Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][N:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[C:15]1([C:12]2[CH:13]=[CH:14][C:9]([C:7]([NH:6][CH2:5][C:4]([OH:21])=[O:3])=[O:8])=[N:10][CH:11]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(-c2ccccc2)cn1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 5-phenyl-pyridine-2-carboxylic acid (0.3 g, 0.00151 mol) in DMF (5 mL) was added DIPEA (0.580 g, 0.00452 mol), HOBt (0.243 g, 0.00180 7 mol) and EDCI.HCl (0.346 g, 0.001807 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.252 g, 0.00181 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.32 g (75%) of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester. To a stirred solution of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester (0.32 g, 0.00113 mol) in a mixture of THF (3.2 mL), methanol (2 mL) and H2O (1 mL) was added LiOH.H2O (0.142 g, 0.00338 mol) and the resulting mixture was stirred at ambient temperature overnight. Volatiles were removed by evaporation and the resulting residue was diluted with water and acidified with 10% HCl. The product was extracted with ethyl acetate, which was dried over sodium sulfate and concentrated under reduced pressure to afford 0.24 g (83%) of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid.
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:22][CH:21]=CCN1C)(=[O:5])=[O:4].[ClH:24]>CN(C=O)C.O.[Pd]=O>[ClH:24].[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:22][CH2:21][N:13]([CH3:14])[CH2:12][CH2:11]1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3CC=CCN3C)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 20.5 h

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methylpyridinyl)-1H-indol-5-yl]-ethenesulphonamide (10 kg) and 10% palladium oxide on charcoal (10 kg, 50% wet paste, added as two charges) in DMF (50L), water (35L) and 2N hydrochloric acid (15.75L) was hydrogenated at atmospheric pressure over 20.5 h. The catalyst was removed by filtration. The filter cake was washed with water (40L). The filtrate was concentrated in vacuo to approximately 30L and cooled to 18°. Ethyl acetate (70L) was added over 1 h and the resulting suspension cooled to 5° and aged for 1 h. The product was collected by filtration, washed with ethyl acetate (20L) and dried in vacuo at 40°-50° overnight (8.87 kg, 79.0% of theory). A portion (0.2 kg) of the solid was recrystallised from hot IMS/water (4:1) (1L) and obtained as fine, off-white crystals (0.143 kg), 71.7% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:51][CH2:52][CH2:53][C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:49]=[CH:50][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:51][CH2:52][CH2:53][C:54]6[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=6)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:42][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: NCCc1cccnc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCCc4cccnc4)cc3F)cn2)cc1
Yield: 185.3 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 3-(2-aminoethyl)pyridine (27.7 μl, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-N-(2-pyridin-3-yl-ethyl)-benzamide as a yellow solid (171 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-306) as a yellow powder (49.8 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][C:17](=[O:19])[CH3:18])[C:9]=3[S:8][C:7]=2[C:6]([CH:20]=[O:21])=[CH:5][CH:4]=1.S(=O)(=O)([OH:24])N.Cl([O-])=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][C:17](=[O:19])[CH3:18])[C:9]=3[S:8][C:7]=2[C:6]([C:20]([OH:24])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2sc3c(NC(C)=O)cccc3c12
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c2sc3c(NC(C)=O)cccc3c12
Temperature: 10 °C

Procedure:
To a solution of 1-methoxy-6-acetamido dibenzo[b,d]thiophene-4-carbaldehyde (800 mg, 0.00266 mol) in THF (15 ml) and water (2 ml) was added sulfamic acid (387 mg, 0.004 mmol) while stirring at 10° C. A solution of 80% sodium chlorite (360 mg, 0.004 mmol) in water (2.0 mL) was added drop wise to the above reaction mixture over a period of 5 min
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
2-({4-[2-(Heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (0.40 g) synthesized in Example 303-2 and 1-fluoro-4-nitrobenzene (0.14 g) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (0.52 mL) was added thereto, and the mixture was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:3) to give the title compound (0.20 g) as a yellow oil.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8]2)[CH2:3][NH:2]1.Br[CH2:18][CH2:19][CH2:20][Cl:21].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][N:2]1[CH2:1][CH:9]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8]2)[CH2:3]1
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CN(CCCCl)CC2C1
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (1.70 g), 1-bromo-3-chloropropane (1.70 mL) and K2CO3 (3.30 g) in acetone was heated to reflux for 10 h, then cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (0.79 g, 35.00%), HPLC: 80.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 303.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([NH:40][CH3:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([N:40]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:41])=[O:31]
Reactant: CNCc1ccccc1
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)c(OC)c3CCN2CC(=O)N(C)Cc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with N-benzyl-N-methyl-amine
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([CH:19]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:21]#[N:22])[C:10]2=[O:29])=[CH:5][CH:4]=1.CC=C(C)C.B(Br)(Br)Br.ClCCl>C(Cl)(Cl)Cl.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([CH:19]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:21]#[N:22])[C:10]2=[O:29])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c(=O)c(C=C(C#N)c3cccnc3)cc3cccnc32)cc1
Agent: BrB(Br)Br
Agent: CC=C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: N#CC(=Cc1cc2cccnc2n(-c2ccc(O)cc2)c1=O)c1cccnc1
Temperature: -40 °C
Reaction time: 15 h
Yield: 8.7 %

Procedure:
2.5 g of 3-[1,2-dihydro-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(3-pyridyl)prop-2-enenitrile, prepared in Example 82, are dissolved in 100 ml of chloroform stabilized with amylene. The yellow solution is cooled to -40° C. and 13.2 ml of a 1 M solution of BBr3 in dichloromethane (2 eq) are then added dropwise at this temperature, with stirring. The mixture is then left to warm up to room temperature and stirring is continued for 15 h. The reaction medium is hydrolyzed by the addition of 100 ml of water, after which the aqueous phase is separated off and extracted several times with dichloromethane. The precipitate which appears is filtered off, washed with acetone and dried to give 0.21 g of 3-[1,2-dihydro-1-(4-hydroxy- phenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(3-pyridyl)prop-2-enenitrile in the form of a yellow solid melting at >317° C. Yield 9%.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O[Li].O>O1CCCC1>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:30]=[CH:31][C:32]([Br:35])=[CH:33][CH:34]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (230) (7.9 g, 14.64 mmol) in tetrahydrofuran (200 mL) was added an aqueous solution (100 mL) of LiOH.H2O (6.15 g, 146.44 mmol). The resulting mixture was refluxed for 16 h. After completion of the reaction the organic solvent was removed on a rotary evaporator and water (30 mL) was added. The aqueous solution was acidified (pH 5) with concentrated HCl at 0° C. to give a white solid which was filtered off. The solid residue was triturated in diethyl ether and filtered. After drying, 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (231) was obtained (6.3 g, 89%) as a white solid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:17](O)=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3]C(C)(C)C)=O.CC[Al](Cl)CC.[CH:26]1[CH:27]=[CH:28][C:29]2N(O)N=N[C:30]=2[CH:31]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH2:45][CH2:46][NH:47][CH2:48][CH:49]=1.C[N+]1([O-])CCOCC1>CN(C=O)C.C(OCC)(=O)C>[CH2:10]([C@@H:9]([NH:8][C:1]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:3])[CH2:17][N:47]1[CH2:46][CH:45]=[C:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[O:37][CH3:36])[CH2:49][CH2:48]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: COc1ccccc1C1=CCNCC1
Reactant: On1nnc2ccccc21
Agent: CC[Al](Cl)CC
Agent: C[N+]1([O-])CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1C1=CCN(C[C@@H](Cc2ccccc2)NC(=O)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of Boc-D-phenylalanine (2.0 g, 7.54 mmol), DEAC (1.45 g, 7.54 mmol), and HOBT (1.53 g, 11.3 mmol) in DMF (20 mL) at 0° C. was added of 1,2,3,6-tetrahydro-4-(2-methoxyphenyl)pyridine (1.87 g, 8.29 mmol), followed by the addition of NMO (1.4 mL, 12.8 mmol). The mixture was stirred under nitrogen for 16 hours at ambient temperature, diluted with ethyl acetate (100 mL) and washed with 0.1 N HCl (25 mL), saturated NaHCO3 (25 mL), H2O (25 mL) and brine (25 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield the required product (100% yield). This was stirred in 40 mL 4.0M HCl/dioxane overnight and concentrated to afford the hydrochloride salt of the deprotected amine. The amide was dissolved in THF (50 mL) and reduced at 0° C. by the addition of 1.0M LAH/THF (23 mL). After Stirring overnight at room temperature, the reaction was quenched with the addition of saturated NH4Cl, filtered through celite, dried over anhydrous Na2SO4, filtered and concentrated to yield the required product. Cyclohexanecarboxylicacid chloride (0.61 g, 4.13 mmol) was added dropwise to a solution of the amine (1.21 g, 3.75 mmol) and triethylamine (1.1 mL, 7.5 mmol) in dichloromethane (20 mL) at 0° C. The mixture was allowed to stir under nitrogen overnight at ambient temperature, concentrated under vacuum, diluted with ethyl acetate (50 mL) and washed with H2O (50 mL) then brine (25 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield crude product. Purification by flash chromatography (elution with ethyl acetate/hexanes) yielded 0.47 g of the above titled free base. The fumarate salt was prepared and crystallized yielding 0.28 g of the title compound as a pale yellow solid, m.p. 146-148° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([SiH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11].C([Si](CC)(CC)/C(/C)=C\C1C=CC=CC=1)C>>[CH2:10]([Si:12]([CH2:15][CH3:16])([CH2:13][CH3:14])/[C:7](/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:8]\[CH3:9])[CH3:11]
Reactant: CC[SiH](CC)CC
Reactant: CC#Cc1ccccc1
Agent: CC[Si](CC)(CC)/C(C)=C\c1ccccc1
Product: C/C=C(/c1ccccc1)[Si](CC)(CC)CC
Temperature: 100 °C
Yield: 86 %

Procedure:
A mixture of 0.125 ml (1.0 mmol) of 1-phenylpropyne, 0.192 ml (1.2 mmol) of triethylsilane, and 8.3 mg (0.01 mmol) of bis(triphenylphosphine)iminium μ-hydridebis(pentacarbonylchromium) was heated in a sealed tube at 100° C. for 16 hours while being stirred. GLC analysis of the reaction mixture revealed that (Z)-β-triethylsilyl-β-methylstyrene and (Z)-α-triethylsilyl-β-methylstyrene were produced in a yield of 86% and 4%, respectively.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.O.[NH2:21][NH2:22]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)NCc2cccnc2)s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(C(=O)NCc2cccnc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Methyl 5-(3-picolylcarbamoyl)thiophene-2-carboxylate (860 mg, 3.11 mmol) in ethanol (34 mL) was stirred with hydrazine monohydrate (1.57 m, 31.1 mmol) at 85° C. for 12 hours. The reaction solution was concentrated and stirred with diethyl ether at 0° C. for 1 hour. The precipitated solid was recovered by filtration and washed with a liquid mixture of diethyl ether and ethanol and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-picolylamide (yield 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([Cl:13])[N:9]=[C:8]2Cl.[NH2:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1.C([O-])(=O)C.[Na+].[OH-].[Na+]>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([Cl:13])[N:9]=[C:8]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Cl)nc(Cl)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c(Nc3ccccc3C)nc(Cl)nc12
Yield: 60.3 %

Procedure:
8-Methoxy-2,4-dichloroquinazoline (3.7 g, 0.016 mol) was stirred in a mixture of water (85 ml), tetrahydrofuran (125 ml), o-toluidine (1.7 g, 0.016 mol) and sodium acetate (2.2 g, 0.027 mol) for a total of 4 days with heating to 50° for a total of 32 hours and the addition of a total of 20 ml 0.01 mol NaOH dropwise over this period maintaining the pH at 7. The reaction mixture was evaporated in vacuo and crystallised from ethanol/water to give 8-methoxy-4-(2-methylphenylamino)-2-chloroquinazoline (2.89 g, 60%) m.p. 218°-220°.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3][CH2:2]1.Cl[C:9]1[N:13]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[N:12]=[CH:11][C:10]=1[C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:25][C:24]([C:10]2[CH:11]=[N:12][N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[C:9]=2[S:7][CH:4]2[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]2)=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2Cl)cc1
Reactant: SC1CCCCC1
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2SC2CCCCC2)cc1

Procedure:
Methyl 4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanylpyrazol-1-yl]benzoate was prepared from cyclohexylthiol and methyl 4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate#15) by the same process used for Intermdiate#96.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20][O-].[Na+].CO.CI>O>[CH3:20][S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCSC
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
In a 200 ml flask equipped with a stirrer and a calcium chloride dryer tube were charged 5.7 g of 1-octadecanthiol, 1.2 g of sodium methoxide and 30 ml of methanol, and the mixture was refluxed for 10 minutes. Then, 3.0 g of methyl iodide was added dropwise to the mixture and reflux was further contented for 30 minutes. The resulting mixture was poured into 200 ml of distilled water, and the resulting precipitate was collected by filtration under reduced pressure to obtain 6.0 g of methyloctadecylsulfide.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C@@:12]2([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH:3]([CH3:4])[C@@H:2]([CH3:1])[O:19]2)=[CH:8][CH:7]=1
Reactant: C/C=C\C
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1
Product: CC1[C@@H](C)O[C@@]1(Cn1cncn1)c1ccc(F)cc1
Yield: 5.3 %

Procedure:
Following a procedure similar to that described in Example 39, but using cis-2-butene and 950 mg (5.68 mmole) of 4'-fluoro-2-(1H-1,2,4-triazol-1-yl)-acetophenone, 80 mg (yield 5.3%) of a 1:1 mixture of stereoisomers at the 3-position of the title compound were obtained, in the form of oil.
Reaction SMILES: C(OC(=O)NC1CCN(C[CH:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)C=[CH:19][C:18]2=[O:29])[CH3:16])CC1)(C)(C)C.FC(F)(F)C(O)=[O:34].NC1CC[N:42]([CH2:45][CH2:46][N:47]2[C:52]3[CH:53]=C(OC)C=CC=3CO[C:48]2=O)CC1>>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]2[O:34][CH2:19][C:18](=[O:29])[N:17]([CH2:15][CH2:16][CH2:48][N:47]3[CH2:46][CH2:45][NH:42][CH2:53][CH2:52]3)[C:26]=2[CH:25]=1
Reactant: COc1ccc2ccc(=O)n(C(C)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Product: COc1ccc2c(c1)N(CCCN1CCNCC1)C(=O)CO2

Procedure:
tert-Butyl{1-[2-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl]piperidin-4-yl}carbamate (Intermediate 119, 500 mg, 1.23 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as a yellow oil, 866 mg (quantitative), and used without further purification for the next step.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CC(=O)OCC>CC#N>[CH2:16]([CH:3]1[NH:2][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[CH2:6][O:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(COCc1ccccc1C(=O)O)Cc1ccccc1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(Cc2ccccc2)COCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a solution of compound 1c (28 g, 87 mmol) obtained above in CH3CN (1.5 L) was added DIPEA (68 g, 520 mmol) at 0° C., followed by BOP-Cl (70 g, 275 mmol). The resulting mixture was stirred at 0° C. for 30 min and then warmed to rt overnight. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in EA, washed with 2N HCl and dried over anhydrous Na2SO4. Concentration in vacuo and purification by CC eluting with PE:EA=1:2 gave compound 1d as a yellow oil (7.0 g, 30% yield). 1H NMR (400 MHz, CDCl3): δ 7.50 (dd, J=7.6, 1.6 Hz, 1H), 7.41-7.34 (m, 2H), 7.28-7.19 (m, 4H), 7.05 (d, J=7.2 Hz, 2H), 5.83 (m, 1H), 4.82 (d, J=14.0 Hz, 1H), 4.61 (d, J=13.6 Hz, 1H), 3.82-3.78 (m, 1H), 3.78-3.67 (m, 1H), 3.58-3.55 (m, 1H), 2.75-2.71 (m, 2H). MS (ESI+): 268 [M+1]+.