Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:24][C:23]1[CH:25]=[CH:26][C:20]([S:17]([O:9][CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([I:1])[CH:3]=[N:4]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: OCCn1cc(I)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCn2cc(I)cn2)cc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
2-(4-Iodo-1H-pyrazol-1-yl)ethanol (Preparation 57, 535 mg, 2.248 mmol) in DCM (11 mL) was treated with triethylamine (1.55 mL, 11.14 mmol) at 0° C. Tosyl chloride (857 mg, 4.50 mmol) was added at 0° C. and the mixture was allowed to warm to room temperature for 18 hours. The organic layer was washed with water, HCl 1M and water (twice). The organic layers were dried, concentrated and purified by silica gel column chromatography eluting with 0 to 30% EtOAc in cyclohexane to give the title compound (817 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)[C:8]#N)=[CH:4][CH:3]=1.[CH:22]([CH:24]=C)=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([N:6]2[CH:24]=[CH:22][CH:8]=[C:7]2[C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: N#CC(Nc1ccc(Cl)cc1)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2cccn2-c2ccc(Cl)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-chloroanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a pale yellow powder (yield 38%), melting at 179-181° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][CH2:32][CH2:33][C:34]#[CH:35]>>[CH2:35]([O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[CH2:34][CH2:33][C:32]#[CH:31]
Reactant: C#CCCC
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: C#CCCCOCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 4-pentine chloride are treated as described in Example 5.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][C:8]3[C:13]([CH:2]12)=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1>C1(C)C=CC=CC=1>[O:6]=[C:5]1[N:1]([C:17]2[N:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH:2]2[C:13]3[C:8]([CH2:7][CH:3]2[CH2:4]1)=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C1CC2Cc3ccccc3C2N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N2C(=O)CC3Cc4ccccc4C32)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (1 g, 5.77 mmol) in toluene (15 ml) was added sodium hydride (0.254 g, 6.35 mmol) at 0° C. The batch was warmed to room temperature and 2-chloro-5-cyanopyridine (0.824 g, 5.77 mmol) was added. The batch was stirred at 95° C. for 2 h. After cooling, the batch was added to ice water and extracted with ethyl acetate (2×). The combined organic phases were concentrated and the residue was purified by column chromatography (hexane/ethyl acetate 7/3) to give 6-(2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-1-yl)pyridine-3-carbonitrile F20 (1.00 g, 63%). LCMS (method A) 1.68 min; ES+: 276 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:10]3)=[CH:4][C:3]=1[OH:25].[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:22])[CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:10]3)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(O)cc2OCC3)n(C(C)C)n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc2c(cc1Br)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
To a solution of 13-bromo-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-ol (5.5 g) in acetone (30 mL) was added K2CO3 (3.03 g, 22.0 mmol) and methyl iodide (1.87 g, 13.1 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and diluted with ethyl acetate (50 mL). After removal of the solvent, the residue was purified by silica gel chromatography using 1-10% MeOH in DCM as eluant to afford the desired product (3.0 g, 65% yield for two steps). LCMS m/z [M+H]+ 418.1.
Reaction SMILES: [Si:1]([O:8][C@H]1CCC[C@@]2(C)[C@H]1CC[C@@H]2[C@H](C)CO)([C:4](C)(C)C)([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1.[CH3:31][Si:32]([CH3:50])([CH3:49])OC(C)(C)[C@H](C)CS(C1C=CC=CC=1)(=O)=O>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:2][Si:1]([O:8][Si:32]([CH3:50])([CH3:49])[CH3:31])([CH3:4])[CH3:3]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: C[C@H](CS(=O)(=O)c1ccccc1)C(C)(C)O[Si](C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[Si](C)(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 10E (200 mg, 0.61 mmol) was dissolved in 2 mL of dichloromethane; 100 mg of 4 Å molecular sieves were added, followed by 15 mg of tetrapropylammonium perruthenate and 75 mg of 4-methylmorpholine N-oxide. The mixture was stirred for 2 hours at ambient temperature, and then filtered through diatomaceous earth to removed solids. The crude product was purified by silica gel chromatography using an Analogix IntelliFlash™ 40, eluting with a gradient of 5% to 30% ethyl acetate in hexanes. The compound of Example 10C (200 mg, 0.63 mmol) was combined with this aldehyde according to the coupling procedure described by Kutner et al. in J. Org. Chem. 1988, 53, 3450-3457. The named product was isolated as a mixture of trimethylsilyl ether (Fraction A) and hydroxyl (Fraction B) after chromatographic purification using an Analogix IntelliFlash 280™, eluting with a gradient of 0% to 50% ethyl acetate in hexanes. These products were combined and carried forward to the next step.
Reaction SMILES: CC1(C)[O:6][C:5](=O)[C@H:4]([C@H:8]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][C@H:16]2[CH3:27])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:3]1.[NH2:29][OH:30]>CC(O)C.O>[OH:30][NH:29][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][C@H:16]1[CH3:27])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C)C[C@@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Solvent: O
Solvent: CC(C)O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 47.5 %

Procedure:
To a solution of (5S)-2,2-dimethyl-5-((1R)-3-methyl-1-{[(2R)-2-methyl-4-(2-pyridinyl)piperazinyl]carbonyl}butyl)-1,3-dioxolan-4-one (517 mg; 1.33 mmol; 1.0 eq) in iPrOH (2.0 mL) was added an aqueous solution of hydroxylamine (391.5 μl; 6.64 mmol; 5.0 eq.) and the resulting reaction mixture was stirred at RT for 40 min. HPLC analyses showed the presence of 2 diastereoisomers (75/25). This reaction mixture was dissolved in water (6 mL) and directly purified by reverse-phase chromatography (major diastereoisomer as the first eluted peak, gradient starting from 100% H2O up to 75% H2O in ACN in 5 min, then isocratic 75% H2O in ACN for 25 min; flow: 50 mL/min) to give the title product (4) as a white powder (230 mg; 47%). 1H NMR (CD3OD, 300 MHz) δ 8.10 (m, 1H), 7.58 (m, 1H), 6.84 (m, 1H), 6.69 (m, 1H), 4.84-4.70 (m, 1H), 4.60 (m, 1H), 4.48 (m, 0.4H), 4.19 (m, 1H), 4.13-3.98 (m, 2H), 3.71-3.55 (m, 0.6H), 3.30-3.07 (m, 2H), 3.05-2.82 (m, 1H), 1.94-1.76 (m, 1H), 1.55-1.38 (m, 3H), 1.35 (d, 1.3H, J=6.7 Hz), 1.23 (d, 1.7H, J=6.7 Hz), 0.93 (m, 6H). M+(ESI): 365.2, M−(ESI): 363.2. HPLC (Condition B), Rt: 2.4 min (HPLC purity: 97.6%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.C(=O)(O)[O-].[Na+].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].O>C(Cl)(Cl)Cl>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[C:3]([NH:2][C:26]([N:25]([CH3:29])[CH3:24])=[O:27])[CH:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1cc(Br)ccc1N1CCc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Nc1cc(Br)ccc1N1CCc2ccccc21
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a stirred mixture, under nitrogen, of 28.9 g (0.10 mole) of 1-(2-amino-4-bromophenyl)indoline hydrochloride and 16.8 g (0.20 mole) of anhydrous powdered sodium bicarbonate in 500 ml of chloroform was added a solution of 21.5 g (0.20 mole) of dimethylcarbamyl chloride in 25 ml of chloroform, over a 10 minute period. The mixture was heated under reflux for 7 hours, and 8.4 g (0.10 mole) of sodium bicarbonate and 10.7 g (0.10 mole) of the dimethylcarbamyl chloride were added. After heating under reflux for 2 days, equivalent amounts (8.4 g of sodium bicarbonate and 10.7 g of dimethylcarbamyl chloride) were added. After three days under reflux, the mixture was cooled and 500 ml of water was added. The phases were stirred vigorously for 0.5 hours and separated. The organic phase was washed three times with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in 200 ml of dichloromethane and adsorbed on a chromatography column containing 1 kg of silica gel packed in and eluted with dichloromethane. The fractions containing product were combined and concentrated to afford 14.5 g (40%) of product. Recrystallization from toluene (charcoal)/hexane gave the analytical sample, mp 119°-121° C.
Reaction SMILES: [CH3:1][C:2]([CH3:38])([P:35](=[O:37])=[O:36])[N:3]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH2:24][CH2:25][NH:26][C:27]2[C:32](Cl)=[CH:31][N:30]=N[C:28]=2Cl)[CH:17]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH3:15])(=[O:6])=[O:5].[CH3:39]C(C)(P(=O)=O)N(C1C=C(C)C=C(OCCNC2C(Cl)=C(Cl)N=NC=2)C=1)S(C1C=CC=CC=1OCC)(=O)=O>>[CH3:1][C:2]([CH3:38])([P:35](=[O:37])=[O:36])[N:3]([C:16]1[CH:17]=[C:18]([O:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:39][CH:28]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH3:15])(=[O:6])=[O:5]
Reactant: CCOc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2cnnc(Cl)c2Cl)c1)C(C)(C)P(=O)=O
Reactant: CCOc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2c(Cl)cnnc2Cl)c1)C(C)(C)P(=O)=O
Product: CCOc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2ccncc2)c1)C(C)(C)P(=O)=O

Procedure:
was produced in a 54% yield analogously to example 5. Oil. MS (m/e)=518. For this 2-ethoxy-benzenesulfonyl chloride is used in step 5c) instead of 2-methoxy-benzenesulfonyl chloride and one obtained N-(3-cyanomethoxy-5-methyl-phenyl)-2-ethoxy-benzenesulfonamide in a 70% yield (Fp. 142° C.) which was reacted analogously to example 5d) to form N-(dimethyloxophosphinyl-methyl)-N-(3-cyanomethoxy-5-methyl-phenyl)-2-ethoxy-benzene-sulfonamide (46% yield, Fp. 139°-141° C.) and this was reacted analogously to example 5e) to form N-(dimethyloxophosphinyl-methyl)-N-[3-(2-amino-ethoxy)-5-methyl-phenyl]-2-ethoxy-benzenesulfonamide (58% yield, oil, MS (m/e)=440) which was reacted analogously to example 5f) to form a mixture of N-(dimethyloxophosphinylmethyl)-N-{3-[2-(3,5-dichloropyridazin-4-ylamino)-ethoxy]-5-methyl-phenyl}-2-ethoxy-benzenesulfonamide and N-(dimethyloxophosphinyl-methyl)-N-{3-[2-(3,4-dichloropyridazin-5-ylamino)-ethoxy]-5-methyl-phenyl}-2-ethoxy- benzenesulfonamide (55%, Fp. 114°-116° C.) from which the title compound was obtained analogously to example 5g) by catalytic hydrogenation.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH:8]=[CH:7]2)[CH2:5][CH2:4][O:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:5]1[C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[CH2:1][CH2:2][O:3][CH2:4]1
Reactant: [H][H]
Reactant: O=C1C=CC2(CCOCC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCC2(CCOCC2)CC1

Procedure:
Under a hydrogen atmosphere 1.30 g (7.82 mmol) 3-oxaspiro[5.5]undec-7-en-9-one were hydrogenated with 0.2 g Pd/C (10%) in 15 ml of ethyl acetate at 50° C. and 3 bar hydrogen pressure for three days. The reaction mixture was suction filtered and evaporated down.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH:23]4[CH2:25][CH2:24]4)[N:20]=[CH:19]3)[CH:12]=[C:7]12.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>O.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>[CH:23]1([C:21]2[N:20]=[CH:19][N:18]([C:13]3[CH:12]=[C:7]4[C:8]5[C:3]([CH2:4][CH2:5][N:6]4[C:16](=[O:17])[CH2:15][N:14]=3)=[C:2]([C:30]3[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=3)[CH:11]=[CH:10][CH:9]=5)[CH:22]=2)[CH2:24][CH2:25]1
Reactant: OB(O)c1ccc(F)nc1
Reactant: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(Br)c3CCN12
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+]
Solvent: O
Solvent: COCCOC
Product: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(-c4ccc(F)nc4)c3CCN12
Temperature: 85 °C
Reaction time: 0.05 h
Yield: 67.4 %

Procedure:
Example 95-1. 9-bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (1.48 g, 3.73 mmol), (6-fluoropyridin-3-yl)boronic acid (1.05 g, 7.45 mmol) and a solution of Na2CO3 (1.97 g, 18.63 mmol) in water (14.5 mL) was treated with DME (58 mL). The suspension was degassed, Pd(PPh3)4 (646 mg, 0.56 mmol) was added and the mixture was heated at 85° C. for 2 h. The mixture was allowed to warm to RT and the solvent was removed under reduced pressure. The residue was dissolved in DCM and extracted with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 1% MeOH in DCM for 3 min, then from 1% MeOH in DCM to 4% MeOH in DCM in 25 min, 4% MeOH in DCM for 5 min) to yield a beige foam (1.04 g). The residue was crystallized from AcOEt to afford the title compound as white crystals (720 mg). UPLC-MS: MS 414.2 (M+H+); UPLC rt 0.95 min. 1H NMR (600 MHz, DMSO-d6) δ ppm 0.66 (d, J=3.4 Hz, 2 H), 0.72-0.84 (m, 2 H), 1.70-1.88 (m, 1 H), 2.84 (br. s., 2 H), 3.72 (br. s., 2 H), 4.24 (br. s., 2 H), 7.18 (s, 1 H), 7.31 (d, J=8.5 Hz, 1 H), 7.43 (s, 1 H), 7.47-7.57 (m, 2 H), 7.97-8.14 (m, 3 H), 8.27 (s, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[C:16](Br)=[C:15]([N+:18]([O-:20])=[O:19])[S:14][CH:13]=1)=[O:11])[CH3:8].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:7]([O:9][C:10]([C:12]1[C:16]([S:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([N+:18]([O-:20])=[O:19])[S:14][CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1csc([N+](=O)[O-])c1Br
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1csc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
An aqueous solution of potassium carbonate (9.90 g, 71.6 mmol, dissolved in 40 mL water) was added to a suspension of 4-bromo-5-nitro-thiophene-3-carboxylic acid ethyl ester (20.06 g, 71.6 mmol) in ethanol at 25° C. Benzyl mercaptan (8.41 mL, 71.6 mmol) was added via pipette, and the dark red reaction mixture was stirred at 25° C. for 4 h and then was concentrated in vacuo to near-dryness. The remaining orange-brown solid was triturated with water (200 mL) and was collected by filtration. After washing with water (200 mL), the resulting solid was air-dried overnight to afford the desired product, 4-benzylsulfanyl-5-nitro-thiophene-3-carboxylic acid ethyl ester (22.63 g, 70.0 mmol, 98%), as a yellow/brown solid. 1H NMR (400 MHz, CDCl3) δ: 1.41 (3H, t, J=7.1 Hz), 4.25 (2H, s), 4.39 (2H, q, J=7.0 Hz), 7.18-7.23 (5H, m), 8.07 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:17]4C=CN=C4)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.N.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:17])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2ccc(F)cc2C1=O
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(C(N)=O)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
15 g (46.1 mmol) of 1-[[8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole are suspended in 75 ml of N,N-dimethylformamide, whereupon the suspension is treated with 7.8 ml (102 mmol) of a 25 percent aqueous ammonia solution, the mixture is stirred at room temperature for 0.75 hour and then poured into 300 ml of water. The product is filtered off under suction after 1 hour, rinsed with water and dried at 85° in a vacuum drying oven. There is obtained 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide of melting point 272°-273°.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([NH:10][C@@H:11]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[C:12]2[C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])[CH:4]=[CH:3]1.[H][H]>[Pd].CCOC(C)=O>[CH2:18]([C:17]1[C:12]([C@H:11]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[NH:10][C:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:1])[NH:7][CH:6]=2)=[O:9])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:19]
Reactant: [H][H]
Reactant: C=Cc1cccnc1[C@@H](NC(=O)c1ccc(=O)[nH]c1)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cccnc1[C@@H](NC(=O)c1ccc(=O)[nH]c1)c1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 100 mL round bottom flask containing (S)-6-oxo-N-((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)-1,6-dihydropyridine-3-carboxamide (40 mg, 0.100 mmol, Example 363) was added EtOAc (20 mL). The resulting mixture was then stirred at 23° C. for 2 min. At this time, Pd/C (10%, 20 mg) was added before a balloon of hydrogen was bubbled through the mixture. The reaction was stirred for 2 h under hydrogen (1 atm) and was then filtered though a plug of Celite® brand filter agent and eluted with EtOAc (50 mL). The solvent was removed, and the material was placed on high vacuum for 1 h to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.67 (d, J=6.9 Hz, 1H), 8.53 (d, J=4.7 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.94 (dd, J=9.6, 2.4 Hz, 1H), 7.36-7.67 (m, 5H), 7.27-7.36 (m, 1H), 6.60 (d, J=9.5 Hz, 1H), 6.50 (d, J=6.7 Hz, 1H), 2.63-2.82 (m, 1H), 2.36-2.62 (m, 1H), 1.11 (t, J=7.5 Hz, 3H). MS (ESI, positive ion) m/z: 402.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of 3,5-dimethyl-4-nitro-benzoic acid (10.0 g, 0.0512 mol) in MeOH (150 mL) is added thionyl chloride (10 ml) at 0° C. and the reaction is heated to 80° C. After 16 h, the reaction mixture is cooled to room temperature and solvent is removed under reduced pressure. The residue is diluted with water (50 ml) and basified with saturated NaHCO3 solution to pH 7-8 and extracted with EtOAc (2×120 mL). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to afford the title compound as a light yellow solid (10.71 g, 98.3%). 1H NMR (400 MHz, DMSO): δ 7.83 (s, 2H), 3.88 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30](=[O:45])[NH:31][CH:32]([C:34](=[O:44])[NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([NH2:43])[N:37]=1)[CH3:33])([CH3:28])([CH3:27])[CH3:26].[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52](O)=[O:53].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:25]([O:29][C:30](=[O:45])[NH:31][CH:32]([C:34](=[O:44])[NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([NH:43][C:52]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][N:46]=2)=[O:53])[N:37]=1)[CH3:33])([CH3:26])([CH3:27])[CH3:28]
Reactant: O=C(O)c1ccccn1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(NC(=O)c2ccccn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (180 mg, 0.47 mmol) is added to a mixture of tert-butyl-N-{1-[(6-amino-4-chloropyridin-2-yl)carbamoyl]ethyl}carbamate J8 (100 mg, 0.32 mmol), pyridine-2-carboxylic acid (60 mg, 0.49 mmol) and DIPEA in NMP (1.5 ml) and the mixture is stirred at RT for 2 h and stirring continued at 50° C. for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 27 mg (20%). HPLC-MS: M+H=420 (Method—2).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][C:3]1=[O:17].[CH2:18](O)[CH2:19][OH:20].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:18]1[CH2:19][O:20][C:3]2([CH2:4][CH2:5][CH2:6][CH:7]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:2]2[CH3:1])[O:17]1
Reactant: CC1C(=O)CCCC1S(=O)(=O)c1ccccc1
Reactant: OCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1C(S(=O)(=O)c2ccccc2)CCCC12OCCO2
Yield: 95 %

Procedure:
To a solution obtained by dissolving 1.4 g of 2-methyl-3-(phenylsulfonyl)-cyclohexan-1-one in 20 ml of benzene, were added 0.41 ml of 1,2-ethanediol and 0.1 g of anhydrous paratoluenesulfonic acid. The resulting mixture was heated under reflux for 4 hours. After the reaction, a 2M aqueous sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl ether, whereby 1,1-(ethylenedioxy)-2-methyl-3-(phenylsulfonyl)-cyclohexane was obtained in the form of white crystals. Yield: 95%