Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:21]=[CH:22][N:23]([CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[C:24]=1[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=1.[NH4+].[OH-]>O.CC(O)=O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:21]=[CH:22][N:23]([CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[C:24]=1[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([S:31]([CH3:32])=[O:2])[N:26]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CSc1nccc(-c2c(-c3ccccc3F)ncn2C2CCN(C)CC2)n1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCC(n2cnc(-c3ccccc3F)c2-c2ccnc(S(C)=O)n2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Potassium persulfate (3.2 g, 7.0 mmol) in water (75 mL) was added to a solution of 4-(fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methylthio-4-pyrimidinyl)imidazole (2.7 g, 7.0 mmol) in glacial AcOH (150 mL). After stirring at ambient temperature for 72 h, the reaction mixture was neutralized by the portion-wise addition of concentrated aqueous NH4OH and extracted with CH2Cl2. The organic extract was washed with brine, dried (MgSO4) and concentrated. The residue was triturated with ethyl ether to afford the title compound as an off-white solid; yield 2.3 g (83%).
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([S:6](=[O:16])(=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH2:4][CH2:3][NH:2]1.[C:17](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:17][N:2]1[CH2:3][CH2:4][N:5]2[S:6](=[O:15])(=[O:16])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH:10]2[CH2:1]1
Reactant: O=C([O-])[O-]
Reactant: O=S1(=O)c2ccccc2CC2CNCCN21
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN2C(Cc3ccccc3S2(=O)=O)C1
Reaction time: 4.5 h
Yield: 78 %

Procedure:
To a solution of the title compound of Example 215 (23.0 mg, 0.0965 mmol) in dimethylformamide (0.75 mL) were added cesium carbonate (94 mg, 0.29 mmol) and methyl iodide (0.0072 mL, 0.12 mmol). After 4.5 h, the reaction was partitioned between dichloromethane (2 mL) and water (2 mL). The aqueous layer was extracted with dichloromethane (2 mL). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was taken up in a minimum amount of 50% aqueous methanol and loaded onto a methanol-activated water-equilibrated 1-g SCX-type cation exchange column. The column washed with water (6 mL) and 50% aqueous methanol (6 mL). The column was eluted with 2N methanolic ammonia (8 mL). This fraction was concentrated in vacuo to provide (−)-1,2,3,4,11,11a-hexahydro-2-methyl-pyrazino[1,2-b][1,2]benzothiazine 6,6-dioxide as a white solid (19 mg, 79%): LCMS (pos. ion spectrum) m/z 253.
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[I:26]N1C(=O)CCC1=O>C(Cl)Cl>[OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[I:26]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C(N1CCc2ccc(I)c(O)c2CC1)C(F)(F)F
Temperature: 15 °C
Yield: 64.9 %

Procedure:
Add 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.037 g, 4.0 mmol) and diisopropylamine (60.7 mg, 0.6 mmol) to anhydrous DCM (350 mL) and stir at 10-20° C. Add slowly a solution of N-iodosuccinimide (1.035 g, 4.6 mmol) in DCM (100 mL) over a period of 3 h. Stir the reaction mixture overnight and gradually warm to ambient temperature. Quench the reaction with saturated aqueous NaHCO3, separate the organic layer, wash the organic layer with 0.1N aqueous HCl, brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:20 to 1:10) to give the desired intermediate as a white solid (1.0 g, 65%). MS (ES+) m/z: 386 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.[Cl-].[S:33]1[CH:37]=[C:36]([CH2:38][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:35]=[CH:34]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:38]\[C:36]4[N:35]=[CH:34][S:33][CH:37]=4)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(C)cc2/C=C\c2cscn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.9 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carbaldehyde (0.50 g), [(1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.95 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs, and further stirred at 50° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 3:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({1-methyl-4-[(Z)-2-(1,3-thiazol-4-yl)ethenyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.16 g, yield 26%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 97-98° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:4][N:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[C:5]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:4][N:3]=2)[CH2:21][CH2:22]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc2c(-c3cccs3)nnc(Cl)c2c1
Product: COc1ccc2c(-c3cccs3)nnc(NC3CCN(Cc4ccccc4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(thiophen-2-yl)phthalazine with 4-amino-1-benzylpiperidine.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17].Cl>CC(O)C>[CH:1]1[C:13]2[C:12](=[N:16][NH2:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: NN=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 70.2 %

