Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][Si](C(C)C)(C(C)C)C(C)C)[N:7]=1)=[O:5])[CH3:2].Cl[CH2:24][C:25](=[O:27])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:24][C:25](=[O:27])[CH3:26])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(S[Si](C(C)C)(C(C)C)C(C)C)n1
Reactant: CC(=O)CCl
Product: CCOC(=O)c1cccc(SCC(C)=O)n1

Procedure:
Prepared according to the procedure described in Example 6, Step 2, using the following starting materials: 6-triisopropylsilanylsulfanyl-pyridine-2-carboxylic acid ethyl ester and chloroacetone.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:73][C:74]1[S:75][C:76]2[CH:81]=[CH:80][N:79]=[CH:78][C:77]=2[N:82]=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:73][C:74]4[S:75][C:76]5[CH:81]=[CH:80][N:79]=[CH:78][C:77]=5[N:82]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1nc2cnccc2s1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4cnccc4s3)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 79.9 %

Procedure:
Using 306 mg of p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-{(S)-1-diphenylmethoxycarbonylethoxyimino}acetamido]-3-chloromethyl-3-cephem-4-carboxylate in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 56 mg of 2-mercaptothiazolo[4,5-c]pyridine, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 276 mg of the title compound in a yield of 80%.
Reaction SMILES: [CH2:1]1[N:6](C(C2C=CC=CC=2)C2C=CC=CC=2)[C@H:5]([CH2:20][OH:21])[C@@H:4]([OH:22])[C@H:3]([OH:23])[C@H:2]1[OH:24]>CO.O.[Pd].[C]>[CH2:1]1[NH:6][C@H:5]([CH2:20][OH:21])[C@@H:4]([OH:22])[C@H:3]([OH:23])[C@H:2]1[OH:24]
Reactant: OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of N-benzhydryl-1-deoxynojirimycin as prepared in Example 2 (Formula VI, 1.00 g, 3.06 mmol) and 20% PD(OH)2 /carbon (0.20 g) in 40 mL of methanol was hydrogenated (60 psig) in a Parr apparatus for 24 h. The mixture was filtered through Celite, and the filtrate was concentrated to a light grey foam. The foam was washed with hexane and then dissolved in water (10 mL) and stirred over Dowex® 50W-X8 ion exchange beads for 2 h. The beads were washed with 1N aqueous NH4OH solution until TLC analysis indicated the product had been completely removed from the resin. The combined ammonia washings were lyophilized to give 0.49 g (99%) of 1-deoxynojirimycin as a white foam, mp 198°-201° C. (literature mp 198°-202° C.: Kinast, G.; Schedel, M. Angew. Chem. Int. Ed. Eng. 1981, 20, 805). The 400-MHz 1H NMR spectrum of the material was identical to that of an authentic sample of 1-deoxynojirimycin (Sigma).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22]C)=[O:21])[CH2:16][C@@H:15]1[NH:24][C:25]([C:27]1[S:28][C:29]3[CH2:30][N:31]([CH3:36])[CH2:32][CH2:33][C:34]=3[N:35]=1)=[O:26])=[O:12])=[CH:5]2.[OH-].[Li+].Cl>O1CCCC1.O>[ClH:1].[C:20]([C@H:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@@H:15]([NH:24][C:25]([C:27]2[S:28][C:29]3[CH2:30][N:31]([CH3:36])[CH2:32][CH2:33][C:34]=3[N:35]=2)=[O:26])[CH2:16]1)([OH:22])=[O:21]
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 149.2 %

