Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[O:19]1[C:23](B(O)O)=[CH:22][C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]1=2>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:20]2[O:19][C:23]3=[CH:22][CH:21]=[CH:27][C:28]3=[CH:29][CH:30]=2)[C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1cc2ccccc2o1
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3cccc-3o2)c1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and benzo[b]furan-2-boronic acid according to the general procedure B. Obtained as an orange solid (711 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:34][CH2:33][C:28]3([O:32][CH2:31][CH2:30][O:29]3)[CH2:27][CH2:26]2)[CH2:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[H][H]>C1(C)C=CC=CC=1.C(O)(C)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:34][CH2:33][C:28]3([O:29][CH2:30][CH2:31][O:32]3)[CH2:27][CH2:26]2)[CH2:21][CH2:20]1
Reactant: [H][H]
Reactant: CCCCCC1CCC(c2ccc(C3=CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1

Procedure:
The compound (4) was dissolved in a mixed solvent of toluene (150 ml) and isopropyl alcohol (100 ml), and palladium on carbon catalyst (NX type of 5% Pd/C; 50% wet; made by N. E. Chemcat; hereinafter referred to as Pd/C) (3.06 g) and potassium carbonate (0.52 g) were added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from heptane and dried, giving 26.35 g of 8-{4-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-cyclohexyl}-1,4-dioxa-spiro[4,5]decane (5). The yield based on the compound (4) was 44.6%.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[C:6](=[O:16])[N:5]([CH3:17])[C:4]=2[N:3]=1.I[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:19][CH3:20])[C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[C:6](=[O:16])[N:5]([CH3:17])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2[nH]c(Br)nc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(Br)nc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 50 °C
Yield: 91.5 %

Procedure:
To a solution of 8-bromo-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.4 g, 1.32 mmol, product of intermediate 16 step 2) in DMF (10 mL) was added iodoethane (0.25 g, 1.58 mmol) and potassium carbonate (0.27 g, 1.98 mmol). The reaction was heated at 50° C. for 2 h. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give 8-bromo-7-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.4 g, 91.7% yield) as white solid. LCMS retention time 1.674 min; LCMS MH+ 331.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[C:4]([O:11]C)[CH:3]=1.Br>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: COc1cc(Cl)cc2c1CCC2
Agent: Br
Solvent: CCOC(C)=O
Product: Oc1cc(Cl)cc2c1CCC2
Temperature: 50 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
To 6-chloro-4-methoxyindane (12.0 g, 0.072 mol) was added hydrogen bromide (30 wt. % in acetic acid, 325 mL) and the reaction mixture was stirred at 50° C. for 24 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (750 mL), washed with water (3×500 mL), saturated aqueous sodium bicarbonate (2×500 m/L), saturated aqueous sodium chloride (500 mL), dried (sodium sulfate) and the solvent was removed in vacuo to provide a brown oil. Purification by flash column chromatography (silica, dichloromethane) provided 10.5 g (80%) of 6-chloroindan-4-ol as a pale yellow solid. mp 56-59° C.; Anal. calcd. for C9H9ClO.0.2H2O: C, 62.77; H, 5.50. Found: C, 62.75; H, 5.26.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].O1CCCC1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[CH2:17]([CH:4]([C:5]#[N:6])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CCCCCCCCBr
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC(C#N)c1ccc(Cl)cc1Cl
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.13 moles as a 50% dispersion in mineral oil) is washed with 100 ml. of dry n-hexane to remove the mineral oil, then blanketed with dry nitrogen and suspended in 250 ml. of freshly distilled tetrahydrofuran. To this sodium hydride suspension is added dropwise at room temperature, a solution of 2,4-dichlorobenzyl cyanide (25 g., 0.13 mole) dissolved in 100 ml. of tetrahydrofuran. When the addition is completed the temperature is maintained at 30° C. for an additional 0.5 hours. A solution of n-octylbromide (27 g., 0.14 mole) is then added dropwise and the resultant reaction mixture is stirred at 40° C. overnight under nitrogen. The reaction mixture is poured into 1 liter of water and extracted with (3×200 ml.) of ether. The combined ether extracts are washed, with water, dilute hydrochloric acid, saturated sodium, bicarbonate solution saturated sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated to give 39.8 g. (100%) of product.
Reaction SMILES: Br[C:2]1[O:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:2]2[O:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Sc2ccc(C=O)o2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 91.5 %

