Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13](=[S:15])[NH2:14])[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)#[N:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O>CC(C)=O>[CH3:12][C:11]1[C:10]([C:13]2[S:15][CH:31]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:14]=2)=[CH:9][N:6]2[C:5]=1[C:4]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=1)=[C:3]([C:1]#[N:2])[CH:8]=[N:7]2
Reactant: Cc1c(C(N)=S)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)=O
Product: Cc1c(-c2nc(-c3ccccc3)cs2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 70 °C
Yield: 80.6 %

Procedure:
A mixture of 423A (15 mg, 0.037 mmol) and 2-bromoacetophenone (7.3 mg, 0.037 mmol) in acetone (3 ml) was heated at 70° C. for 1 h. Cooled to rt, hexanes (1 ml) was added, then the resulting mixture was cooled to −50° C., filtered, the solid was washed with hexanes to give the hydrobromide salt of 423 (14.9 mg, 69%) as a yellow powder. It has a retention time of 8.16 min (standard LC1 method, 8 min run). LCMS Found: (M+H)+=500.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:4]=1[CH:21]=[N:22][OH:23].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[C:25]#[CH:26].[O-]Cl.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:4]=1[C:21]1[CH:26]=[C:25]([C:24]([O:28][CH2:29][CH3:30])=[O:27])[O:23][N:22]=1
Reactant: COc1cc(OC)c(C=NO)c(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: C#CC(=O)OCC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2Oc2ccc([N+](=O)[O-])cc2)no1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirred solution of 1-[2,4-dimethoxy-6-(4-nitrophenoxy)phenyl]-N-hydroxymethanimine (2.06 g, 6.7 mmol) and ethyl propiolate (3.28 mL, 32.4 mmol, 5 eq.) in DCM was slowly added drop wise 15% NaOCl solution (65 mL) at 0° C. After stirring overnight, the organic phase was separated and the aqueous was extracted twice with DCM. The organic phases were pooled and washed with 1 M Na2SO3 solution, then with brine and dried over Na2SO4. The solvent was removed and the residue was carefully chromatographed on silica gel eluting with hexane/ethyl acetate 8/2 to provide the title compound (1.6 g, 57% yield)
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[N:12]=[CH:11][C:10]=1[C:23]#[N:24])[C:3]([O:5]CC)=[O:4].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:23]([C:10]1[CH:11]=[N:12][N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[C:9]=1[CH:8]=[CH:2][C:3]([OH:5])=[O:4])#[N:24]
Reactant: CCOC(=O)C(Cl)Cc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1C=CC(=O)O
Yield: 68.1 %

Procedure:
A stirred slurry of 0.35 gram (0.0009 mole) of ethyl 2-chloro-3-[4-cyano-1-(2,3,4-trichlorophenyl)-1H-pyrazol-5-yl]propionate and 0.24 gram (0.002 mole) of potassium carbonate in 35 mL of 50% aqueous ethanol was heated at reflux for one hour. The reaction mixture was then cooled and concentrated under reduced pressure, leaving a residue. The residue was dissolved in water, and the solution was washed once with methylene chloride. The aqueous layer was stirred and acidified by the dropwise addition of concentrated hydrochloric acid. Upon acidification, the mixture was stirred for one hour, and the resultant solid was collected by filtration. The solid was dried, yielding 0.21 gram of 3-[4-cyano-1-(2,3,4-trichlorophenyl)-1H-pyrazol-5-yl]acrylic acid; m.p. 215°-219° C. A small sample was recrystallized from ethanol and water to raise the m.p. to 226.5°-228.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1>C1COCC1>[CH2:1]([CH:9]1[CH2:10][CH2:11][CH2:12][C:7](=[O:13])[CH2:8]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]Cl
Reactant: O=C1C=CCCC1
Solvent: C1CCOC1
Product: CCCCC1CCCC(=O)C1
Temperature: -78 °C
Yield: 94 %

