Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:10]=1>>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[C:11]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:10]=[C:9]2[O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: Oc1ccccc1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccccc3)c2c1

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (7-Methoxy-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:36].CO>>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: N
Solvent: CO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 80 °C

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.371 mmol) and ammonia in MeOH 7M (6 ml, 42.0 mmol) and heating to 80° C. overnight, the title compound was obtained as an off-white solid (158 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (s, 1H), 7.93 (d, J=5.1 Hz, 1H), 7.40-7.56 (m, 3H), 7.35-7.41 (m, 1H), 7.28-7.35 (m, 1H), 7.20-7.28 (m, 1H), 6.71 (s, 2H), 5.79 (d, J=5.1 Hz, 1H), 1.35 (s, 9H). MS (ESI): 520.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[NH:14]C(=O)N[C:11]3=[O:16])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-:17].[Ba+2].[OH-]>O>[CH:7]1[C:6]([CH:10]([NH2:14])[C:11]([OH:16])=[O:17])=[CH:5][C:4]2[CH:3]=[CH:2][NH:1][C:9]=2[CH:8]=1
Reactant: [OH-]
Reactant: O=C1NC(=O)C(c2ccc3[nH]ccc3c2)N1
Agent: [Ba+2]
Solvent: O
Product: NC(C(=O)O)c1ccc2[nH]ccc2c1

Procedure:
17.3 g (0.08 mole) of 6e are stirred analogously to Example 1d with 92.12 g (0.292 mole) of barium hydroxide in 560 ml of water at 100° C. for 24 hours.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:33])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.95 min; [M+H]+=442.07.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:3]=1[C:4](OC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].ClCCl>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[C:3]=1[CH2:4][OH:5]
Reactant: CCN(CC)Cc1cccc(Cl)c1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(CC)Cc1cccc(Cl)c1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
To methyl 2-chloro-6-[(diethylamino)methyl]benzoate (3.97 g, 15.5 mmol) in anhydrous THF (100 mL) was added a solution of diisobutylaluminium hydride (1 M in toluene, 35 mL, 35 mmol). The reaction mixture was stirred at room temperature for 90 minutes. A Rochelle's salt solution (200 mL) and dichloromethane (200 mL) were added. The mixture was stirred at room temperature for 2 hours. The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording {2-chloro-6-[(diethylamino)methyl]phenyl}methanol (3.0 mg, 85% yield), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C([O-])=O)[C:5]([O:8][CH:9]([C:11]#[N:12])[CH3:10])=[CH:6][CH:7]=1.[OH-:16].[K+].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([OH:16])[C:5]([O:8][CH:9]([C:11]#[N:12])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C#N)Oc1ccc(Cl)cc1C(=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CC(C#N)Oc1ccc(Cl)cc1O
Reaction time: 8 h