Procedure:
To a solution of 2-bromo-5-furaldehyde (20.0 g, 114.29 mmol) in acetone (200 mL) was added 4-methoxybenzenethiol (15.5 mL, 125.75 mmol) and potassium carbonate (20 g). The reaction mixture was stirred at room temperature for 19 hours, and then filtered and concentrated on a rotary evaporator. The solid obtained was recrystallized from hexanes (300 mL) and ethyl acetate (50 mL) to give yellowish crystals (24.50 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH:9]([CH2:10][C:11](=[O:15])[NH:12][N:13]=3)[CH2:8][CH2:7][C:6]=2[CH:16]=1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([N:13]1[CH:14]2[CH:9]([CH2:8][CH2:7][C:6]3[CH:16]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=32)[CH2:10][C:11](=[O:15])[NH:12]1)[CH2:18][CH2:19][CH3:20]
Reactant: Nc1ccc2c(c1)CCC1CC(=O)NN=C21
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCN1NC(=O)CC2CCc3cc(N)ccc3C21

Procedure:
A solution of dl-8-amino-4,4a,5,6-tetrahydro-2H-benzo(h)-cinnolin-3-one (3 g) and n-butyl-bromide (5.7 g) in acetone (75 ml) is heated at reflux temperature in the presence of fine powdered potassium carbonate (5 g). The mixture is filtered, the acetone is evaporated and the residue is partitioned between water and ethyl acetate. The usual work-up affords a crude compound (3.9 g) which is crystallized from methanol to yield dl-1-n-butyl-8-amino-4,4a,5,6-tetrahydro-2H-benzo(h)-cinnolin-3-one m.p. 141°-142° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[CH3:25][SH:26].C[O-].[Na+]>CO>[CH3:25][S:26][CH2:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1
Reactant: CS
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CSCc1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
2-Chloromethyl-1-phenylmethyl-1H-imidazo-[4,5-c]quinolin-4-amine hydrochloride (Example 28, prepared from 2.11 g of the alcohol) was added to a solution of methanethiol (1.33 g; 0.028 mol) and sodium methoxide (1.5 g; 0.028 mol) in methanol. The solid dissolved upon addition and a cream colored solid precipitated during addition. After stirring at room temperature for several hours the mixture was diluted with water. The solid was filtered from the mixture, washed with water, and dried. A crude yield of 2.3 g was obtained. The product was purified by silica gel flash chromatography (10% methanol in ethyl acetate eluent) and recrystallized from methanol/dichloromethane to give a cream colored solid, m.p. 217-219° C. Analysis: Calculated: C, 68.2; H, 5.4; N, 16.8. Found: C, 67.5; H, 5.3; N, 16.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)[CH:7]=1.[OH-].[Li+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(Sc2cc(Cl)ccc2OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(Cl)cc1Sc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from step (i) (0.24 g), lithium hydroxide (0.036 g) in methanol (30 ml) and water (5 ml) was stirred at RT overnight then acidified with 2M hydrochloric acid. The mixture was extracted with ethylacetate, the organics dried and evaporated under reduced pressure, yield 0.23 g
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([C:23]([F:26])([F:25])[F:24])[CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.FC(F)(F)C1CCC(CNC2C=CC(F)=C(F)C=2)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:34][C:29]1[CH:28]=[C:27]([N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([C:23]([F:25])([F:26])[F:24])[CH2:19][CH2:18]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:35])=[O:3])=[CH:8][N:9]=2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCC(C(F)(F)F)CC2)c2ccc(F)c(F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1ccc(NCC2CCC(C(F)(F)F)CC2)cc1F
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCC(C(F)(F)F)CC2)c2ccc(F)c(F)c2)s1

