml of toluene and 900 ml of ethanol. The reaction mixture is cooled to 0° and 88.3 g of thionyl chloride are added dropwise within 30 minutes. The cooling is removed and the mixture is stirred for 18 hours. The reaction mixture is filtered and the filtrate is concentrated. The residue is separated by means of flash chromatography (2 kg of silica gel 60, 40-63 μm, eluant F). The product-containing fractions are combined, concentrated by evaporation and dried under a high vacuum. The title compound is obtained in the form of a slightly yellowish oil. Rf (F)=0.2; Rf (B)=0.52.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]=O)=[N:22][CH:23]=1>C1COCC1.O>[F:17][C:18]1[CH:19]=[CH:20][C:21](/[CH:24]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:22][CH:23]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(F)cn1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a suspension of sodium hydride (55 wt %, 1.97 g) in THF (200 ml) was added at 0° C. ethyl (diethoxyphosphoryl)acetate (9.3 g), and the mixture was stirred at 30 min. To this mixture was added a solution of the compound (4.7 g) obtained in step 1 in THF (200 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. The mixture was diluted with water (500 mL), extracted with ethyl acetate (500 mL), dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (25% ethyl acetate/hexane) to give ethyl (2E)-3-(5-fluoropyridin-2-yl)prop-2-enoate (6.2 g, 85%) as a white powder.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC([CH2:32][N:33]3[CH2:38][CH2:37][N:36](C4C=CC=CC=4)[CH2:35][CH2:34]3)=C(C(OC)=O)N=1)CC2)=O.C1C=CC(N2CCNCC2)=CC=1.[OH:65][C:66]1[CH:73]=[CH:72][C:69]([CH:70]=O)=[CH:68][CH:67]=1.CN1CCNCC1>>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:70][C:69]2[CH:72]=[CH:73][C:66]([OH:65])=[CH:67][CH:68]=2)[CH2:35][CH2:34]1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CN1CCN(c2ccccc2)CC1
Agent: CN1CCNCC1
Agent: c1ccc(N2CCNCC2)cc1
Product: CN1CCN(Cc2ccc(O)cc2)CC1

Procedure:
Compound 89A was prepared in a similar manner to the synthesis of compound 62A by substituting compound 45C and phenylpiperazine with 4-hydroxybenzaldehyde and 1-methylpiperazine, respectively: ESI (+)/MS: 207 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=1[CH3:29]>CN(C)C=O>[CH3:3][C:1]([C:5]1[CH:6]=[C:7]([O:11][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=2[CH3:29])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cccc(C(C)(C)C)c1

Procedure:
3-t-Butylphenol (7.5 g) and potassium carbonate (6.9 g) are added to a solution of 1-chloro-2,5-dimethyl-4-nitrobenzene (9.5 g) in dimethylformamide (60 ml) under an inert atmosphere. The reaction mixture obtained is refluxed for 5 h and then partitioned in a water/diisopropyl ether mixture. The organic phase is washed with a basic aqueous solution and then with water at pH 7. Drying over magnesium sulphate and then addition of carbon black, followed by filtration through Celite gives, after concentration, the title product.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:13]([O:20][CH2:21][CH:22]([NH2:25])[CH:23]=[CH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(#N)C.O>[CH2:13]([O:20][CH2:21][CH:22]([NH:25][C:1](=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:23]=[CH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CC(N)COCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: C=CC(COCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzyl carbonochloridate (4.7 g, 27.4 mmol) was added dropwise over a period of 30 minutes to a mixture of 1-(benzyloxy)but-3-en-2-amine hydrochloride (3.9 g, 18 mmol) and Hunig's base (10.0 mL, 54.8 mmol) in acetonitrile (100 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to afford benzyl [1-(benzyloxy)but-3-en-2-yl]carbamate. MS ESI calc'd. for C19H22NO3 [M+H]+ 312. found 312. 1H NMR (300 MHz, CD3OD) δ 7.34-7.25 (m, 10H), 5.87-5.79 (m, 1H), 5.25-5.08 (m, 4H), 4.51 (s, 2H), 4.38-4.36 (m, 1H), 3.54-3.44 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][S:8][CH2:9][CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].Cl.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)C>[CH3:23][N:24]([CH2:26][C:5]1[O:1][C:2]([CH2:6][CH2:7][S:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:3][CH:4]=1)[CH3:25]
Reactant: C=O
Reactant: O=C1c2ccccc2C(=O)N1CCSCCc1ccco1
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1ccc(CCSCCN2C(=O)c3ccccc3C2=O)o1
Reaction time: 16 h
Yield: 72.3 %

Procedure:
2-[[2-(2-Furanyl)ethyl]thio]ethyl-1H-isoindole-1,3(2H)-dione (0.5 g), dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were heated together under reflux in ethanol. After 5 hr further dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were added and the heating continued for a further 16 hr. Solvent was removed, the residue basified and extracted with ethyl acetate to give an oil which after column chromatography (silica/methanol) gave 2-[2-[[2-[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-1H-isoindole-1,3(2H)dione as a pale oil (0.43 g). Analysis Found: C, 61.48; H, 6.13; N, 7.63; C19H22N2O3S.3/4H2O requires: C, 61.35; H, 6.37; N, 7.53%.
Reaction SMILES: [Br:1]Br.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[N:14]3[CH:23]=2)=[CH:7][CH:6]=1)#[N:4]>C(Cl)Cl.CC(O)=O>[Br:1][C:23]1[N:14]2[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)cn12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(Br)n12
Yield: 88 %

Procedure:
Br2 (1.0 eq.) was added, dropwise, to a solution of (A2) in DCM/AcOH=1:1 (0.05 M) at RT and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched by the addition of sat. aq. NaHCO3. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column chromatography on silica using a gradient of EtOAc/Petroleum ether from 30:70 to 50:50 to yield (88%) the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.24 (2H, d, J=8.4 Hz), 8.00 (2H, d, J=8.6 Hz), 7.93 (1H, d, J=8.6 Hz), 7.55-7.45 (2H, m), 4.02 (3H, s). MS (ES+) C16H10BrN3O2 requires: 355/357, found: 356/358 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1(O)[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C@H]2CC[C@H](CCC)CC2)[CH2:14][CH2:13]1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33](S(O)(=O)=O)=[CH:32][CH:31]=1.O.[C:42]1(C)C=CC=C[CH:43]=1>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C@H:33]2[CH2:34][CH2:35][C@H:30]([CH2:40][CH2:42][CH3:43])[CH2:31][CH2:32]2)[CH3:19])[CH2:14][CH:13]=1
Reactant: CCC[C@H]1CC[C@H](CCC2CCC(O)(c3ccc(OCC)c(F)c3Cl)CC2)CC1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCC[C@H]1CC[C@H](C(C)C2CC=C(c3ccc(OCC)c(F)c3Cl)CC2)CC1

Procedure:
16.4 g of the compound (8), 0.2 g of p-toluenesulfonic acid and 80 mL of toluene were mixed, and the mixture was refluxed under heating for 2 hours while water distilled out was removed. After cooling the resulting reaction mixture to 25° C., 200 mL of water and 200 mL of toluene were added to and mixed with the reaction mixture, which was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography using a mixed solvent of heptane and toluene (heptane/toluene=4/1 by volume) as eluent, and then further purified by recrystallization from a mixed solvent of heptane and ethanol (heptane/ethanol=2/1 by volume) to obtain 6.2 g of 2-chloro-4-ethoxy-3-fluoro-1-(4-(2-(trans-4-propylcyclohexyl)-2-ethyl)-cyclohexa-1-enyl)benzene (No. 103). The yield based on the compound (7) was 42.4%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:18][OH:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCOC(C)=O>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](C=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of [(S)-3-(4-bromo-phenyl)-1-hydroxymethyl-propyl]-carbamic acid tert-butyl ester (11.5 g) and triethylamine (27.9 ml) in DMSO (70 ml) was added dropwise sulfur trioxide-pyridine complex (16.0 g) while the reaction mixture was cooled in a ice bath. The mixture was then stirred at room temperature for 30 min to afford a yellow solution. The reaction mixture was poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane/EtOAc 3/1) to afford [(S)-3-(4-bromo-phenyl)-1-formyl-propyl]-carbamic acid tert-butyl ester as a yellow oil (7.3 g, 64%). MS (EI): 343 ([{81Br}M]+), 341 ([{79Br} M]+), 287 ([{81Br}M-C4H8]+), 285 ([{79Br} M-C4H8]+), 214 ([{81Br}M-C4H8—CO2]+), 212 ([{79Br} M-C4H8—CO2]+), 171, 169, 103, 57 ([C4H9]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:36])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:25]([NH:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:26])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:34][CH3:35])=[CH:13][CH:12]=1)=[O:10].[OH-].[K+]>O.CO>[Cl:36][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:34][CH3:35])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)CNC(=O)Nc1ccc2oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NC(=O)NCC(=O)O)cc12
Yield: 35.5 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylamino carbonylamino)-dibenzo[b,d]furan-1-carboxamide (Example 50) (150 mg, 0.28 mmol) was hydrolysed using potassium hydroxide (2 eq.) in 3 ml water and 3 ml methanol for 30 min. at room temperature. The solid precipitated was filtered and washed with methanol to obtain the product as white solid (50 mg).mp: >250° C.