Procedure:
(1R*,2S*,4S*)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine (180 mg) was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and water (2 ml), and lithium hydroxide (17 mg) was added to stir the mixture at room temperature for 45 minutes. After adding 1N hydrochloric acid, the reaction mixture was concentrated under reduced pressure, a small amount of water was added to the residue, and solids deposited were collected by filtration to obtain the title compound (140 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([S:14]([C:17]3[CH:18]=[C:19]([OH:25])[C:20]([OH:24])=[CH:21][C:22]=3[CH3:23])(=[O:16])=[O:15])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:33](Br)[C:34]([OH:36])=[O:35].Cl>CN(C)C=O>[CH3:23][C:22]1[C:17]([S:14]([C:12]2[CH:11]=[CH:10][C:8]3[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6][C:7]=3[CH:13]=2)(=[O:16])=[O:15])=[CH:18][C:19]2[O:25][CH:33]([C:34]([OH:36])=[O:35])[O:24][C:20]=2[CH:21]=1
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccc2nc(C(C)(C)C)sc2c1
Reactant: O=C(O)C(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1S(=O)(=O)c1ccc3nc(C(C)(C)C)sc3c1)OC(C(=O)O)O2
Reaction time: 21 h

Procedure:
39.6 g (approximately 0.105 mol) of 4-[(2-tert.butyl-6-benzothiazolyl)-sulphonyl]-5-methyl-1,2-benzenediol and 72.3 g (0.523 mol) of potassium carbonate are stirred in 300 ml of dimethylformamide at room temperature under inert gas protection. In the course of 20 minutes there is added dropwise thereto half of a solution of 45.6 g (0.209 mol) of dibromoacetic acid in 100 ml of dimethylformamide. The reaction mixture is subsequently stirred for 21 hours at 100° and, during this time, the remainder of the dibromoacetic acid solution is added in small portions. For working up, the dimethylformamide is distilled off in a rotary evaporator under a water jet vacuum. The residue is dissoled in water and adjusted to pH 1-2 with concentated hydrochloric acid. The precipitated acid is extracted three times with ethyl acetate. The combined ethyl acetate solutions are washed once with water, dried over sodium sulphate, filtered and concentrated by evaporation. The residue is dissolved in 500 ml of ethanol, and after the addition of 0.5 ml of concentrated hydrochloric acid the solution is left to stand at room temperature for 10 days. During this time, the ethyl ester of 5-methyl-6-[(2 -tert.-butyl-6-benzothiazolyl)-sulphonyl]-1,3-benzodioxole-2-carboxylic acid is precipitated in the form of colourless crystals. The crystal suspension is cooled to 0° and the crystals are filtered off. 90 ml of 2N sodium hydroxide solution are added to the crystals, still moist with ethanol, and the mixture is stirred for 2 hours at room temperature, a solution being formed. This is acidified with concentrated hydrochloric acid and the precipitated acid is extracted three times with ethyl acetate. The ethyl acetate solutions are washed with water, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo to dryness. The residue is recrystallised from ethyl acetate, yielding 5-methyl-6-[(2-tert.-butyl-6-benzothiazolyl)-sulphonyl]-1,3-benzodioxole-2-carboxylic acid in the form of colourless crystals having a melting point of 247° (decomposition), after sintering from 203°.
Reaction SMILES: [OH2:1].O.P([O-])([O-])(O)=O.[Na+:8].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[O-:17][Si:18]([O-:20])=[O:19].[Na+].[Na+]>>[Si:18]([O-:1])([O-:20])([O-:17])[O-:19].[Na+:8].[Na+:8].[Na+:8].[Na+:8]
Reactant: O=[Si]([O-])[O-]
Reactant: O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
1104 g of disodium hydrogenphosphate dihydrate, 683 g of anhydrous sodium sulfate and 683 g of anhydrous soda are dissolved in 50 kg of water glass having the composition as in Example 1, and the solution is spray-dried in a laboratory spray dryer (spray tower) from Anhydro to give an amorphous sodium silicate having an active substance content of about 83%. 15 kg of the amorphous sodium silicate are heat-treated at 720° C. for 90 min in a muffle furnace (Nabertherm, model W1000/H). The chilled product (about 10 kg) is pulverized using a jaw crusher and a disk mill.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][S:9]([NH:12][C:13](=O)OC(C)(C)C)(=[O:11])=[O:10])([O-:3])=[O:2].[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][S:9]([NH:12][CH2:13][CH3:23])(=[O:11])=[O:10])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCNS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude tert-butyl N-(3-nitrobenzylsulfamoyl)carbamate, triphenylphosphine (2 g) and diisopropyl azadicarboxylate (DIAD, 1.6 g) were dissolved in THF (20 mL) and ethanol (0.47 mL). The solution was stirred at ambient temperature overnight. The reaction solution was evaporated to dryness. The residue was dissolved in methanol (10 mL) and treated with 4.0 M HCl in dioxane (10 mL). It was stirred at rt overnight and then evaporated. The residue was diluted with ethyl acetate (100 mL) and washed with NaHCO3 aq. (2×100 mL). The organic solution was evaporated and purified by flash column chromatography (EtOAc/hexane=1/2, 1/1) to give N-(3-nitrobenzyl)-N′-ethylsulfamide. 1H NMR (DMSO-d6): δ 1.02 (t, J=7.2 Hz, 3H), 2.82 (p, J=6.9 Hz, 2H), 4.14 (d, J=6.6 Hz, 2H), 6.93 (t, J=5.4 Hz, 1H), 7.54 (t, J=6.3 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 8.20 (s, 1H); LCMS: purity: 1.2 g, 88.4%; MS (m/e): 260.16 (MH+).
Reaction SMILES: [OH-:1].[Na+].[C:3]([CH2:6][CH2:7][S:8][CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]#[N:21])[C:14]=2[CH2:13][O:12][C:11]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=4)[N:29]=3)=[CH:25][C:10]1=2)([OH:5])=[O:4].O>C(O)C>[C:20]([C:19]1[C:14]2[CH2:13][O:12][C:11]3[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=5)[N:29]=4)=[CH:25][C:10]=3[CH:9]([S:8][CH2:7][CH2:6][C:3]([OH:5])=[O:4])[C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:1])[NH2:21]
Reactant: N#Cc1cccc2c1COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2SCCC(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1cccc2c1COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
40 ml of a 1N-sodium hydroxide aqueous solution was added to 0.85 g of the compound 11-(2-carboxyethylthio)-2-(7-chloroquinolin-2-yl)methoxy-7-cyano-6,11-dihydrodibenz[b,e]oxepine obtained in Example 15 dissolved in 10 ml of ethanol and the mixture was refluxed under heating for 2 hours. After completion of the reaction, water was added to the residue obtained by removing the solvent, the mixture was adjusted to about pH 3 with 1N-hydrochloric acid and crystals precipitated were dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and condensed. The resulting residue was applied to silica gel column chromatography to obtain 0.25 g of the title compound as slightly yellow powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=O)=[CH:9][CH:8]=1)[CH3:2].CO.[CH3:28][NH:29][NH2:30]>>[CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:29]([CH3:28])[N:30]=[C:15]3[C:16]4[C:21]([CH2:22][CH:14]23)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CNN
Reactant: CCN(CC)CCOc1ccc(C=C2Cc3ccccc3C2=O)cc1
Solvent: CO
Product: CCN(CC)CCOc1ccc(C2C3Cc4ccccc4C3=NN2C)cc1

Procedure:
A solution of 26.4 g (0.08 mole) of 2-[[4-[2-(diethylamino)ethoxy]phenyl]methylene]-2,3-dihydro-1H-inden-1-one in 250 ml of methanol containing 3.7 g (0.08 mole) of methyl hydrazine is heated at reflux for 4 hours. After cooling, 9.1 g starting material is recovered.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6]O)=[C:4]([F:14])[CH:3]=1.S(Cl)([Cl:17])=O>O1CCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6][Cl:17])=[C:4]([F:14])[CH:3]=1
Reactant: CC(C)Oc1cc(CO)c(F)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)Oc1cc(CCl)c(F)cc1Cl
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Then, 6.7 g of 4-chloro-2-fluoro-5-isopropoxybenzylalcohol was dissolved in 70 ml of tetrahydrofuran, to which 1 ml of pyridine was added, and the mixture was cooled to 5° C. Then, 5 ml of thionyl chloride was slowly added dropwise at 5° to 10° C., and the mixture was stirred at 5° C. for 1.5 hours. After completion of the reaction, the reaction mixture was filtered to separate the precipitated crystals, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, which afforded 7.3 g of 4-chloro-2-fluoro-5-isopropoxybenzyl chloride.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7]C)=O)(=[O:3])[CH3:2].C(C(CCCCCC)C(O)=O)(=O)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:57][CH:58]([C:60]1[C:61](=[O:77])[NH:62][C:63]([CH2:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[C:69]([O:75][CH3:76])[CH:68]=2)=[N:64][N:65]=1)[CH3:59]>ClCCl>[C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([NH:57][CH:58]([C:60]1[C:61](=[O:77])[NH:62][C:63]([CH2:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[C:69]([O:75][CH3:76])[CH:68]=2)=[N:64][N:65]=1)[CH3:59])=[O:7])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1OC
Reactant: CCCCCCC(C(C)=O)C(=O)OC
Agent: CCCCCCC(C(C)=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O

Procedure:
601 g (3.0 mmol) of methyl 2-acetyloctanoate (Example 18A) are hydrolysed to 2-acetyloctanoic acid according to Example 19A. The acid in 20 ml of dichloromethane is reacted analogously to Example 23A with 1.08 g (8.0 mmol) of 1-hydroxy-1H-benzotriazole, 1.62 g (16.0 mmol) of 4-methylmorpholine, 1.53 g (8.0 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 870 mg (3.0 mmol) of 6-(1-aminoethyl)-3-(3,4-methoxybenzyl)-1,2,4-triazin-5(4H)-one (Example 12A) to give 2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}octanamide.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][S:16]([C:12]1[CH:11]=[C:10]([S:7]([N:6]2[C:2]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[CH:3][C:4]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:5]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:17]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cccnc2)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1)C(=O)OC(C)(C)C
Yield: 66.7 %

Procedure:
Using tert-butyl [(5-bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (459 mg), 3-pyridineboronic acid (222 mg), sodium carbonate (287 mg) and tetrakis(triphenylphosphine)palladium (53.1 mg), a procedure as in Reference Example 267 was performed to give the title compound as a white solid (yield 305 mg, 67%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]2[CH2:26][NH:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:27]=1)(=[O:16])=[O:15].C(N(CC)CC)C.CN1CCCC1=O>O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:25]2[CH2:24][CH2:23][CH2:22][C:21]3[CH:27]=[C:17]([S:14]([CH3:13])(=[O:15])=[O:16])[CH:18]=[CH:19][C:20]=3[CH2:26]2)[CH:11]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCCNC2
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)CCCN(c1cc(Cl)c3ccccc3n1)C2
Temperature: 100 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
The mixture of 2,4-dichloroquinoline (126 mg, 0.637 mmol), 7-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (144 mg, 0.637 mmol), triethylamine (0.106 mL, 0.765 mmol) and N-methyl-2-pyrrolidone (2 mL) was heated with stirring in a sealed tube for 4 hours at 100° C. The resulting mixture was diluted with water and extracted with ethyl acetate (15 mL×3). The organic layers were combined and washed with brine (15 mL×3), and then dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:5) to afford 55.6 mg of product as a white solid (yield was 22.5%). MS obsd. (ESI+) [(M+H)+] 387.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][CH:17]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][N:18]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:43]1[CH:44]=[CH:45][CH:46]=[C:41]([O:15][CH2:16][CH:17]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:20][CH2:19][N:18]2[C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Reactant: Oc1cccnc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(COc2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of diisopropylazodicarboxylate (2.67 mL, 13.5 mmol) in THF (25 mL) was added dropwise over 1 h to a solution of 4-tert-butyl 1-benzyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (4.52 g, 12.9 mmol), 3-hydroxypyridine (1.35 g, 14.2 mmol) and triphenylphosphine (3.55 g, 13.5 mmol) in THF (75 mL) at 15° C. After complete addition, the reaction mixture was allowed to warm to rt and stir overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (10 to 40% EtOAc in Hexanes gradient). This gave 0.9055 g (16%) of the title compound. Rf=0.35 in 80% EtOAc/Hexanes; LC-MS: RT=9.85 min; [M+H]+=428.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[N:11][CH:12]=1)[CH3:2].[ClH:28]>CCO.O1CCOCC1>[ClH:28].[ClH:28].[NH:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:10]2[N:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:27])=[CH:8][CH:9]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)/C=C/c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(NC2CCNCC2)nc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-1-piperidinecarboxylate (2.8 g) in EtOH (20 ml) was added 4N HCl in dioxane (18.6 ml), the mixture was stirred at 23° C. for 30 minutes. The precipitate was collected, washed with IPE, dried under reduced pressure to give ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[N:12]=[N:13][N:14]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1)=O.Cl>O1CCCC1>[C:16]([N:14]1[CH:15]=[C:11]([CH2:9][OH:8])[N:12]=[N:13]1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a suspension of lithium aluminum hydride (6.17 g: 0.163 Mol.) in tetrahydrofuran (600 ml) under ice cooling is added 1-trityl-1,2,3-triazol-4-ylcarboxylic acid methyl ester (40.0 g: 0.108 Mol.), and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added dropwise aqueous tetrahydrofuran under ice cooling. The mixture is neutralized with 10% hydrochloric acid, filtered to remove insoluble material, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The resulting crystals are washed with ether to give 1-trityl-1,2,3-triazol-4-yl-methanol (33.4 g) as white crystals. Yield: 91%. mp. 200° to 201° C.
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)[CH:4]([C:10]([Cl:13])([CH3:12])[CH3:11])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:15](=O)(O)[O-:16].[Na+]>CO>[Cl:13][C:10]([CH3:12])([CH3:11])[CH:4]([CH:3]([O:16][CH3:15])[O:2][CH3:1])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C([O-])O
Reactant: COC(=O)CC(C(Cl)OC)C(C)(C)Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(C(OC)OC)C(C)(C)Cl
Reaction time: 3 h

Procedure:
The solution of Step A of Example 1 was added to methanol at a low temperature and the mixture was stirred at 5°-10° C. for 3 hours and was poured into aqueous sodium bicarbonate solution. The mixture was filtered and the decanted aqueous phase was extracted with methylene chloride. The organic phase was washed with aqueous sodium bicarbonate solution and evaporated to dryness under reduced pressure to obtan 11 g of residue. The latter was chromatographed over silica gel and was eluted with a 9-1 petroleum ether (b.p.=40°-70° C.)-ethyl acetate mixture to obtain 8.66 g of methyl 4-chloro-4-methyl-3-dimethoxymethyl-pentanoate with a boiling point of 62° C. at 0.05 mm Hg which was identical to the product of Step A of Example 3.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:12]2[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=2[NH:10][C:9]1=[O:26])(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[NH2:7][C@@H:8]1[C:9](=[O:26])[NH:10][C:11]2[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=2[N:13]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(CCCC(F)(F)F)c2ccccc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(CCCC(F)(F)F)c2ccccc2NC1=O

Procedure:
In an analogous procedure to that described in Example 1d), the treatment of the [(S)-4-oxo-1-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester with hydrochlorid acid (37%) in dioxane yielded the title compound as a light yellow solid; MS (m/e): 288 (M+H)+.