Procedure:
The title compound was prepared via {2-[3-(3,4-difluoro-phenyl)-3-(4-trifluoromethyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 4-trifluoromethyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10]OC)=[CH:5][C:4]=1[CH3:13].[ClH:14].[NH:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[ClH:14].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[N:16][NH:15][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:5][C:4]=1[CH3:13]
Reactant: COC=Cc1ccc(OC)c(C)c1
Reactant: NNc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CC=NNc2ccncc2)cc1C
Yield: 39.2 %

Procedure:
To a solution of 1-methoxy-2-methyl-4-(2-methoxyvinyl)benzene (17 g) and 4-hydrazinopyridine hydrochloride (15.4 g) in ethanol (300 ml), p-toluenesulfonic acid (2.7 g) was added, with stirring. The reaction mixture was stirred under reflux for 2 hrs, filtered, and the filtrate was concentrated in vacuo. The residue was recrystallized from methanol to yield 10.9 g (39%) of product, mp 224-226° C.
Reaction SMILES: [C:1]([NH:6][NH:7][C:8]([C:10]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:11]=1)=O)(=[O:5])[CH2:2][CH2:3][CH3:4].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:11]=[C:10]([C:8]3[O:5][C:1]([CH2:2][CH2:3][CH3:4])=[N:6][N:7]=3)[C:14]=2[CH3:15])=[CH:17][CH:18]=1
Reactant: CCCC(=O)NNC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CCCc1nnc(-c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)o1
Yield: 61.3 %

Procedure:
N-butanoyl-N′-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl]-hydrazine (0.35 g, 0.75 mmol) obtained in Step 1 was added to a microwave reactor containing Burgess reagent (0.45 g, 1.88 mmol) in THF (2 mL). The capped reactor was placed in a microwave reactor and the mixture was irradiated at 140° C. for 15 min. The reaction product was purified by preparative HPLC to provide the title compound (0.21 g, 0.46 mmol, 61%) as yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[CH2:7]([NH:9][C:10](=[S:13])[NH:11][NH2:12])[CH3:8].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1.N(C(=S)N)N.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH2:7]([NH:9][C:10]([NH:11][NH:12][C:4](=[O:6])[CH2:3][O:2][CH3:1])=[S:13])[CH3:8]
Reactant: COCC(=O)O
Reactant: CCNC(=S)NN
Agent: CC(C)N=C=NC(C)C
Agent: NNC(N)=S
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=S)NNC(=O)COC
Reaction time: 19 h
Yield: 42.6 %

