Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].Cl>C1C=CC=CC=1.O1CCOCC1>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[Cl:14])[C:4]([CH2:8][CH2:9][CH3:10])=[N:3]1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCCc1cc(=O)n(C)[nH]1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCCc1nn(C)c(O)c1C(=O)c1ccccc1Cl
Temperature: 50 °C
Yield: 9.2 %

Procedure:
1.4 g. of 1-methyl-3-n-propyl-5-pyrazolone is dissolved in 10 ml. of dioxane with heating and then 1.5 g. of calcium hydroxide is added to the resulting solution. 1.75 g. of 2-chlorobenzoyl chloride is added dropwise with stirring at 50° C. After completion of the dropwise addition, the mixture is heated under reflux for 1 hour. After completion of the reaction, the reaction mixture is allowed to cool and 100 ml. of a 2N hydrochloric acid solution is added thereto. The mixture is extracted with 70 ml. of chloroform and an organic layer is separated. The layer is washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off from the layer to give 2 g. of brown oily residue. The residue thus obtained is dissolved in a small amount of benzene and adsorbed on a silica gel column, which is then eluted with benzene: ethanol (50:1) to give 0.6 g. of crystals. The crystals are recrystallized from methanol-water (7:3) to give 0.25 g. of the desired product as colorless columns having a melting point of 125°-126° C. Yield 9.2%
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:21])[C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:28])(=O)=O.O>ClCCl>[NH2:13][C@H:10]([CH2:11][O:12][CH3:28])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC[C@@H](N)C(=O)NCc1ccccc1
Temperature: -10 °C
Reaction time: 4 h

Procedure:
Accordingly to a solution of the compound tert-butyl [(R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxoethyl]carbamate of Formula-XXI in dichloromethane, charged the phase transfer catalyst and cooled the reaction mass to −10° C. and charged dilute solution of sodium hydroxide. Maintaining the temperature at −10° C.-0° C. charged dimethyl sulfate and maintained the reaction under stirring for 3-5 hours. Charged water at the end of the reaction, stirred, separated the organic layer and extracted the aqueous layer with the dichloromethane. Combined the organic layer and acidified with concentrated hydrochloric acid. Charged water to the clear solution and stirred. Separated the aqueous layer and extracted the organic layer further with water. Combined the entire aqueous layer and adjusted the pH to 12 with aqueous sodium hydroxide solution. Extracted the aqueous layer with dichloromethane and separated the organic layer. Extracted the aqueous layer further with dichloromethane to ensure the complete extraction of the desired product. The organic layer is washed and concentrated to isolate the compound (2R)-2-amino-N-benzyl-3-methoxypropanamide of Formula-VIII.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1)c1csc(N)n1
Yield: 32.4 %

Procedure:
Ethyl 4-chloro-2-(4-chlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 37.2 g.), thiourea (9.82 g.), sodium acetate 3 hydrate (17.55 g.), water (80 ml.) and ethanol (80 ml.) were treated in similar manner to that of Example P-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetate (syn isomer, 12.86 g.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([CH:11]=[O:12])=[CH:3][CH:2]=1.[CH3:13][Mg]Br.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([CH:11]([OH:12])[CH3:13])=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ncccc12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(O)c1ccnc2ncccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
[1,8]Naphthyridine-4-carbaldehyde (0.300 g, 1.90 mmol) was dissolved in a mixture of anhydrous toluene (10 mL) and anhydrous THF (10 mL). The solution was cooled to 0° C. and methyl magnesium bromide (1.62 mL of 1.4M in THF/toluene) was added slowly and the solution stirred 1 h while allowing to warm to RT. Satd. aq. ammonium chloride was added until the solution reached a bright yellow color and precipitate was apparent. The solution was passed through a syringe filter and into water, where it was extracted with EtOAc (3×30 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated under vacuum. The product was purified (SGC using MeCN:hexanes eluant in 1:1 ratio initially, then switching to DCM:MeOH:NH4OH eluant in 89:10:1 ratio to finish the compound elution) yielding the title compound (0.079 g). MS (ESI+) for m/z 175 (M+H)+. 1H NMR (CDCl3) δ 8.73 (m, 1H), 8.64 (d, 1H), 8.38 (m, 1H), 7.52 (d, 1H), 7.25 (dd, 1H), 6.32 (bs, 1H), 5.58 (dd, 1H), 1.48 (s, 3H).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([NH2:22])[CH:18]=2)=[CH:13][CH:12]=1.[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29])[CH3:24]>C1COCC1.C(OCC)(=O)C>[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:28]([NH:22][C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)[O:21][N:20]=1)=[O:29])[CH3:24]
Reactant: Nc1cc(-c2ccc(F)cc2)on1
Reactant: CCOC(=O)CC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Yield: 832.3 %

Procedure:
Diisopropyl carbodiimide (0.07 mL, 0.45 mmol) and 5-(4-fluoro-phenyl)-isoxazol-3-ylamine (67 mg, 0.037 mmol) were added to a stirred solution of malonic acid monoethyl ester (50 mg, 0.37 mmol) in THF (1 mL) and stirring was continued at reflux temperature for 4 hrs. The mixture was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate and washed with water, followed by brine solution. The organic layer collected was dried over Na2SO4 and concentrated under reduced pressure to afford 90 mg (81.8% Yield) of N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid ethyl ester.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[CH:49]=[CH:48][CH:47]=[CH:46][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]1)(=O)C.[H-].[Na+].CI>CN(C)C=O>[C:8]([CH2:46][NH:4][CH2:5][CH2:6][C:7]1[CH:49]=[CH:48][CH:47]=[CH:46][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:23][CH:24]=2)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]1)(=[O:9])[CH3:7]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNC(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNCC(C)=O)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.099 g of tert-butyl 3-{2-[2-(2-acetylaminoethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 14a) in 3 ml of N,N-dimethylformamide is admixed with stirring at room temperature with 0.023 g of sodium hydride dispersion (55%). After 30 minutes at room temperature, a solution of 0.055 ml of methyl iodide in 0.4 ml of N,N-dimethylformamide is added dropwise. The reaction mixture is stirred at 75° C. over 18 hours, cooled, poured onto water and extracted with tert-butyl methyl ether (2×). The combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.09 (1.5:1 EtOAc-heptane); Rt=5.84.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCCC)c4ccccc4)ccc3n2C)cc1
Yield: 31 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)amide hydrochloride and n-hexyl chloroformate. Yield: 31% of theory, C36H44N6O5 (640.8); Rf value: 0.42 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=641; (M+H+Na)++=332; (M+Na)+=663.
Reaction SMILES: Cl[Si:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[C:6]1([Si:2]2([CH:12]=[CH2:13])[CH2:5][CH2:4][CH2:3]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cl[Si]1(c2ccccc2)CCC1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=C[Si]1(c2ccccc2)CCC1
Yield: 70 %

Procedure:
A dry 250 ml three neck round bottom flask equipped with a dropping funnel and condenser with nitrogen inlet system. Was placed 4.2 g (23 mmole) 1-chloro-1-phenyl-1-silacyclobutane in 40 ml THF. With stirring, 25 ml (0.1M) vinyl magnesium bromide (in THF) was added dropwise. The mixture was stirred for additional 6 h. Work up, the mixture was distilled to collect 2.8 g 82°-83° C./3.0 mmHg 70% yield was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:17]([C:18]5[C:23]=3[C:22]=2[CH:21]=[CH:20][CH:19]=5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>CCCCCC.O1CCCC1>[CH:9]1[C:8]2=[C:22]3[C:21]([C:5]4[C:4]2=[CH:3][CH:2]=[CH:7][CH:6]=4)=[CH:20][CH:19]=[CH:18][C:23]3=[C:11]([C:12]2[CH:13]=[C:14]([B:29]([OH:34])[OH:30])[CH:15]=[CH:16][CH:17]=2)[CH:10]=1
Reactant: Brc1cccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A flask was charged with 9.2 g of 3-(3-bromophenyl)fluoranthene and 129 mL of tetrahydrofuran. After cooling the reaction solution to −70° C., 17.2 mL of a 1.65 M hexane solution of n-butyllithium was added dropwise to the reaction solution. The mixture was stirred at −70° C. for 2 hours. After the dropwise addition of 17.7 mL of triisopropyl borate to the reaction solution, the reaction solution was stirred at −70° C. for 1 hour. The reaction solution was then stirred for 5 hours while heating the reaction solution to room temperature. After the addition of 2 M hydrochloric acid to the reaction solution so that the reaction solution had a pH in the acidic region, the reaction solution was extracted with ethyl acetate. After removing the aqueous phase, the organic phase was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering the organic phase, the solvent was evaporated under reduced pressure. The residue was washed with a hexane-ethyl acetate mixture to obtain 7.9 g of the target 3-(fluoranthen-3-yl)phenylboronic acid (yield: 95%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)C.O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([CH2:11][CH:8]3[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Cc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C1CCC(Cc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 26.6 %

Procedure:
The mixture of (R)-4-(6-((4-tert-butylcyclohexyl)methyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (18.6 mg, 0.0000490 mol) and lithium hydroxide (12.9 mg, 0.000539 mol) in ethanol (1 mL, 0.02 mol) and water (0.50 mL, 0.028 mol) was heated to reflux overnight. The solvent was removed under vacuum and the residue was partitioned between water/CH2Cl2. The aqueous was extensively extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into methylene chloride and subjected to chromatography with MeOH/CH2Cl2 (10:90 to 80:20) to give (R)-2-amino-2-(6-((4-tert-butylcyclohexyl)methyl)naphthalen-2-yl)propan-1-ol as a white solid (4.6 mg, 26%). LCMS: Rf=1.76 min 337.36 [M-NH2]+. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.88 (s, 1 H), 7.77 (d, J=8.0 Hz, 1 H), 7.74 (d, J=7.0 Hz, 1 H), 7.56 (s, 1 H), 7.52 (dd, J=1.8, 8.7 Hz, 1 H), 7.32 (d, J=8.3 Hz, 1 H), 3.82-3.75 (m, 1 H), 3.72-3.67 (m, 1 H), 2.80 (d, J=8.0 Hz, 2 H), 2.69 (br. s., 1 H), 2.08 (br. s., 1 H), 1.64 (d, J=12.9 Hz, 2 H), 1.56 (br. s., 5 H), 1.46 (tt, J=4.0, 13.0 Hz, 2 H), 1.38-1.24 (m, 2 H), 1.03 (tt, J=3.1, 11.9 Hz, 1 H), 0.91 (s, 9 H).
Reaction SMILES: [C:1]1(O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]([O:15]CC)([O:12][CH2:13][CH3:14])(OCC)[CH3:8]>C(O)(=O)C(C)(C)C>[CH2:3]([C:1]1[C@@H:5]([CH2:8][C:7]([O:12][CH2:13][CH3:14])=[O:15])[CH2:4][CH2:3][CH:2]=1)[CH2:2][CH2:1][CH2:5][CH3:4]
Reactant: CCOC(C)(OCC)OCC
Reactant: OC1=CCCC1
Agent: CC(C)(C)C(=O)O
Product: CCCCCC1=CCC[C@@H]1CC(=O)OCC
Yield: 73 %

Procedure:
A mixture of the cyclopentenol obtained according to Example 1 (5 g, 32.5 mmol) with triethyl orthoacetate (47.2 ml=42.1 g, 260 mmole, 8 eq.) was heated to 145° (temp. of oil bath 160°) under a nitrogen current in a reactor which was equipped with a Vigreux column and a condenser, while adding continuously, over 4 h, pivalic acid (232 mg, 2.28 mmole, 7 mol %) in triethyl orthoacetate (5.9 ml=5.26 g, 32.5 mmole, 1 eq.). During the reaction, the formed ethanol, as well as the ethyl acetate and a little orthoacetate, were removed by distillation. The reaction mixture was heated for 1 more hour, then cooled to 20°, hydrolyzed with diluted aqueous NaHCO3 and extracted with ether. The organic layer was washed 2× with water and once with brine, dried over Na2SO4 and evaporated, to give 15.4 g of crude product. After distillation of the heads (6.6 g, 50°/1.1×102Pa), 5.30 g (95°/1.1×102Pa) of (+)-ethyl (1R)-2-pentyl-2-cyclopentene-1-acetate were obtained (yield 73%), having an enantiomeric purity of 90% e.e. (chiral column of the type Megadex®5).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:31]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)=[O:32])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCN(C)CC4)nc3cc21

Procedure:
4-Methyl-piperazine-1-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and 4-methyl-1-piperazinecarbonyl chloride. The title compound was obtained as light yellow powder (50 mg).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.ClC(Cl)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([CH3:23])[CH3:22].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([C:34]#[N:35])[CH:25]=1>O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:15]=1[CH2:20][C:21]([CH3:23])([CH3:22])[N:35]=[C:34]2[C:26]1[CH:25]=[N:24][C:33]2[C:28]([CH:27]=1)=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: CC(C)=Cc1ccccc1F
Reactant: N#Cc1cnc2ccccc2c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: O
Product: CC1(C)Cc2c(F)cccc2C(c2cnc3ccccc3c2)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
Trifluoromethane sulfonic acid (0.52 mL) were added while cooling with ice to a dichloroethane (0.58 mL) solution of an about 4:7 mixture of 1-fluoro-(2-methylpropen-1-yl)benzene and 1-fluoro-(2-methylpropen-2-yl)benzene (87.3 mg, 0.58 mmol) and quinoline-3-carbonitrile (89.6 mg, 0.58 mmol), and after stirring for 18 hours at room temperature, the solution was poured into water followed by extraction with ethyl acetate and applying the resulting residue to chromatography to obtain 82.2 mg of the target compound (yield: 47%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]([OH:11])[C:8]([CH3:13])([CH3:12])[C:7]=2[CH:14]=1)#[N:2].[OH-].[Na+].[BH4-].[Na+]>CO.O>[OH:10][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]=1[C:8]([CH3:13])([CH3:12])[CH2:9][OH:11]
Reactant: CC1(C)c2cc(C#N)ccc2OC1O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CO)c1cc(C#N)ccc1O
Yield: 59.4 %

Procedure:
5-Cyano-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (2.0 g), prepared as in Example 10, was dissolved in methanol (10 ml) and added to sodium hydroxide (1.7 g) in water (25 ml) at 10°-15° C. with stirring. To this solution was added sodium borohydride (0.5 g), and the mixture was stirred at ambient temperature for 11/2 hours. After acidification with hydrochloric acid (6 ml) at 8°-12° C., the mixture was filtered and the product washed with water and dried yielding 1.8 g. Recrystallisation from toluene gave 1.2 g of product, mp 129°-130° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:31]([O:32][CH3:33])=[O:34])=[CH:20][CH:21]=1)(=[O:4])=[O:3]
Reactant: COC(=O)C1CCNC(Cc2ccc(S(C)(=O)=O)cc2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(S(C)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Methyl 2-(4-(methylsulfonyl)benzyl)piperidine-4-carboxylate (5.88 g, 18.88 mmol) was dissolved in DIPEA (4.93 mL, 28.32 mmol) and dichloromethane (150 mL). Methyl carbonochloridate (2.141 g, 22.66 mmol) was added dropwise and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue partitioned between 1 M KHSO4 and diethyl ether. The organic layer was dried over Na2SO4, filtered through celite and evaporated to yield dimethyl 2-(4-(methylsulfonyl)benzyl)piperidine-1,4-dicarboxylate (5.5 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.[C:9]([O:17][C@@H:18]1[C@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:21]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:20][C@H:19]1Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:9]([O:17][C@@H:18]1[C@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:21]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:20][C@H:19]1[S:8][C:5]1[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC[C@H]1O[C@@H](Cl)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: S=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@@H](Sc2ncc(Cl)cn2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (4.3 mmol), 2,3,5-tri-O-benzoyl-β-D-ribofuranosyl chloride (4.3 mmol) and triethylamine (4.3 mmol) in dichloromethane (25 ml) was stirred together at room temperature for 4 h, the mixture evaporated and the residue triturated with water; the residue was the title compound; yield 28% 1H NMR (CDCl3): δ4.75 (CH2), 6.0-6.5 (4 H), 7.2-8.2 (3 Ph), 8.50 (H-4, H-6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[N:23][C:24]([C:27](=[O:29])[CH3:28])=[N:25][CH:26]=2)=[N:6][CH:7]=1.[CH3:30][Mg]Br>C1COCC1.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[N:23][C:24]([C:27]([OH:29])([CH3:30])[CH3:28])=[N:25][CH:26]=2)=[N:6][CH:7]=1
Reactant: CC(=O)c1ncc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Yield: 47.4 %

Procedure:
A solution of 1-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)ethanone (Example 73) (12 mg, 0.03 mmol) in THF (5 mL) was treated with methylmagnesium bromide (0.09 mL, 0.3 mmol, 3.0 M in THF) at rt. Upon completion of the reaction as judged by TLC analysis, the solution was diluted with saturated aq NH4Cl solution and extracted with EtOAc. The organic layer was removed, dried over MgSO4, filtered and concentrated giving rise to an oil. The oil was purified on silica gel to afford the title compound (6.3 mg). LC/MS: m/e 443.0 (M+H)+. 1H NMR (500 MHz, Acetone-d6): δ 1.54 (s, 6H), 4.56 (s, 1H), 7.39 (m, 2H), 7.47 (d, J=8.5 Hz, 1H), 7.82 (m, 1H), 8.25 (m, 2H), 8.45 (d, J=2.5 Hz, 1H), 9.39 (s, 2H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][NH:11][C:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[O:9])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A solution of 3-pyridinecarbonyl chloride hydrochloride (3.87 g) in dichloromethane (100 ml) was added to a suspension of 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (5.0 g) and potassium carbonate (10 g) in dichloromethane (100 ml), and the mixture stirred at ambient temperature for 2 hours before pouring into water (500 ml). The organic layer was washed with water (250 ml), dried over magnesium sulphate and the solvent was evaporated. The residue was purified by flash chromatography over silica eluting with a 20:1 mixture of dichloromethane and methanol. Appropriate fractions were combined and the solvent removed in vacuo to give N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (3.22 g) as an orange oil.