Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C@H:8]1[C@@H:14]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:13]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:12]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[O:11][CH:9]1[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].C([O:46][C:47](=[O:54])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]Br)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C[N+](C)(C)C.COCCOCCOC>[C:1]([O:7][C@H:8]1[C@@H:14]([O:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])[C@H:13]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:12]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[O:11][CH:9]1[O:10][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][C:47]([OH:54])=[O:46])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OC[C@H]1OC(O)[C@@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: O=C(CCCCCBr)OCc1ccccc1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: COCCOCCOC
Product: CC(C)(C)C(=O)OC[C@H]1OC(OCCCCCC(=O)O)[C@@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 10 °C

Procedure:
A mixture that consists of 51.66 g (100 mmol) of 2,3,4,6-tetra-O-pivaloyl-mannopyranose, 0.55 g (5 mmol) of tetramethylammonium chloride and 82.93 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of diethylene glycol dimethyl ether is cooled to 10° C. At 10° C., 35.7 g (150 mmol) of 6-bromohexanoic acid benzyl ester is added in drops within 10 minutes while being stirred vigorously. It is stirred for two hours at 10° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol, mixed with 5 g of palladium (10%) on activated carbon and hydrogenated until hydrogen absorption is completed. Catalyst is filtered out, rewashed with ethanol, and the combined solutions are evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@@H:7]([C:10]([OH:12])=[O:11])[CH2:8][OH:9].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([O:20][C:21]([NH:6][C@@H:7]([C:10]([OH:12])=[O:11])[CH2:8][OH:9])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 10 h

Procedure:
Sodium bicarbonate (240 g) was added to a mixture of D-serine (100 g) and water (800 ml) at 0-5° C. Benzylchloroformate (50% solution in toluene)(480 ml) was added to the reaction mixture and stirred for 10 hours at 0-5° C. The organic and aqueous layers were separated and washed the aqueous layer with toluene. Aqueous layer pH was adjusted to 1.5 with hydrochloric acid and extract the reaction mixture in to ethyl acetate. Distilled off the solvent from the extracted reaction mixture under reduced pressure to get the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[C:21](Cl)=[CH:20][C:17]([NH:18][CH3:19])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1.C(O)(C(F)(F)F)=O.O>CN(C=O)C>[Cl:13][C:14]1[C:21]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:20][C:17]([NH:18][CH3:19])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1
Reactant: C1COCCN1
Reactant: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(N2CCOCC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Morpholine (174 mg, 2.0 mmol) followed by potassium carbonate (304 mg, 2.2 mmol) were added to a mixture of 4,5-dichloro-N-methyl-2-nitroaniline (442 mg, 2.0 mmol) in DMF (10 mL) and stirred at rt overnight. The reaction mixture was acidified with TFA:H2O 1:1 and purified by chromatography to give the sub-title compound.
Reaction SMILES: [CH2:1]([C:8]1(Br)[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Cl:22])=[C:15]([Cl:21])[CH:16]=3)[NH:11][C:10]=2[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Br-]>CN(C=O)C.O>[CH2:1]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Cl:22])=[C:15]([Cl:21])[CH:16]=3)[NH:11][C:10]=2[C:9]=1[OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2[nH]c3cc(Cl)c(Cl)cc3c2CCC1(Br)Cc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1c(Cc2ccccc2)ccc2c1[nH]c1cc(Cl)c(Cl)cc12
Temperature: 90 °C
Yield: 28.8 %

Procedure:
To a stirred solution of 2-benzyl-2-bromo-6,7-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.3 g, 0.71 mmol) in anhydrous DMF (5 mL), LiBr (68 mg, 0.78 mmol) followed by Li2CO3 (52 mg, 0.71 mmol) were added. The reaction mixture was heated to 90° C. for 1 h, cooled to room temperature and diluted with water. The reaction mixture was extracted with EtOAc (3×20 mL) to obtain the crude material which was purified by silica gel chromatography [EtOAc-hexane (3:17) as eluant] to give the title compound as a light brown solid (0.07 g, 30%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 10.98 (s, 1H), 9.18 (s, 1H), 8.29 (s, 1H), 7.74 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.26-7.25 (m, 4H), 7.24-7.23 (m, 1H), 6.92 (d, J=8.0 Hz, 1H), 4.11 (s, 2H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.[CH2:6]([NH:12][C:13](=[S:16])SC)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)C>[CH2:6]([N:12]1[C:13]([SH:16])=[N:3][N:2]=[N:1]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCNC(=S)SC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCn1nnnc1S
Temperature: 90 °C
Yield: 103 %

Procedure:
Sodium azide (155.9 g.) and water (0.8 l.) were added under stirring to a solution of methyl N-hexyldithiocarbamate (430 g.) in ethanol (1.7 l.) and the resulting mixture was refluxed for 3.5 hours at 90° C. Ethanol was distilled off from the reaction mixture and the residue was washed with diethyl ether (1 l.), adjusted to pH 2.0 with conc. hydrochloric acid and extracted with diethyl ether (1 l.). The extract was washed with water, dried over magnesium sulfate and concentrated to give an oil of 1-hexyl-1H-tetrazole-5-thiol (431.3 g.).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)[CH:22]=[S:23]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH:22]=[S:23])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=S
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: S=CN1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 20.0 g (0.08 mole) of 4-diphenylmethylpiperidine, 14.2 g (0.16 mole) of N,N-dimethylthioformamide and 50 ml of toluene was refluxed for 12 hours, cooled, and washed with water. The organic layer was separated, dried and stripped to an oil which was treated with diethyl ether to give a solid. Recrystallization of this material afforded a white crystalline solid, 4-(diphenylmethyl)-1-piperidinecarbothioaldehyde, m.p. 152°-154° C.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:10]1[CH2:11][CH2:12][CH:8]([C:7]2[C:2]([O:29][C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:14]4[S:13][C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[N:15]=4)=[CH:28][CH:27]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Fc1ncccc1C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCOC2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A glass microwave reaction vessel was charged with 2-fluoro-3-(tetrahydrofuran-3-yl)pyridine (1.00 g, 5.98 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (1.56 g, 6.44 mmol) and cesium carbonate (4.88 g, 14.98 mmol) in DMSO (10 mL). The reaction mixture was sealed under argon and was heated thermally at 100° C. for 24 h. The reaction was cooled to rt and diluted with water. The product turned into a gum and the aqueous solution was decanted. The gum was stirred over MeOH for 1 h resulting in a precipitate that was filtered, washed with MeOH and dried in vacuo to give the title compound as a white crystalline solid. MS (ESI, pos. ion) m/z: 389.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][N:10]1[C:19]([C:20]#[N:21])=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:28][CH3:29])[CH:16]=2)[C:11]1=[O:30])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+]>[Ni].C(O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][N:10]1[C:19]([CH2:20][NH2:21])=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:28][CH3:29])[CH:16]=2)[C:11]1=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(C#N)c(-c3ccccc3)c2c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(CN)c(-c3ccccc3)c2c1
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A suspension of 113 (3.04 g, 7.26 mmol), raney nickel, ammonium hydroxide (10 mL), and ethanol (50 mL) were combined in a Parr jar and hydrogenated at 55 psi for 18 h. The contents of the Parr jar were filtered through Celite and the filtrate was rotary evaporated to give 114 as a white solid (2.72 g, 6.43 mmol, 88.6%).
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:35])[CH:11]([NH:23][C:24](=[O:34])[C@H:25](Br)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:36](O)(=[S:38])[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([NH:9][C:10](=[O:35])[CH:11]([NH:23][C:24](=[O:34])[C@@H:25]([C:36](=[S:38])[CH3:37])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(O)=S
Reactant: O=C(NCCc1ccccc1)C(NC(=O)[C@H](Br)Cc1ccccc1)C(=O)NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=S)[C@@H](Cc1ccccc1)C(=O)NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Yield: 92 %

Procedure:
Prepare by the method of Example 1.4 using N,N′-diphenethyl-2-((R)-2-bromo-3-phenylpropionylamino)malonamide (0.11 g, 0.21 mmol), thioacetic acid (0.05 mL, 0.62 mmol), and cesium carbonate (0.10 g, 0.31 mmol) in dimethylformamide (8 mL). Purify by chromatography on silica gel eluting with 1/1 hexane ethyl acetate to give the title compound (92%).
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24](=[O:36])([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:25][CH:26](Cl)[CH3:27].C(O)(C)C.CCCCCC.[K+].[Br-]>>[CH2:30]([O:29][C:24]([O:25][CH:26]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:27])=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CCCCCCOC(=O)OC(C)Cl
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCCC
Product: CCCCCCOC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 11, piroxicam (3.00 g, 9.1 mmol) and alpha-chloroethyl hexyl carbonate (2.85 g, 13.6 mmol) were converted to chromatographed title product, isolated as a yellow solid which was crystallized from isopropyl alcohol/hexane (280 mg, 0.5 mmol, 6.1%): mp 86°-87° C.; IR (KBr) 1764, 1678 cm-1 ; 1H NMR (CCl3) delta 0.87 (t, J=7 Hz, 3H), 1.05-1.39 (m, 6H), 1.41-1.60 (m, 2H), 1.75 (d, J=6 Hz, 3H), 3.10 (s, 3H), 4.00 (t, J=7 Hz, 2H), 6.36 (q, J=6 Hz, 1H), 7.06-7.17 (m, 1H), 7.63-7.86 (m, 5H), 8.31-8.42 (m, 2H), 9.39 (br s, 1H); precise mass calcd for C24H29N3O7S m/e 503.1737, found 503.1761.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C([O-])(=O)C.[Na+].[CH2:12]([N:14]([CH2:36][CH3:37])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[C:22]([C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:26][CH:25]=2)=O)=[CH:17][CH:16]=1)[CH3:13].O>C(O)(=O)C>[OH:5][C:4]1[N:3]=[N:2][C:21]([C:18]2[CH:19]=[CH:20][C:15]([N:14]([CH2:36][CH3:37])[CH2:12][CH3:13])=[CH:16][CH:17]=2)=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[CH:28][CH:29]=2)[N:6]=1
Reactant: NNC(N)=O
Reactant: CCN(CC)c1ccc(C(=O)C(=O)c2ccc(N(CC)CC)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)c1ccc(-c2nnc(O)nc2-c2ccc(N(CC)CC)cc2)cc1

Procedure:
Semicarbazide hydrochloride (1.57 g, 14.2 mmol) and sodium acetate (1.41 g, 17.3 mmol) are added to a solution of 1,2-bis(4-diethylaminophenyl)-ethane-1,2-dione prepared according to example 2 (5 g, 14.2 mmol) in acetic acid (20 ml). The mixture is heated at reflux for 12 hours. After returning to ambient temperature, the reaction mixture is poured into water. The raw solid is collected by filtration and washed with water. The residue is recrystallized in acetic acid. After filtration and washing with water, 3 g (54%) of a yellow solid are obtained after drying. δH (200 MHz, CDCl3), 1.18 (t; 12H), 3.45 (q; 8H), 6.65 (d; J 7.8; 4H), 7.87 (d; J 7.8; 4H), 10.4 (s; 1H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[C:17]([C:19]3[C:23]4[CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][C:27](=[O:28])[C:22]=4[S:21][C:20]=3[N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:16]=[CH:15][N:14]=2)[CH:8]=1)(=O)=O.C(O[C:44](=O)[NH:45][CH:46]1[CH2:49][NH:48][CH2:47]1)(C)(C)C.CC(C)([O-])C.[K+].[H-].[Na+].CI>O1CCOCC1.CN(C=O)C.CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd]>[CH3:29][C:25]1([CH3:30])[CH2:24][C:23]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:9]4[CH:8]=[CH:7][CH:12]=[C:11]([N:48]5[CH2:47][CH:46]([NH:45][CH3:44])[CH2:49]5)[CH:10]=4)[CH:18]=3)=[C:20]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[S:21][C:22]=2[C:27](=[O:28])[CH2:26]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4cccc(OS(=O)(=O)C(F)(F)F)c4)c3)c2C1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1[c-]cccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CI
Product: CNC1CN(c2cccc(-c3cc(-c4c(N5CCOCC5)sc5c4CC(C)(C)CC5=O)ccn3)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.8 %

Procedure:
A mixture of Example 360 (200 mg, 0.35 mmol), azetidin-3-ylcarbamic acid tert-butyl ester (125 mg, 0.71 mmol), potassium tert-butoxide (60 mg, 0.49 mmol) and acetato(2′-di-tert-butylphosphino-1,1′-biphenyl-2-yl)palladium(II) (10 mg, 0.02 mmol) in 1,4-dioxane (3.0 mL) was heated in a sealed tube at 100° C., under microwave irradiation, for 30 minutes. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane). To a solution of the obtained solid in DMF (10 mL) was added sodium hydride (60% dispersion in oil, 10 mg, 0.24 mmol) and the reaction was stirred at room temperature for 30 minutes. Methyl iodide (18 μL, 0.29 mmol) was added and stirring was continued at room temperature for 18 h. Further sodium hydride (60% dispersion in oil, 10 mg, 0.24 mmol) was added and stirring was continued for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane). To a solution of the obtained solid in DCM (8 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was partitioned between DCM (20 mL) and saturated aqueous sodium hydrogencarbonate solution (20 mL). The organic phase was concentrated in vacuo and was purified by column chromatography (SiO2, 0-20% MeOH/DCM) to give the title compound (5 mg, 31%) as a clear glass. δH(CD3OD) 8.68 (1H, d, J 5.1 Hz), 7.91 (1H, s), 7.44 (1H, dd, J 5.3, 1.7 Hz), 7.39-7.29 (2H, m), 7.14-7.08 (1H, m), 6.68-6.60 (1H, m), 4.29-4.17 (2H, m), 4.02-3.91 (1H, m), 3.74-3.56 (6H, m), 3.15-3.01 (4H, m), 2.64 (2H, s), 2.47 (2H, m), 1.05 (6H, s). LCMS (ES+) 503.3 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4](NC1CC1)=[O:5].[C:13]1([CH2:23][NH2:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: NCc1cccc2ccccc12
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CC[C@H](N)[C@H](O)C(=O)NCc1cccc2ccccc12

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using naphthalen-1-ylmethanamine in the seventh step (step B7).
Reaction SMILES: [N:1]([C:4]1[C:8]([CH3:9])=[CH:7][S:6][C:5]=1[C:10]([O:12]C)=O)=[C:2]=[S:3].[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>>[CH3:9][C:8]1[C:4]2[NH:1][C:2](=[S:3])[N:22]([CH2:21][CH2:20][CH2:19][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[C:10](=[O:12])[C:5]=2[S:6][CH:7]=1
Reactant: NCCCn1ccnc1
Reactant: COC(=O)c1scc(C)c1N=C=S
Product: Cc1csc2c(=O)n(CCCn3ccnc3)c(=S)[nH]c12

Procedure:
The compound was synthesized starting from methyl 3-isothiocyanato4-methylthiophene-2-carboxylate (0.853 g, 4.0 mmol) and 3-(1H-imidazol-1-yl)propan-1-amine (0.5 g, 4.0 mmol) as described above.
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.S(Cl)(Cl)=O.C[N:16](C=O)C.[OH-].[NH4+]>C(Cl)Cl>[CH3:1][C:2]1([C:8]([NH2:16])=[O:10])[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: CC1(C(=O)O)CC=CCC1
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C(N)=O)CC=CCC1
Reaction time: 8 h

Procedure:
To a solution of 1-methylcyclohex-3-ene-1-carboxylic acid, 52a, (54.0 g, 385.2 mmol) dissolved in CH2Cl2 (200 mL) was added thionyl chloride (56.2 mL, 770.4 mmol) and 1 mL of DMF. The reaction was warmed to reflux for 3 hrs, then cooled and concentrated in vacuo. The residue was redissolved in 200 mL of CH2Cl2. To the reaction was added ammonium hydroxide (148.2 mL of 13 M solution, 1.9 mol) slowly. The reaction was stirred overnight. The reaction was extracted into CH2Cl2 and water. The organic phase was concentrated in vacuo and purified via flash silica gel chromatography (EtOAc), yielding 25 g of 1-methylcyclohex-3-ene-1-carboxamide.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH3:14].[H][H]>C1COCC1.[Pd]>[NH2:10][C:6]1[C:5]([NH:13][CH3:14])=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([NH:2][CH3:1])=[O:15]
Reactant: [H][H]
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1NC
Agent: [Pd]
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(N)c1NC
Reaction time: 3 h

Procedure:
To a stirred solution of N-methyl-2-(methyl-amino)-3-nitrobenzamide (17; 0.22 g, 0.00104 mol) in THF (10 ml) was added 10% palladium on carbon (catalytic amount) portion wise at room temperature. The reaction mixture was allowed to stir under the atmosphere of hydrogen gas supplied by balloon at room temperature for 3 h. The reaction mixture was filtered through CELITE® and filtrate was concentrated to afford the desired product 3-amino-N-methyl-2-(methyl-amino) benzamide after drying and carry forward to next step by checking LCMS. LCMS (ES) m/e MS (M+1=180) Purity: 85.6%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1I)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=1)#[CH:19]>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[C:19]#[C:18][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1cccc(Cl)c1I
Reactant: C#Cc1cccc(S(=O)(=O)CCC)c1
Product: CCCS(=O)(=O)c1cccc(C#Cc2c(Cl)cccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 79, starting from (3-chloro-2-iodo-phenoxy)-acetic acid tert-butyl ester (Intermediate 94) and 1-ethynyl-3-(propane-1-sulfonyl)-benzene (Intermediate 42), the title compound was obtained a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Br:12][C:13]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.N1C=CC=CC=1.O>C(Cl)Cl>[Br:12][C:13]1[CH:22]=[CH:21][C:20]([NH:23][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(Br)c2cccnc12
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Br)c2cccnc12)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 43.5 %

Procedure:
Benzenesulfonyl chloride (72 μl, 0.57 mmol) was added to a solution of 5-bromoquinolin-8-ylamine hydrochloride (84 mg, 0.38 mmol) in pyridine (150 μl, 1.89 mmol) and DCM (5 ml) and the mixture was stirred at room temperature for 20 h. Water (5 ml) was added and the organic phase was separated. The aqueous phase was extracted with DCM and the combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude residue was purified by trituration from DMSO/MeOH (1:2) to give the title compound (60 mg, 44%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][N:9]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][N:9]([C:10]1[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1)[CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1N
Yield: 87.9 %

Procedure:
A mixture of 1.6 g (0.0045 mole) of 3-[butyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-propionic acid tert-butyl ester (IV-44) in 50 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration of the filtrate under reduced pressure gave 1.3 g of 3-[(5-amino-2-chloro-pyrimidin-4-yl)-butyl-amino]-propanoic acid tert-butyl ester (V-44). This material was used directly in the next step without further purification.