Procedure:
3-Chloro-6-(1-cyanoethoxy)-phenyl-formate (56.4 g., 0.25 mole) is added to a solution of 85% potassium hydroxide (17.1 g., 0.26 mole) in 95% alcohol (200 ml.) at ambient temperature, and the mixture then stirred overnight under nitrogen. The reaction mixture is treated with a slight excess of dilute hydrochloric acid, and most of the alcohol removed under reduced pressure. The product is extracted with ether, the ethereal extract is washed with water, then with 5% sodium carbonate solution and again with water. The ethereal extract then is dried over magnesium sulfate and then over calcium sulfate and the ether removed by evaporation yielding 3-chloro-6-(1-cyanoethoxy)-phenol, which is crystallized from chloroform-petroleum ether.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[C:47]([C:49]1[CH:57]=[CH:56][C:52]([C:53](Cl)=[O:54])=[CH:51][CH:50]=1)#[N:48]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:53](=[O:54])[C:52]2[CH:56]=[CH:57][C:49]([C:47]#[N:48])=[CH:50][CH:51]=2)[CH2:42][CH2:41]1)=[O:39]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)N2CCC(C(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[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-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4-cyanobenzoyl chloride as starting materials in 20% yield. LCMS for C32H29ClN7O2 (M+H)+: m/z=578.2.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])=[N+:2]=[N-:3].C(N(CC)CC)C.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: [N-]=[N+]=NCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a solution in which the 2-(2-(2-azidoethoxy)ethoxy)ethanol (3.05 g, 17.40 mmol) compound of Chemical Formula 8 was dissolved in methylene chloride (15 mL), 4-dimethylaminopyridine (DMAP) (212.6 mg, 1.74 mmol), triethylamine (TEA) (7.28 mL, 52.20 mmol) and tosyl chloride (3.98 g, 20.88 mmol) were added consecutively at room temperature. The post-reaction mixture obtained after stirring the reaction mixture for 12 hours at room temperature was partitioned to distilled water (40 mL) and ethyl acetate (120 mL). The organic layer was separated, washed with saturated salted water (15 mL), dried with anhydrous sodium sulfate, and vacuum distilled to give 2-(2-(2-azidoethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (5.15 g, 90%). 1H NMR (500 MHz, CDCl3) δ 7.79 (d, 2H, J=8.2 Hz), 7.33 (d, 2H, J=8.2 Hz), 4.15 (t, 2H, J=5.0 Hz), 3.69 (t, 2H, J=5.0 Hz), 3.63 (t, 2H, J=5.5 Hz), 3.59 (s, 4H), 3.36 (t, 2H, J=5.0 Hz), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 144.9, 133.0, 129.9 (2), 128.0 (2), 70.8, 70.7, 70.1, 69.3, 68.8, 50.7, 21.7.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH:7]=[N:8][OH:9])[C:4]([CH3:11])([CH3:10])[O:3]1.[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:9][N:8]=[C:7]([Cl:13])[C@H:5]1[C:4]([CH3:11])([CH3:10])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CC1(C)O[C@@H](C=NO)C(C)(C)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H](C(Cl)=NO)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
(S)-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13 g, 75.1 mmol) was dissolved in DMF (200 mL) and cooled in an ice bath. 1-Chloropyrrolidine-2,5-dione (10.0 g, 75.1 mmol) was added and the reaction was stirred overnight while slowly warming to ambient temperature. The pale yellow solution was poured into water (1.5 L) and extracted with EtOAc. The organic layers were washed with water and brine, dried, filtered and concentrated. The residue was purified over silica gel (40% EtOAc in hexanes) to afford (R)-N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride (12.4 g, 59.7 mmol), 79.6% yield).
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:19]([OH:26])(=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[C:19]([OH:26])(=[O:25])[CH:20]([CH2:21][C:22]([OH:24])=[O:23])[OH:1]
Reactant: O=C(O)CCC(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CC(O)C(=O)O
Temperature: 33 °C

Procedure:
The coryneform bacterium cells prepared after culturing were added to 500 ml of the reaction stock solution in a reaction container under the nitrogen gas atmosphere. Glucose 200 mM and sodium carbonate 200 mM were added, and the reaction temperature was maintained at 33° C. to perform a reaction producing an organic compound. An oxidation-reduction potential was initially −200 mV, but was reduced immediately after the initiation of the reaction, and the reaction was continued by maintaining the oxidation-reduction potential at −400 mV. After the reaction for 3 hours, the reaction medium solution was analyzed by liquid chromatography, indicating that succinic acid 163 mM (19.2 g/L) and malic acid 5 mM (0.67 g/L) were produced. Lactic acid was not detected.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([N:30]2[CH:36]3[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]3)[CH2:32][C:31]2=[O:39])=[CH:26][CH:25]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH:36]6[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]6)[CH2:32][C:31]5=[O:39])=[CH:28][N:29]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCCC1
Reactant: Nc1ccc(N2C(=O)CN3CCC2CC3)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C(=O)CN5CCC4CC5)cn3)nc2n1C1CCCCCC1
Yield: 77 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide was combined with 4-(6-aminopyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one and gave 7-cycloheptyl-N,N-dimethyl-2-(5-(3-oxo-1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (103 mg) in 77% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.73 (s, 1H), 8.66 (d, J=9.09 Hz, 1H), 8.17 (d, J=2.02 Hz, 1H), 8.14 (s, 1H), 7.55 (dd, J1=9.09 Hz, J2=2.53 Hz, 1H), 6.45 (s, 1H), 4.53 (m, 1H), 3.95 (s, 2H), 3.83 (m, 1H), 3.21 (m, 10H), 2.64 (m, 2H), 2.42 (m, 2H), 2.14-1.54 (m, 12H); HRMS m/z 517.3049 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:27]=[CH:26][C:13]3[N:14]([C:18](=O)[CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[CH:21]4)[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([S:7]([C:10]2[CH:27]=[CH:26][C:13]3[N:14]([CH2:18][CH2:19][N:20]4[CH:24]=[CH:23][NH:22][CH2:21]4)[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cn1ccnc1)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2CCN1C=CNC1

Procedure:
7-Benzenesulfonyl-4-[2-(3H-imidazol-1-yl)-ethyl]-3,4-dihydro-2H-benzo[1,4]oxazine was prepared by reducing 1-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-imidazol-1-yl-ethanone with BH3:THF using the procedure of Example 9. mp: 61.5-64.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1.Cl[CH:21]([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Na]>C(O)C.C(OCC)C>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:17])[F:18])[C:12]([CH3:19])=[N:11]2)=[CH:4][C:5]=1[O:9][CH:21]([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: CCOC(=O)C(F)Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(F)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Yield: 35.3 %

Procedure:
To a stirred mixture of 2.0 g (0.0065 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 0.91 g (0.0065 mole) of ethyl chlorofluoroacetate in 50 mL of ethanol was added a solution of 0.15 g (0.0065 mole) of sodium in 5 mL of ethanol. The reaction mixture was heated at reflux for 34 hours. The mixture was cooled, and the solvent was removed by evaporation under reduced pressure, leaving a residue. This residue was dissolved in diethyl ether, and the solution was washed first with water, followed by an aqueous 10% sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate, then filtered. The filtrate was evaporated under reduced pressure to yield 0.95 g of ethyl [2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]fluroacetate as an oil, Compound 51.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:20][C:21]([CH3:22])=[O:23])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCC2=O
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc2c(CC(C)=O)coc12

Procedure:
A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and 1-triphenylphosphoranylidene-2-propanone (4.77 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, 1-(7-methoxy-1-benzofuran-3-yl)acetone, was obtained as a red oil. Yield: 1.4 g (68%); (M+H): 205.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[C:19]([NH:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Solvent: CC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(NC(=S)NC(=O)c3ccccc3)cc2)cs1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
To an ice-cold solution of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (300 mg) prepared in a similar manner according to Step 6 of Production Example 1 in acetone (5 ml) was added benzoyl isothiocyanate (187 mg) and the mixture was refluxed for 2 hours. The reaction mixture was cooled to 0° C. The precipitated crystals were filtered and washed with ice-cold acetone to give N-{4-[2-(4-{[(benzoylamino)carbonothioyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide (359 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([CH2:12][C:13](O)=[O:14])#[N:11].CN(C)CCCN=C=NCC.Cl.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13](=[O:14])[CH2:12][C:10]#[N:11]
Reactant: Nc1ccc(F)cc1Br
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC(=O)Nc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
A mixture of 2-bromo-4-fluoroaniline (10.0 g, 52.6 mmol), cyanoacetic acid (5.36 g, 63.1 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide•hydrochloride (15.1 g, 78.9 mmol), 1H-1,2,3-benzotriazol-1-ol (10.6 g, 78.9 mmol), triethylamine (10.9 mL, 78.9 mmol) and N,N-dimethylformamide (150 mL) was stirred at room temperature for 16 hr. The mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a pad packed with NH silica gel. The solvent was evaporated under reduced pressure, and the obtained residue was washed with hexane and collected by filtration to give the title compound (8.04 g, 59%) as a white solid.
Reaction SMILES: O[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C1(C)C=CC(S([Cl:35])(=O)=O)=CC=1.Cl>N1C=CC=CC=1>[Cl:35][CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CO)[C@@]3(C)CC(=O)[C@@H]12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCl)[C@@]3(C)CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
21-Hydroxy-5α-pregnane-3,11,20-trione (3.0 g.) in anhydrous pyridine (15 ml.) was treated with toluene-4-sulphonyl chloride (3.0 g.) and the pale orange solution was stirred at room temperature for 3 hours. The cold solution was vigorously stirred during the slow addition of ice-cold water (200 ml.) and hydrochloric acid (2N;50 ml.). The yellow crystalline precipitate was filtered off, washed well with water and dried in vacuo at 60°, and the resulting crude product (2.4 g.) was recrystallized from acetone/petrol to give crude title compound (1.13 g.) as an off-white crystalline solid, m.p. 168°-172°, [α]D + 137° (c 1.13).
Reaction SMILES: [OH:1][CH:2]([CH:12]1[CH:19]2[CH:15]([O:16][C:17](=[O:20])[CH2:18]2)[CH2:14][CH:13]1[CH3:21])[CH:3]=[CH:4][C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:22]([O:1][CH:2]([CH:12]1[CH:19]2[CH:15]([O:16][C:17](=[O:20])[CH2:18]2)[CH2:14][CH:13]1[CH3:21])[CH:3]=[CH:4][C:5]([CH3:10])([CH3:11])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:24])[CH3:23]
Reactant: CCCCC(C)(C)C=CC(O)C1C(C)CC2OC(=O)CC21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCC(C)(C)C=CC(OC(C)=O)C1C(C)CC2OC(=O)CC21

Procedure:
Following the procedure of example VII, 48.9 g, of crude, optically active [3aR-[3a alpha,4alpha(1S*,2E), 5beta,6a alpha-]]-4-[1-(hydroxy)-4,4-dimethyl-2-octenyl]hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one was acetylated with 60 ml of acetic anhydride and 0.5 g of 4-dimethylaminopyridine in 400 ml of ethyl acetate. The product was crystallized from 60 ml of hexane giving 30.05 g of optically active [3aR-[3alpha,4alpha(1S*,2E),5beta,6a alpha-]]-4-[1-(acetyloxy)-4,4-dimethyl-2-octentyl]-hexahydro- 5-methyl-2H-cyclopenta[b]furan-2-one in colorless crystals with mp 83°-83.5°.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:22][N:23]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([C:12]1[N:13]([CH3:18])[C:14]2[C:10]([CH:11]=1)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=2)=[O:21]
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Reactant: CNCCc1ccccc1
Product: CN(CCc1ccccc1)C(=O)c1cc2c(O)cccc2n1C

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and N-methylphenethylamine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=309.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH:53]=2)[NH:48][C:47]=1[C:63](O)=[O:64].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56](=[O:57])[O:58][C:59]([CH3:60])([CH3:61])[CH3:62])[CH:53]=2)[NH:48][C:47]=1[C:63]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:64]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)c(Cl)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
HATU (0.119 g, 0.314 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.055 g, 0.209 mmol), 3-chloro-5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.065 g, 0.209 mmol) and diisopropylethylamine (0.055 mL, 0.314 mmol) in DMF (1 mL). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.033 g, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 9.28 (br. s., 1H), 8.44 (t, 1H), 7.78 (br. s., 2H), 7.48 (d, 2H), 7.35-7.45 (m, 2H), 7.26-7.32 (m, 1H), 7.19-7.26 (m, 1H), 4.58 (d, 2H), 1.42 (s, 9H). ES MS: m/z 601 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:49][CH2:50][CH:51]([NH2:62])[C:52]1[NH:56][C:55]2[CH:57]=[CH:58][C:59]([Cl:61])=[CH:60][C:54]=2[N:53]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:61][C:59]1[CH:58]=[CH:57][C:55]2[NH:56][C:52]([CH:51]([NH:62][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:50][OH:49])=[N:53][C:54]=2[CH:60]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NC(CO)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C(=O)NC(CO)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 68 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 2-hydroxy-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 68%; Rf value: 0.40 (silica gel; dichloromethane/ethanol=95:5); C22H23ClN4O3 (426.90); mass spectrum: (M+H)+=427/429 (chlorine isotope) and (M−H)-=425/427 (chlorine isotope).