Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(=O)C.Br[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1.[CH:24]([C:26]1[CH:35]=[CH:34][C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=1)=[CH2:25].C1(CNCC2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C>[O:30]1[C:29]2[CH:34]=[CH:35][C:26](/[CH:24]=[CH:25]/[C:8]3[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=3)=[CH:27][C:28]=2[O:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=Cc1ccc2c(c1)OCCO2
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc3c(c2)OCCO3)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
To N,N-dimethylacetamide 24 mL solution of tert-butyl 4-bromo-2-nitrobenzoate 3.0 g were added 2,3-dihydro-6-vinylbenzo[1,4]dioxin 2.4 g, N,N-dicyclohexylmethylamine 4.0 mL and palladium acetate 0.11 g at room temperature, and it was stirred under nitrogen atmosphere at 120° C. for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=10:1] to give tert-butyl 4-((E)-2-(2,3-dihydrobenzo[1,4]dioxin-6-yl)vinyl)-2-nitrobenzoate 1.5 g of yellow solid.
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:7].[CH3:9][C:10]1([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[NH2:7][C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[NH:8][CH:26]1[CH2:25][CH2:24][N:23]([C:10]2([CH3:9])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:28][CH2:27]1
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@@H]3CCCC[C@@H]3N)CC2)CC1
Temperature: 25 °C

Procedure:
To a solution of cis-cyclohexane-1,2-diamine (0.850 mL, 7.22 mmol) in dichloromethane (10 mL) was added with tert-butyl 4-methyl-4-(4-oxo-1-piperidyl)piperidine-1-carboxylate (1.39 g, 3.61 mmol) in dichloromethane (5 mL) followed by sodium triacetoxyborohydride (0.918 g, 4.33 mmol) and the mixture stirred at room temperature over night. The mixture was then quenched with 1 N NaOH and dichloromethane was added. The phases were separated and aqueous phase was extracted with dichloromethane. The combined organic phases were dried and concentrated in vacuo to give the title product, which was used for the subsequent step without further purification. MS (M+1): 395.37.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[C:28]([F:31])([F:30])[F:29].[H-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]([C:16]1[C:17]([C:28]([F:30])([F:31])[F:29])=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: CCOC(=O)NCc1ccccc1Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1Cl)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Yield: 18.5 %

Procedure:
Ethyl 2-chlorobenzylcarbamate (809.9 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (932.3 mg) were dissolved in tetrahydrofuran (20 ml), and to the solution was added sodium hydride (151.6 mg) under ice-cooling. The reaction mixture was heated at reflux for 5 hours. After allowing to cool, to the reaction mixture was added 1N hydrochloric acid (200 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (100 g, hexane:ethyl acetate=5:1) to give the title compound (0.286 g, 19%).
Reaction SMILES: C(Cl)(Cl)[Cl:2].[NH2:5][C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]([CH3:26])[C:24](=[O:27])[N:23]([CH3:28])[C:22](=[O:29])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>O>[ClH:2].[CH3:26][N:25]1[C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][O:10][C:9]3[CH:30]=[CH:31][C:6]([N:5]([S:40]([CH3:39])(=[O:42])=[O:41])[S:40]([CH3:39])(=[O:42])=[O:41])=[CH:7][CH:8]=3)[CH2:19][CH2:18]2)=[CH:21][C:22](=[O:29])[N:23]([CH3:28])[C:24]1=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: ClC(Cl)Cl
Reactant: Cn1c(N2CCN(CCCOc3ccc(N)cc3)CC2)cc(=O)n(C)c1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cl
Product: Cn1c(N2CCN(CCCOc3ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc3)CC2)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
15 ml of a chloroform solution containing 1.0 g of 6-[4-(3-[4-aminophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione obtained in Example 6 and 2.5 ml of triethylamine was added to 5 ml of a chloroform solution containing 1.5 g of methanesulfonyl chloride, and the solution was then stirred at room temperature for 30 minutes. Afterward, water was added to the solution, and this solution was then subjected to separation, drying, concentration and purification through a silica gel column chromatograph (chloroform/methanol=50/1). Next, the thus obtained 1,3-dimethyl-6-[4-(3-[4-dimethanesulfonylaminophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione was treated with an HCl/methanol solution in an ordinary manner to obtain 0.75 g of crystalline 1,3-dimethyl-6-[4-(3-[4-dimethanesulfonylaminophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.hydrochloride (Compound 83).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][OH:20])[CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[N:38]1([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][C@H:39]1[C:48](O)=[O:49].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C@@H:3]([NH:2][C:48]([C@@H:39]2[CH2:40][C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:47][N:38]2[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:49])[C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH2:19][OH:20])[CH2:8][CH2:7]2)=[O:5])=[CH:23][CH:24]=1
Reactant: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2CCO)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2CCO)CC1
Yield: 57.2 %

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step f) using (2R)-2-amino-3-{4chlorophenyl)-1-(4-[2-(hydroxyethyl)phenyl]-piperidyl}-propan-1-one hydrochloride (Step e) (846 mg, 2.0 mmol), DIEA (0.40 mL, 2.0 mmol), Boc-L-TicOH (Bachem Company) (544 mg, 2.8 mmol), HOAT (Aldrich) (382 mg, 2.8 mmol) and EDC (Aldrich) (544 mg, 2.84 mmol) in DMF (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (739 mg). MS (EST, pos. ion) m/z: 646 (M+1); MS (ESI, neg. ion) m/z: 644 (M−1). Calc'd for C37H44ClN3O5: 645.30.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3][CH2:4][OH:5].[Na].Cl[C:14]1[NH:19][C:18](=[O:20])[C:17]([F:21])=[CH:16][N:15]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3][CH2:4][O:5][C:14]1[NH:19][C:18](=[O:20])[C:17]([F:21])=[CH:16][N:15]=1
Reactant: CC(C)=CCCC(C)=CCO
Reactant: O=c1[nH]c(Cl)ncc1F
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)=CCOc1ncc(F)c(=O)[nH]1
Yield: 61 %

Procedure:
23.1 g of 3,7-dimethyl-2,6-octadien-1-ol and 3.4 g of metal sodium are added to 200 ml of absolute toluene, and the mixture is stirred at 40° to 50° C until the metal sodium has been completely dissolved. Subsequently 7.4 g of 2-chloro-5-fluoropyrimidin-4-one is added to the solution, and the mixture is refluxed for 8 hours. The solvent is distilled off from the resulting reaction mixture, 30 ml of water is added to the residue and the pH of the mixture is adjusted to 4-5 with dilute hydrochloric acid. The resulting mixture is extracted with 200 ml of chloroform and the extract is concentrated. Purification of the residue by silica gel column chromatography gives 8.3 g of slightly yellow oily 2-(3,7-dimethyl-2,6-octadien-1-oxy)-5-fluoropyrimidin-4-one in a yield of 61.0%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7]2.[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.CCOC(C)=O>[CH3:15][O:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=2)[N:10]=1)=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2cncc(Br)c2n1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1ccc2cncc(Br)c2n1
Reaction time: 16 h

Procedure:
8-Bromo-[1,6]naphthyridine-2-carboxylic acid methyl ester (2) is prepared by combining compound 1 (1 equiv.), cesium carbonate (1.1 equiv.) and methyl iodide (1.1 equiv.) in DMF (10 mL) and stirring for 16 hrs. at room temperature. The reaction is concentrated in vacuo to give a brown solid, which is dissolved in EtOAc (50 mL) and washed with water (2×50 mL). The EtOAc layer is dried over sodium sulfate, filtered, and concentrated in vacuo to afford a purple solid. The crude product is purified via silica gel chromatography (EtOAc) to yield (2) as a yellow solid, 65%, LC/MS (M+H) 269.0.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:8]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[Cl:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:14]=1
Reactant: Brc1ccc(CN2CCOC(c3cccnc3)C2)cc1
Reactant: OB(O)c1ccccc1Cl
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: CCO
Solvent: Cc1ccccc1
Product: Clc1ccccc1-c1ccc(CN2CCOC(c3cccnc3)C2)cc1
Temperature: 120 °C
Yield: 97 %

Procedure:
105 mg of 4-(4-Bromo-benzyl)-2-pyridin-3-yl-morpholine was combined with 74 mg of 2-Chlorophenyl boronic acid, 36 mg of tetrakis(triphenylphosphine)palladium(0), 1.055 mL of 2M sodium carbonate solution, 2.8 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 365, 97% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: OCCc1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccs1
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a stirred and cooled (0° C.) mixture of 13 g of 2-thiopheneethanol and 15.3 g of N,N-diethylethanamine in 90 ml of dichloromethane there were added dropwise 8.6 ml of methanesulfonyl chloride. Stirring was continued for 1/2 hour and then the reaction mixture was washed with ice-water, dried, filtered and evaporated. The residue was taken up in 2,2'-oxybispropane and the whole was evaporated again, yielding 20 g (95.7%) of 2-thiopheneethanol methanesulfonate (ester) (interm. 9);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([Cl:20])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)c(Br)c1
Reaction time: 1 h

Procedure:
To 3-bromo-4-chloro-benzoic acid (9.4 g, 40 mmol) in dry DCM (100 mL), was added DMF (0.5 mL) followed by addition of oxalyl chloride (22.5 mL, 55 mmol, 2M in DCM) slowly. The mixture was stirred for 1 hr, then concentrated to yield 3-bromo-4-chloro-benzoyl chloride as an off-white solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][OH:26].FC1C=C(F)C=CC=1N>>[OH:26][CH2:25][CH2:24][O:23][C:22]1[CH:21]=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(OCCO)c1
Agent: Nc1ccc(F)cc1F
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OCCO)c1
Yield: 48.3 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 294 mg of 2-(3-aminophenoxy)ethanol in 20 place of the 2,4-difluoroaniline. 180 mg of N-[3-(2-hydroxyethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][C@H:4]([NH:16][S:17]([C:20]1[S:21][C:22]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:24]=1)(=[O:19])=[O:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:34][I:35]>>[I-:35].[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C@@H:4]([NH:16][S:17]([C:20]1[S:21][C:22]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:24]=1)(=[O:19])=[O:18])[CH2:3][N+:2]([CH3:34])([CH3:1])[CH3:33])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(C#Cc2ccccc2)s1
Reactant: CI
Product: C[N+](C)(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(C#Cc2ccccc2)s1
Product: [I-]

Procedure:
According to the method described in example S76b, (R)-benzyl 4-(dimethylamino)-3-(5-(phenylethynyl)thiophene-2-sulfonamido)butanoate was reacted with methyl iodide to give the title compound as a yellow solid (quantitative). ESI 497.3 [M]+, calcd for [C26H29N2O4S2]+ 497.16.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[Br:17]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 23.05 g of 3-methyl-4'-chlorobenzophenone, 70 cc of carbon tetrachloride, 16.02 g of N-bromosuccinimide and 90 mg benzoyl peroxide was refluxed for 4 hours and then was added to 100 cc of carbon tetrachloride. The mixture was filtered hot and the filter was washed with 100 cc of boiling carbon tetrachloride. 200 cc of the solvent were distilled off under reduced pressure and the mixture was cooled and iced for 1 hour. The mixture was vacuum filtered and the recovered crystals were empasted with iced carbon tetrachloride and dried under reduced pressure. The residue was crystallized from ethanol to obtain 17.5 g of 3-bromomethyl-4'-chlorobenzophenone melting at 138°-139° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:29])[C:9]1=[O:30])(=[O:3])[CH3:2].[Br:31]Br>CC(O)=O.CC(=O)OCC.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=3)=[C:17]([Br:31])[C:11]=2[N:10]([CH3:29])[C:9]1=[O:30])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)cc2n(C)c1=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)c(Br)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
To a solution of 3-(1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (See Intermediate 1, 170 mg, 0.40 mmol) in HOAc (3 mL) was added Br2 (76.6 mg, 0.48 mmol). The reaction was stirred at RT for 2 h then diluted with EA (10 mL) and water (5 mL). The organic layer was washed with water (3×20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1) to give 3-(7-bromo-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (150 mg, 74.4% yield) as a yellow oil. LCMS: MH+ 504 and TR=1.739 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:13])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:2]=[CH2:3].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[O:13][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(O)cc(OC)c1
Reactant: O=Cc1ccc(F)cc1
Product: C=CCOc1cc(OC)cc(Oc2ccc(C=O)cc2)c1

Procedure:
The product from Example 90A and 4-fluorobenzaldehyde were processed as in Example 61C to provide the title compound. MS (DCI) m/z 285 (M+H)+.
Reaction SMILES: [Na].[CH2:2](O)[CH2:3][CH2:4][CH3:5].[H][H].S(C1C=CC(C)=CC=1)([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)=O>>[CH2:13]([O:12][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCO
Reactant: [H][H]
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Product: CCCCCCCC/C=C\CCCCCCCCOCCCC
Temperature: 25 °C
Yield: 63.2 %

