Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.C(OC(C)C([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]([CH3:22])[CH2:14][C:13]1([CH3:24])[CH3:23])=O)(=O)C.OS(O)(=O)=O.N>C(O)(=O)C.O>[NH2:12][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:16]=1[CH:15]([CH3:22])[CH2:14][C:13]2([CH3:23])[CH3:24]
Reactant: CC(=O)OC(C)C(=O)N1c2ccccc2C(C)CC1(C)C
Agent: CC(=O)[O-]
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC1CC(C)(C)c2cccc(N)c21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
The acetate compound prepared in B (ii) (55 g, GC purity 91%, 0.172 moles) was added over 45 minutes to 98% H2SO4 (50 ml) at 25°-60° C. (exotherm). After stirring for a further 30 minutes at 60° C., water (50 ml) containing acetic acid (10 ml) was cautiously added dropwise and the mixture heated at 100° C. for 3 hours. Petrol (60/80 b.p., 100 ml) was added and the mixture basified to pH 9 with 35% aqueous ammonia (150 ml). Separation of the organic layer, drying (MgSO4) and solvent flash gave the desired product (22.6 g, GC purity 92%, yield 69%). NMR analysis using chiral solvating agent [(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol] showed a 70/30 mixture of enantiomers in favour of the (-)-isomer.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8])([CH3:3])[CH3:2].O.C(O)(=O)C>C(O)C.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8]
Reactant: CNC(=O)c1cc([N+](=O)[O-])ccc1SC(C)C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CNC(=O)c1cc(N)ccc1SC(C)C
Temperature: 115 °C
Yield: 93 %

Procedure:
A suspension of 16B (1.2 g, 4.7 mmol) in a mixture of ethanol (30 mL), water (5 mL), and acetic acid (3.3 mL, 5.8 mmol) was heated by a 115° C. oil bath. Iron powder (1.80 g, 32.2 mmol) was added portionwise over 1 h. The reaction mixture was cooled to rt, filtered, and washed with ethyl acetate. Sodium bicarbonate solution was added until it was basic. The reaction mixture was extracted with ethyl acetate (3×) and the combined organics were washed with saturated sodium bicarbonate and brine, dried (MgSO4), and concentrated in vacuo to give 16C (0.98 g, 93%) as a beige solid. MS (ESI) m/z 225.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1.C(O[C:25]1(O[Si](C)(C)C)[CH2:27][CH2:26]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:25]1([N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]3[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=3[N+:19]([O-:21])=[O:20])[CH2:2]2)[CH2:27][CH2:26]1
Reactant: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NS(=O)(=O)c1ccc(NCC2CN(C3CC3)CCO2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 369B (0.633 g) and (1-ethoxycyclopropoxy)trimethylsilane (1.601 mL) in anhydrous methanol (15 mL) and acetic acid (1.717 mL) was refluxed for 30 minutes and allowed to cool to room temperature. Sodium cyanoborohydride (0.377 g) was then added and the mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated to dryness. The residue was mixed with 5% aqueous Na2CO3 solution (25 mL) and extracted with ethyl acetate. The crude product was purified on a silica gel column eluting with 5% to 10% methanol in dichloromethane to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][CH2:21][CH3:22])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][CH2:21][CH3:22])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: CCCc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1OC
Temperature: 140 °C
Yield: 24.8 %

Procedure:
To a solution of 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (200 mg, 622 μmol, prepared as described in example 31) in NMP (2.1 mL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (402 mg, 1.86 mmol) in 3 portions approximately every 12 h and heated to 140° C. in the periods between additions. After a total of 36 h, the mixture was cooled, diluted with ethyl acetate and brine, then the organic phase separated and washed with brine (3×). The organic phase was then concentrated in vacuo and the residue obtained was purified by chromatography (silica, 1 to 5% methanol in dichloromethane) to give tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-methoxy-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (77 mg, 154 μmol, 25%) as a light brown solid. MS (EI/CI) m/z: 502.2 [M+H].
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9]CC(N(OC)C)=O.C([N:19]([CH2:30][CH3:31])[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[CH3:28])C>>[ClH:27].[Cl:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]2[C:22]=1[CH:28]=[C:30]([CH2:31][CH2:9][N:5]1[CH2:6][CH2:7][CH2:8][C@@H:4]1[CH2:3][O:2][CH3:1])[NH:19][C:20]2=[O:29]
Reactant: CCN(CC)C(=O)c1cccc(Cl)c1C
Reactant: COC[C@H]1CCCN1CCC(=O)N(C)OC
Product: COC[C@H]1CCCN1CCc1cc2c(Cl)cccc2c(=O)[nH]1
Product: Cl
Yield: 43.4 %

Procedure:
In the same manner as in Example 20b and using (R)-3-(2-methoxymethylpyrrolidin-1-yl)-N-methoxy-N-methylpropanamide (3.2 g) and N,N-diethyl-3-chloro-2-methylbenzamide (3.2 g), (R)-5-chloro-3-[2-(2-methoxymethylpyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one hydrochloride (1.1 g) was obtained.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Reactant: Nc1nccs1
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(c3nccs3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)pyrimidineacetaldehyde, (uridinedialdehyde), (6.05 g) was dissolved in water (25 ml). To a solution was added 2-aminothiazole (2.50 g). The mixture was stirred at ambient temperature overnight to give a clear solution. The solution was subjected to column chromatography on HP-20 resine, which was eluted with water and then 50% aqueous acetone. The elution was condenced in vacuo and lyophilized to give white powder of 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-thiazolyl)morpholin-2-yl]uracil (8.09 g).
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[NH:5][CH2:4][CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[C@@H:26]1[CH2:28][O:27]1>CCO>[OH:27][C@H:26]([C:17]1[CH:18]=[CH:19][C:20]2[C:21](=[O:25])[O:22][CH2:23][C:24]=2[C:16]=1[CH3:15])[CH2:28][N:5]1[CH:6]2[CH:1]([CH2:7]2)[N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCNC2CC21
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(C(=O)OC(C)(C)C)C3CC32)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
In a microwave vial charged with stirring bar, tert-butyl (±)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (341 mg, 1.72 mmol) was dissolved in EtOH (20 mL). 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (654 mg, 3.44 mmol) was added. Then mixture was sealed and put on microwave reactor. It was heated up to 145° C. and was stir at 145° C. for 60 minutes. After cooling down to room temperature, solution was transferred to a round bottom flask and was concentrated on rotavapor to give crude product, which was purified by ISCO (80 gram silica gel column, eluted by 0-10% MeOH/DCM gradient). Removing solvent gave the title compound. LC/MS: (M+1)+=389.14;
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[OH:14][CH2:15][CH2:16][NH:17][CH:18]([CH3:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1.[BH4-].[Na+]>>[C:28]([CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([N:17]([CH2:16][CH2:15][OH:14])[CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=2)[CH3:32])=[CH:21][CH:22]=1)([O:30][CH3:31])=[O:29]
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)COc1ccc(CC(C)N(CCO)CC(O)c2csc(C(F)(F)F)n2)cc1
Reaction time: 3 h

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole and N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine. Before the reduction with sodium borohydride, the mixture is heated to boiling for 3 hours to complete the reaction. The base is then purified on a silica gel column using ethyl acetate as mobile phase.
Reaction SMILES: CO.[C:3]1([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:10][C:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][OH:19])[N:13]([CH:20]([CH3:22])[CH3:21])[CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1.C(OCC)(=O)C>[C:23]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][C:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH:18]=[O:19])[N:13]([CH:20]([CH3:22])[CH3:21])[CH:12]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)n1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)n1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1C=O
Reaction time: 5 h
Yield: 54.2 %

Procedure:
To a methanol solution (120 ml) of 1.600 g of 3-diphenylmethoxy-6-hydroxymethyl-1-isopropyl-4-pyridone is added 10.00 g of active manganese dioxide at room temperature, and the mixture is stirred for 5 hours, then at 50° C. for 1 hour. After insolubles are removed by filtration, the filtrate is condensed under reduced pressure and the residue is subjected to flash column chromatography on 100 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of benzene-ethyl acetate (1:2) to perform separation and purification. The title compound (0.862 g) is obtained as colorless foam.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].C(O)CCCCCCC.[OH-].[Na+:20]>CCCCCCC>[C:1]([O-:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].[Na+:20]
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCCCO
Solvent: CCCCCCC
Product: C=C(CC(=O)O)C(=O)[O-]
Reaction time: 8 h

