Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:21])[CH:8]=1.[H-].[Na+].[Cl:24][C:25]1[CH:38]=[CH:37][C:28]2[S:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[C:31]([CH3:32])[C:27]=2[CH:26]=1>CN(C=O)C>[Cl:24][C:25]1[CH:38]=[CH:37][C:28]2[S:29][C:30]([S:33]([NH:6][C:7]3[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:21])[CH:8]=3)(=[O:34])=[O:35])=[C:31]([CH3:32])[C:27]=2[CH:26]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(N)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
Into 10 mL of THF was dissolved 135 mg of methyl 4-amino-5-methanesulfonyl-2-methylbenzoate, followed by addition of 22 mg of sodium hydride (oily, 60%) at room temperature. After 20 minutes of stirring at the same temperature, 130 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at 0° C., followed by 1 hour of stirring at room temperature and 5 hours of heating under refluxing. Further, 1 mL of DMF, 22 mg of sodium hydride (oily, 60%) and 50 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene were added and the mixture was heated under refluxing for 2.5 hours. After-confirmation of disappearance of the starting material, the reaction was terminated by adding saturated aqueous ammonium chloride solution at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/2) to obtain 102 mg of the title compound as colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].IC.[OH-].[K+].[CH3:20]S(C)=O>O>[CH3:20][N:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:11]1=[O:15]
Reactant: CS(C)=O
Reactant: O=C1NCCN1c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 21 parts of 1-(4-nitrophenyl)-2-imidazolidinone, 16 parts of iodomethane, 10 parts of potassium hydroxide and 200 parts of dimethyl sulfoxide was stirred for 3 hours at room temperature. Another portion of 16 parts of iodomethane and 10 parts of potassium hydroxide were added. Stirring was continued overnight. 300 Parts of water were added to the reaction mixture and the whole was stirred. The precipitated product was filtered off and crystallized from 4-methyl-2-pentanone, yielding 16.5 parts (74%) of 1-methyl-3-(4-nitrophenyl)-2-imidazolidinone; mp. 214.1°-215.5° C. (7).
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[C:12]([O:17][CH:18]([O:20][C:21]([NH:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]1)=[O:22])[CH3:19])(=[O:16])[CH2:13][CH2:14][CH3:15].C(=O)(O)[O-].[Na+:38].C(#N)C>O>[C:12]([O:17][CH:18]([O:20][C:21]([NH:23][CH2:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([C:31]([O-:33])=[O:32])[CH2:29][CH2:30]1)=[O:22])[CH3:19])(=[O:16])[CH2:13][CH2:14][CH3:15].[Na+:38]
Reactant: CCCC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Following the general procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 946 mg (3.0 mmol) of trans-4-{[1-(butanoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid 10 was reacted with 252 mg (3.0 mmol) of sodium bicarbonate (NaHCO3) in 20 mL of a mixture of acetonitrile and water (1:1) to yield 1.02 g (quant.) of the title compound 11 as a colorless powder. 1H NMR (400 MHz, DMSO-d6): δ=0.73-0.84 (m, 2H), 0.87 (t, J=6.8 hz, 3H) 1.08-1.20 (m, 2H), 1.20-1.32 (m, 1H), 1.38 (d, J=5.2 Hz, 3H), 1.46-1.56 (m, 2H), 1.60-1.74 (br. m, 3H), 1.76-1.83 (br. m, 2H), 2.25 (t, J=7.2 Hz, 2H), 2.78 (t, J=6.0 Hz, 2H), 6.65 (q, J=5.2 Hz, 1H), 7.41 (t, J=5.6 Hz, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.18 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[NH2:4].[Na].[F:23][CH2:24][C:25](O)=[O:26].[I-].ClC1C=CC=CN1C>CN(C)C=O.C(N(CC)CC)C>[F:23][CH2:24][C:25]([NH:4][C@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[CH2:2][OH:1])=[O:26]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Reactant: O=C(O)CF
Agent: CN1C=CC=CC1Cl
Agent: [I-]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO)NC(=O)CF