Procedure:
A THF (5 mL) suspension of CuBr.Me2S (26.3 mg, 0.128 mmol) was treated with 1.0 equiv of n-BuLi at -78° C. under an argon atmosphere. The mixture was allowed to warm up slightly with the formation of a bright yellow solid. The mixture was again cooled to -78° C. and treated with Li(CHIRAMT) formed from compound 4 (85.8 mg, 0.261 mmol) and n-BuLi (1.0 equiv). The yellow slurry was stirred with gradual warming until a homogeneous burgundy solution was obtained. In the case of R--Me, a homogeneous mixture was not obtained even after prolonged stirring at room temperature, and it was evident that unreacted (CuMe)n was still present. The solution was cooled to -78° C. and THF (8 mL each) solutions of n-BuMgCl (25.0 equiv) and cyclohexenone (0.3068 g, 3.19 mmol) were added dropwise and simultaneously over a 5 min period. The resulting reaction mixture was stirred for an additional 10 min at -78° C., quenched with saturated aqueous NH4Cl solution (7 mL), and worked up as described in the previous section. Pure 3-butylcyclohexanone (0.4617 g, 94%) was obtained as checked by glc.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].[CH:14]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:21]([NH:20][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:22])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: O=C=NC1CCCCC1
Solvent: CCO
Product: N#CCc1c[nH]c2ccc(NC(=O)NC3CCCCC3)cc12
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 7.0 g (0.041 mole) of 5-aminoindole-3-acetonitrile in 100 ml of abs ethanol, at 0° under nitrogen atmosphere, was added 5.23 ml (0.041 mole) of cyclohexylisocyanate dropwise. After stirring at 0° for one hour the product was filtered and recrystallized from ethanol to give 6.78 g (56% yield) of desired product: m.p. 233°-234°; i.r. (Nujol) 3300, 3275, 2245 and 1622 cm-1.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13](O)=[O:14])=[C:10]([F:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>ClCCl>[F:1][C:2]1[C:11]([CH2:12][C:13]([Cl:20])=[O:14])=[C:10]([F:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)Cc1c(F)cc2ncccc2c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1c(F)cc2ncccc2c1F
Temperature: 0 °C

Procedure:
(5,7-Difluoro-quinolin-6-yl)-acetic acid (1 g, 4.48 mmol) was added to an oven-dried round-bottom flask and suspended in dichloromethane (18 ml) The suspension was maintained under nitrogen atmosphere and cooled to 0° C. Next, the oxalyl chloride (470 uL, 5.38 mmol) was added slowly, followed by a catalytic amount of dimethylformamide. The solution was allowed to warm to room temperature over 2 hours. The solution was then concentrated in vacuo and dried via azeotropic distillation with toluene to afford the title compound. ES-MS m/z: 238 (M+H+) of methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:36]1([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:44][CH2:43][C:42]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (7.87 mmol) and THF/H2O (3/1, 80 mL) were combined. 4-Phenyl-piperidine-4-carboxylic acid amide hydrochloride (2.8 g, 11.64 mmol, 1.5 eq.) and potassium carbonate (3.3 g, 23.88 mmol, 3 eq.) were added. The mixture was heated to reflux for 72 h. The mixture was concentrated in vacuo. The aqueous residue was extracted with dichloromethane. The organic phase was extracted with H2O (50 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by chromatography on silica gel (350 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane to give the title compound: Rf =0.12 (silica gel, 6% methanol in dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:19][CH2:18][C@H:17]3[CH2:20][OH:21])[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([O:25]CC)=[O:24])=[CH:7]1.[OH-].[Li+].Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:19][CH2:18][C@H:17]3[CH2:20][OH:21])[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([OH:25])=[O:24])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CC[C@H]3CO)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccc(N4CC[C@H]4CO)nc32)c(OC)c1

Procedure:
A mixture of EXAMPLE 4A (1 g) and 0.1M lithium hydroxide (40 mL) in ethanol (50 mL) was stirred for 24 hours, adjusted to pH 4 with 1M hydrochloric acid, treated with water, and filtered.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[N:13]([CH2:19][CH2:20][OH:21])[C:12]([CH2:23][CH3:24])([CH3:22])[CH:11]1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[N:13]([CH2:19][CH2:20][O:21][C:33](=[O:35])[CH3:34])[C:12]([CH2:23][CH3:24])([CH3:22])[CH:11]1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC1(C)CC(OC(=O)c2ccccc2)C(C)C(C)(CC)N1CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC1(C)CC(OC(=O)c2ccccc2)C(C)C(C)(CC)N1CCOC(C)=O
Yield: 42.8 %

Procedure:
To a solution of 2.5 g of 2,6-diethyl-1-(2-hydroxyethyl)-2,3,6-trimethyl-4-piperidyl benzoate (Compound 45 - prepared following the procedure described in Preparation 9) in 50 ml of dimethylformamide were added 2.0 g of triethylamine and 1 g of acetic anhydride; the mixture was then heated at 80°-90° C. for 5 hours. When the reaction was complete, the reaction mixture was concentrated and 50 ml of benzene were added. The mixture was then washed with, in turn, an aqueous solution of sodium carbonate and water, and was dried over anhydrous sodium sulphate. After removing the solvent, the residue was subjected to distillation under reduced pressure, giving 1.2 g of Compound 50 as a colourless oil (bp 195° C./0.0008 mmHg).
Reaction SMILES: C[O-].[Na+].[S:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5]1.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.O>CN(C)C=O>[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1/[CH:20]=[C:5]1\[S:4][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]\1=[O:14]
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1CSc2ccccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2S/C1=C\c1ccc[nH]1
Temperature: 120 °C

Procedure:
Sodium methoxide (0.28 g, 5.2 mmol) was added to a solution of 2H-1,4-benzothiazin-3(4H)-one (0.60 g, 4 mmol) and pyrrol-2-carboxaldehyde (0.49 g, 5.2 mmol) in dry N,N-dimethylformamide (3.5 ml) (hereinafter “DMF”). The mixture was heated at 120° C. for 6.5 h, allowed to cool and poured into water (60 ml). The precipitate was collected by filtration and washed with water. The precipitate was dissolved in ethyl acetate and the insoluble black residue was filtered out. The filtrate was concentrated, then chromatographed on a silica column using a gradient of 100% dichloromethane to (100:1) dichloromethane:ethanol as the mobile phase. The first eluted product was the (E)-isomer.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C=O)C>[Cl:19][CH2:18][CH2:17][CH2:16][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:12]
Reactant: ClCCCBr
Reactant: Cc1ccc2c(c1)CCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)CCC(=O)N2CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A reaction flask was charged with 6-methyl-3,4-dihydro-1H-quinolin-2-one (107LH05) (0.300 g, 1.26 mmol) in dry DMF (5 mL) under Argon. NaH (60% in oil, 0.055 g, 1.38 mmol) was added and the mixture was stirred at rt for 1 h. Then 1-bromo-3-chloropropane (0.198 g, 1.24 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash CC (SiO2; DCM) to give the crude title compound (107LH14) (0.257 g).
Reaction SMILES: [Na].[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([NH:26][C:25]3[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=3)=[O:20])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1
Reactant: O=C(O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Reactant: Nc1ccc(F)cc1
Agent: [Na]
Product: O=C(Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1)Nc1ccc(F)cc1

Procedure:
The product is prepared by following the procedure described in step 3b of example 1b, but using 670 mg of the sodium salt of [4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid and 762 mg of 4-fluoroaniline. 300 mg of 2-[4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(4-fluorophenyl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5]2.C([Li])CCC.[C:24]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29])#[N:25]>O1CCCC1>[OH:29][CH:28]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5]2)[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[C:24]#[N:25]
Reactant: N#Cc1ccccc1C=O
Reactant: C[Si](C)(C)CCOCn1ccc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2cc(C(O)c3ccccc3C#N)ccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
To a solution of 5-bromo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indole (0.96 g, 2.9 mmol) in tetrahydrofuran (30 mL) cooled to −78° C. was added n-butyllithium (1.6 M in hexanes, 2.2 mL, 3.5 mmol). After stirring for 15 min at −78° C., 2-cyanobenzaldehyde (0.58 g, 4.4 mmol in 2 mL tetrahydrofuran) was quickly added. After stirring for 30 min at −78° C. and allowing to warm to room temperature, the reaction mixture was quenched with an excess of saturated aqueous ammonium chloride solution, then diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted (2×100 mL ethyl acetate). The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 1:1 hexanes/ethyl acetate) gave 0.68 g (61%) of 2-{hydroxy[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indol-5-yl]methyl}benzonitrile. 1H NMR (400 MHz, CDCl3): 7.99 (d, 1H), 7.60 (d, 1H), 7.57 (m, 2H), 7.53 (d, 1H), 7.27 (m, 2H), 7.10 (dd, 1H), 6.56 (m, 2H), 5.52 (s, 2H), 3.50 (m, 2H), 0.51 (m, 2H), 0.00 (s, 9H); MS (EI) for C22H26N2O2Si: 379 (MH+).
Reaction SMILES: [O:1]([C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH:19]=[C:11]1[C:10](=[O:13])[CH2:9][N:8]([C:6]([O:1][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:7])[CH2:12]1)[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C

Procedure:
A solution of 1-(tert-butoxylcarbonyl)-3-pyrrolidone (4.10 g) and N,N-dimethylformamide dimethyl acetal (30.0 mL) was heated to 140° C. for 1 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in a minimum amount of dichloromethane and triturated with hexane to yield a yellow precipitate. LC-MS=241.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]Br.OS([O-])=O.[Na+]>C(O)(=O)C>[Br:11][C:6]1[C:2]([OH:1])=[C:3]([C:7]([O:9][CH3:10])=[O:8])[S:4][CH:5]=1
Reactant: BrBr
Reactant: COC(=O)c1sccc1O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1scc(Br)c1O
Reaction time: 16 h

Procedure:
To a solution of 31 g (0.2 mole) of methyl 3-hydroxy-2-thiophenecarboxylate in 400 milliliters (mL) of glacial acetic acid was added 31.3 g (0.2 mole) of Br2 over 45 minutes (min). After 16 hours (hr), another 31.3 g of Br2 was added over 6 hr and the reaction was stirred another 18 hr. The reaction mixture was poured into aqueous NaHSO3 and extracted with ether. The organic phase was separated, washed with water (2×300 mL), dried over MgSO4, filtered and concentrated to a viscous oil. This oil (47 g) was dissolved in 200 mL of methanol and after 48 hr at 15° C., 36 g (77%) of light pink crystals were collected by filtration. mp 79-80° C. 1H NMR (300 MHz, CDCl3): δ 9.8 (br, 1H); 7.4 (s, 1H); 3.9 (s, 3H). Anal. Calc'd for C6H5BrO3S: C, 30.04; H, 2.23; S, 13.52. Found: C, 30.04; H, 1.92; S, 14.01.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[C:10]([NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[C:9]([CH3:20])=[CH:8][C:7]=1[CH3:21])(=[O:5])=[O:4].C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>O1CCCC1>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[C:10]([N:12]([C:29](=[O:32])[CH2:30][CH3:31])[S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])[C:9]([CH3:20])=[CH:8][C:7]=1[CH3:21])(=[O:5])=[O:4]
Reactant: CCC(=O)Cl
Reactant: CNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)N(c1cc(S(=O)(=O)NC)c(C)cc1C)S(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of N-methyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide (2 g) and triethylamine (0.7 g) in tetrahydrofuran (20 ml), propionyl chloride (0.45 g) was added, and the resultant mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated, admixed with 5% hydrochloric acid and extracted with chloroform. The extract was concentrated to give an oily substance, which was purified by silica gel chromatography. Recrystallization from a mixture of toluene and hexane gave 1.17 g of N-methyl-2,4-dimethyl-5-(N-propionyl-N-trifluoromethanesulfonylamino)benzenesulfonamide (Compound No. 16). M.P., 101°-103° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH2:15]([CH:17]1[O:22][C:21]2[CH:23]=[C:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([O:41]CCCC)=[O:40])[CH2:34]4)=[N:31][CH:32]=3)[CH:25]=[CH:26][C:20]=2[N:19]([C:46](=[O:54])[NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:18]1)[CH3:16]>C(Cl)Cl>[CH2:15]([CH:17]1[O:22][C:21]2[CH:23]=[C:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34]4)=[N:31][CH:32]=3)[CH:25]=[CH:26][C:20]=2[N:19]([C:46](=[O:54])[NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:18]1)[CH3:16]
