Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](O)=[O:34]>>[OH:20][C:16]1[CH:17]=[C:18]2[C:13]([CH2:12][CH2:11][CH:10]([N:9]([CH2:21][CH2:22][CH3:23])[CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][N:4]([C:33]([C:25]4[NH:24][C:32]5[C:27]([CH:26]=4)=[CH:28][CH:29]=[CH:30][CH:31]=5)=[O:34])[CH2:3][CH2:2]3)[CH2:19]2)=[CH:14][CH:15]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Product: CCCN(CCN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1)C1CCc2ccc(O)cc2C1
Yield: 84.8 %

Procedure:
Compound 40c was prepared following Procedure G using 39a (100 mg, 0.32 mmol) and indole-2-carboxylic acid (61 mg, 0.38 mmol) to give 40c (125 mg, 86%) after column chromatography. 1H NMR (400 MHz, CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.42-1.64 (m, 3H), 1.94 (brs, 1H), 2.51-2.75 (m, 14H), 2.88-2.96 (m, 1H), 3.95 (brs, 4H), 6.53 (brs, 1H), 6.59-6.61 (m, 1H), 6.75 (s, 1H), 6.90 (d, 1H, J=12.0 Hz), 7.11-7.18 (m, 1H), 7.22-7.26 (m, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.62 (d, 1H, J=8.0 Hz), 9.72 (s, 1H). The free base of 40c was converted into HCl salt. m.p. 203-205° C. Anal. [C28H36N4O2.2HCl.1.2H2O] C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([F:44])[CH:43]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:10]=[C:9]2[NH:34]C(=O)C(F)(F)F.C(N(CC)CC)C>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([F:44])[CH:43]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[N:10]=[C:9]2[NH2:34]
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cc3cc(F)cc(F)c3)cc12)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cc3cc(F)cc(F)c3)cc12

Procedure:
N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide (450 mg, 0.75 mmol) was dissolved in methanol (6 mL) and triethylamine (1.5 mL) and the solution was refluxed for 3 hours. The solvents were removed under reduced pressure and the residue was purified by flash chromatography (eluant: DCM). Title compound was isolated as white foam (300 mg, yield 80%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16](OC)=[O:17])[CH:11]=[CH:12][C:13]=1[CH3:14].O.[OH-].[Na+]>C(OCC)C>[CH3:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[CH3:14])[CH2:15][CH2:16][OH:17]
Reactant: COC(=O)Cc1ccc(C)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(CCO)cc1C
Reaction time: 16 h

