Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=O)=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].CSC.B>O1CCCC1>[NH2:26][CH2:24][C:23]1[CH:27]=[CH:28][C:20]([CH2:19][N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Cl:1])[C:3]2=[O:29])=[CH:21][CH:22]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(N)=O)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(CN)cc1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
The compound of Example 606 (10.0 g, 23.38 mmol) was suspended in tetrahydrofuran (100 mL) and cooled in an ice-bath. Borane dimethyl sulfide (29.9 mL, 2.0 M in tetrahydrofuran, 59.7 mmol) was added. The resulting mixture was heated to reflux overnight and then cooled in an ice-bath. Additional borane dimethyl sulfide (5.85 mL, 2.0 M in tetrahydrofuran, 11.7 mmol) was added. The resulting mixture was heated to reflux overnight and the cooled to room temperature. The flask was fitted with a distillation head and the reaction was partially concentrated. Additional borane dimethyl sulfide (5.85 mL, 2.0 M in tetrahydrofuran, 11.7 mmol) was added. The mixture was heated to reflux overnight and the cooled in an ice-bath. The reaction was quenched by the addition of 1.0 N HCl (75.0 mL) then partially concentrated. The aqueous layer was made alkaline with 2.5 N NaOH and a precipitate developed. The solid was collected by filtration washing with diethyl ether to give a pale purple solid (3.00 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ 7.64 (app q, J=7.9 Hz, 1H), 7.44 (d, J=7.9 Hz, 2H), 7.32 (app dt, J=2.4, 9.9 Hz, 1H), 7.14 (app dt, J=1.9, 8.5 Hz, 1H), 7.13 (d, J=7.9 Hz, 2H), 6.61 (s, 1H), 5.27 (s, 4H), 3.90 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:37][C:38]1[C:46]2[C:45]([N:47]3[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]3)=[N:44][CH:43]=[N:42][C:41]=2[NH:40][CH:39]=1>CC#N>[CH3:37][C:38]1[C:46]2[C:45]([N:47]3[CH2:52][CH2:51][CH:50]([NH:53][C:12](=[O:14])[C:11]4[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH:10]=4)[CH2:49][CH2:48]3)=[N:44][CH:43]=[N:42][C:41]=2[NH:40][CH:39]=1
Reactant: O=C(O)c1cccc(OCCN2CCCC2)c1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: Cc1c[nH]c2ncnc(N3CCC(NC(=O)c4cccc(OCCN5CCCC5)c4)CC3)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-{[2-(1-pyrrolidinyl)ethyl]oxy}benzoic acid D38 (200 mg) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (171 mg, 0.98 mmol) was dissolved under argon in MeCN (20 ml) and cooled down to 0° C. Then N-methylmorpholine (0.3 ml) was added and the mixture was stirred at 0° C. for 2 hours. To this mixture was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (240 mg) in small portions, afterwards the reaction was then warmed up to room temperature. After stirring for 16 hours, the reaction was filtered and concentrated to give crude product. This product was purified by prep-HPLC (A 0.01% NH4HCO3/Water, B: ACN, 0˜8 min 25-50%, 50%˜60% 8-12 min, 60%˜95% 12-15 min, 95˜95% 15-18 min) to give 50 mg of white solid of desired product E43. LCMS [MH+] 449.2@1.52 min (5 min run)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4].[CH2:25](O)[CH:26]=[CH:27][CH:28]=[CH:29]C.[CH:32]1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:17]([C:13]1[CH:12]=[C:11]([CH:10]2[C:5]([C:3]([O:2][CH2:1][CH:25]=[CH:26][CH:27]=[CH:28][CH3:29])=[O:4])=[C:6]([CH3:24])[NH:7][C:8]([CH3:23])=[C:9]2[C:20]([O:22][CH3:32])=[O:21])[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: CC=CC=CCO
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CC=CC=CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Yield: 89.1 %

Procedure:
664 mg (2 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylic acid 3-methyl ester, 206 mg (2.1 mM) of 2,4-hexadien-1-ol, 433 mg (2.1 mM) of dicyclohexylcarbodiimide and 257 mg (2.1 mM) of 4-dimethylaminopyridine were dissolved in 20 ml of dichloroethane, and refluxed for 2 hours. Insoluble matters were filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography, and 734 mg of methyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained (yield 89%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][S:2]([O:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[CH:7]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cnc2ccccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-hydroxyquinol-3-yl methanesulphonate (0.48 g) and potassium carbonate (0.28 g) in dry dimethylformamide (20 ml) was stirred for 2 hours at ambient temperature. Methyl iodide (0.15 ml) was then added and the stirring at ambient temperature continued overnight. The solvent was removed under reduced pressure and the residue was triturated with water (10 ml). The resultant mixture was extracted extracts were evaporated to dryness. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (39:1) followed by crystallisation from industrial methylated spirit (10 ml) to give the novel compound ]-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 206°-208°.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:26](O)=[O:27])[NH:11][C:12](=[O:25])[C:13]([CH3:24])([CH3:23])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=O.C1CC[CH:40]([N:43]=C=NC2CCCCC2)CC1>CN(C=O)C>[OH:35][CH:34]([C:26](=[O:27])[C@H:10]([CH2:9][S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:11][C:12](=[O:25])[C:13]([CH3:23])([CH3:24])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:33][CH2:32][CH2:31][CH2:40][NH2:43]
Reactant: CC(C)(CSCc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(CSCc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)C(O)CCCCN
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a stirred solution of S-benzyl-N-(3-benzylthio-2,2-dimethyl-propionyl)-L-cysteine (4.18 g) and N-hydroxysuccinimide (1.15 g) in DMF (10 ml), DCC (2.06 g) dissolved in DMF (10 ml) was added dropwise under ice cooling and the mixture was stood overnight. The mixture was filtered and 5-aminopentanol (1.55 g) dissolved in DMF (30 ml) was added to the filtrate. The mixture was stirred for 3 hr. at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. Ethyl acetate layer was washed with saturated sodium bicarbonate solution, water and then saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 3.4 g (69%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:19])[N:17]([CH3:20])[CH2:16][CH2:15][N:14]([CH3:21])[C:13]=3[CH:22]=2)=[N:6][CH:7]=1.CO.C(Cl)[Cl:37]>>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[C:18](=[O:19])[N:17]([CH3:20])[CH2:16][CH2:15][N:14]([CH3:21])[C:13]=2[CH:22]=1.[Cl:37][C:5]1[N:4]=[C:3]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:2]([Cl:1])=[CH:7][N:6]=1.[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:19])[N:17]([CH3:20])[CH2:16][CH2:15][N:14]([CH3:21])[C:13]=3[CH:22]=2)=[N:6][CH:7]=1
Reactant: ClCCl
Agent: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)N(C)CCN(C)C3=O)ncc1Cl
Solvent: CO
Product: CN1CCN(C)c2cc(N)ccc2C1=O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl

Procedure:
Part 3C. 2-[5-Chloro-2-(1,4-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methylbenzamide. This compound was prepared according to Example 411f. From 8-amino-1,4-dimethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (100 mg, 0.49 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methylbenzamide (144 mg, 0.49 mmol) was obtained 97 mg (43%) of the title compound following flash chromatography (silica gel, 20% MeOH/DCM); m.p. 243-247° C.; MS: m/z=466/468 (M+H)+, Cl-isotope pattern; 1H-NMR (DMSO-d6, δ): 11.64 (s, 1H), 9.57 (s, 1H), 8.76 (m, 2H), 8.27 (s, 1H), 7.76 (d, 8 Hz, 1H), 7.50 (t, 7 Hz, 1H), 7.40 (d, 7 Hz, 1H), 7.33 (d, 8 Hz, 1H), 7.20 (s, 1H), 7.15 (t, 7 Hz, 1H), 3.42 (t, 5 Hz, 2H), 3.25 (t, 5 Hz, 2H), 3.04 (s, 3H), 2.81 (s, 3H), 2.68 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([S:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)(=[O:10])=[O:9])[CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[C:23]([Mg]Br)#[C:24][CH3:25]>C1COCC1>[O:1]=[C:2]([C:23]#[C:24][CH3:25])[CH2:7][N:6]([S:8]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=[O:10])=[O:9])[CH2:5][CH2:4][NH:3][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccs2)CC1=O
Reactant: CC#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(=O)CN(CCNC(=O)OC(C)(C)C)S(=O)(=O)c1cccs1
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
A solution of tert-butyl 2-oxo-4-(2-thiophenylsulfonyl)-1-piperazinecarboxylate (600 mg, 1.73 mmol) in THF (8 mL) at 0° C. was added to a solution of 1-propynylmagnesium bromide (0.5 M in THF, 5.0 mL, 2.50 mmol, Sigma-Aldrich, St. Louis, Mo.). After 1.5 h at 0° C., additional 1-propynylmagnesium bromide (3.0 mL, 1.50 mmol) was added. After an additional 50 min, the mixture was quenched with ice (20 g) and saturated aqueous NH4Cl (15 mL). EtOAc (20 mL) was added and the aqueous layer was further extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel using (10 to 50% EtOAc in hexane) to give tert-butyl (2-((2-oxo-3-pentyn-1-yl)(2-thiophenylsulfonyl)amino)ethyl)carbamate as yellow oil (540 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[NH:12][C:13]([NH:15]/[N:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1)=[S:14].Cl[CH2:41][C:42](=[O:44])[CH3:43].C(N(CC)CC)C.O>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1/[N:12]=[C:13]1\[S:14][CH2:41][C:42]([CH3:43])([OH:44])[N:15]\1/[N:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(/C=N/NC(=S)Nc4c(Cl)cccc4C(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCC(C)=O
Product: CC1(O)CS/C(=N\c2c(Cl)cccc2C(F)(F)F)N1/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of (E)-N-(2-chloro-6-(trifluoromethyl)phenyl)-2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (111 mg, 0.19 mmol) in butanone (2 mL) was added chloroacetone (0.02 mL, 0.27 mmol) and triethylamine (0.05 mL, 0.38 mmol), and the reaction was stirred at 75° C. for 16 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel containing water (5 mL), and was extracted twice with dichloromethane. The organic extracts were filtered through a phase separator, adsorbed onto silica gel, and purified by flash chromatography (0-20% ethyl acetate/B, where B=1:1 dichloromethane/hexanes). The title compound was isolated as a yellow solid (60.5 mg, 50%): mp 97° C. (dec); 1H NMR (400 MHz, CDCl3) δ 9.72-9.57 (m, 1H), 8.58 (s, 1H), 8.24 (d, J=8.4 Hz, 2H), 7.88-7.72 (m, 4H), 7.56 (dt, J=18.3, 5.8 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.09 (t, J=8.0 Hz, 1H), 3.49 (d, J=13.3 Hz, 1H), 3.35 (m, 2H), 1.86 (d, J=14.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ−58.01, −62.05, −62.22; ESIMS m/z 642 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH:7]([NH:13][C:14](=[O:40])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:64]1[C:69](=[O:70])[CH2:68][CH2:67][C:65]1=[O:66])=[N+](C)C)C>C1COCC1.C(#N)C>[O:66]=[C:65]1[CH2:67][CH2:68][C:69](=[O:70])[N:64]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][CH:7]([NH:13][C:14](=[O:40])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:41]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)O)C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
2-(19-tert-Butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester (6.52 g, 11.17 mmol) was dissolved in THF (100 mL), DIPEA (2.14 mL) was added followed by a solution of TSTU (3.70 g, 12.29 mmol) in acetonitrile (25 mL). The mixture was stirred overnight at RT, then it was evaporated resulting in a brownish residue which was recrystallised from acetonitrile. After cooling overnight at 5° C. a powder was formed. This was dissolved in THF and dried with MgSO4, filtered and evaporated to dryness to afford 6.17 g (81%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].[CH3:18][N:19]1[CH2:23]C[C@@H:21](O)[CH2:20]1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:20][CH2:21][C@@H:1]([O:2][C:3](=[O:17])[C:4]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[OH:5])[CH2:23]1
Reactant: COC(=O)C(O)(c1ccco1)C1CCCCC1
Reactant: CN1CC[C@@H](O)C1
Solvent: Cc1ccccc1
Product: CN1CC[C@@H](OC(=O)C(O)(c2ccco2)C2CCCCC2)C1
Yield: 21.2 %

Procedure:
5.0 g (0.021 mol) of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid methyl ester were dissolved in 150 ml of dry toluene. To this solution 2.12 g (0.021 mol) of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19) and 500 mg (0.021 mol) of HNa were added and the mixture was refluxed using a Dean-Stark system for 24 hours. The reaction mixture was cooled, and extracted with HCl 2N. The aqueous layer was basified with K2CO3 and extracted with AcOEt (3×100 ml). The organic layers were combined, dried over Na2SO4 and evaporated to dryness to yield a residue which was purified by chromatography on silica gel eluting with chloroform plus isopropanol (0%→10%). Appropriate fractions were combined and evaporated to give 1.37 g (21%) of the title product as an oil.
Reaction SMILES: [C:1]([OH:14])(=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[N+:40]([C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:45][CH:44]=1)([O-:42])=[O:41].C(NC1CCCCC1)(NC1CCCCC1)=O>CN(C=O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]([N:52]2[CH2:53][CH2:54][N:49]([C:46]3[CH:45]=[CH:44][C:43]([N+:40]([O-:42])=[O:41])=[CH:48][CH:47]=3)[CH2:50][CH2:51]2)=[O:14])[CH:12]=[C:9]([O:10][CH3:11])[C:7]=1[OH:8]
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(OC)c1O
Reaction time: 7 h

Procedure:
In a 100 ml flask, 0.99 g (5 mmoles) of syringic acid, 0.74 g (5.5 mmoles) of hydroxybenzotriazol, 1.10 g (5.5 mmoles) of dicyclohexylcarbodiimide and 1.04 g (5 mmoles) of 1-(4-nitrophenyl)piperazine are dissolved in 10 ml of DMF. After agitation at ambient temperature for 7 hours, the mixture is filtered and the precipitate rinsed with 20 ml of DMF followed by 100 ml of chloroform 2 g of a yellow powder is obtained, containing approximately 20% of dicyclohexylurea. The product is used as it is in the following stage.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:13])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(F)c(C(F)(F)F)c1
Yield: 64390 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-61 by using 4-fluoro-3-(trifluoromethyl)aniline (3.0 g, 0.016 mmol), NaNO2 (1.73 g, 0.025 mmol), SnCl2.2H2O (9.39 g, 0.041 mmol) and conc. HCl (100 mL) to afford 2.0 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]#[CH:25].O>CN(C)C=O>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH2:25][C:24]#[CH:23])[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 3.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 250 ml of dimethylformamide under argon was added 0.6 g of sodium hydride (50% in oil). The mixture was stirred for one hour, then 1.38 ml of propargyl bromide was added. This mixture was stirred for 12 hours then poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3) as the eluent. Fractions containing the desired product were collected, evaporated in vacuo and recrystallized from dichloromethan-hexane to give 2.5 g of orange crystals mp 195°-198° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11]C)[CH:10]=1)[CH:6]=O.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[OH2:20]>>[O:11]=[C:9]1[CH2:10][C:3](=[O:2])[CH:4]=[C:5](/[CH:6]=[C:13]2/[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]/2)[CH2:8]1
Reactant: O
Reactant: c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Product: O=C1C=C(/C=C2\CCCCC2=O)CC(=O)C1
Temperature: 25 °C
Yield: 74 %

Procedure:
10.79 g (0.11 mol) of cyclohexanone and 10.4 g (0.12 mol) of morpholine were added to 20 mL benzene, refluxed azeotropically after a trap was equipped, when no water was generated, benzene and morpholine were evaporated under reduced pressure to give enamine. 6.54 g (0.043 mol) of enamine and 5.40 g (0.033 mol) of 3,5-dimethoxybenzaldehyde were added to 20 mL benzene, refluxed azeotropically after a trap was equipped until no water was generated in a total of 8 h, after cooling to room temperature, 6 mol/L hydrochloric acid was added slowly with stirring, and stirred at room temperature for 2 h, the benzene layer was separated, the aqueous layer was extracted with benzene layer, benzene layers were combined and dried over anhydrous sodium sulfate, after evaporating the solvent under reduced pressure and recrystallizing with petroleum ether and ethanol, E-2-(3,5-dioxobenzylidene)cyclohexanone was obtained as yellow needles, yield: 74%, mp 55.0˜56.6. 1H-NMR: δ: 7.41 (s, 1H, ═CH), 6.53 (d, 2H, J=2.0 Hz, ArH), 6.45 (t, 1H, J=2.0 Hz, ArH), 3.80 (s, 6H, OCH3), 2.84 (dt, 2H, J=1.9, 6.5 Hz, CH2), 2.54 (t, 2H, J=6.6 Hz, CH2), 1.90 (m, 2H, CH2), 1.78 (m, 2H, CH2).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[C:10]1([B:16](O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>O1CCCC1>[CH3:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:8][O:9][B:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:1][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: CC(CO)(CO)C(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C(=O)O)COB(c2ccccc2)OC1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a suspension of 2,2-bis(hydroxymethyl)propionic acid (131 g, 0.98 mole) in tetrahydrofuran (500 ml) was added a solution of phenylboronic acid (122 g, 1.0 mole) in tetrahydrofuran (500 ml). The mixture was stirred for 3 h and toluene (1.0 L) was added. Water was removed by azeotropic distillation with toluene. Heptanes (500 ml) was added to the precipitated product, heated to reflux and cooled. The mixture was filtered and washed with heptanes (2×300 ml). The solids were dried under vacuum at 70–75° C. until constant weight to give 94% yield. 1H NMR: δ (DMSO-d6) 7.65 (d, 2H, Ar), 7.40 (m, 3H, Ar), 4.35 (d, 2H, CH2), 3.92 (d, 2H, CH2), 1.17 (s, 3H, CH3)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[S:17](Cl)(Cl)=[O:18].ClC1C(C(OCC)=O)[N:24](C)C2C=1C(=S=O)C(C)=CC=2.N>CCOCC>[NH2:24][S:17]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[N:2]([CH3:1])[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc2cc(C)ccc2n1C
Reactant: CCOC(=O)C1C(Cl)=C2C(=CC=C(C)C2=S=O)N1C
Agent: N
Solvent: CCOCC
Product: CCOC(=O)c1c(S(N)=O)c2cc(C)ccc2n1C
Yield: 61 %

Procedure:
10.0 gm (51 millimols) of ethyl 1,5-dimethyl-indole-2-carboxylate were reacted analogous to Example 18(b) with 28 ml of thionyl chloride, and the thus obtained yellow crystals (ethyl 3-chloro-sulfinyl-1,5-dimethyl-indole-2-carboxylate) was reacted with a solution of ammonia in ether at -70° C. to yield 8.8 gm (61% of theory) of ethyl 3-aminosulfinyl-1,5-dimethyl-indole-2-carboxylate; M.p.: 118° C.