Procedure:
Sodium (2.33 g, 0.10 mol) was placed in a three-necked, 250-mL round-bottom flask equipped with nitrogen inlet, mechanical stirrer and drying tube, and 1-butanol (36.6 mL, 0.4 mol) was added to the flask. The reaction mixture was left in a hood overnight, by which time evolution of hydrogen had ceased and all of the sodium appeared to have reacted. Oleyl tosylate (17 g, 0.04 mol, made from oleyl alcohol and tosyl chloride) dissolved in 1-butanol (9.15 mL, 0.1 mol) was added. The solution, which began to turn yellow immediately, was packed in ice and allowed to warm to room temperature over 15 hr. The reaction mixture was washed with water. The organic phase was dissolved in ether and extracted with 10% Na2CO3 and with saturated NaCl. The ether phase was dried over anhydrous potassium carbonate and filtered, and the solvent was removed on a rotary evaporator. The resulting pale-orange oil was distilled (155-168° C. at 0.6 torr) to yield 8.2 g (64%) of 2 as an oil: NMR δ 0.9-2.2 (m, 38 H, --CH3 and --CH2 --), 3.2 (t, J=6 Hz, 4 H, --CH2 --O), 5.28 (t, J=4.5 Hz, 2 H, olefinic); IR:3010 (olefinic C--H), 1120 cm-1 (C--O). Anal. Calcd.: C, 81,41; H, 13.66. Found: C, 81.44; H, 13.68.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH:13]([C:15]1[CH2:16][O:17][CH2:18][CH2:19][CH:20]=1)=O>C(O)C>[F:12][C:11]1[C:2]([NH:1][CH2:13][C:15]2[CH2:16][O:17][CH2:18][CH2:19][CH:20]=2)=[CH:3][C:4]2[O:8][C:7](=[O:9])[NH:6][C:5]=2[CH:10]=1
Reactant: O=CC1=CCCOC1
Reactant: Nc1cc2oc(=O)[nH]c2cc1F
Solvent: CCO
Product: O=c1[nH]c2cc(F)c(NCC3=CCCOC3)cc2o1
Yield: 27.9 %

Procedure:
To a solution of 6-amino-5-fluoro-benzoxazolin-2-one (0.97 g, 5.7 mmole) and 3-formyl-5,6-dihydro-2H-pyran (0.71 g, 6.3 mmole) in ethanol (40 ml) were added molecular sieves (4A, 1 g). The mixture was heated under reflux for 3 hours. Upon cooling, the reaction mixture was filtered and the filtrate was concentrated to yield a solid product, which was washed with ethanol. This product was dissolved in methanol (200 ml) and then sodium borohydride was added in portions at room temperature. Stirring was continued for hours. The reaction mixture was concentrated and water was added. The organic material was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was recrystallized from methanol to afford 420 mg of the title product (28%): m.p. 175°-176° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:12])([F:13])([F:16])([F:14])[F:15])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Acetamidophenylsulphur pentafluoride (27.0 g) was added during 5 minutes to a stirred mixture of concentrated nitric acid and concentrated sulphuric acid (1 part:2 parts by volume) at 0°-5° C. After 5 minutes acetic acid (1 part) was added and stirring continued at 5° C. for 1.5 hours. The mixture was added to ice/water, extracted (ethyl acetate) and the extract washed (sodium carbonate solution), dried (magnesium sulphate) and evaporated. The residue was triturated with ether to give 4-acetamido-3-nitrophenylsulphur pentafluoride (30.0 g), m.p.135°-138° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27])[C:6]1[N:7]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][C:10]=1[C:11]#[N:12])=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O.CCOC(C)=O>[N:28]([CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27])[C:6]1[N:7]=[C:8]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[S:9][C:10]=1[C:11]#[N:12])=[O:4])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(Cl)cccc1CN(C(=O)CCl)c1nc(N2CCOCC2)sc1C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1CN(C(=O)CN=[N+]=[N-])c1nc(N2CCOCC2)sc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a solution of 2-chloro-N-[(3-chloro-2-methylphenyl)methyl]-N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (200 mg, 0.470 mmol) (prepared according to the procedures of example 59) in N,N-Dimethylformamide (DMF) (2 mL) was added sodium azide (92 mg, 1.410 mmol) at rt. The mixture was stirred at rt for 3 hr before diluted in 100 ml EtOAc and washed with 20 mL H2O twice. The organic layer was concentrated to give 200 mg crude product (99%), which was used in the next step without further purification. LC/MS (ES) m/z=432.2 (M+H).