Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CC[O:5][CH2:4]C1.[CH3:8][C@@H:9]1[NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([NH2:20])[C:12]=2[NH:11][CH2:10]1.ClC(OC(Cl)(Cl)Cl)=O>ClCCl>[CH3:8][C@@H:9]1[NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:19]3[NH:20][C:4](=[O:5])[N:11]([C:12]=23)[CH2:10]1
Reactant: CN1CCOCC1
Reactant: C[C@H]1CNc2c(N)cccc2CN1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C[C@H]1Cn2c(=O)[nH]c3cccc(c32)CN1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
300 ml of dichloromethane and 22.8 ml of 4-methylmorpholine are added to 12.7 g (0.072 mol) of (S)-3-methyl-2,3,4,5-tetrahydro-(1H)-1,4-benzodiazepin-9-amine. The mixture is then poured into a solution of 9.1 ml (0.0072 mol) of trichloromethyl chloroformate in 340 ml of dichloromethane cooled beforehand with an ice bath. The mixture is left stirring for 10 minutes at 0° C. and then for 20 minutes at room temperature. The solvent is evaporated under vacuum and the residue taken up in 200 ml of water and 34 ml of dioxane. The mixture is heated in a water bath for 45 minutes and then a concentrated aqueous ammonia solution is added. The mixture is left to cool, is sucked dry, is washed with water and is dried under vacuum. There are obtained 11.5 g of product which is recrystallized from boiling water. There are obtained 7.6 g of product which is used as is in the following stage.
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].C(N(CC)CC)C.[CH3:20][C:21](=[N:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](=[N:44][O:45][CH3:46])[CH:42]=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>[Cl-].[Na+].O.C(O)CCC>[CH3:46][O:45][N:44]=[C:41]([CH:42]1[NH:9][CH2:10][CH2:11][S:12]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][O:33][N:32]=[C:21]([CH3:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=1
Reactant: CON=C(C=O)c1ccccc1CON=C(C)c1cccc(C(F)(F)F)c1
Reactant: NCCS
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CON=C(c1ccccc1CON=C(C)c1cccc(C(F)(F)F)c1)C1NCCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Toluene (2.5 ml), butanol (2.5 ml), cysteamine hydrochloride (0.29 g, 2.54 mmol) and triethylamine (0.26 g, 2.54 mmol) were added to 2-[(α-methyl-3-trifluoromethylbenzylidene) aminooxymethyl]-α-methoxyiminophenylacetaldehyde (0.48 g, 1.27 mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetatein-hexane) to give 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxymethyl]phenyl thiazolidin-2-yl ketone O-methyloxime (0.52 g, yield 93.6%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26](Br)[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:13])([F:12])[F:1])[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]
Reactant: CCOC(=O)c1ncc2cc(Br)sc2c1O
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: CCOC(=O)c1ncc2cc(-c3ccccc3C(F)(F)F)sc2c1O

Procedure:
The title compound was prepared from 2-(trifluoromethyl)phenyl boronic acid and 2-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester, example 21.d, under conditions analogous to experimental example 21.e; MS: (+) m/z 367.9 (M+1)
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:20])([F:19])[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=O)[CH:9]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:10]1[CH:9]=[C:8]([C:7]([F:20])([F:19])[F:6])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(C(F)(F)F)c2ccccc2[nH]1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Cl)nc2ccccc12
Temperature: 90 °C
Yield: 29 %

Procedure:
DMF (cat.) was added to a solution of 4-trifluoromethyl-1H-quinolin-2-one 465 (160 mg, 0.75 mmol) in POCl3 (2 ml) and the mixture was heated at 90° C. for 1 h. After cooling, the mixture was concentrated in vacuo and the residue was poured into an ice cold solution of NaHCO3 solution. The aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (50 mg, 29%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: COc1ccc2c(c1)C(C)=NCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc2c(c1)C(C)NCC2

Procedure:
In close analogy to the procedure described above, 1-Methyl-7-methoxy-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH:16][CH2:17][NH:18][OH:19])=[CH:4][CH:3]=1.C[Si]([N:24]=[C:25]=[O:26])(C)C.[NH4+].[Cl-]>O1CCOCC1>[OH:19][N:18]([CH2:17][CH:16]=[CH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:25]([NH2:24])=[O:26]
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCC=Cc1ccccc1Sc1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)N(O)CC=Cc1ccccc1Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[3-[2-(4-fluorophenylthio)phenyl]prop-2-enyl]hydroxylamine (1.30 g; 4.7 mmol) in 24 ml of dry dioxane was added trimethylsilylisocyanate dropwise and the reaction mixture stirred at room temperature overnight. The mixture was poured into saturated NH4Cl and extracted twice with diethyl ether. The organics were combined, washed with 1N HCl and twice with water, and then brine, and dried over MgSO4. The solids were recrystallized from ethyl acetate and washed with cold diethyl ether to afford 0.76 g of the subtitle compound mp 124°-125° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17]([OH:19])=O)[CH2:14][N:15]=1)=[CH:7]2.[NH2:31][CH2:32][C@H:33]([OH:35])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[OH:35][C@H:33]([CH3:34])[CH2:32][NH:31][C:17](=[O:19])[CH2:16][CH:13]1[S:12][C:11]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:3][C:2]=3[CH3:1])=[N:15][CH2:14]1
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: C[C@@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC[C@@H](C)O)S3)[nH]c12
Reaction time: 15 h
Yield: 78 %

Procedure:
To a solution of [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg) and (R)-(−)-1-amino-2-propanol (78 mg) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole (137 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane and recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (264 mg, yield 78%) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].O>CN(C)C=O.C(OCC)(=O)C>[O:7]=[C:2]1[CH2:3][O:4][CH2:5][CH2:6][N:1]1[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CN1CCOCC1=O)OCc1ccccc1
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Under an argon atmosphere, to a solution of morpholin-3-one (220 mg, 2.2 mmol) in N,N-dimethylformamide (2.2 ml) was added sodium hydride (105 mg, 2.6 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then, benzyl bromoacetate (379 μl, 2.4 mmol) was added, and the mixture was stirred for 2 hr. To the reaction solution were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (321 mg, yield 59%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12]>C(Cl)Cl>[NH2:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:12]
Reactant: CN1CCNCC1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of 1-methylpiperazine (2.5 g, 24.96 mmol) in DCM (30 mL) at 0° C. was added a solution of Intermediate 69A (1.13 g, 5.63 mmol) in DCM (10 mL) slowly. The reaction was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography, (SiO2, 24 g, 0-10% MeOH/DCM) to give Intermediate 69B (0.77 g, 52%) as a yellow oil. HPLC: Rt=0.360 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=265 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH:16]=[O:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@H](C=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 10 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (3.0 g) in acetonitrile (20 mL) was added Dess-Martin reagent (5.1 g), and the mixture was stirred at 10° C. for 4 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.0 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16](=[O:32])[N:17]([CH3:31])[C@@H:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(C)(C)C.[ClH:34]>CO.CCOCC>[ClH:34].[ClH:34].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([N:17]([CH3:31])[C@@H:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:32]
Reactant: CN(C(=O)Cc1ccccc1CNC(=O)OC(C)(C)C)[C@H](CN1CCCC1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN(C(=O)Cc1ccccc1CN)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 7a in methanol (0.1 M) at 0° C. was added a solution of hydrochloric acid (5.5 eq) in ether (2.0 M). The reaction was stirred at room temperature overnight. The methanol was removed under reduced pressure and the resulting crystals were triturated with ether, filtered off and dried to afford a white solid. (99%) 1H NMR (400 MHz, DMSO-d6) δ 10.91 (br s, 1H), 8.21 (br s, 2H), 7.26-7.54 (m, 9H), 6.15 (m, 1H), 3.79-4.32 (m, 9H), 3.65 (m, 2H), 3.54 (m, 1H), 3.16 (m, 3H), 2.94 (s, 3H). Mass Spectral Analysis m/z=352.3 (M+H)+ tR=3.44 min (97%)
Reaction SMILES: N1C(C2C=CC([C:12]3[C:21](C)=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=4)[N:13]=3)=CC=2)=NN=N1.[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][O:23][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:32]1[CH:33]=[CH:34][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=1)[CH:21]=[CH:20]2
Reactant: COc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)c(C)cc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3n2)cc1
Temperature: 120 °C
Yield: 40.9 %

Procedure:
A mixture of 2-chloro-6-methoxyquinoline (Intermediate 1, 200 mg, 1.0 mmol), 4-(methoxycarbonyl) phenylboronic acid (205 mg, 1.1 mmol), Pd(dppf)Cl2 (366 mg, 0.5 mmol) and sodium carbonate (212 mg, 2.0 mmol) in 1,4-dioxane/water (3 mL/0.6 mL) was heated to 120° C. by microwave for 1 h. The precipitates were filtered; washed with EA (10 mL), acetone (10 mL) and water (10 mL) separately; dried to afford product (120 mg, 40.9%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH3:16]>>[Cl:1][C:2]1[N:11]=[C:10]([NH2:16])[C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1Cl
Product: COc1cc2nc(Cl)nc(N)c2cc1Cl
Yield: 58 %

Procedure:
Reaction of 2,4,6-trichloro-7-methoxyquinazoline with ammonia as described above afforded 2,6-dichloro-4-amino-7-methoxyquinazoline as a white solid, M.P., 300° C. in 58% yield.
Reaction SMILES: [NH4+].[Cl-].[Cl:3][C:4]1[C:5](=[O:22])[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1>CCO.[Fe]>[NH2:10][C:8]1[CH:9]=[C:4]([Cl:3])[C:5](=[O:22])[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: COc1ccc(Cn2cc([N+](=O)[O-])cc(Cl)c2=O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(Cn2cc(N)cc(Cl)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A saturated aqueous solution of NH4Cl (99 mL) was added to a solution of 3-chloro-1-(4-methoxy-benzyl)-5-nitro-1H-pyridin-2-one (Step O5) (6.8 g, 23.0 mmol) in EtOH (300 mL). After stirring for 15 min, iron powder (6.4 g, 115 mmol) was added and the resulting mixture was heated to reflux, stirred for 1 h, cooled to rt and concentrated. The residue was diluted with EtOH and the mixture was filtered through a pad of celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH, 100:0→96.5:3.5). ESI-MS: tR=0.61 min, [M+H]+ 265/267 (LC-MS 1); Rf=0.53 (9:1 CH2Cl2/MeOH).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:11]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:13]([N+:16]([O-])=O)=[N:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O>C(O)(=O)C.[Zn]>[CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:11]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:13]([NH2:16])=[N:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1N
Temperature: 105 °C
Yield: 96 %

Procedure:
5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-2-nitro-pyridine (0.39 mmol) is dissolved in acetic acid (4 ml). After addition of water (1.2 ml), zinc powder (6.3 eq.) is added and the reaction suspension is heated to 105° C. for 90 minutes. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-ylamine is obtained as yellow oil in a yield of 96%. HPLC (method C): 1.21 min, LC-MS (method A): 0.55 min, 339.15 (MO.
Reaction SMILES: [C:1](#[N: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]([CH2:22]N)[OH:21]>C(Cl)Cl.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:2]([C:1]1[O:21][CH2:20][CH2:22][N:19]=1)[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: CCCCCCCCCCCCCCCCCC#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC1=NCCO1
Temperature: 115 °C
Reaction time: 88 h
Yield: 99.6 %

Procedure:
A stirred mixture of about 50.0 grams (0.19 mole) stearonitrile, about 11.7 grams (0.19 mole) ethanolamine, and about 1.2 grams (0.0048 mole) cadmium acetate dihydrate is heated at about 115 degrees C. to about 125 degrees C. under nitrogen for about 88 hours. The mixture is cooled and then dissolved in about 450 ml of methylene chloride and dried over magnesium sulfate. The mixture is then filtered. Residual solvent is removed from the filtrate by vacuum. About 58.6 grams of light yellow solid is obtained. The solid is recrystallized from about 300 ml of hexane. The recrystallized material is collected, washed, and dried, yielding about 4.7 grams with a melting point of about 77 degrees C. to about 90 degrees C. The resulting filtrate, rinses, material removed in the initial filtration step and about 200 ml additional hexane are combined, heated, and filtered using gravity. The product is stored in a refrigerator for several days. The formed crystals are collected, rinsed, and dried at 50 degrees C. under vacuum, yielding about 36.3 grams of white solid with a melting point of about 50 degrees C. to about 54 degrees C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:12])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9].[C:13]1([CH:23]=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]=[C:23]([C:13]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=1)[NH:10][C:8]2=[O:9]
Reactant: O=Cc1cccc2ccccc12
Reactant: COc1ccc(N)c(C(N)=O)c1
Product: COc1ccc2nc(-c3cccc4ccccc34)[nH]c(=O)c2c1

Procedure:
Compound 17 was synthesized from 5-methoxy-2-aminobenzamide (9) (1.2 g, 7.3 mmol) and 1-naphthaldehyde (14) (1.1 g, 7.3 mmol): yield 1.5 g (70%); pale yellow needles; mp 174 to 175° C.; 1H NMR (DMSO-d6) δ 3.87 (3H, s, OCH3), 7.22-7.34 (2H, m, 2×ArH), 7.53-7.72 (5H, m, 5×ArH), 7.95-8.22 (3H, m, 3×ArH), 12.62 (1H, br s, NH) ppm; MS (ESI) m/z 302; Anal. (C19H14N2O2): C, H, N.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]([C:26](O)=[O:27])[C:16]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(O)[C:17]([OH:19])=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OC(=O)C)(=O)C>[Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[C:26](=[O:27])[O:19][C:17](=[O:18])[C:16]=2[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(C(C(=O)O)C(O)(C(=O)O)C2CCCC2)CC1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C2=C(C3CCCC3)C(=O)OC2=O)CC1
Temperature: 130 °C
Reaction time: 15 h

Procedure:
3-(4-((Tert-butyldimethylsilyl)oxy)cyclohexyl-2-cyclopentyl-2-hydroxysuccinic acid (190 mg, 0.46 mmol) was dissolved in acetic anhydride (7.0 ml), and the mixture was stirred at 130° C. for 15 hr. The mixture was allowed to cool, and excess acetic anhydride was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate=95:5) to give the title compound as a light yellow compound (65 mg, yield 37%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=2)=[CH:4][CH:3]=1.[NH2:28][CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:28][CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])[N:19]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CN)CO
Reactant: Cc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc12
Solvent: CC#N
Product: Cc1nccn2c(-c3ccnc(NCC(C)(C)CO)n3)c(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 16.7 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methylimidazo[1,2-a]pyrazine (1.50 g, 391 mmol) in ACN (30 mL) was added 3-amino-2,2-dimethyl-1-propanol (Lancaster, 2.0 g, 20 mmol). The reaction mixture was heated to about 80° C. After about 1.5 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure. The resulting crude material was purified by silica gel chromatography with DCM/MeOH/NH4OH (step-wise gradient, 990:9:1 then 980:18:2) to give an oil after concentration. The oil was dissolved in a minimum amount of DCM and heptane was added until a white precipitate formed. The suspension was concentrated under reduced pressure. The resulting solid was triturated with heptane and filtered to give the title compound (1.36 g, 86%): LC/MS (Table 1, Method g) Rt=2.41 min; MS m/z: 407.2 (M+H)+.
Reaction SMILES: S([CH2:11][N+:12]#[C-:13])(C1C=CC(C)=CC=1)(=O)=O.[C:14]([O:23][CH2:24][CH3:25])(=[O:22])/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18].CC(C)([O-])C.[K+].[Na+].[Cl-]>C1COCC1>[NH:12]1[CH:13]=[C:15]([C:14]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)/C=C/C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]cc1C(=O)OCC
Reaction time: 2 h
Yield: 43.6 %

Procedure:
Tosylmethyl isocyanide (9.8 g, 50 mmol), diethyl fumarate (8.2 mL, 50 mmol) and dry THF (1000 mL) were added dropwise to a stirred suspension of potassium t-butoxide (11.2 g, 100 mmol) and THF (150 mL). The mixture was stirred for 2 hours, saturated NaCl (500 mL) was added, and the mixture was extracted with THF (2×250 mL). The organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give a solid. The solid was recrystallized from MeOH to give the title compound 4.6 g (44%) (mp 148-149° C.). 1H NMR (DMSO) δ 1.22 (t, 3H, CH3), 4.18 (q, 2H, CH2), 7.39 (s, 2H, ArH), 11.8 (bs, 1H, NH).