Reactant: CCCCOC(=O)CC1CCN(c2ncc(-c3ccc4c(c3)OC(CC)CN4C(=O)Nc3ccccc3)cn2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1CN(C(=O)Nc2ccccc2)c2ccc(-c3cnc(N4CCC(CC(=O)O)C4)nc3)cc2O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
Trifluoroacetic acid (0.109 mL, 1.43 mmol) and triethylsilane (44 μL, 0.28 mmol) were successively added at room temperature to a solution of crude ted-butyl 2-(1-(5-(2-ethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidin-3-yl)acetate B-8 (59.0 mg, 0.11 mmol) in anhydrous methylene chloride (0.25 mL) under an atmosphere of argon. The reaction mixture was stirred at room temperature for 12 h, then concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2-(1-(5-(2-ethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidin-3-yl)acetic acid B-9 (22.3 mg, Yield=42% over 2 steps). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01 (t, J=Hz, 3H), 1.63-1.74 (m, 3H), 2.12-2.18 (m, 1H), 2.42 (d, J=7.25 Hz, 2H), 2.52-2.64 (m, 1H), 3.15 (dd, J=7.88, 10.88 Hz, 1H), 3.46 (dd, J=7.88, 12.60 Hz, 1H), 3.48 (t, J=7.56 Hz, 1H), 3.63-3.69 (m, 1H), 3.80 (dd, J=7.41, 11.35 Hz, 1H), 4.03 (br d, J=13.08 Hz, 1H), 4.16 (q, J=6.69 Hz, 1H), 7.00 (t, J=7.41 Hz, 1H), 7.15 (br d, J=8.67 Hz, 1H), 7.18 (s, 1H), 7.29 (t, J=7.41 Hz, 2H), 7.50 (d, J=8.36 Hz, 2H), 7.51 (d, J=8.83 Hz, 1H), 8.66 (s, 2H), 9.14 (s, 1H), 12.22 (br s, 1H); MS (ESI) [M+1]+ 488.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH2:17])[CH:11]=[C:10]([Br:18])[N:9]=1.C(N(CC)CC)C>O>[CH2:5]([O:4][C:2](=[O:3])[NH:17][C:12]1[CH:11]=[C:10]([Br:18])[N:9]=[C:8]([Br:7])[C:13]=1[N+:14]([O-:16])=[O:15])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of ethyl chloroformate (5.96 g) in anhydrous 2-methyl THF (50 ml) was added drop-wise to a solution of 2,6-dibromo-3-nitro-pyridin-4-ylamine (15.00 g) and triethylamine (10.1 g) in anhydrous 2-methyl THF (100 ml) at 0° C., keeping the addition rate such that the reaction temperature did not rise above 5° C. The reaction mixture was allowed to warm to room temperature then left to stir under nitrogen for 1 hour. A further portion of ethyl chloroformate (0.54 g) was added and the mixture was left to stir for a further 1 hour. Water (50 ml) was added and the layers separated. The aqueous layer was extracted with EtOAc (50 ml) and the combined organics were dried (MgSO4) and evaporated to a brown solid. This solid was pre-absorbed onto silica (˜19 g) then columned on Isco Companion on a silica column (330 g, Redisep), eluting with EtOAc:heptane. The gradient was kept isocractic at 10:90 for 1 column volume (CV), then increased linearly from 10:90 to 30:70 over 6 CVs. This provided the title compound (12.6 g) as a pale yellow foamy solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][OH:22].[OH-].[Na+].C(O)C>O>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([S:15][CH2:19][CH2:20][CH2:21][OH:22])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCSc1nc2ccc(Cc3ccccc3)cc2[nH]1
Yield: 65.4 %

Procedure:
12.02 g (50 mmoles) of 5-benzyl-benzimidazoline-2-thione, 4.72 ml of 3-chloro-1-propanol, 2.0 g (50 mmoles) of sodium hydroxide dissolved in water and ethanol are reacted as described in the above Example. The recovering of the product is carried out similarly. 9.76 g (65.4%) of title product are obtained. M.p.: 103°-105° C.