Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1>C1(C)C=CC=CC=1>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([C:3](=[O:4])[CH2:2][N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]2)=[CH:6][CH:7]=1)#[N:10]
Reactant: CCOC(=O)C[C@H]1CCCNC1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H]1CCCN(CC(=O)c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 68.1 %

Procedure:
To a mixture of 4-(2-bromoacetyl)benzonitrile (5.5g, 24.55 mmol) in toluene was added (R)-ethyl 2-(piperidin-3-yl)acetate (4 g, 23.36 mmol). The reaction mixture was stirred for 4 days at room temperature and then stirred from one day at 50° C. Solvents were removed in vacuo. The resulting solids were triturated with EtOAc. The solid material was filtered and washed with EtOAc. The solid material was collected and dried to yield 5 g of (R)-ethyl 2-(1-(2-(4-cyanophenyl)-2-oxoethyl)piperidin-3-yl)acetate. MS (M+1)=314. HPLC Peak RT=0.77 minutes.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=2[CH2:3]1.[C:21]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)(Cl)Cl>[C:21]([N:26]1[CH2:31][CH2:30][N:29]([CH:2]2[C:8]3[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=3[S:6][C:5]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=3[CH2:3]2)[CH2:28][CH2:27]1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)N1CCNCC1
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(Cl)C2
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3ccc(OC)cc3Sc3ccc(SC)cc32)CC1
Temperature: 0 °C

Procedure:
24 G. of 10-chloro-10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin in 100 ml. of chloroform are heated with 55 ml. of 1-carbethoxypiperazine under reflux conditions for 20 hours. The mixture is poured on to ice/water and extracted with chloroform. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained crude 1-carbethoxy-4-(10,11-dihydro-3-methoxy-8-methylthiodibenzo[b,f]thiepin-10-yl)-piperazine.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH3:3][N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:11]=2)[CH2:8][CH2:9]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(C#N)cc23)CC1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
NaH (26 mg, 1.07 mmol) was added in several batches to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (200 mg, 0.76 mmol) in DMF (2 mL) at 0-5° C., and the mixture was maintained for 1 hour at room temperature. Benzenesulfonyl chloride (222 mg, 1.24 mmol) was then added, and the resulting solution was maintained at room temperature for an additional 4 hours. The mixture was filtered, and the filter cake was washed with ethanol (2×10 mL) and diethylether (2×10 mL) to afford 250 mg (86%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indole-5-carbonitrile as a white solid. 1H NMR (DMSO) δ 8.41 (s, 1H), 8.14 (d, 2H), 8.07 (d, 2H), 7.78 (d, 1H), 7.71 (d, 2H), 7.61 (t, 1H), 6.35 (s, 1H), 3.79 (2H), 3.34 (s, 2H), 2.80-2.87 (m, 5H).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])=[O:26])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].[OH-].[Na+].Cl.C(OCC)(=O)C>CO.O>[Cl:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:34])[C:27]=1[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@@H:4]([C:3]([OH:35])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[S:7])=[CH:19][CH:20]=1)=[O:26]
Reactant: COCCC1(C(=S)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCC1(C(=S)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-methoxyethyl) cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (4.00 g, 7.44 mmol) in methanol (18 mL) was added a solution of NaOH (421 mg, 10.5 mmol) in water (3 mL). The mixture was stirred for 2 h and then acidified (pH˜1-2) with 0.5N HCl. The reaction mixture was poured into a separatory funnel containing ethyl acetate (150 mL) and water (25 mL). The separated aqueous layer was back-extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the residual material by RP-HPLC (15-95% acetonitrile-water gradient over 25 min) provided 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-L-phenylalanine (3.05 g, 78%). HR MS: Obs. mass, 545.1043. Calcd. mass, 545.1045 (M+Na).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13]C)[CH:9]=[CH:8]2)[CH3:2].Br.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH2:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCc1c(F)cnc2ccc(OC)nc12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1c(F)cnc2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
A suspension of 8-ethyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (1.045 g, 5.07 mmol) in glacial acetic acid (10 ml) at rt under argon, was treated with 33% HBr in acetic acid (10 mL). After stirring at rt for 18 h, the solvents were evaporated under reduced pressure. More glacial acetic acid (10 ml) was added to the reaction mixture and the solvent was removed to give a yellow solid. As this residue was placed in water (ca. 50 ml) a white precipitate came out of solution. The pH was adjusted to pH 6-7 by addition of solid sodium hydrogen carbonate. The mixture was then stirred at rt for 2 h, after which the solid was isolated by filtration with suction to give a white damp solid. This product was dried on the sinter with suction for 2 h then dried in a vacuum oven over 18 h at 40° C. to give the title compound as an white solid (0.81 g, 83%).
Reaction SMILES: [OH:1]O.[C:3]1([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19](=[O:25])[NH:20]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.O>[C:3]1([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19](=[O:25])[NH:20]3)=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OO
Reactant: O=c1ccc2c(OCCCCSc3ccccc3)cccc2[nH]1
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc2c(OCCCCS(=O)c3ccccc3)cccc2[nH]1