Procedure:
Methoxyacetic acid 360 mg, 3.99 mmol), 4-ethyl-3-thiosemicarbazide (581 mg, 4.87 mmol), diisopropylcarbodiimide (615 mg, 4.87 mmol) and hydroxybenzotriazole (69.6 mg, 0.51 mmol) were mixed in dimethylformamide (10 ml) and stirred under argon at ambient temperatures for 19 h. After evaporation to dryness the crude was used directly in the next step. MS (ESI) m/z 192 (M+1). Step 2: 4-Ethyl-5-methoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione: N-Ethyl-2-(methoxyacetyl(hydrazinecarbothioamide (760 mg crude, 4 mmol) and sodium bicarbonate (560 mg, 6.6 mmol) were suspended in water (15 ml) and refluxed for 5 h. After cooling and filtration the filtrate was acidified with concentrated hydrochloric acid, followed by extraction with ethyl acetate. After evaporation to dryness the crude was recrystallized in ethyl acetate/heptane. Filtration and recrystallization of the mother liquor gave a combined yield of 325 mg (47%) of the title compound. 1H NMR (CDCl3), δ (ppm): 4.47 (s, 2H), 4.13 (q, 2H), 3.37 (s, 3H), 1.38 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]2[NH:7][C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH:18](=O)[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:18]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]=2[NH:7][C:8](=[O:12])[CH2:9]1)[CH3:19]
Reactant: CC=O
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CC(=O)Nc2cc([N+](=O)[O-])c(OC)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of 7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (400 mg, 1.69 mmol) in methanol (100 mL) was added acetaldehyde (2.0 mL, 30 mmol) followed by acetic acid (0.29 mL, 5.0 mmol). The mixture was stirred for 20 minutes at room temperature whereupon sodium triacetoxyborohydride (1.10 g, 5.0 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (0-5% MeOH-EtOAc) gave 4-ethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (330 mg, 72%) as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.60 (s, 1H), 7.35 (s, 1H), 3.91 (s, 3H), 3.86 (s, 2H), 3.35 (s, 2H), 2.55 (q, J=6 Hz, 2H), 1.06 (t, J=6 Hz, 3H); MS (m/e) 266 (M+1); mp 168° C. (dec.).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)O1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]([C:32]2([C:35]3[CH:45]=[CH:44][C:38]4[O:39][C:40]([F:43])([F:42])[O:41][C:37]=4[CH:36]=3)[CH2:34][CH2:33]2)=[O:31])[CH:26]=[CH:25][C:24]=1[CH3:46].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.COCCOC>[F:43][C:40]1([F:42])[O:39][C:38]2[CH:44]=[CH:45][C:35]([C:32]3([C:30]([NH:29][C:27]4[CH:26]=[CH:25][C:24]([CH3:46])=[C:23]([C:9]5[CH:10]=[CH:11][C:12]([CH:15]6[CH2:16][CH2:17][C:18](=[O:20])[NH:19]6)=[CH:13][CH:14]=5)[N:28]=4)=[O:31])[CH2:34][CH2:33]3)=[CH:36][C:37]=2[O:41]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC1(C)OB(c2ccc(C3CCC(=O)N3)cc2)OC1(C)C
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: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C2CCC(=O)N2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (43 mg, 0.15 mmol), N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (37 mg, 0.10 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol) were placed a reaction tube. DME (1 mL) and saturated aqueous Na2CO3 (100 μL) were added and the reaction vial was stirred under N2 atmosphere at 80° C. overnight. The mixture was filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(4-(5-oxopyrrolidin-2-yl)phenyl)pyridin-2-yl)cyclopropanecarboxamide ESI-MS m/z calc. 491.2, found 492.3 (M+1)+. Retention time 1.75 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.12 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.44-7.34 (m, 6H), 4.71 (t, J=7.1 Hz, 1H), 2.50-2.44 (m, 1H), 2.27-2.23 (m, 5H), 1.81-1.72 (m, 1H), 1.53-1.50 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1C=CC=CC=1.[S:13](=[O:16])(=[O:15])=[O:14]>S(=O)(=O)(O)O>[C:3]1([S:13]([OH:16])(=[O:15])=[O:14])[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)=O
Reactant: CCCCCC
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: O=S(=O)(O)c1ccccc1

Procedure:
A fifty-fifty (50/50) hexane mixture by volume of polypropyl benzene alkylates was charged to a continuous sulfonation unit. 20% sulfur trioxide (SO3) by weight in sulfuric acid (H2SO4) was charged to the unit. Spent sulfuric acid (H2SO4) was continuously removed in a two phase non-aqueous system leaving a polypropenyl benzene sulfonic acid product containing 7.4% by weight residual sulfuric acid (H2SO4). At this stage, water was added to dilute the residual sulfuric acid (H2SO4) to 85% by weight, including the sulfuric acid (H2SO4) generated from unused sulfur trioxide (SO3). The aqueous phase was separated from the resultant two phase aqueous-organic system, leaving the organic phase containing 0.98% by weight sulfuric acid (H2SO4). Hexane was added to the organic phase followed by addition of Calcium Carbonate (CaCO3). The resulting mixture was treated with SX-5W oil to reduce the viscosity of the sulfonic acid and also make a 30% by weight active product sulfonate. The product mixture was heated at 215° F. to strip the hexane. The hexane-stripped product was filtered to yield a sulfonic acid and oil product mixture containing less than 0.4%* by weight sulfuric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][N:14]([CH3:25])[C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:9]=1[CH2:11][CH2:12][CH2:13][N:14]([CH3:25])[C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(CCCC(=O)Nc1ccccc1N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(CCCc1nc2ccccc2[nH]1)C(=O)OCc1ccccc1
Yield: 57.7 %

Procedure:
20.1 g (59 mmol) of benzyl [3-[(2-aminophenyl)carbamoyl]propyl]methylcarbamate are dissolved in 450 ml of toluene and treated with 7 g (37 mmol) of p-toluenesulphonic acid. The reaction mixture is thereafter heated to reflux for 2 hours, whereby the water formed is removed from the reaction mixture by means of a water separator. After evaporation and dissolution of the residue in ethyl acetate the solution is washed twice with saturated aqueous sodium bicarbonate solution and twice with saturated aqueous soiium chloride solution. The organic phase is dried over magnesium sulphate and evaporated. Chromatography of the crude product on silica gel with ethyl acetate as the elution agent yields 11 g (58%) of benzyl [3-(2-benzimidazolyl)propyl]methylcarbamate, m.p. 83°-86°.
Reaction SMILES: [H-].[Na+].[I-].[Na+].[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:17]=1)=[N:13][C:14](=[S:16])[N:15]=2)([O-:7])=[O:6].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])=[O:26]>CN(C)C=O.O>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[NH:27][C:25](=[O:26])[N:24]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:16][C:14]1[NH:13][C:12]2[CH:17]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][C:11]=2[N:15]=1
Reactant: CCCCCCCN(CCCCCBr)C(=O)Nc1ccc(F)cc1F
Reactant: O=[N+]([O-])c1ccc2c(c1)=NC(=S)N=2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCCCCSc1nc2ccc([N+](=O)[O-])cc2[nH]1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 337 %

Procedure:
Part E. To a suspension of sodium hydride (0.04 g, 60% mineral oil dispersion, 0.001 mol; washed free of mineral oil with hexane) and sodium iodide (0.15 g; 0.0011 mol) in N,N-dimethylformamide (10 mL) under a nitrogen atmosphere, cooled to 0°, a solution of 6-nitrobenzimidazol-2-thione (0.975 g; 0.005 mol) in N,N-dimethylformamide (5 mL) was added slowly. The reaction mixture was stirred for 30 minutes and then a solution of N-(5-bromopentyl)-N'-(2,4-difluorophenyl)-N-heptylurea (0.42 g, 0.001 mol) in N,N-dimethylformamide (5 mL) was added. The reaction mixture was stirred for 1 hour and then allowed to warm to ambient temperature and stirred an additional 24 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated to give a viscous oil. The product was purified by flash chromatography on silica gel eluting with hexane:ethyl acetate (75:25::v:v) to give the title compound (1.2 g, 0.00337 mol) as a solid, mp 120°-122°. 1H NMR (DMSO-d6) δ13.25 (bs,1H), 8.27 (bs,1H), 8.05 (d,1H,J=7.6 Hz), 7.91 (s,1H), 7.57 (d,1H,J=7.6 Hz), 7.4-7.3 (m,1H), 7.25-7.12 (m,1H), 7.0-6.8 (m,1H), 3.37-3.16 (m,6H), 1.85-1.72 (m,2H), 1.6-1.35 (m,6H), 1.27-1.1 (m,8H), 0.83 (t,3H,J=6.8 Hz).