Procedure:
Two hollow fiber modules (4×13, LiquiCell X40, Membrana) were assembled such that 3 continuous loops could be operated: (1) itaconic acid solution (2) solvent system (3) stripping solution. An itaconic acid solution (2 L, 60.0 g/L acid, pH 2.2) was circulated through the shell side of module 1. The ternary organic solvent system (20% TOA, 20% octanol, heptane) was circulated through the lumen of both modules. Lastly, aqueous sodium hydroxide (0.46 M) was circulated shell side of module 2. The volume ratios were 1:1:1. The three loops were run at 0.5 L/min. The simultaneous extraction and stripping were monitored for IA concentration and pH. In 7 hours 63% was recovered (5.4 g/L-hr) and the pH dropped to 4.7. The run was allowed to proceed overnight (25 hours total) resulting in an overall 78% recovery in the form of monosodium itaconate from the fermentation broth.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>CCOC(C)=O.O.C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: OC1CCCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(OC2CCCCCC2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Add 6-chloro-pyridin-3-ol (2 g, 15.4 mmol), cycloheptanol (1.93 g, 17 mmol), tri-n-butylphosphine (4.67 mL, 19.3 mmol), and ADDP (4.87 g, 19.3 mmol) to THF (60 mL) at 0° C. under a nitrogen atmosphere. Stir the mixture at 0° C. for 1 h and at room temperature for 12 h. Dilute with EtOAc (50 mL), add water (50 mL) and separate the layers. Extract the aqueous layer with EtOAc (4×30 mL). Wash the combined organic extracts with water (30 mL) and brine (20 mL). Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (2.36 g, 68%). MS (APCI+) m/z: 226 (M H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5]O.[H-].[Na+].CS([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O.[C:34]1(C)C=CC=CC=1>>[CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][CH2:34][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: CN(C)CC(O)CO
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCCC(O)CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A toluene (10 mL) solution of 3-(dimethylamino)-1,2-propanediol (98%, 1.00 g, 8.39 mmol, 1.0 equiv)) was carefully added dropwise to a toluene suspension (5 mL) of NaH (60%, 0.34 g, 8.39 mmol, 1.0 equiv) at 0° C. under argon and the resultant was stirred for 15 minutes. A toluene solution (5 mL) of linoleyl methanesulfonate (2.87 g, 8.39 mmol, 1.0 equiv) was added dropwise to the stirring mixture and the reaction was then stirred for 18 hours at 90° C. The mixture was then cooled to room temperature and quenched by the slow addition of ethanol (10 mL). The mixture was concentrated and the residue was taken up with deionized water (20 mL) and extracted three times with EtOAc (30 mL). The combined organic extracts were washed with deionized water (20 mL), dried (MgSO4), filtered, and concentrated. Chromatographic purification of the residue (0-5% MeOH in chloroform) provided 1-(dimethylamino)-4-((9Z,12Z)-octadeca-9,12-dienyloxy)butan-2-ol, a thick, clear oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[NH:7][C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:12])[F:13])[N:7]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[CH3:26])[C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)c2nc(C(F)F)[nH]c2c1
Reactant: Cc1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(Br)cc([N+](=O)[O-])cc21
Reaction time: 0.33 h
Yield: 106.5 %

Procedure:
To a 100 mL round bottomed flask containing DMF (17 mL) was added 4-bromo-2-(difluoromethyl)-6-nitro-1H-benzo[d]imidazole (2.3 g, 7.88 mmol), 1-(bromomethyl)-3-chloro-2-methylbenzene (2.4 g, 10.93 mmol) and potassium carbonate (2.3 g, 16.64 mmol). The resultant suspension was heated to 70° C. and after stirring for 20 minutes LC/MS indicated that almost all starting material had been consumed so the heat was turned off and the reaction was allowed to stir overnight at rt. The next day the mixture was diluted with 75 mL H2O and stirred for 10 minutes resulting in the precipitation of a light brown solid. The solid was isolated by filtration and was washed 3× with H2O and 3× with hexanes to provide 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-6-nitro-1H-benzo[d]imidazole (4.2 g, 8.39 mmol, 107% yield) as light brown solid. The NMR and LC/MS were consistent with desired product and the crude product will be used in subsequent reactions without further purification. LC/MS: MS (ES+) m/e 431.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J=2.02 Hz, 1H), 8.45 (d, J=2.02 Hz, 1H), 7.32-7.68 (m, 2H), 6.99-7.12 (m, 1H), 6.06 (d, J=7.58 Hz, 1H), 5.90 (s, 2H), 2.47 (s, 3H)
Reaction SMILES: [BrH:1].Br.CC(O)=O.C1(C)C=CC(S([N:16]2[CH2:29][CH2:28][N:27](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][CH2:25][N:24](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:23][C:22]3[N:50]=[C:18]([CH:19]=[CH:20][CH:21]=3)[CH2:17]2)(=O)=O)=CC=1>CC(O)=O>[BrH:1].[C:18]12[CH:19]=[CH:20][CH:21]=[C:22]([N:50]=1)[CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH:16][CH2:17]2
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)Cc3cccc(n3)CN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: c1cc2nc(c1)CNCCNCCNC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
A solution of HBr and AcOH was prepared by mixing 48% HBr and glacial ACOH in a 64:35 ratio. To 112 mL of the HBr/AcOH mixture was added 5.5 g (8.2 mmol) of 3,6,9-tris(p-tolylsulfonyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (prepared by the procedure of Example B) and the reaction mixture was heated at mild reflux with constant stirring for 72 hrs. The reaction mixture was then cooled to room temperature and concentrated to approximately 1/10 of the original volume. The remaining solution was stirred vigorously and 15-20 mL of diethyl ether was added. A off-white solid formed which was filtered, washed with diethyl ether, and dried in vacuo. The dry tetrahydrobromide salt was then dissolved in 10 mL of water, adjusted to pH 9.5 with NaOH (50% w/w) and continuously extracted with chloroform for 4 hrs. After drying over anhydrous sodium sulfate, the chloroform was evaporated to give a light-tan oil which gradually crystallized upon standing at room temperature to yield 1.2 g (71%) of the title product, mp 86°-88° C. and further characterized by:
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][N:4]=1.[C-:13]#[N:14].[K+]>C(O)C.O>[C:13]([CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][N:4]=1)#[N:14]
Reactant: [C-]#N
Reactant: ClCc1n[nH]c2ccc(Cl)cc12
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1n[nH]c2ccc(Cl)cc12
Temperature: 5 °C
Yield: 69.9 %

Procedure:
A solution of 3-chloromethyl-5-chloro-1H-indazole (4.5 g) in ethanol (50 ml) is dropwise added to a solution of potassium cyanide (17 g) in water (10 ml) while stirring at 5° C, and the resulting mixture is stirred at room temperature for 2 hours and at 50° C for 2 hours. The reaction mixture is cooled and the precipitated potassium chloride is removed by filtration. The filtrate is concentrated under reduced pressure, admixed with water and extracted with ether. The ether layer is washed with water, dried over anhydrous magnesium sulfate and concentrated to give 3-cyanomethyl-5-chloro-1H-indazole (3.0 g) as resinous material.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][S:6][CH3:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@@H:3]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4][CH2:5][S:6][CH3:7])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CSCC[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of (S)-tert-butyl 1-hydroxy-4-(methylthio)butan-2-ylcarbamate (1.0 g, 1.0 eq, Chem-Impex, Catalog #03206) in DCM at −25° C. was added triethylamine (2.5 eq), followed by methanesulfonyl chloride (2.0 eq). The mixture was stirred at −25° C. for 1 h and RT for 30 min, washed with 1 N HCl, sat. NaHCO3 and brine, dried and concentrated to give a residue, which was purified by flash chromatography column on silica gel using ethyl acetate and hexane (1:2) as eluent to give (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butyl methanesulfonate (1.1 g, 75%). 1H NMR (CDCl3, 300 MHz) d 4.25 (m, 2H, OCH2), 4.0 (br s, 1H, BocNHCH), 3.05 (s, 3H, SO2CH3), 2.55 (m, 2H, SCH2), 2.15 (s, 3H, SCH3), 1.85 (m, 2H, BocNHCHCH2CH2S), 1.45 (s, 9H, OC(CH3)3).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][N:24]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[CH:25]=[O:26]>>[OH:7][C:3]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[C:4]=1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:29]1[NH:30][C:31]2[C:36]([C:28]=1[CH2:27][N:24]([CH3:23])[CH:25]=[O:26])=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2
Reactant: Cc1ccc(C2(C)C(=O)CC2=O)cc1
Reactant: Cc1ccc2c(CN(C)C=O)c[nH]c2c1
Reactant: O=Cc1ccccc1
Product: Cc1ccc(C2(C)C(=O)C(C(c3ccccc3)c3[nH]c4cc(C)ccc4c3CN(C)C=O)=C2O)cc1

Procedure:
Using general procedure C, 2-methyl-2-p-tolyl-cyclobutane-1,3-dione (from Example 4.1) was reacted with benzaldehyde and N-methyl-N-(6-methyl-1H-indol-3-ylmethyl)-formamide to give the title compound as a red solid. MS: 476.6 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[I-].C[S+](C)(C)=O.O=C1C[CH:19]2[N:21]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH:16]([CH2:17][CH2:18]2)C1>O1CCCC1.C1(C)C=CC=CC=1.O>[O:4]1[CH2:1][C:2]21[CH2:5][CH:19]1[N:21]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH:16]([CH2:17][CH2:18]1)[CH2:3]2
Reactant: O=C1CC2CCC(C1)N2C(=O)OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)N1C2CCC1CC1(CO1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, a thermometer, and a condenser was charged tetrahydrofuran (163 mL), potassium tert-butoxide (6.6 g, 95% pure) and trimethylsulfoxonium iodide (13.0 g). The mixture was heated to reflux and stirred for 3 hours. A solution of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10.0 g) in tetrahydrofuran (37 mL) was added in one portion. The reaction mixture was refluxed for another 2 hours. The mixture was cooled to room temperature and diluted with toluene (100 mL) and water. The water layer was separated and extracted with toluene (2×50 mL). The combined organic layers were washed with water (3×40 mL) and concentrated under vacuum to provide the title compound.