Procedure:
0.165 ml of 30% hydrogen peroxide, dissolved in 8 ml of glacial acetic acid, were added to 0.56 gm of 5-(4-phenylmercapto-butoxy)-carbostyril. The mixture was diluted with water and extracted twice with chloroform. The chloroform extract was washed with dilute sodium carbonate solution and with water, dried over magnesium sulfate and evaporated. The residue was admixed with ethyl acetate, yielding colorless crystals with a melting point of 155°-157° C.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[Cl:25])[C:5](OCC)=[O:6])(=O)[CH3:2].[NH2:26][NH:27]C(N)=S.C[O-].[Na+]>CO>[Cl:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[C:1]([CH3:2])=[N:26][NH:27][C:5]=1[OH:6]
Reactant: NNC(N)=S
Reactant: CCOC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCCCCCCc2c(C)n[nH]c2O)c(Cl)c1
Yield: 55.2 %

Procedure:
A mixture of 11.1 g (0.03 m) of ethyl 2-acetyl-8-(2-chloro-4-methoxyphenoxy)octanoate, 2.73 g (0.03 m) of thiosemicarbazide and 1.62 g (0.03 m) of sodium methoxide in 15 ml of methanol was heated at reflux for 24 hours. The solid product was collected, washed with 50% aqueous ethanol and recrystallized from ethanol to give 5.6 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3-methyl-1H-pyrazol-5-ol, m.p. 145°-146° C.; MIC=6 microg/ml (herpes 2). (During this reaction the thiocarbamyl group (CSNH2) of the thiosemicarbazide was cleaved so that the reaction product is the same as that obtained when unsubstituted hydrazine is used.)
Reaction SMILES: Cl.C(O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[CH2:13][N:12]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:11][CH2:10]2.[OH-].[Na+]>[Fe].O.ClCCl.C(Cl)(Cl)Cl.CO>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[CH2:13][N:12]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)[CH2:11][CH2:10]2
Reactant: COc1cc2c(cc1OC)CN(CCc1ccc([N+](=O)[O-])cc1)CC2
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: COc1cc2c(cc1OC)CN(CCc1ccc(N)cc1)CC2
Temperature: 80 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Iron (1.27 kg, 23.48 mol), hydrochloric acid (127 mL, 1.54 mol) and 6.7 L of 50% aqueous ethanol were added to a reactor, and stirred for 1 hour at 80° C. 6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline (1.3 kg, 3.91 mol) obtained in Step 1-1 was slowly added thereto for one hour, followed by stirring for 3 hours at 80° C. After checking completion of the reaction by thin layer chromatography (eluent: chloroform/methanol=15/1), the reaction mixture was cooled to room temperature. 5.3 L of dichloromethane and 5.3 L of water were added thereto, the reaction mixture was neutralized by adding 804 mL of 10% aqueous sodium hydroxide. The resulting mixture was filtered through a Celite pad and washed with 3 L of methylenechloride. The organic layer was collected, dried over magnesium sulfate, and then filtered. The solvent was removed under reduced pressure, and dried with hot air at 40° C. in an oven to obtain the title compound (1.05 kg, 90%).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]([OH:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C(Cl)(Cl)(Cl)Cl>[C:2]1([C:1]2[O:20][C:11]3[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccccc2)c1O
Agent: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.8 ml of CCl4 in 5 ml of acetonitrile were added to 30 mmol of the compound from Example XIV, 30 mmol of benzoic acid, 50 mmol of triphenylphosphine and 120 mmol of triethylamine in 100 ml of acetonitrile at 3° C. under argon in the course of 15 min and the mixture was stirred at room temperature for 20 hours and concentrated, diethyl ether was added to the residue, the solid was filtered off with suction, the filtrate was concentrated and the residue was separated on silica gel. M.p.: 77° C. (white needles)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([CH:15]=2)[NH2:14])[CH:4]=1.[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:14][C:13]1[CH:15]=[C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:10]=[CH:11][C:12]=1[CH3:16])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: COc1ccnc(-c2ccc(C)c(N)c2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(-c2ccc(C)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a suspension of 5-(4-methoxypyridin-2-yl)-2-methylaniline (200 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (310 mg) and diisopropyl-ethylamine (0.374 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (310 mg), and the mixture was stirred for 2 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(5-(4-methoxypyridin-2-yl)-2-methylphenyl)guanidine (357 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>C(O)(C)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2F)cc1
Solvent: NC1CCCCC1
Solvent: CC(C)O
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2F)cc1
Yield: 69 %

Procedure:
Prepared analogous to Example 25 from 4-(2'-fluoro-4'-chloro-4-biphenylyl)-4-oxo-butyric acid. Yield: 69% of theory; m.p. of the cyclohexylamine salt: 165°-167° C. (from isopropanol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([NH:19][CH2:20][C@H:21]([OH:41])[CH2:22][O:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32]COC)=[C:26]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:25]=3)[CH3:18])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])[CH3:2].[ClH:42].CCOC(C)=O>C(O)C>[ClH:42].[CH2:1]([O:3][C:4]([C@@H:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([NH:19][CH2:20][C@H:21]([OH:41])[CH2:22][O:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([OH:32])=[C:26]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:25]=3)[CH3:18])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1COc2cc(C[C@@H](C)NC[C@H](O)COc3cc(NS(C)(=O)=O)c(OCOC)c(OC)c3)ccc2O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@H]1COc2cc(C[C@@H](C)NC[C@H](O)COc3cc(NS(C)(=O)=O)c(O)c(OC)c3)ccc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
To a solution of 6-[2-(R)-[2-(S)-hydroxy-3-[3-methanesulfonamido-5-methoxy-4-(methoxymethoxy)phenoxy]-propylamino]propyl]-2,3-dihydro-1,4-benzodioxine-2-(R)-carboxylic acid ethyl ester (100 mg) obtained in Example 26 in ethanol (10 mL) was added 4N—HCl/AcOEt (1.0 mL, 4.0 mmol) at room temperature. This solution was stirred at room temperature for 16 hours and then concentrated to dryness under reduced pressure, affording the title compound (100 mg). Yield: 85%
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:21]1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](=[O:33])[CH3:32])=[CH:23][N:22]=1)([CH3:3])[CH3:2].[CH3:34][Mg]Cl>C1COCC1>[CH:1]([C@@H:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:21]1[N:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[C:24]([C:31]([OH:33])([CH3:34])[CH3:32])=[CH:23][N:22]=1)([CH3:3])[CH3:2]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1cnc(N2CCn3c(cc4ccc(S(C)(=O)=O)cc43)[C@H]2C(C)C)nc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)[C@@H]1c2cc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(C)(C)O)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a solution of (R)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (5 mg, 0.01 mmol) in THF (1 mL) was added LaCl3-2LiCl (0.2 mL, 0.12 mmol, 0.6M) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h. MeMgCl (0.3 mL, 0.9 mmol, 3M) was added to the formed mixture and then the reaction mixture was stirred at 0° C. for 1 h. The reaction was quenched with sat. NH4Cl (5 mL) at 0° C. and then extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated, purified by preparative TLC eluting with PE/EtOAc 1:1 and then by SFC separation to afford (R)-2-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (1.20 mg, 24.68% yield, Isomer 1) as a colorless oil. Analytical chiral HPLC: tR=6.394 min in 15 min chromatography (Method: OJ-H—3—5—40—2.35 ML). LC-MS m/z 497.3 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.75 (s, 1H), 7.93 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.62 (d, J1=8.4 Hz, J2=1.6 Hz, 1H), 6.48 (s, 1H), 5.89 (d, J=8.8 Hz, 1H), 5.16-5.12 (m, 1H), 4.32-4.28 (m, 1H), 4.14-4.07 (m, 1H), 3.86-3.77 (m, 1H), 3.07 (s, 3H), 2.34-2.25 (m, 1H), 1.92 (s, 1H), 1.68 (s, 6H), 1.18 (d, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][NH:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][N:35]([C@H:36]1[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]1)[C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:2]([F:1])[CH:3]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: COc1ccc(C=CC(=O)O)cc1F
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc1F

Procedure:
Using 2.0 g of 3-fluoro-4-methoxycinnamic acid (Example 99), 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that performed in Example 81 was carried out. As a result, 2.21 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-fluoro-4-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[BH4-].[Na+].O.Cl>O1CCCC1>[Br:1][C:2]1[C:3]([OH:13])=[C:4]([CH:10]([CH3:11])[OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(C)=O)c(O)c1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)O)c(O)c1Br
Reaction time: 2 h

Procedure:
64.3 g (0.262 mole) of 3'-bromo-2'-hydroxy-4'-methoxyacetophenone (prepared according to the method of T. M. CRESP et al., J. Chem. Soc. Perkin Trans., Part 1, (1973), 340-345) dissolved in 560 ml of tetrahydrofuran, are added dropwise in the course of 80 minutes and at a temperature of from 13° to 18° C. to a suspension of 13.89 g (0.367 mole) of sodium borohydride in 300 ml of tetrahydrofuran. Thereafter, stirring is continued for 2 hours at ambient temperature. The reaction mixture is decomposed by the addition of 140 ml of tetrahydrofuran containing 3 ml of water, then 60 ml of water are added again thereto. The mixture is acidified by the addition of 415 ml of a 1N aqueous solution of hydrochloric acid. The tetrahydrofuran is removed under reduced pressure and the aqueous phase is extracted 4 times with dichloromethane. The organic phases are dried over anhydrous sodium sulfate and then distilled. The residue obtained(70 g) is used as such in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][CH2:10][C:9]=2[C:16](OC)=[O:17])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[O:11][CH2:10][C:9]=2[CH2:16][OH:17])=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(c2ccc(Cl)cc2)CC(C)(C)OC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC1(C)CC(c2ccc(Cl)cc2)=C(CO)CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 38C (1.6 g) in ether (20 mL) was added LiAlH4 (1.2 g). The mixture was stirred at room temperature for 4 hours. The mixture was acidified carefully with 5% aqueous HCl and extracted with ethyl acetate (100 mL×3) and the combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of solvent, the crude product was loaded on a column and eluted with 10% ethyl acetate in hexane to give the product.
Reaction SMILES: [Li].[C:2]1([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(OC)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=CC(=C)C.[Cl-].[NH4+]>N.C1COCC1.CO>[C:2]1([CH:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCCCCCCCC(OC)(c1ccccc1)c1ccccc1
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CO
Solvent: C=CC(=C)C
Product: C=CCCCCCCCCC(c1ccccc1)c1ccccc1
Yield: 105.4 %

Procedure:
Lithium wire, 0.75 g, was dissolved in 300 mL of ammonia at -78° C. A solution of 10.1 g of 11,11-diphenyl-11-methoxyundec-1-ene in 20 mL of THF was added to the lithium solution and the mixture was stirred at reflux for 30 min. To a reaction vessel were added sequentially 5 mL isoprene, 5 mL of methanol, and 10 g of ammonium chloride and the ammonia allowed to evaporate at room temperature. Diethyl ether was added to the mixture and the solution was washed with water and brine (saturated aqueous sodium chloride). The organic layer was dried and concentrated in vacuo to give 9.7 g of 11,11-diphenylundec-1-ene which is characterized by:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:11]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:12][CH:13]=[C:14]([O:17][CH3:18])[C:15]=2[N:16]=1)=[O:6].Cl.[NH:29]1[CH2:32][CH:31]([OH:33])[CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[OH:33][CH:31]1[CH2:32][N:29]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:11]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:12][CH:13]=[C:14]([O:17][CH3:18])[C:15]=3[N:16]=2)=[O:6])[CH2:30]1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CC(O)C4)c3)nc12
Temperature: 150 °C
Yield: 14.9 %

Procedure:
A stirred suspension of 200 mg (0.44 mmol) 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide, 487 mg (4.44 mmol) azetidin-3-ol hydrochloride and 2.17 g (6.66 mmol) cesium carbonate in 6 ml N-methyl-pyrrolidone in a thick-walled glass pressure tube fitted with a teflon cap was heated at 150° C. for 6 h. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (methanol/dichloromethane) followed by trituration in ether afforded 29 mg (15%) 2-(3-hydroxy-azetidin-1-yl)-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide as a brown crystalline solid. ES-MS m/e (%): 443 (M+H+, 100).