Procedure:
9-Fluorenone (200 g, 1.1 mol, from Aldrich, Milwaukee, Wis.) and hydrazine monohydrate (160 ml, 3.3 mol, from Aldrich, Milwaukee, Wis.) were dissolved in 1000 ml of 2-propanol in a 2000 ml 2-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. Concentrated hydrochloric acid (4 ml) was then added, and the mixture was refluxed for one hour. The mixture was cooled slowly to room temperature, and the crude solid product was harvested by filtration. The solid was washed with isopropanol and then recrystallized from dioxane to obtain 150 g (74% yield) of 9-fluorenone hydrazone.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[C:24]([O:23][C:21]([N:11]([CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:28])=[O:2])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1cccc(CN(Cc2ccc(Cl)cc2Cl)C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1cccc(C(=O)O)c1)Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
0.85 g (2.00 mmol) of 3-{[tert-Butoxycarbonyl-(2,4-dichloro-benzyl)-amino]-methyl}-benzoic acid methyl ester was dissolved in 20 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was stirred for 5 h then poured into water. The resulting solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 3. The product was extracted 3 times with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6].[Cl:23][CH2:24][CH:25]=O.C([BH3-])#N.[Na+].Cl>O.CO>[Cl:22][C:3]1[C:2]([NH:1][CH2:25][CH2:24][Cl:23])=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6]
Reactant: O=CCCl
Reactant: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(NCCCl)c1Cl

Procedure:
Prepared according to the method described in Example 63 from 3-amino-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-yl)methylbenzamide from Example 54 (0.7 g), 50% chloroacetaldehyde in water (0.353 ml), sodium cyanoborohydride (0.159 g), 50% hydrochloric acid in methanol (0.385 ml) and methanol (10 ml), giving the subtitled compound as a white solid (0.777 g) after purification by flash column chromatography eluting with 3:1 iso-hexane:ethylacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].C1(C)C=C(C)C=C(C)C=1S(O[NH2:26])(=O)=O>O1CCCC1>[NH2:26][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ccn(N)c2c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.735 g 6-methoxyindole and 5 ml tetrahydrofuran (THF) is added to a suspension of 0.44 g of 60% sodium hydride in 10 ml THF at 0° C. After 15 minutes a mixture 1.07 g O-mesitylsulfonyl-hydroxylamine and 15 ml THF is added. Stirring at 0° C. is continued for 1.5 hours. The mixture is poured into ice cold water, extracted with ethyl acetate, and purified by flash chromatography.
Reaction SMILES: Br[CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[I:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[I:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Oc1cccc(I)c1
Reactant: CCOC(=O)CCCCCCCCC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCCC(C)Oc1cccc(I)c1
Temperature: 75 °C
Reaction time: 14 h
Yield: 33.3 %

Procedure:
To a stirred solution of ethyl 10-bromoundecanoate (9.7 g, 33.0 mmol) in dry DMF (66 ml) was added 3-iodophenol (7.99 g, 36.3 mmol) and potassium carbonate (5.02 g, 37.6 mmol). The reaction was immersed in an oil bath which was warmed to 75° C. over 0.5 hr. After stirring for 14 hrs under an N2 atmosphere, the oil bath temperature was increased to 85° C. After stirring for an additional 4 hrs at 85° C., the reaction was allowed to cool, diluted with DMF (200 ml), filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up in ether (500 ml). The organic phase was washed with water (100 ml), 1M aqueous sodium hydroxide (100 ml), water (2×100 ml) and brine (100 ml), dried (Na2SO4), filtered and evaporated in vacuo to provide crude ethyl 10-(3-iodophenoxy)undecanoate which was contaminated with olefinic esters. Flash column chromatography (silica, 1-2%; EtOAc in hexanes) provide ethyl 10-(3-iodophenoxy)-undecanoate as a clear oil (4.75 g, 33.3%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]#[C:4][CH:5]=[O:6].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.S(=O)(=O)(O)O>O.CCOCC>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]#[C:4][CH:5]=[O:6]
Reactant: CCCCC[C@H](O)C#CC=O
Reactant: C1=COCCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CCCCC[C@@H](C#CC=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of (4S)-4-hydroxy-2-nonynal (41.6 g., 0.27 mole) and dihydropyran (33.6 g., 0.4 mole) is cooled to 5° by means of an ice bath and is treated with 0.2 mole of concentrated sulfuric acid. This is allowed to warm to room temperature and stand 17 hours. It is then diluted with water. The oily product is taken up in ether, washed with sodium bicarbonate solution and water and dried over sodium sulfate. Distillation affords (4S)-4-(2-tetrahydropyranyloxy)-2-nonynal as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][C:10](=[O:33])[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13].[BH4-].[Na+]>C(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH:10]([OH:33])[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]=[CH:23][C:24]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])=[CH:25][N:26]=2)[CH2:17][CH2:16]1)(=[O:13])=[O:14]
Reactant: O=C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(CC(O)CCCc1ncccn1)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a stirred solution of 5-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]piperazin-1-yl}sulfonyl)pentan-2-one (9.47 g, 19.4 mmol) in DCM/MeOH (100 mL/100 mL) was added NaBH4 (807 mg, 21.3 mmol) portionwise and the reaction stirred at room temperature. The reaction was then quenched by addition of a saturated solution of NH4Cl (250 mL) and the organics removed in vacuo. The aqueous residue was then extracted with EtOAc (2×250 mL), combined organics washed with brine (250 mL), dried (MgSO4), filtered and concentrated in vacuo to give 5-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]piperazin-1-yl}sulfonyl)pentan-2-ol as a white solid (9.10 g, 18.6 mmol, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.N[C@H](C([NH:19][CH:20]1[C:26](=[O:27])[N:25]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:21]1=[O:40])=O)C>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:19][C@H:20]([C:26]([C:20]2([NH2:19])[C:26](=[O:27])[N:25]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:21]2=[O:40])=[O:27])[CH3:21])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white solid (melting point=211-212° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.44 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[N:9]([S:12]([C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[C:10]=[O:11]>C(Cl)Cl>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:10]([NH:9][S:12]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[O:11])=[N:7][CH:6]=1
Reactant: Nc1ncc(Cl)cn1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-5-chloropyrimidine (1.3 g) was suspended in 20 ml of methylene chloride and to this was added with stirring 2.4 g of methyl 2-(isocyanatosulfonyl)-benzoate. After stirring for three hours at ambient temperature, the desired product, 2-{[(5-chloropyrimidin-2-yl)aminocarbonyl]aminosulfonyl}benzoic acid, methyl ester, which had precipitated as a white solid, was filtered off. It melted at 217°-221° and showed peaks in the nuclear magnetic resonance spectrum (trifluoroacetic acid solvent) at 4.0δ (singlet) for OCH3, 9.0δ for H at the 4- and 6-position of the hetero ring and at 7.9δ and 8.2-8.4δ for aromatic H, consistent for the above-named product.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([O:8][C:9](=[O:42])[NH:10][C:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([C:25]3[N:26]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[CH:27]=[C:28]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:29]=3)=[O:24])=[CH:18][CH:17]=2)=[CH:14][N:13]([CH3:41])[N:12]=1)([CH3:7])([CH3:6])[CH3:5]>O1CCCC1>[CH3:40][N:38]([CH3:39])[S:35]([N:26]1[CH:27]=[C:28]([CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[N:29]=[C:25]1[C:23]([OH:24])([CH3:1])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[C:11]([NH:10][C:9](=[O:42])[O:8][C:4]([CH3:7])([CH3:5])[CH3:6])=[N:12][N:13]([CH3:41])[CH:14]=2)=[CH:17][CH:18]=1)(=[O:37])=[O:36]
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (0.04 mL, 0.11 mmol) was added to a 0° C. solution of tert-butyl[4-(4-{2-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylpropyl)-1H-imidazol-2-yl]-2-oxoethyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate (32 mg, 0.06 mmol) in tetrahydrofuran (3 mL). After stirring at 0° C. for 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford tert-butyl [4-(4-{2-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylpropyl)-1H-imidazo 1-2-yl]-2-hydroxypropyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate which was used in the subsequent step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[N:14]([CH3:36])[C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:22]1[C:31]([CH2:32][CH3:33])=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[C:24]([O:34]C)[N:23]=1)=[CH:17][CH:16]=2)=O)(C)(C)C.Cl>>[CH2:32]([C:31]1[CH:30]=[C:25]([C:26]([OH:28])=[O:27])[C:24](=[O:34])[NH:23][C:22]=1[C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:36])[C:13]([C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[CH:21]2)[CH3:33]
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2c(c1)cc([C@H]1CCCN1C(=O)OC(C)(C)C)n2C
Agent: Cl
Product: CCc1cc(C(=O)O)c(=O)[nH]c1-c1ccc2c(c1)cc([C@H]1CCCN1)n2C
Yield: 107.3 %