Procedure:
Lithium aluminium hydride (0.4 g) was added in portions to a solution of methyl 3,4-dimethylphenylacetate (3.0 g--see Preparation 16) in anhydrous diethyl ether (50 ml). When the addition was complete, the mixture was heated under reflux for 1 hour then allowed to stand at room temperature for 16 hours. Water (0.5 ml) was carefully added dropwise followed by 15% aqueous sodium hydroxide (0.5 ml) and finally more water (2 ml). The resulting solid precipitate was filtered off and washed with diethyl ether (3×20 ml). The filtrate and washings were combined, dried (MgSO4) and concentrated in vacuo to give the title compound as a colourless oil which was used directly--see Preparation 18).
Reaction SMILES: [CH2:1]([N:3]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:24]1[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[O:27][C:28]=1[Cl:29]>COCCOC.O.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:29][C:28]1[O:27][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=1[C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=1
Reactant: CCn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(Cl)o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CCn1nccc1-c1cc(C(=O)OC)oc1Cl
Temperature: 75 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To a 100 mL sealed flask was added 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.61 g, 11.74 mmol), potassium carbonate (3.25 g, 23.48 mmol), methyl 4-bromo-5-chloro-2-furancarboxylate (1.85 g, 8.33 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.16 g, 0.31 mmol) in 1,2-Dimethoxyethane (DME) (30 mL) and H2O (5 mL). After stirring for 2 h at 75° C., the reaction solution was diluted with DCM (100 mL) and washed with H2O. The organic layer was dried Na2SO4, filtered and concentrated. The residue was purified on silica gel [EtOAc/hexanes, 10-30%] to give the product (0.8 g, 50.1%) as an off-white solid: LC-MS (ES) m/z 255 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[C@@H:12]2[C@@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@@H:13]2[O:20][CH3:21])(=O)=O)=CC=1.C[O-].[Na+].C(O)(=O)C>CO>[CH3:21][O:20][C@@H:13]1[C@@H:12]2[C@H:16]([O:17]2)[C@@H:15]([CH2:18][OH:19])[O:14]1
Reactant: CO[C@H]1O[C@H](CO)[C@H](O)[C@H]1OS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CO[C@H]1O[C@H](CO)[C@H]2O[C@H]12
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Compound 35.5 (46.83 g, 147.26 mmol) was dissolved in anhydrous methanol 300 mL, cooled to 0° C. and treated with 25% NaOMe in MeOH. The mixture was allowed to rise to r.t. and stirred for 8 h. The mixture was then neutralized with acetic acid and the solvent was concentrated under reduced pressure. The residue was dissolved in EtOAc, filtered and the organic layer was washed with 200 mL water. The organic layer was collected and the aqueous layer was extracted with 4×100 mL ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a column chromatography to give compound 35.6 (18.18 g, 85% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.CC1(C)C(C)(C)[O:21][B:20](B2OC(C)(C)C(C)(C)O2)[O:19]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)=[CH:3][C:2]([B:20]([OH:21])[OH:19])=[N:7]1
Reactant: Cn1nc(Cl)cc(Nc2ccncn2)c1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cn1nc(B(O)O)cc(Nc2ccncn2)c1=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 263a (500 mg, 2.11 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.68 g, 10.6 mmol), Pd(dppf)Cl2 (170 mg, 0.20 mmol), X-phos (170 mg, 0.40 mmol), potassium acetate (410 mg, 4.21 mmol), and dioxane (30 mL). The system was subjected to 3 cycles of vacuum/argon flush and stirred at 50° C. for 6 h. LCMS indicated that 263a was totally converted to 263b.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])C)=[CH:10][CH:9]=1)[CH3:6])(=[O:3])[CH3:2].C(NC(C)CC1C=CC(C(O)=O)=CC=1)(=O)C>>[C:1]([NH:4][CH:5]([CH3:6])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][OH:16])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)Cc1ccc(C(C)=O)cc1
Agent: CC(=O)NC(C)Cc1ccc(C(=O)O)cc1
Product: CC(=O)NC(C)Cc1ccc(CO)cc1

Procedure:
The ester hydrochloride used as starting material is prepared in the following manner: N-acetyl-4-acetylamphetamine (m.p. 99°-100° C.) is oxidized to 4-(2-acetamidopropyl)-benzoic acid (m.p. 207°-208° C.), this is reduced to give 4-(2-acetamidopropyl)-benzyl alcohol (oil) which is then oxidized to 4-(2-acetamidopropyl)-benzaldehyde (m.p. 84°-86° C.) and this is condensed with malonic acid to give 4-(2-acetamidopropyl)-cinnamic acid (m.p. 207°-208° C.) which is hydrogenated to give β-[4-(2-acetamidopropyl)-phenyl]-propionic acid (m.p. 93°-96° C.). Subsequent acid hydrolysis gives the hydrochloride of β-[4-(2-aminopropyl)-phenyl]-propionic acid which is esterified to give the above-mentioned ethyl ester hydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][CH:17]([NH:21][C:22](=O)[CH2:23][Cl:24])[C:18]([NH2:20])=[O:19])=[O:8].CC1NC=CN=1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:22]([CH2:23][Cl:24])=[N:21][C:17]([C:18]([NH2:20])=[O:19])=[N:16]1)=[O:8]
Reactant: NC(=O)C(N=Nc1ccccc1C(=O)c1ccccn1)NC(=O)CCl
Agent: Cc1ncc[nH]1
Solvent: CCO
Product: NC(=O)c1nc(CCl)n(-c2ccccc2C(=O)c2ccccn2)n1

Procedure:
A solution of 0.3 g. of [2-(2-pyridinecarbonyl)-phenyl]azo-(2-chloroacetamido)acetamide and 0.82 g. of 2-methylimidazole in 12ml. of ethanol is refluxed for one hour and then cooled. The precipitated crystals are collected by filtration to give 1-[2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxamide as crystals. Recrystallization from chloroform-ethanol gives colorless needles, melting at 228° to 229° C. (decomposition).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][C:28]1[O:32][N:31]=[CH:30][C:29]=1[S:33](Cl)(=[O:35])=[O:34]>>[CH3:27][C:28]1[O:32][N:31]=[CH:30][C:29]=1[S:33]([N:21]1[CH2:20][CH2:19][C:16]2([C:15](=[O:24])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=3)[CH2:18][CH2:17]2)[CH2:23][CH2:22]1)(=[O:35])=[O:34]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Cc1oncc1S(=O)(=O)Cl
Solvent: CC(=O)O
Product: Cc1oncc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 5-methyl-isoxazole-4-sulfonyl chloride. White solid. MS (ESI): 460.3 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH:4]=[CH:5][C:6]([OH:8])=O.S(Cl)(Cl)=O.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>ClCCl.CN(C)C=O>[CH2:14]([N:16]([CH2:17][CH3:18])[C:6](=[O:8])[CH:5]=[CH:4][CH2:3][CH:2]([CH3:1])[CH3:9])[CH3:15]
Reactant: CC(C)CC=CC(=O)O
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)C=CCC(C)C
Temperature: 28.5 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-methylhex-2-enoic acid (formula-3) (20 grams) in dichloromethane (250 ml), 2 ml of dimethyl formamide was added. To this mixture thionyl chloride (24.1 grams) was added. The reaction mixture was stirred for 2.5 hours at 28-29° C. The reaction mixture was cooled to 0-5° C. and diethyl amine was added to the reaction mixture at 5-8° C. until the pH reached to 8.5. The reaction mixture was stirred for 1.5 hours at 0-5° C. The reaction mixture was quenched with water. Separated the aqueous and organic layers. The organic layer was washed with 5% sodium bicarbonate solution and was dried over anhydrous sodium sulphate. The solvent was distilled off completely under vacuum to provide the title compound as solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][CH:14]([O:21]CC)[CH2:15][C:16](OCC)=O)[CH3:12]>[N+](C)([O-])=O.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:16]([CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:21])[O:10][CH2:9][CH2:8]2
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: OCCc1cccc(Br)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)CC1OCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Titanium tetrachloride (1M in methylene chloride, 51 ml) is added over a period of 10 min to an ice-cooled mixture of 2-(3-bromophenyl)ethanol (XLV, 4.34 g, 21.6 mmol) and ethyl 3,3-diethoxypropionate (LXXXV, 4.93 g, 25.9 mmol) in nitromethane (5 ml). After stirring for 10 min, the ice bath is removed and the mixture is allowed to stir at 20-250 for 5 hr, at which time it is poured onto ice/aqueous hydrochloric acid (~1N). The mixture is extracted with dichloromethane and backwashed with hydrochloric acid (0.5N)/saline and saline. The organic phase is separated dried over sodium sulfate, concentrated, and the residue chromatographed on silica gel eluting with ethyl acetate/hexane (5/95). The appropriate fractions are pooled and concentrated to give ethyl (6-bromoisochroman-1-yl)acetate (LXXVII), NMR (CDCl3) 1.28, 2.66-2.87, 2.96, 3.768, 3.807, 4.11, 4.21, 5.19, 6.93 and 7.28 δ.
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(Cl)Cl.O=[Mn]=O>[N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCc1csc(-n2ccnc2)n1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1csc(-n2ccnc2)n1

Procedure:
MnO2 (3.28 g; 37.75 mmol) was added to a solution of (2-imidazol-1-ylthiazol-4-yl)methanol (0.33 g; 1.82 mmol), prepared as described in the above step, in CH2Cl2 (30 ml).
Reaction SMILES: [N:1]([C:4]1[C:13]2[CH:12]=[N:11][C:10]([S:14][CH3:15])=[N:9][C:8]=2[N:7]([CH:16]2[CH2:18][CH2:17]2)[C:6](=[O:19])[CH:5]=1)=[N+]=[N-].C(Cl)Cl.CO>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[C:13]2[CH:12]=[N:11][C:10]([S:14][CH3:15])=[N:9][C:8]=2[N:7]([CH:16]2[CH2:18][CH2:17]2)[C:6](=[O:19])[CH:5]=1
Reactant: CSc1ncc2c(N=[N+]=[N-])cc(=O)n(C3CC3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1ncc2c(N)cc(=O)n(C3CC3)c2n1
Reaction time: 2 h
Yield: 125.2 %

Procedure:
Palladium hydroxide on carbon (10% wt., 150 mg) was added to a solution of 5-azido-8-cyclopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.5 g) in glacial acetic acid (80 mL) and the resulting mixture was stirred under H2 (balloon pressure) for 2 h. A mixture of DCM and MeOH (80/20, 100 mL) was added and the resulting mixture was filtered over a CELITE™ pad and the filter cake was washed with a mixture of DCM and MeOH (80/20, 500 mL). The filtrate was concentrated under reduced pressure to give 1.7 g 5-amino-8-cyclopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a green solid without further purifications. MS=248.9 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH2:10][OH:11].C(N(CC)CC)C>ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][S:2]([O:11][CH2:10][C:9]1[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=[C:7]([Br:6])[CH:8]=1)(=[O:4])=[O:3]
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(Br)cc(C(F)(F)F)c1
Temperature: -78 °C
Yield: 65.6 %

Procedure:
Methanesulfonyl chloride (342 mg) was added dropwise to a stirred solution of 3-bromo-5-(trifluoromethyl)benzyl alcohol (560 mg) and triethylamine (417 μl) in dry dichloromethane (20 ml) at -78° C. under a dry nitrogen atmosphere. The reaction was maintained at -78° C. for 30 minutes and then allowed to warm to room temperature over 2 hours. After this period the reaction mixture was diluted with 5% aqueous citric acid and the organic layers were separated, dried over MgSO4, filtered and the solvent removed under reduced pressure to give 1-(methanesulfonyloxymethyl)-3-bromo-5-(trifluoromethyl)benzene as a yellow oil (480 mg) 1H NMR (360 MHz,CDCl3) δ 3.06 (3H,s),5.24 (2H, s), 7.59 (1H, s), 7.75 (1H, s), 7.94 (1H, s).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2].ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:47]>>[C:1]([C:3]1[C:4]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:9][NH:8][C:7]=12)(=[O:47])[NH2:2]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)OCc1ccccc1
Product: NC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)OCc1ccccc1

Procedure:
The desired product was prepared from benzyl 2-(3-cyano-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate using the procedure similar to step 2 for compound 2. MS (ESI) m/e [M+1]+ 577.9.
Reaction SMILES: [CH2:1]([CH2:11][C:12](=[O:14])[CH3:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]>[Pd]>[CH3:10][CH:8]([CH2:7][CH2:6][CH2:5][CH:3]([CH2:2][CH2:1][CH2:11][C:12]([CH3:13])=[O:14])[CH3:4])[CH3:9]
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Agent: [Pd]
Product: CC(=O)CCCC(C)CCCC(C)C

Procedure:
In analogy to the procedure and apparatus described in Example 1 but employing a 0.5% (wt./wt.) Pd on Al2O3 catalyst (DEGUSSA, E257H/D) geranylacetone was hydrogenated to produce hexahydropseudoionone. The process parameters were as stated below:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCOC(C)=O.[CH3:15][N:16](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([C:15]#[N:16])[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)ncn1
Temperature: 120 °C
Yield: 21 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (3.0 g, 23 mmol), zinc (II) cyanide (5.4 g, 46 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.2 mmol) in dry DMF (50 mL) was heated to 120° C. under nitrogen atmosphere for 15 hours. EtOAc (100 mL) was added and the insoluble precipitate was removed by filtration. The filtrate was diluted with water (100 mL), and extracted with EtOAc (3×50 mL). The combined organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a pale yellow solid (0.6 g, 21% yield). LCMS (ESI) m/z: 121.2 [M+H+].
Reaction SMILES: CC1N2C3C(C=CC2=CN=1)=CC(SC1C=C(C2(O)CCOCC2)C=CC=1)=CC=3.COC1(C2C=C(SC3C=C4C(=CC=3)N3C(C)=NC=C3C=C4)C=CC=2)CCOCC1.[F:58][C:59]1[CH:60]=[C:61]([C:85]2([C:91]#[N:92])[CH2:90][CH2:89][O:88][CH2:87][CH2:86]2)[CH:62]=[C:63]([S:65][C:66]2[CH:67]=[C:68]3[C:73](=[CH:74][CH:75]=2)[N:72]2[C:76]([C:79]4C=CC=CC=4)=[N:77][CH:78]=[C:71]2[CH:70]=[CH:69]3)[CH:64]=1.FC1C=C(C2(C(N)=O)CCOCC2)C=C(SC2C=C3C(=CC=2)N2C(C4C=CC=CC=4)=NC=C2C=C3)C=1>>[F:58][C:59]1[CH:60]=[C:61]([C:85]2([C:91]#[N:92])[CH2:90][CH2:89][O:88][CH2:87][CH2:86]2)[CH:62]=[C:63]([S:65][C:66]2[CH:67]=[C:68]3[C:73](=[CH:74][CH:75]=2)[N:72]2[C:76]([CH3:79])=[N:77][CH:78]=[C:71]2[CH:70]=[CH:69]3)[CH:64]=1
Reactant: N#CC1(c2cc(F)cc(Sc3ccc4c(ccc5cnc(-c6ccccc6)n54)c3)c2)CCOCC1
Agent: COC1(c2cccc(Sc3ccc4c(ccc5cnc(C)n54)c3)c2)CCOCC1
Agent: Cc1ncc2ccc3cc(Sc4cccc(C5(O)CCOCC5)c4)ccc3n12
Agent: NC(=O)C1(c2cc(F)cc(Sc3ccc4c(ccc5cnc(-c6ccccc6)n54)c3)c2)CCOCC1
Product: Cc1ncc2ccc3cc(Sc4cc(F)cc(C5(C#N)CCOCC5)c4)ccc3n12

Procedure:
4-[3-(1-Methyl-imidazo[1,5-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-ol (Compound 4-2); 7-[3-(4-Methoxy-tetrahydro-pyran-4-yl)-phenylsulfanyl]-1-methyl-imidazo[1,5-a]quinoline (Compound 4-3); 4-[3-Fluoro-5-(1-phenyl-imidazo[1,5-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carbonitrile (Compound 4-4); 4-[3-Fluoro-5-(1-phenyl-imidazo[1,5-a]quinolin-7-ylsulfanyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid amide (Compound 4-5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:12]([OH:15])[CH2:13][OH:14])[CH:6]=[C:5]2[CH3:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:12]([OH:15])[CH2:13][O:14][S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30])[CH:6]=[C:5]2[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cn([C@@H](c2ccccc2)[C@H](O)CO)c2ccc(F)cc12
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2cc(C)c3cc(F)ccc32)cc1

Procedure:
A solution of (2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol (1.03 g, 3.4 mmol) and p-toluenesulfonyl chloride (0.78 g, 4.1 mmol) in anhydrous pyridine (11 ml) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester. The product was used in the next step without further purification. To a solution of toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (1.6 g, 3.4 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (8.6 mL, 17 mmol) and the reaction stirred for 12 hours. Upon completion, the reaction was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 20% MeOH/dichloromethane) to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. The ethanol was removed in vacuo and the clear oil was triturated with ether/dichloromethane to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride as a white solid. MS (ESI) m/z 313
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:17][C@@H:12]2[O:13][C:14](=[O:16])[CH2:15][C@@H:11]2[C@H:10]1[CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(C(C)(C)C)(C)C>CO.[Pd]>[OH:8][C@@H:9]1[CH2:17][C@@H:12]2[O:13][C:14](=[O:16])[CH2:15][C@@H:11]2[C@H:10]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCCCCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A mixture of 5-2 (595 mg, 1.62 mmol) and 5% Pd/C (556 mg, 0.17 mmol) in methanol (80 mL) was stirred under 1 atm H2 pressure (balloon) overnight. The mixture was then filtered through Celite and the filtrate evaporated. Purification of the residue by flash chromatography on silica gel (Isco Combiflash unit) gave the title compound (396 mg, 96%).