Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][C:17]([C:27](=[O:29])[NH2:28])([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:37](N)=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][C:17]4([N:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:37][NH:28][C:27]4=[O:29])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: NC(=O)C1(Nc2ccccc2)CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Reactant: NC=O
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC1)CC2
Temperature: 170 °C

Procedure:
To 16 g of 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-carbamoyl-4-anilinopiperidine is added 30 g of formamide, the temperature is raised slowly, and the mixture is heated at 170° C for 14 hours. After cooling water is added to the reaction mixture, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The precipitated crystals are collected by filtration and recrystallized from chloroform to give 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 249°-253° C.
Reaction SMILES: F[C:2]1[C:7](/[CH:8]=[N:9]/[NH:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=2[F:19])=[C:6](I)[CH:5]=[CH:4][N:3]=1.IC1C=CN=C2N(C3C(F)=CC(F)=CC=3F)N=CC=12.CC1(C)C(C)(C)[O:44][B:43](B2OC(C)(C)C(C)(C)O2)[O:42]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:19][C:12]1[CH:13]=[C:14]([F:18])[CH:15]=[C:16]([F:17])[C:11]=1[N:10]1[C:2]2=[N:3][CH:4]=[CH:5][C:6]([B:43]([OH:44])[OH:42])=[C:7]2[CH:8]=[N:9]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Fc1cc(F)c(N/N=C/c2c(I)ccnc2F)c(F)c1
Agent: CC(=O)[O-]
Agent: Fc1cc(F)c(-n2ncc3c(I)ccnc32)c(F)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1c(F)cc(F)cc1F

Procedure:
To a 48 mL pressure bottle containing (E)-2-fluoro-4-iodo-3-((2-(2,4,6-trifluorophenyl)hydrazono)methyl)pyridine (230 mg, 0.582 mmol), were added Intermediate 77A (133 mg, 0.355 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (330 mg, 1.30 mmol), potassium acetate (350 mg, 3.57 mmol), and anhydrous DMSO (8 mL). The reaction mixture was purged with argon, treated with PdCl2(dppf).CH2Cl2(64 mg, 0.087 mmol), and heated to 85° C. for 1.25 h to give the desired intermediate. LC/MS (Condition B): ret. T=2.9 min, (M+H)+ 294.03.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([OH:10])=[O:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:18]([NH:26][CH:27]([S:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28](O)=[O:29])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:2]([N:6]([C:28](=[O:29])[CH:27]([S:31][C:32](=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH:26][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][C:8]([OH:10])=[O:9])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(NC(SC(=O)c1ccccc1)C(=O)O)c1ccccc1
Reactant: CC(C)(C)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)N(CC(=O)O)C(=O)C(NC(=O)c1ccccc1)SC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
16.8 g (0.1 mole) of tert.-butyl glycine hydrochloride were suspended in 100 ml of dry acetonitrile, 10.1 g (0.1 mole) of triethylamine were added and the mixture was stirred for a short time at room temperature. A solution of 31.5 g (0.1 mole) of N-benzoyl-α-(benzoylthio)-glycine in 400 ml of dry acetonitrile and 20.6 g (0.1 mole) of dicyclohexylcarbodiimide were added to the mixture, and stirring was continued for 3 hours at room temperature. The precipitated dicyclohexylurea was filtered off, the filtrate was evaporated down under reduced pressure and the residue was taken up with ethyl acetate. The solution was filtered once again, the filtrate was evaporated down and the residue was chromatographed with 1:1 cyclohexane/ethyl acetate over a column containing deactivated silica gel. Crystallization from ethyl acetate gave 27.8 g of tert.-butyl N-[N-benzoyl-α-(benzoylthio)-glycyl]-glycine of melting point 157°-160° C. (Rf=0.50 in 1:1 cyclohexane/ethyl acetate). The product was dissolved in 100 ml of dry dioxane, 100 ml of 6N HCl/dioxane were added and the mixture was left to stand for 3 hours at 20° C. 500 ml of ethyl acetate were then added to the mixture, the organic phase was extracted by shaking with three times 500 ml of water, dried with anhydrous sodium sulfate and evaporated down under reduced pressure, and the residue was crystallized from diethyl ether. 22.8 g (61%) of N-[N-benzoyl-α-(benzoylthio)-glycyl]-glycine, melting point 194°-197° C. (Rf=0.31 in system I) were obtained.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.Cl>C1COCC1.[OH-].[Na+]>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: CCOC(=O)c1ccc(Oc2ccc3c(c2)COB3O)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
The title bis-acid compound was prepared by hydrolysis of the corresponding carboxylic acid ethyl ester. Ethyl 6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate (2.99 g, 10 mmol) was dissolved in freshly opened THF (100 mL), and 1N NaOH (38 mL) was added. The mixture was stirred at room temperature under N2 overnight. Then 6N HCl (6.5 mL) was added, rotary evaporated to remove THF, filtered and washed with water and then hexane. The solid was dried overnight under high vacuum to afford the title bis-acid compound (2.57 g, 9.48 mmol, yield 94.8%) as a slightly brown solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:8]=2[S:9][CH:10]=1)(=[O:5])=[O:4].O1CC[CH2:19]OO1>CS(O)(=O)=O.FC(F)(F)C(O)=O>[Cl:15][C:11]1[C:8]2=[C:7]3[C:14]([CH2:1][N:2]([CH3:19])[S:3](=[O:4])(=[O:5])[C:6]3=[CH:10][S:9]2)=[CH:13][CH:12]=1
Reactant: CNS(=O)(=O)c1csc2c(Cl)cccc12
Reactant: C1COOOC1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2ccc(Cl)c3scc(c23)S1(=O)=O
Temperature: 35 °C
Reaction time: 2 h

Procedure:
0.2 g of 7-chloro-benzo[b]thiophene-3-sulphonic acid-methylamide are dissolved in 3 ml of methanesulphonic acid at 35° C. and combined with a solution of 0.03 g of trioxane in 0.9 ml trifluoroacetic acid. After 2 h stirring at 35° C. the reaction mixture is poured onto 100 ml of ice water and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried with Na2SO4, evaporated down in vacuo and then purified by chromatography. Yield: 0.06 g. M.p.: 146° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10]([SH:12])[CH3:11].C1(O)C=CC=CC=1>>[CH2:10]([S:12][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:11]
Reactant: OCc1ccc(O)cc1
Reactant: CCS
Solvent: Oc1ccccc1
Product: CCSCc1ccc(O)cc1
Temperature: 85 °C
Yield: 65 %

Procedure:
A mixture of 62 g (0.5 mol) of 4-hydroxymethyl-phenol, 37 g (0.6 mol) of ethylmercaptan and 230 g of phenol was first heated, in a flask equipped with stirrer and reflux condenser, under normal pressure to about 85° C. in the course of about 15 minutes, and was then heated further in such a way that there was always a moderate reflux and that ultimately a final temperature of about 130° C. in the flask was reached. After a reaction time of 18 hours at 85°-130° C., the mixture was cooled and worked up by distillation. 4-Ethylthiomethyl-phenol was obtained in a yield of 65% of theory.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([P:23](Cl)(Cl)=[O:24])=[CH:19][CH:18]=1>>[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([P:23]2(=[O:24])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CSc1ccc(P(=O)(Cl)Cl)cc1
Product: CSc1ccc(P2(=O)c3ccccc3CN2c2ccccc2)cc1
Yield: 11 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 4-methylthiophenyl phosphonic dichloride. The reaction of the dilithio compound and the 4-methylthiophenyl phosphonic dichloride was conducted at -76° C. to yield a beige solid. The beige solid was recrystallized from ethyl acetate to yield 1-(4-methylthiophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.1 g, 11% yield) as a white solid having a melting point of 164°-167° C. and the following analysis:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[F:14][C:15]([F:49])([F:48])[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]3[CH:39]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=3)[CH:33]=2)[N:17]=1>C1COCC1>[N:1]1([S:44]([C:40]2[CH:39]=[C:38]([C:34]3[CH:33]=[C:32]([C:18]4[N:17]=[C:16]([C:15]([F:14])([F:48])[F:49])[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=5)[N:19]=4)[CH:37]=[CH:36][N:35]=3)[CH:43]=[CH:42][CH:41]=2)(=[O:45])=[O:46])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N1CCCC1
Temperature: 0 °C
Yield: 86.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of pyrrolidine (0.065 g, 0.91 mmol), triethylamine (0.09 ml, 0.63 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.20 g, 0.34 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane/hexane) yielded the title compound as a white solid (0.17 g, 85%). MS (ISP) 578.6 [(M+H)+]; mp 184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH2:28]1[CH:32]([OH:33])[CH2:31][NH:30][CH2:29]1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:30]1[CH2:29][CH2:28][CH:32]([OH:33])[CH2:31]1
Reactant: OC1CCNC1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2nccc(N3CCC(O)C3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1,1-Trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (20 g, 65 mmol) was dissolved in DMF and treated with triethylamine (12 mL, 84 mmol) and DL-3-pyrrolidinol (7.4 g , 84 mmol.) The reaction mixture was stirred overnight at room temperature. The resulting reaction mixture was diluted with water (200 mL) and stirred for 1 h. The resulting precipitate was filtered off, washed with diethyl ether, and air dried to afford the title compound: LC-MS m/z 246 (M+H)+
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:26][CH2:27][Cl:28].C([O-])([O-])=O.[K+].[K+]>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]([CH2:26][CH2:27][Cl:28])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClCCBr
Reactant: CCOC(=O)C1CCCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCl)CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To DIPA (3.22 mL) was added dropwise a 2.64 M solution of n-butyl lithium in hexane (7.97 mL) at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added ethyl 1-benzylazepane-4-carboxylate (5.0 g), followed by stirring for 30 minutes. Next, a solution of 1-bromo-2-chloroethane (3.02 g) in THF was added dropwise thereto, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture was added an aqueous K2CO3 solution, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia). Desired fractions were collected, and concentrated under reduced pressure. After concentration under reduced pressure, to the residue, a part of which was solidified, was added EtOAc, followed by purification by silica gel column chromatography (EtOAc) to obtain ethyl 1-benzyl-4-(2-chloroethyl)azepane-4-carboxylate (4.11 g) as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](OC)=[O:18])[CH:15]=3)[N:10]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:40][NH2:41]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:40][NH2:41])=[O:18])[CH:15]=3)[N:10]([C:21]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc2c(c1)c(-c1ccnc(C)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NN)cc23)ccn1
Temperature: 100 °C
Yield: 102 %

Procedure:
The mixture of methyl 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylate (50 mg, 0.1 mmol) and hydrazine (6.3 mg, 0.2 mmol) in DMF (0.23 mL) was heated at 100° C. under microwave condition for 45 min. The reaction mixture was quenched with water, and extracted with EtOAc. The combined organic layer was dried and concentrated to give 52 mg of crude product. The crude was brought to next step without further purification.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.NC1C=CNN=1.[NH2:32][C:33]1[CH:37]=[C:36]([C:38]2[O:39][CH:40]=[CH:41][CH:42]=2)[NH:35][N:34]=1>O1CCCC1>[O:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[C:36]1[NH:35][N:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[NH:5][C:4]2=[O:13])[CH:37]=1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Reactant: O=C1Nc2ccc(Cl)cc2/C1=C/O
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1=CNc1cc(-c2ccco2)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and substituting 3-amino-5-(2-furyl)-pyrazole for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one is reacted with 0.280 gms. 3-amino-5-(2-furyl)-pyrazole by refluxing in tetrahydrofuran.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH:27]([OH:29])[CH3:28])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[CH3:42][S:43](Cl)(=[O:45])=[O:44].CO>C(Cl)Cl.CN(C=O)C>[CH3:42][S:43]([O:29][CH:27]([C:18]1[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])=[N:20][C:21]2[N:12]([C:10](=[O:11])[NH:9][C:6]3[CH:5]=[C:4]([NH:30][CH2:31][CH2:32][O:33][CH3:34])[C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=1)[CH3:28])(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(C(C)O)c(C(OC)OC)nc32)ncc1C#N
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCNc1cc(NC(=O)N2CCCc3cc(C(C)OS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of (racemic) N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(1-hydroxyethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 183, 198 mg, 0.421 mmol) and NEt3 (80 μl, 0.574 mmol) in DCM (8 ml) and DMF (0.5 ml) at 0° C. was added a solution of methanesulfonyl chloride (40 μl, 0.513 mmol) and the slurry was continued to stir at 0° C. for 4 h, after which it was directly used in the next step. (UPLC-MS 3) tR 1.15 min; ESI-MS 484.8 [M; Me-ether of MeOH quench]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@@H:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:5][C@H:4]([C:15]([O:17]C)=O)[C@H:3]1[C:19]([N:21]1[CH2:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].[OH:33][NH2:34].Cl.C[O-].[Na+]>CO>[OH:33][NH:34][C:15]([C@H:4]1[CH2:5][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:7][N:2]([CH3:1])[C@@H:3]1[C:19]([N:21]1[CH2:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20])=[O:17]
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](Oc2ccncc2)CN(C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of methyl (2S,3S,5S)-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxylate (70 mg, 0.0002 mol) in methanol (0.6674 mL, 0.01648 mol) was added 1.640 M of N-hydroxyamine in Methanol (2.01 mL) made from the corresponding HCl salt and sodium methoxide. After stirred at rt for 1 h, the mixture was acidified with 1N HCl. The resultant mixture was applied directly on RP-HPLC to afford the product as a TFA salt (56 mg, 63.4%). MS (ESI): (M+H)+=437.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([CH2:21][CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.C([Li])CCC.[CH:28]1([N:34]=[C:35]=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([NH:34][C:35]([C:11]2[N:12]([CH2:21][CH3:22])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C=NC1CCCCC1
Reactant: CCn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-ethylimidazole (43 mg, 0.12 mmol) from Example 41, Step A (lower Rf isomer) in THF (2 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.092 mL, 0.15 mmol). The reaction was stirred for 1 hr and then cyclohexyl isocyanate (0.032 mL, 0.25 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (3×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound. HPLC/MS: 476 (M+1), 478 (M+3); Rt=4.99 min.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:21]=[N:20][CH:19]=[C:18]4[C:13]=3[CH2:14][CH2:15][CH2:16][NH:17]4)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:22].O=[CH:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl.C1COCC1>[C:29]([O:28][C:27](=[O:33])[NH:26][CH2:25][CH2:24][N:17]1[C:18]2[C:13](=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]([CH3:1])[C:3](=[O:22])[CH2:4][CH2:5]4)[CH:21]=[N:20][CH:19]=2)[CH2:14][CH2:15][CH2:16]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCN4)ccc21
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCCN4CCNC(=O)OC(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
To a solution of 1-methyl-6-(1,2,3,4-tetrahydro-1,7-naphthyridin-5-yl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-5, 0.1 g, 0.341 mmol) in DCE (3 mL)/THF (1.5 mL) were added tert-butyl 2-oxoethylcarbamate (0.081 g, 0.511 mmol), acetic acid (0.02 g, 0.341 mmol) and the reaction mixture was stirred at room temperature for 10 min. Then, sodium triacetoxyborohydride (0.144 g, 0.682 mmol) was added and stirring was continued at room temperature over night. Then, the mixture was diluted with DCM, poured into aq NaHCO3 and extracted with DCM (2×25 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by reverse phase HPLC on a Gemini-NX column, eluting with a 20 to 98% MeOH—H2O (0.05% TEA) gradient to give the title compound (0.036 g, 24%) as a white foam. MS: 437.2 (M+H+).
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24]1[CH:39]=[CH:38][CH:37]=[CH:36][C:25]=1[CH2:26][NH:27][C:28](=[O:35])[C@H:29]([C@H:31]([CH2:33][CH3:34])[CH3:32])[NH2:30].C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:27]([CH2:26][C:25]3[CH:36]=[CH:37][CH:38]=[CH:39][C:24]=3[O:23][CH3:22])[C:28](=[O:35])[C@H:29]([C@H:31]([CH2:33][CH3:34])[CH3:32])[NH2:30])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1OC
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1OC)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 79.5 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (179 mg, 0.61 mmol, 1.0 eq), L-isoleucine 2-methoxybenzylamide (308 mg, 1.23 mmol) and dichloromethane (2 mL), was treated with triethylamine (515 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (783 uL, 2.0 eq), to provide 254 mg (79%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] 2-methoxybenzylamide.
Reaction SMILES: [CH3:1][C@H:2]([NH2:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1C=CC=CC=1>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([NH:10][CH:2]([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: C[C@H](N)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(C)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dextro amphetamine (200 g) and triethylamine (164 g) were dissolved in 1500 ml. of benzene. A solution of p-toluene sulfonyl chloride (310g) in 500 ml. of benzene was added dropwise to the cooled solution during one hour. The reaction mixture was stirred for three hours at room temperature, then allowed to stand for approximately 16 hours (over night) at room temperature (approximately 20° C.). The salts were filtered off and the benzene solution was washed with dilute HCl, water and brine. Evaporation of the solvent afforded an oil.