Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH:3]1[Cl:20].N12CCCCC1C=NCCC2.O>CN(C)C=O>[Cl:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[C:3]=1[Cl:20]
Reactant: NC(=O)N1c2ccccc2C(Cl)C(Cl)(Cl)c2ccccc21
Agent: C1=NCCCN2CCCCC12
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1c2ccccc2C(Cl)=C(Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 8.33 g of crude 10,11-dihydro-10,10,11-trichloro-5H-dibenz[b,f]azepine-5-carboxamide in 35 ml of dimethyl formamide is treated at 0°-10° C with 9.1 ml (0.61 mole) of 1,5-diazabicyclo[5.4.0]undec-5-ene and stirred for 1 hour at room temperature. The brown solution is then poured into a mixture of water and ice and the resultant suspension is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed over silica gel (particle size: 0.063-0.2 mm) with ethyl acetate as eluant. The homogeneous fractions are combined, concentrated by evaporation and recrystallised from ethyl acetate to yield 10,11-dichloro-5H-dibenz[b,f]azepine-5-carboxamide which melts at 265°-270° C.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:45])[C:16](=[O:17])[N:15]2[CH:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH2:21][CH:14]2[N:13]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[Cl:44])(=[O:36])=[O:35])[CH2:12]1)C1C=CC=CC=1.[Si](I)(C)(C)C>C(#N)C>[NH2:10][C:11]1([CH3:45])[C:16](=[O:17])[N:15]2[CH:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19](=[O:25])[N:20]([CH:22]([CH3:23])[CH3:24])[CH2:21][CH:14]2[N:13]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[Cl:44])(=[O:36])=[O:35])[CH2:12]1
Reactant: CC(C)N1CC2N(C(=O)C(C)(NC(=O)OCc3ccccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC(C)N1CC2N(C(=O)C(C)(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
A solution of benzyl[6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-methyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate in 2 ml of acetonitrile is cooled to 0° C. in an ice bath, and 0.05 ml (0.35 mmol) of TMSI is added.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[I:6][C:7]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:9]([CH:10]=O)[C:8]=1[OH:19].C(N(CC)CC)C>C(Cl)Cl>[O:3]=[S:1]1(=[O:4])[N:2]=[CH:10][C:9]2[CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=[C:7]([I:6])[C:8]=2[O:19]1
Reactant: CC(C)(C)c1cc(I)c(O)c(C=O)c1
Reactant: NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(I)c2c(c1)C=NS(=O)(=O)O2
Temperature: 20 °C
Yield: 13.7 %

Procedure:
To a solution of sulfamoyl chloride (13.8 g, 0.12 mole) in anhydrous methylene chloride (75 ml) is added a solution of 3-iodo-5-(1,1-dimethylethyl)salicylaldehyde (6 g., 0.02 mole) and triethylamine (12.1 g, 0.12 mole) in anhydrous methylene chloride (100 ml.) dropwise with stirring at 20° C. Upon completing the addition, the resulting reaction mixture is stirred at 20° C. for 3 days. Removal of the solvent in vacuo leaves a tacky residue which is partitioned between ether and 2 N hydrochloric acid. After separating the phases, the organic phase is washed with water and saturated bromine, dried over sodium sulfate and filtered. Evaporation of the filtrate leaves an oily residue (6 g.) which is chromatographed on silica gel (300 g.) with benzene. Elution with benzene (840 ml.) gives recovered 3-iodo-5-(1,1-dimethylethyl)salicylaldehyde (2.2 g., 37% recovery), m.p. 76°-78° C. Continued elution with benzene (500 ml.) provides an impure solid (2.4 g.) which is triturated with hexane (20 ml.) and filtered to afford the title compound as a pale yellow solid (1.0 g, 14%), m.p. 130°-134° C. Crystallization from hexane-benzene (9.1; viv) gives an analytical sample of 2,2-dioxo-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine, m.p. 135°-136° C.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[Cl:21][C:22]1[C:23]([F:35])=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26]>N1C=CC=CC=1.CO>[Cl:21][C:22]1[C:23]([F:35])=[C:24]([CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=1)[C:25]([NH:20][C:18]1[O:19][C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[N:16][N:17]=1)=[O:26]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1cc(C(F)(F)F)cc(Cl)c1F
Reaction time: 18 h
Yield: 34.8 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 3-chloro-2-fluoro-5-trifluoromethylbenzoyl chloride (250 uL) was added directly into the solution. The reaction mixture formed a red solution with a small amount of white precipitate. It was left to stir for 18 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (83.4 mg). Yield 34.8%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([C@H:34]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:35](O)=[O:36])[CH2:29][CH2:28][CH2:27]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([C@H:34]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:35]([N:6]1[CH2:5][CH2:4][N:3]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)(=[O:16])=[O:15])=[CH:12][CH:13]=3)[C:2](=[O:1])[CH2:7]1)=[O:36])[CH2:29][CH2:28][CH2:27]2
Reactant: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: CC(C)C[C@H](C(=O)O)N1CCCc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C(=O)C1)N1CCCc2cc(Cl)ccc21
Yield: 100 %

Procedure:
Synthesized according to general procedure 14, method B. The reaction was set up with 4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15 mmol), (R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-4-methylpentanoic acid (28 mg, 0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg, 0.20 mmol), and DMF (0.20 mL) to obtain the desired amide as a white solid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=602.0; tR=3.50 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)#[N:27]>>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)(=[O:36])=[O:35])=[CH:32][CH:33]=1)#[N:27]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)c4ccc(C#N)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 286 was prepared analogous to compound of example 284 by reaction of compound of example 223 with 4-cyanobenzene sulfonyl chloride. The compound of example 286 was used directly without isolation, for the preparation of compound of example 287.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][P:10]([O:15][CH2:16][CH3:17])(=[O:14])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][P:10](=[O:14])([O:11][CH2:12][CH3:13])[O:15][CH2:16][CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(C/C=C/c1ccccc1)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CCCc1ccccc1)OCC
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A solution of compound 5e (30 mg) in ethanol (5 mL) was hydrogenated over 10% Pd/C (5 mg) at atmospheric pressure. The mixture was vigorously stirred at r.t for 3 h, whereupon the catalyst was removed by filtration and the filtrate concentrated under reduced pressure to afford 7a as a colorless oil (30 mg, 99% yield). 1H NMR (CDCl3) δ1.30 (t, J=7.1 Hz, 6 H), 1.69-1.77 (m, 2 H), 1.91-1.94 (m, 2 H), 2.69 (t, J=7.5 Hz, 2 H), 4.04-4.10 (m, 4 H), 7.16-7.30 (m, 5 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[I-].[CH3:23][C:24]1([CH2:28][Zn+])[CH2:27][O:26][CH2:25]1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:23][C:24]4([CH3:28])[CH2:27][O:26][CH2:25]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: COC(=O)c1nc2n(c1I)C1CC(C1)c1ccc(Br)cc1-2
Reactant: CC1(C[Zn+])COC1
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1nc2n(c1CC1(C)COC1)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 90 °C
Reaction time: 0.02 h
Yield: 40.4 %

Procedure:
A solution of methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (75 mg, 0.16 mmol) in 1 mL DMA was sparged with nitrogen and treated with ((3-methyloxetan-3-yl)methyl)zinc(II) iodide (1.11 mL, 0.59 M, 0.65 mmol) reagent while nitrogen was sparging. After 1 min, solid Pd(PPh3)4 (ca. 10 mol %) was added and the mixture stirred at 90° C. overnight. The mixture was diluted with ammonium chloride and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. Purification by flash column chromatography (12 g isco, 10-100% EtOAc) gave 27 mg of methyl 10-bromo-3-((3-methyloxetan-3-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This product was taken up in 1 mL of DMF and treated with 0.2 mL formamide then 0.2 mL of 25% wt NaOMe in MeOH. After 1 hour at room temp, the mixture was diluted with ammonium chloride and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. This material was used in subsequent operations without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:21]([CH3:22])[CH3:20])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CNC
Solvent: CS(C)=O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and dimethylamine (5.6 N in EtOH, 8.7 mL, 48.8 mmol) in DMSO (35 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (2.81 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=O.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:26]=[C:17]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(Br)cc12
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 60 %

Procedure:
5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (100 mg, 0.323 mmol) and o-phenylene diamine (38.5 mg, 0.356 mmol) were dissolved in dry THF (6 mL), and 2N HCl (2 drops) were added. The solution was heated at a gentle reflux for 30 min, and then 1N sodium bisulfite (2 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (100 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 60% yield. 1H NMR (400 MHz, CDCl3): δ 9.86 (s, 1H), 8.79 (d, 1H, J=1.2 Hz), 7.83 (m, 1H), 7.50-7.41 (m, 3H), 7.25-7.22 (m, 2H), 5.69 (dd, 1H, J=2.8 and 8.8 Hz), 3.98 (m, 1H), 3.80 (m, 1H), 2.53 (m, 1H), 2.19 (m, 2H), 1.76 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]([CH3:21])=[CH:16][C:17]([O:19]C)=[O:18])[CH:8]=[CH:7][C:6]=2[C:5]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:4][CH2:3]1.O.[OH-].[Li+]>>[CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]([CH3:21])=[CH:16][C:17]([OH:19])=[O:18])[CH:8]=[CH:7][C:6]=2[C:5]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)C=C(C)C#C[Se]c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C#C[Se]c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C)cc1)=CC(=O)O

Procedure:
In a manner similar to that of Example 1 g, by reacting 0.23 g (0.5 mmol) of methyl 5-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanyl)-3-methylpent-2-en-4-ynoate with 0.23 g (5.5 mmol) of lithium hydroxide monohydrate, a pale yellow solid is obtained (0.05 g; yield=23%; m.p.=166° C.).
Reaction SMILES: [OH:1][C:2]([C:5]([OH:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[B:27](O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[CH3:3][C:2]1([CH3:4])[C:5]([CH3:7])([CH3:6])[O:8][B:27]([C:18]2[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:1]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Solvent: CCOCC
Product: CC1(C)OB(c2cc(C(F)(F)F)ccc2OCc2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Pinacol (1.82 g) was added to a solution of the product from example 32 step (ii) (4.54 g) in ether (40 ml) and stirred at RT for 20 h. The reaction was diluted with ether (100 ml), washed with brine, dried (MgSO4) and evaporated. Yield 5.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1>>[C:29]([O:28][C:26]([N:23]1[CH2:22][CH2:21][CH:20]([O:19][C:16]2[CH:17]=[N:18][C:13]([N:9]3[C:6]4=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]4[CH:11]=[CH:10]3)=[CH:14][CH:15]=2)[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: COc1cnc2[nH]ccc2c1
Product: COc1cnc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using 5-methoxy-1H-pyrrolo[2,3-b]pyridine and tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate. (0.09 g, 45%); MS: 425(M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:26][C:27]([N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[OH:14][C:13]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([C:8]([N:32]2[CH2:33][CH2:34][CH2:35][N:29]([C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:28])[CH2:30][CH2:31]2)=[O:9])=[CH:11][C:12]=1[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Solvent: CC#N
Product: CC(C)(C)c1cc(C(=O)N2CCCN(C(=O)OCc3ccccc3)CC2)cc(C(C)(C)C)c1O
Reaction time: 6 h

Procedure:
A mixture of 13.4 g (0.05 mol) of 3,5-di-tert.-butyl-4-hydroxybenzoyl chloride and 12.4 g (0.053 mol) of 1-benzyloxycarbonylhomopiperazine in 200 ml of acetonitrile is heated under reflux, with stirring, for 6 hour. The solvent is then removed by distillation under reduced pressure, the residue is partitioned between methylene chloride and dilute hydrochloric acid, and the organic phase is separated off and washed with saturated brine. After drying over sodium sulfate and removal of the solvent by distillation under reduced pressure, the crystalline residue is digested with hot diisopropyl ether, filtered off with suction, washed with diisopropyl ether and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:36].[OH-]>>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)N1CCOCC1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)N3CCOCC3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-4-morpholinesulfonamide (96 mg, 0.177 mmol) in NH4OH (4 mL), heated in a microwave reactor for 40 min at 120° C. the title compound was obtained as a yellow solid (20 mg, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.86 (s, 1H), 7.87 (d, J=5.3 Hz, 1H), 7.54 (td, J=6.8, 3.5 Hz, 1H), 7.19-7.31 (m, 2H), 6.54 (s, 2H), 5.80 (d, J=5.3 Hz, 1H), 3.68 (t, J=4.4 Hz, 4H), 3.48-3.55 (m, 4H), 3.43 (t, J=4.4 Hz, 4H), 2.96-3.03 (m, 4H). MS (ESI): 521.8 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH:11]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.[NH2:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)(O)[O-].[Na+]>C(O)CCC>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:27][C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:6][CH2:7]2)=[CH:21][CH:22]=1
Reactant: Nc1ncccn1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(CCCCl)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(CCCNc3ncccn3)CC2)cc1

Procedure:
A mixture of equivalent amounts of 1-(3-chloropropyl)-N,α-bis(4-fluorophenyl)-4-piperidinemethanamine, 2-aminopyrimidine, and sodium bicarbonate in 1-butanol is heated at reflux temperature until the reaction is complete. The solvent is removed and the residual material partitioned between water and methylene chloride. The methylene chloride layer is dried and concentrated to obtain the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]#[N:20])[S:16][CH:15]=2)[C:9]1=[O:21])(C)(C)C.[ClH:23]>CCOC(C)=O>[ClH:23].[NH2:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]#[N:20])[S:16][CH:15]=2)[C:9]1=[O:21]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2csc(C#N)c2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1cc(CN2CCC(N)C2=O)cs1
Reaction time: 3 h

Procedure:
[1-(5-Cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester (4 g, 13.8 mmol) is added to a solution of 100 mL of EtOAc sat. with HCl gas at 0° C. After 3 hours, the solution is concentrated. The title compound (3.3 g, 13.5 mmol) is obtained as a white solid.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:7][C:8]([F:20])([F:19])[C:9]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:10][CH:11](O)[CH3:12].C([Li])CCC.C(Cl)(=O)C(C)=C>>[C:1]([O:6][CH:11]([CH3:12])[CH2:10][C:9]([C:8]([F:7])([F:19])[F:20])([OH:14])[C:15]([F:16])([F:18])[F:17])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(O)CC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)[O-]
Agent: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Product: C=C(C)C(=O)OC(C)CC(O)(C(F)(F)F)C(F)(F)F

Procedure:
The title compound was prepared in the same fashion as the above described methacrylate using 142 g (0.63 mol) of 1,1,1-trifluoro-2-trifluoromethyl-2,4-pentanediol, 793 mL (1.27 mol) of n-butyllithium (1.6 M in hexane) and 73 g (0.69 mol) of methacryloyl chloride to yield, after distillation at 67° C. at 1.0 mm Hg, 142 g (76%) of the 2° methacrylate as a clear, colorless oil.
Reaction SMILES: [CH2:1]([NH2:19])[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].[CH2:20]1[O:22][CH:21]1[CH2:23][OH:24]>C1(C)C=CC=CC=1>[CH2:1]([NH2:19])[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].[OH:24][CH2:23][CH:21]([OH:22])[CH3:20]
Reactant: OCC1CO1
Agent: CCCCCCCCCCCCCCCCCCN
Solvent: Cc1ccccc1
Product: CC(O)CO
Temperature: 60 °C

Procedure:
Approximately 280 g of octadecylamine and about 0.35 liter of toluene were charged to a glass reactor and warmed to about 60° C. Over a 3 hour period of time, 38 g of glycidol were slowly added in small increments with agitation while maintaining a temperature of 60° to 65° C. The reactor contents were then heated at about 90° C. for 26 additional hours. The solvent was removed by vacuum distillation and the resulting product formed a pale yellow waxy solid after cooling.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(F)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([OH:16])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:20])=O>ClCCl>[C:1]([Cl:20])(=[O:16])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCC/C=C/C(=O)O
Solvent: ClCCl
Product: CCCCCCCCCCC/C=C/C(=O)Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
(E)-tetradec-2-enoic acid (18.7 g) was dissolved in anhydrous dichloromethane (200 ml) under nitrogen with stirring. The solution was cooled in ice-water bath for 30 min. Oxalyl chloride (9.1 ml) was added dropwise. The reaction mixture was slowly warm up to room temperature overnight. The solvent was removed under vacuum. The product was obtained as clear oil (20.0 g, 99%) and used in next step synthesis without further purification.