Procedure:
5.0 gr of sphingosine (16.70) mM), prepared according to Example 4, are reacted with 2.1 gr of the sodium salt of fluoroacetic acid (20.88 mM), in the presence of 5.3 gr of 2-chloro-1-methylpyridine iodide (20.88 mM) and 5.8 cc of triethylamine (42.00 mM) in 80 cc of dimethylformamide, at room temperature overnight. The solvent is evaporated, and the residue is gathered in CH2Cl2 and washed with H2O. It is anhydrified and purified by chromatography, eluting with a mixture of CH2Cl2 /ethyl acetate/CH3CH 70:30:1 v/v/v.
Reaction SMILES: C(O)(=O)C.Cl.[CH3:6][O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:16]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11]1)=[O:9]>C(#N)C>[CH3:6][O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]1)=[O:9]
Reactant: COC(=O)N1CCCC(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)N1CCCC(N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Add acetic acid saturated with HCl(g) (100 mL, ˜3N in HCl) to 3-(trityl-amino)-piperidine-1-carboxylic acid methyl ester (6.51 g, 16.2 mmol). Stir the solution vigorously at room temperature for 2 hours. Concentrate the reaction, follow this by addition of acetonitrile and concentration to assist in the removal of acetic acid (×2). Partition the resulting material between 1N HCl and ethyl acetate, separate the layers, extract the organic layer with 1N HCl. Basify the combined aqueous layers with 5N sodium hydroxide, extract with 20% isopropanol/chloroform (×3). Dry the combined organic layers over magnesium sulfate and concentrate to give 2.45 g of the title compound as a white solid, 95% yield. 1H NMR: consistent with structure. MS (ion spray) 158 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>N1C=CC=CC=1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[C:3]([S:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
A mixture of 4'-amino-3'-(2,4-difluorophenylthio)acetophenone (2.0 g) and methanesulfonyl chloride (1.0 g) in pyridine (20 ml) was stirred overnight at room temperature. The mixture was poured into cold diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give yellow crystals of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (1.3 g).
Reaction SMILES: [CH:1]1([N:6]([CH3:33])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:20](=[O:21])[C:19]([CH:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][C:24]([O-:26])=O)=[CH:18][NH:17]3)=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:43][C:44]([F:48])([F:47])[CH2:45][NH2:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([N:6]([CH3:33])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:20](=[O:21])[C:19]([CH:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][C:24]([NH:46][CH2:45][C:44]([F:48])([F:47])[F:43])=[O:26])=[CH:18][NH:17]3)=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C1CCCC1)S(=O)(=O)c1ccc(-n2[nH]cc(C(CC(=O)[O-])c3ccccc3)c2=O)nc1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C1CCCC1)S(=O)(=O)c1ccc(-n2[nH]cc(C(CC(=O)NCC(F)(F)F)c3ccccc3)c2=O)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.5 %

Procedure:
To a solution of 200 mg (0.43 mmol) of 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-phenylpropanoate, 0.3 mL (1.7 mmol) of DIEA and 30 μL (0.43 mmol) of 2,2,2-trifluoroethylamine in 1 mL of DCM are added, at 0° C., 207 mg (0.64 mmol) of TBTU. The medium is stirred for 12 hours at room temperature. A further 0.3 mL of 2,2,2-trifluoroethylamine is then added and the medium is heated at 40° C. for 6 hours. The medium is taken up in 20 mL of DCM, washed successively with water (2×10 mL) and brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure, and then purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 32 mg of 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-phenyl-N-(2,2,2-trifluoroethyl)propanamide are thus obtained in the form of a powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([C:11]2[NH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].O[CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C>>[NH2:19][CH2:18][CH2:17][N:14]1[CH:13]=[CH:12][C:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([Cl:2])[CH:10]=2)=[N:15]1
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCO
Agent: Cl
Product: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl

Procedure:
The title compound was prepared using the method of Example 34(c) starting from 2.3 g of 2-chloro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride, 1.7 ml dipea and 1.7 g tert-butyl 2-hydroxyethylcarbamate yielding 2.08 g of the product. 1H-NMR (400 MHz; d6-DMSO): δ 1.56 (s, 2H), 2.97 (t, 2H), 4.13-4.17 (t, 2H), 6.97 (s, 1H), 7.87 (d, 1H), 7.93-8.02 (m, 2H), 8.10 (d, 1H).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)CC(C)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:23][CH2:22]1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: Clc1ccccc1N1CCNCC1
Solvent: CC(C)CCO
Product: O=c1[nH]c(N2CCN(c3ccccc3Cl)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-(2-chlorophenyl)piperazine (84.9 μl; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 and worked up; yield: 65 mg (37%), crystals;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.C(OC(=O)[N:33]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:34]1[S:35][C:36]([CH:40]=O)=[C:37](Cl)[N:38]=1)(C)(C)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:40][C:36]3[S:35][C:34]([NH:33][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=4)=[N:38][CH:37]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1nc(Cl)c(C=O)s1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Fc1ccc(CNc2ncc(Cc3c[nH]c4ncc(Cl)cc34)s2)cc1
Temperature: 0 °C
Yield: 51.1 %

Procedure:
To a solution of 5-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (626, 300 mg, 0.69 mmol) in tetrahydrofuran (10 mL) at −20° C. was added dropwise iso-propyl-magnesium chloride (2M in tetrahydrofuran, 0.44 mL, 0.88 mmol). The reaction mixture was allowed to warm to 0° C. over 10 minutes and then cooled to −40° C. To this reaction mixture was added a solution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (625, 211 mg, 0.63 mmol) in tetrahydrofuran (5 mL). The reaction mixture was allowed to warm to 0° C. over 30 minutes and then quenched with brine (50 mL). The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude material which was purified by silica gel column chromatography (0-30% ethyl acetate/heptane) to provide the desired compound as a foam (120 mg, 30%), consistent with structure by 1H-NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH:14][S:15]([NH2:18])(=[O:17])=[O:16])[O:9][C:8]=2[CH:19]=1)([O-])=O.[N+](C1C=C(O)C(=CC=1)O)([O-])=O>CO.Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH:14][S:15]([NH2:18])(=[O:17])=[O:16])[O:9][C:8]=2[CH:19]=1
Reactant: NS(=O)(=O)NC[C@H]1COc2ccc([N+](=O)[O-])cc2O1
Agent: [Pd]
Agent: Cl
Agent: O=[N+]([O-])c1ccc(O)c(O)c1
Solvent: CO
Product: Nc1ccc2c(c1)O[C@@H](CNS(N)(=O)=O)CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S )-(−)-N-(2,3-Dihydro-7-nitro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide (1.2 g, 4.15 mmol), was prepared from 4-nitrocatechol according to the process outlined in Example 4. The (2S)-(−)-N-(2,3-Dihydro-7-nitro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide, was then combined with 10% Pd/C in methanol (120 mL) and shaken under hydrogen atmosphere (39 psi) at room temperature for 3 h. The solids were filtered and washed with 10% M in DCM and the filtrate was evaporated in vacuo to yield crude product. The crude product was dissolved in 0.2 N HCl (25 mL), frozen and lyophilized to yield the title compound as a white flaky solid, as the corresponding hydrochloride salt.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][OH:17].O>CS(C)=O>[OH:17][CH2:16][CH2:15][N:14]([CH3:13])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CNCCO
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: CN(CCO)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.3 %

Procedure:
A solution of 4-fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol) in DMSO (3.5 mL) was added with 2-methylaminoethanol (0.52 mL, 6.5 mmol) and stirred at 100° C. for 5.0 hours. The reaction mixture was added with water and was washed with hexane/ethyl acetate (4/1) to remove impurities. After removing the impurities, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4-[N-(2-hydroxyethyl) methylamino]-2-nitrobenzaldehyde (0.20 g, 75%).
Reaction SMILES: [N+]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]3[CH:13](CC(O)=O)[CH2:14][NH:15][C:16](=[O:17])[C:8]3=[CH:7][C:6]=2[CH:5]=1)([O-])=O.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[C:16]1(=[O:17])[C:8]2=[CH:7][C:6]3[CH:5]=[CH:4][CH:12]=[CH:11][C:10]=3[N:9]2[CH2:13][CH2:14][NH:15]1
Reactant: O=C(O)CC1CNC(=O)c2cc3cc([N+](=O)[O-])ccc3n21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCn2c1cc1ccccc12

Procedure:
A solution of the acid derivative of formula (VII) (57 mg, 0.2 mmol, 2 eq), DIPEA (0.068 ml, 0.39 mmol, 4 eq.), PyBOP (102.75 mg, 0.2 mmol, 2 eq.) in dry DMA (2.0 ml) was stirred for 30 min then was added to resin of example 6 (0.1 mmol, 1 eq.) and the final suspension was shaken for 20 h at 25° C. The resin was washed sequentially with DMF (1 ml), DCM (1 ml), DMF (1 ml), DCM (1 ml), MeOH (1 ml), water (1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), MTBE (1 ml, 2 cycles) and then air dried.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15](Cl)[C:16]([CH3:22])=[N:17]2.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.CCOC(C)=O>[Br:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]([CH3:22])=[N:17]2
Reactant: Nc1ccccc1
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc2cccc(Br)c2nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
LHMDS (1.0M in THF; 14.37 ml, 14.37 mmol) was added to a solution of 5-bromo-3-chloro-2-methylquinoxaline (126e, 0.74 g, 2.87 mmol) and aniline (1.309 ml, 14.37 mmol, Alfa Aesar, Ward Hill, Mass.) in dioxane (28.7 ml) at RT, and the resulting mixture was stirred at RT for 30 min. The mixture was diluted with EtOAc (200 ml), added to a separatory funnel, and washed with saturated aq. NH4Cl (2×150 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel (100% hexanes to 20% EtOAc/hexanes) provided 8-bromo-3-methyl-N-phenylquinoxalin-2-amine (183a, 71% yield) as a brown oil. MS (ESI, pos. ion) m/z: 314.2/316.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Br[C:25]1[C:30]([F:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1>>[F:31][C:30]1[C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])=[N:26][CH:27]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:29]=1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cc2F)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 478 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[CH:5][CH:4]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:7]1[N:6]=[CH:5][CH:4]=[C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)[N:8]=1
Reactant: CSc1nccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 53.8 %

Procedure:
6-Cyano-2-methylthiopyrimidine (1.37 g, 9.06 mmol) and methyl thiosalicylate (3.05 g, 18.1 mmol) were dissolved in toluene (30 ml), and triethylamine (3.80 ml, 27.2 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (1.40 g, 54%) as pale yellow crystals.
Reaction SMILES: ClC1N=C([NH:8][CH2:9][CH2:10][S:11]([OH:14])(=[O:13])=[O:12])C=C(Cl)N=1.Cl[C:17]1[CH:22]=[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:20]=[C:19]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[N:18]=1>>[N:28]1([C:19]2[N:18]=[C:17]([NH:8][CH2:9][CH2:10][S:11]([OH:14])(=[O:13])=[O:12])[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:20]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Reactant: O=S(=O)(O)CCNc1cc(Cl)nc(Cl)n1
Product: O=S(=O)(O)CCNc1cc(N2CCCC2)nc(N2CCCC2)n1

Procedure:
The 2-(2,6-dichloropyrimidin-4-ylamino)ethanesulfonic acid (III, EXAMPLE 97, 3.0 g) is dissolved in pyrrolidine (IV, 125 ml) and heated to reflux. Solvent evaporation gives a semisolid which is chromatographed on 155 g of silica gel eluting with chloroform/3.9M ammonia in methanol (7/3). An initial fraction of 150 ml is collected followed by 15 ml fractions. Fractions 8-18 contained the desired product. Solvent evaporation and drying under high vacuum gives a solid (a portion of which) is rechromatographed on 155 g silica gel and eluting with the same solvent system as described above. The appropriate fractions are pooled and concentrated to give the title compound, which is used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:12])([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]([CH3:13])[CH2:5][CH2:4][NH:3]1.[CH3:14][C:15]([CH3:17])=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:1][CH:2]1[C:7]([CH3:12])([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]([CH3:13])[CH2:5][CH2:4][N:3]1[CH:15]([CH3:17])[CH3:14]
Reactant: CC(C)=O
Reactant: CC1CCNC(C)C1(C)CCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(C)C(C)(CCCO)C1C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 2,3,4-trimethyl-3-piperidinepropanol (13.0 g, 70 mmol), acetone (400 mL), methanol (300 mL), sodium cyanoborohydride (4.4 g, 70 mmol), 3A molecular sieves (30 g) and acetic acid (4.0 mL, 70 mmol) was stirred under a nitrogen atmosphere for 2 hours. The pH was readjusted to a pH of 5 by the addition of 1.5 mL of additional acetic acid and the reaction mixture was stirred for 24 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water (200 mL) and acetone (20 mL) and was acidified with concentrated hydrochloric acid. The mixture was basified with 10% NAOH and extracted with ether (4×300 mL) . The ether extracts were combined, washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by a Kugelrohr distillation at 0.1 mm Hg and 100-110° C. to afford 15.7 g (99%) of 2,3. 4-trimethyl-l- (1-methylethyl)-3-piperidinepropanol as a colorless oil.
Reaction SMILES: [NH:1](F)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])O.N[C@H](C(O)=O)C[C:14](O)=[O:15].C(OC(=O)C)(=O)C>C(O)=O>[CH:14]([NH:1][C@@H:2]1[C:7](=[O:8])[O:9][C:4](=[O:6])[CH2:3]1)=[O:15]
Reactant: O=C(O)C[C@H](NF)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: O=CN[C@H]1CC(=O)OC1=O

Procedure:
F-Asp=O is prepared by reacting L-aspartic acid with formic acid in the presence of an effective amount of acetic anhydride under conditions sufficient to form N-formyl-L-aspartic anhydride. Then an effective amount of acetic anhydride and a C3 -C6 secondary alcohol are added to the reaction mixture to consume excess formic acid. The resulting N-formyl-L-aspartic anhydride reaction mixture is suitable for further reactions without modifications.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: Brc1cccc(N2CCNCC2)c1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 70 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.