Procedure:
(R)-Methyl 6-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1-methyl-1H-indol-5-yl)-5-ethyl-2-methoxynicotinate (0.190 g, 0.38 mmol) was heated with 6M HCl (2.0 mL) at 80° C. for 2.5 h until complete conversion to the product was observed by LC/MS. HCl was removed under reduced pressure, residue triturated with Et2O and solid was collected by filtration. (R)-5-ethyl-6-(1-methyl-2-(pyrrolidin-2-yl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.149 g, 96%) was obtained as yellow solid.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)(C)C>[N+:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=[N+]([O-])CCc1ccccc1
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
To a stirring mixture of trans-β-nitrostyrene (5.25 g, 0.035 mol) and silica gel (10 g, 230-400 mesh) in chloroform (400 mL) and isopropanol (75 mL) at room temperature, was slowly added sodium borohydride (5.50 g, 0.145 mol) over a period of 45 min. The reaction mixture was stirred for an additional 15 min and then carefully quenched with 10% hydrochloric acid (20 mL). Separated solid was filtered and washed with chloroform (50 mL). Combined filtrate and washing was washed with water (1×20 mL), brine (1×20 mL) and dried over anhydrous sodium sulfate. Solvent evaporation at reduced pressure gave a crude material which was purified by flash chromatography (silica gel, 8% ethyl acetate-hexane) to give 2.86 g of 1-nitro-2-phenylethane as a colorless oil (spicy odor); Rf (10% ethyl acetate in hexane) : 0.40; 1H-NMR (300 MHz, CDCl3) 7.40-7.20 (m, 5H), 4.60 (t, 2H), 3.30 (t, 2H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[Br:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[Br:9][CH:10]([CH3:14])[C:11]([O-:13])=[O:12]
Reactant: CC(Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(Br)C(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
N-hydroxysuccinimide (4.51 g, 39.22 mmol) and 2-bromopropionic acid (2.9 mL, 32.68 mmol) were dissolved in anhydrous DCM (1000 ml) in a 2000 mL round-bottomed flask under nitrogen equipped with a magnetic stirrer. The flask was then cooled to 0° C. with an ice bath before the dropwise addition of a solution of N,N′-Dicyclohexylcarbodiimide (6.70 g, 32.68 mmol) in 50 mL of anhydrous DCM. After addition, the mixture was stirred at room temperature overnight. The reaction mixture was then filtered and the solvent evaporated to give a yellow solid that was purified by flash chromatography (CC, SiO2, Et2O, Rf(ester)=0.31). Obtained 7.2 g (28.91 mmol, 74%) of product as a white solid. Melting point: 69-70° C. 1H NMR (CDCl3) δ (ppm) 1.96 (d, 3H, CH(CH3)Br, J=6.78 Hz), 2.86 (s, 4H, Hcycl), 4.61 (q, 1H, CH(CH3)Br, J=7.03 Hz). 13C NMR (CDCl3) δ (ppm) 21.67 (1C, CH(CH3)Br) 25.74 (2C, Ccycl) 34.97 (1C, CH(CH3)Br), 166.17 (1C, C═O), 168.69 (2C, Ccycl=O). IR (solid, ATR cell) ν (cm−1) 1808, 1781 (Ccycl═O), 1729 (C═O). Mass spectroscopy (+EI, m/z) 248.964. Elem. Anal. Theoretical for C7H8NO4Br: C, 33.62; H, 3.22; N, 5.60. Found: C, 33.47; H, 3.16; N, 5.46.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]([O:26][C:27](=[O:30])[CH2:28][NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:19]([O:26][C:27](=[O:30])[CH2:28][NH:29][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH3:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCC(Br)C(=O)Cl
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Br)C(=O)NCC(=O)OCc1ccccc1

Procedure:
65.96 g (355.7 mmol) of α-bromobutyric acid chloride is added in drops at 0° C. to 100 g (296.4 mmol) of glycine benzyl ester p-toluenesulfonic acid salt and 89.98 g (889.2 mmol) of triethylamine in 500 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated.