Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14](O)[C:15]=3[N:16]=2)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:29])=O>CN(C=O)C>[Cl:29][C:14]1[C:15]2[N:16]=[C:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:19])([CH3:1])[CH2:3][CH2:4]3)[S:9][C:10]=2[N:11]=[C:12]([CH3:18])[N:13]=1
Reactant: Cc1nc(O)c2nc(C3CCC(C)(C)CC3)sc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-ol (16.2 g) and toluene (160 mL) were added DMF (10 mL) and phosphorous oxychloride (11 mL), followed by stirring at 95° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added chloroform, and the mixture was neutralized with a 1 M aqueous NaOH solution in an ice bath and extracted with chloroform. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain 7-chloro-2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine (13.2 g).
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:62]([O:64][C:65](=[O:74])[CH2:66][C@H:67]1[CH2:72][CH2:71][C@H:70]([NH2:73])[CH2:69][CH2:68]1)[CH3:63]>CN(C=O)C>[CH2:62]([O:64][C:65](=[O:74])[CH2:66][C@H:67]1[CH2:68][CH2:69][C@H:70]([NH:73][C:8](=[O:10])[CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:71][CH2:72]1)[CH3:63]
Reactant: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)O)C1CCCCC1
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H]1CC[C@H](NC(=O)C(C2CCCCC2)n2c([C@H](OC)c3ccccc3)nc3cc(F)ccc32)CC1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of cyclohexyl-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetic acid (350 mg, 0.88 mmol, 1.0 equiv) in DMF (5 mL) was added triethylamine (179 mg, 240 μL, 1.77 mmol, 2.0 equiv) and HATU (403 mg, 1.06 mmol, 1.2 equiv) and the mixture stirred at 40° C. After 15 min, trans-(4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (235 mg, 1.06 mmol, 1.2 equiv; [CAS RN 76308-26-4]) was added and stirring continued at 50° C. for 2 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was used in the consecutive step without further purification. MS (ISP): 564.7 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].S(=O)(=O)(O)O>C(#N)C.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:15](=[O:17])[CH3:16])(=[O:12])=[O:11])=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(C(C)=O)cc1Cl
Reaction time: 0.67 h

Procedure:
To a solution of the product obtained in step 2 (0.40 mg, 1.71 mmol) in ACN (3 ml) was added acetic anhydride. Concentrated sulphuric acid (2.8 μl, 5 mg, 51 μM) was added at 60° C. and the reaction mixture was stirred for 40 min at that temperature. The cooled reaction mixture was diluted with water, extracted with dichloromethane, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The desired product was obtained (yield: 460 mg, 97%) and used in the following step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:23][C:24]([O:26][CH2:27]C)=[O:25]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][N:11]1[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc(COCC2CN2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1CC1COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of 2-[(benzyloxy)methyl]aziridine (0.42 g, 2.57 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.90 mmol) in dichloromethane (15 mL) under an atmosphere of nitrogen, ethyl bromoacetate (0.39, 2.5 mmol) was added over a period of 1 h. The resultant mixture was allowed to slowly warm up to room temperature and stirred overnight. The resultant mixture was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 70% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH:1]([Cl:4])([Cl:3])[Cl:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[O:16])[CH:10]=[C:11]([CH:13]=[O:14])[CH:12]=1.[OH-].[K+]>CN(C=O)C.CO>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]([OH:16])[C:1]([Cl:4])([Cl:3])[Cl:2])[CH:10]=[C:11]([CH:13]([OH:14])[C:1]([Cl:4])([Cl:3])[Cl:2])[CH:12]=1
Reactant: ClC(Cl)Cl
Reactant: COc1cc(C=O)cc(C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(C(O)C(Cl)(Cl)Cl)cc(C(O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 0.60 g (5 mmol) of chloroform in 2 mL DMF was added 0.1 64 g (1.0 mmol) of 5-methoxy-1,3-diformylbenzene (Provent, C; Chautemps, P.; Gellon, G.; Pierre, J.-L. Tetrahedron Lett. 1996, 347 1393-96). The reaction mixture was chilled to 0° C. and a solution of 39.5 mg (0.7 mmol) of potassium hydroxide in 0.2 mL of methanol was added. The reaction mixture was stirred for 20 min at 0° C., then was quenched by addition of 1 mL of 1 N hydrochloric acid. The reaction mixture was adjusted to pH=7, then extracted with EtOAc. The organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:16])=O.[BH4-].[Na+].S(=O)(=O)(O)O>O1CCCC1.C(O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:15]([N:6]2[CH2:7][C@H:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH2:9][C@H:5]2[CH2:3][OH:2])=[O:16])=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (79.4 g: 205 mmole) in a mixture of tetrahydrofuran (200 ml) and ethanol (300 ml), sodium borohydride (14 g) is added in several portions under ice cooling. The mixture is stirred at room temperature for 4 hours. The reaction mixture is neutralized with conc. sulfuric acid, concentrated in vacuo to approximately a half volume, diluted with water, and extracted with ethyl acetate. The extract is successively washed with aqueous sodium hydrogen carbonate, water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=1:2) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (58.7 g). Yield: 81.7%. NMR δ(CDCl3) ppm: 1.8 to 2.2(m, 1H), 2.3 to 2.5(m, 1H), 3.01(s, 3H), 3.57 (d, J=4.4 Hz, 1H), 3.64(d, J=4.4 Hz, 1H), 3.81(s, 3H), 3.82 to 4.3(m,3H), 5.09(s, 2H), 5.21(br s, 1H), 6.89(d, J=8.8 Hz, 2H), 7.31(d, J=8.8 Hz,2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[CH:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br.COC1C=CC(CC2C=CC(C[Br:32])=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[CH:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][Br:32])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=Cc2ccc(CO)cc2)cc1
Reactant: COc1ccc(Cc2ccc(CBr)cc2)cc1
Agent: Br
Solvent: ClCCl
Product: COc1ccc(C=Cc2ccc(CBr)cc2)cc1

Procedure:
4-(4-Methoxystyryl)benzyl bromide was prepared from 55 g. of 4-(4-methoxystyryl)benzyl alcohol and hydrogen bromide in 750 ml. of methylene dichloride according to the procedure of Example 1, part (e); yield 50 g., m.p. 147°-148° C. when recrystallized from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:30][CH2:29][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])=[O:19])[C:9]3=[O:28])[C:6]=2[CH:7]=1.BrC1C=CC2C3(COC=2C=1)C1C(=CC=CC=1)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])C3=O>>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:6]3[CH:7]=[C:2]([C:50]4[CH:51]=[N:40][CH:47]=[CH:48][CH:49]=4)[CH:3]=[CH:4][C:5]=3[O:30][CH2:29]2)[C:9]1=[O:28]
Reactant: O=C(CN1C(=O)C2(COc3ccc(Br)cc32)c2ccccc21)Nc1ccccc1F
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Product: O=C(CN1C(=O)C2(COc3ccc(-c4cccnc4)cc32)c2ccccc21)Nc1ccccc1F
Yield: 55 %

Procedure:
Following the procedure as described in EXAMPLE 37, and making non-critical variations using 2-(5-bromo-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide to replace 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, the title compound was obtained (55% yield) was obtained as a white solid: mp 98-100° C.; 1H NMR (300 MHz, CDCl3) δ 8.60-8.53 (m, 2H), 8.14 (dd, 1H), 7.65 (dd, 1H), 7.41 (dd, 1H), 7.32-6.90 (m, 11H), 5.02 (d, 1H), 4.76 (d, 1H), 4.72 (d, 1H), 4.56 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 177.9, 164.8, 160.9, 154.2, 151.0, 147.1,141.7, 134.2, 131.7, 131.5, 129.9, 129.4, 129.1, 125.1, 124.6, 124.5, 124.2, 124.0, 122.5, 122.2, 115.1, 114.8, 111.0, 109.1, 80.0, 58.1, 44.6; MS (ES+) m/z 466.4 (M+1).
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]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH2:22][C:21]([C:29]([O:31]C)=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.O>[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]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.3 %

Procedure:
To a solution of methyl 7-[4-(2-butoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.94 g) in THF-water (20-20 ml) was added 1N aqueous solution of sodium hydroxide (8.0 ml) at room temperature and the mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and to the residue was added 1N hydrochloric acid (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.23 g) as colorless crystals.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:5][CH2:4]1)=[O:2].[CH2:23]([S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26])[CH3:24]>>[CH2:23]([S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:21]\[C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:12]=1[CH2:11][CH2:10][CH2:9][N:6]1[CH2:5][CH2:4][N:3]([CH:1]=[O:2])[CH2:8][CH2:7]1)(=[O:26])=[O:27])[CH3:24]
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(C=O)CC1)CCCC2
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C=O)CC1)CCCC3)C(=O)N2
Yield: 65.3 %

Procedure:
3-[3-(4-Formyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (91 mg, 0.3 mmol), prepared as described in Example 8, Steps 1-4 above, was condensed with 5-ethylsulfonyloxindole (67 mg, 0.3 mmol, 50%pure) following the procedure used in Example 1 above. The reaction mixture was purified by flash chromatography using (dichloromethane: methanol 30/1, 20/1, 15/1) to give (100 mg, 64% yield) of the desired product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:29][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccccc4F)c3O2)cc1
Product: CNCC1Cc2cc(Cl)cc(-c3ccccc3F)c2O1

Procedure:
The title compound was prepared (0.037 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.142 g, 0.33 mmol) and methylamine (0.102 g, 3.3 mmol). mp 159-161° C.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C(O)(=O)C>CO.[Pd]>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:2][CH2:3]2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Reaction time: 96 h
Yield: 29.6 %

Procedure:
Benzyl 1-piperazinecarboxylate (5.00 g) and tert-butyl 4-oxopiperidine-1-carboxylate (4.52 g) were dissolved in methanol (100 ml), and acetic acid (2.34 ml) and 10% palladium on carbon (1.55 g) were added thereto, followed by stirring under a hydrogen atmosphere for 4 days. The catalyst was removed by filtration, and the filtrate was concentrated. To the residue were added acetone (50 ml) and water (50 ml) to dissolve, and sodium hydrogencarbonate (6.67 g) was added and stirred while cooling in an ice bath. Benzyl chloroformate (3.89 ml) was added thereto, followed by stirring in an ice bath for 3.5 hr. Part of the reaction mixture was concentrated, and ethyl acetate:tetrahydrofuran=1:1 (200 ml) and water (100 ml) were added thereto, followed by stirring at room temperature for 10 min. The organic layer was separated. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. This was concentrated, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=50:1). Fractions containing the target compound were concentrated to provide the titled compound as a pale yellow oil (2.71 g, 29.6%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]#[CH:6])[C@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C=O.[CH:17](NC(C)C)(C)C.Cl>O.[Cu](Br)Br.O1CCOCC1>[CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5]=[C:6]=[CH2:17])[C@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)NC(C)C
Reactant: C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Br[Cu]Br
Agent: C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C=C=C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 80 °C

Procedure:
A mixture of 131 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-ethynyl-cyclopropane-carboxylate, 32 g of paraformaldehyde, 111 ml of diisopropylamine, 31 g of copper bromide and 1,300 ml of dioxane was heated at 80° C. for 161/2 hours and was cooled to 20° C. and diluted with water. The mixture was adjusted to a pH of 1 with aqueous N hydrochloric acid and was extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 1-1 hexane-methylene chloride mixture yielded 44 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])[C:15]([N:16]([CH3:17])[CH3:18])=[O:19]
Reactant: CN(C)C(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1cc(Cl)c(F)c(CN)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (3-chloro-5-dimethylcarbamoyl-2-fluoro-benzyl)-carbamic acid tert-butyl ester (115 mg, 0.33 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL). The reaction mixture was stirred for 1 h at ambient temperature and the solvent was removed in vacuo to give the title compound. MS (LC/MS): 231.0 [M]+. tR (HPLC conditions c): 2.59 min.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[C:8]([OH:15])=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:15][C:8]1[C:7]([Cl:6])=[CH:12][C:11]([Cl:13])=[C:10]([Cl:14])[N:9]=1)[O:4][CH3:5]
Reactant: Oc1nc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Oc1nc(Cl)c(Cl)cc1Cl

Procedure:
Methyl 3,5,6-trichloro-2-pyridyl carbonate was prepared by reacting methyl chloroformate with 3,5,6-trichloro-2-pyridinol at 0° C.-5° C. in the presence of an equivalent of pyridine as acid acceptor and using methylene chloride as the reaction solvent.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8](=O)[C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N1CCCC(=O)C(=O)C1)(=O)C.Br.Br.[NH2:27][CH2:28][C:29]([NH2:31])=[NH:30]>>[NH2:31][C:29]1[CH:28]=[N:27][C:8]2[CH2:9][CH2:10][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6][C:7]=2[N:30]=1
Reactant: CC(=O)N1CCC(=O)C(=O)CC1
Reactant: N=C(N)CN
Agent: Br
Agent: CC(=O)N1CCCC(=O)C(=O)C1
Product: CC(=O)N1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 13 by reacting a mixture of 1-acetyl-hexahydroazepine-4,5-dione and 1-acetyl-hexahydroazepine-3,4-dione (prepared from 1-acetylhexhydroazepine-4-ones by selenium dioxide oxidation in dioxane/water) with 2-amino-acetamidine dihydrobromide.
Reaction SMILES: C([O:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:38])[CH:18]([C:24]2[CH:33]=[CH:32][C:31]3[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=3[CH:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd].CCCCC>[CH3:34][C:30]1([CH3:35])[CH2:29][CH2:28][C:27]([CH3:36])([CH3:37])[C:26]2[CH:25]=[C:24]([CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O:16][C:13]3[CH:12]=[CH:11][C:10]([C:9]([OH:39])=[O:8])=[CH:15][CH:14]=3)=[O:38])[CH:33]=[CH:32][C:31]1=2
Reactant: CCCCCC(C(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: CCCCCC(C(=O)Oc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
403 mg of (RS)-Benzyl-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanoyloxy]-benzoate in 10 ml of ethyl acetate with 80 mg of palladium on carbon (10% w/w) was subjected to an atmospheric pressure of hydrogen for 1 hour. The mixture was filtered over Celite and washed with about 10 ml ethyl acetate. The solution was evaporated, giving a colorless oil. Trituration in pentane gave a white amorphous solid, 303 mg, m.p. 133-135° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].C(=O)=O.C(O)(C)C.C1([Mg]Br)C=CC=CC=1.[CH:28](=[O:32])[CH:29]([CH3:31])[CH3:30]>O1CCCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc([N+](=O)[O-])c(I)c1
Reactant: CC(C)C=O
Agent: Br[Mg]c1ccccc1
Agent: O=C=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)C(O)c1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.7 %

Procedure:
To a solution of 3-iodo-4-nitrobenzonitrile (314 mg, 1.14 mmol) in anhydrous tetrahydrofuran (5.5 mL) cooled at minus 45° C. (dry ice-isopropanol bath) under nitrogen atmosphere, phenylmagnesium bromide (2 M in THF, 3.16 mL, 6.32 mmol) was added at a rate to keep the temperature at or below minus 40° C. Upon completion of the addition the mixture was stirred for five minutes, then isobutyraldehyde (0.957 mL, 10.54 mmol) was added. The mixture was allowed to gradually warm up to room temperature, then quenched with saturated NH4Cl (2 mL) and poured into water (50 mL)/dichloromethane (50 mL). The organic layer was separated; aqueous layer was extracted three times with dichloromethane (25 mL each). Combined organic extract was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to yield racemic (RS)-1-(5-cyano-2-nitrophenyl)-2-methyl-1-propanol (57 mg, 23%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 1 H, J=8.1 Hz, Ph-H), 7.74 (s, 1 H, Ph-H), 7.21 (d, 1 H, J=8.1 Hz, Ph-H), 4.72 (d, 1 H, J=3.6 Hz, Ph-CH), 2.33 (br. s, 1 H, OH), 2.03 (m, 1 H, CHCH(CH3)2), 1.04 (d, 3 H, J=6.8 Hz, CH3), 0.89 (d, 3 H, J=6.6 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 147.78 (C), 140.25 (CH), 131.40 (CH), 131.24 (CH), 118.36 (C), 112.27 (CN), 103.82 (C), 80.80 (CH), 33.56 (CH), 19.70 (CH3), 15.62 (CH3).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH:11]=2)[CH:2]=1.[NH3:31]>CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:28])[F:30])[CH:11]=2)[CH:2]=1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cccnc32)cc1OCc1ccccc1C(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cccnc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 20, 4.41 g of methyl 5-(3H-imidazo[4,5-b]pyridin-3-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B5b) and 400 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])[C:2]#[CH:3].S(Cl)([Cl:20])=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([Cl:20])=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])[C:2]#[CH:3]
Reactant: C#CCOc1c(OC)cc(C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Yield: 85.6 %

Procedure:
To 100 ml of toluene were added 13.0 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoic acid, 9.5 g of thionyl chloride and 50 mg of DMF, and the mixture obtained was heated under reflux for 3 hours. Then, the reaction mixture was concentrated. The solid obtained was washed with hexane to obtain 12.0 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride represented by the formula: