Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]([O:39][C@H:40]1[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[CH:43](OC(=O)C)[O:42][C@@H:41]1[C:53]1[N:54]=[N:55][N:56]([CH2:58][CH3:59])[N:57]=1)(=[O:38])[CH3:37].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClC(Cl)(Cl)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:46]([O:45][C@@H:44]1[C@H:40]([O:39][C:36](=[O:38])[CH3:37])[C@@H:41]([C:53]2[N:54]=[N:55][N:56]([CH2:58][CH3:59])[N:57]=2)[O:42][C@H:43]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:48])[CH3:47]
Reactant: CCn1nnc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reactant: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)NCCN5CCCCC5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A suspension of 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide (Preparation 11) (0.2 g, 0.42 mmol) in 1,1,1-trichloroethane (10 ml) was treated with N,O-bis(trimethylsilylacetamide) (0.65 ml, 2.65 mmol) and the mixture was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the residue was twice azeotroped with toluene. The residue was dissolved in toluene (5 ml) and treated sequentially with a solution of (2R,3R,4R)-4,5-bis(acetyloxy)-2-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (WO-A-9967265) (0.175 g, 0.51 mmol) in toluene (5 ml) and then trimethylsilyltriflate (0.1 ml, 0.55 mmol). The mixture was heated under reflux for 3 hours and then allowed to stand at room temperature overnight. The solution was diluted with ethyl acetate (40 ml), washed sequentially with saturated aqueous sodium hydrogen carbonate solution (20 ml) and brine (20 ml) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (93:7 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to afford the title compound (0.235 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[C:26](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:27]>ClCCl>[CH:14]1([N:13]([CH:17]2[CH2:19][CH2:18]2)[C:11]([C:9]2[N:8]([CH2:20][CH3:21])[C:6]3=[N:7][C:2]([N:1]=[C:26]=[S:27])=[C:3]4[N:24]=[CH:23][N:22]([CH3:25])[C:4]4=[C:5]3[CH:10]=2)=[O:12])[CH2:16][CH2:15]1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Solvent: ClCCl
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (194.5 mg, 0.575 mmol) in dichloromethane (2874 μL) in a round bottom flask under nitrogen was added 1,1′-thiocarbonyldi-2(1H)-pyridone (133 mg, 0.575 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. N,N-Dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide was isolated as a yellow sticky solid. Material was used as is in subsequent reactions.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)c(CBr)c1
Reactant: O=C1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCc3cc(Cl)ccc3Br)cc21
Reaction time: 18 h
Yield: 88.7 %

Procedure:
To a stirred solution of 7-hydroxy-1-tetralone (13.9 g, 85.7 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g, 89% yield) was isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([CH2:11][C:12](OCC)=[O:13])[C:8]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:7]=3[C:6]=2[CH:5]=[C:4]([Cl:29])[CH:3]=1.[Li+].[BH4-].[OH-].[Na+].CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][OH:13])[C:8]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21][C:7]=3[C:6]=2[CH:5]=[C:4]([Cl:29])[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)cc(Cl)c31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3c(Cl)cc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
A solution of tert-butyl 7,9-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (3.00 g, 6.80 mmol) in dry THF (30 mL) was cooled to 0° C. Then, LiBH4 (0.44 g, 20.2 mmol) was added and the reaction was allowed to warm slowly to rt. After 18 h, additional LiBH4 (0.44 g, 20.2 mmol) was added. After an additional 24 h, the reaction was diluted with H2O followed by addition of 10% aqueous NaOH and extraction with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage 40M, SIM) with heptane/EtOAc (1:1) to give 2.37 g of impure product. Then, crystallization from EtOAc/heptane gave 2.21 g (82%) of ivory crystals: mp 183-184° C.; IR (diffuse reflectance) 1693, 1658, 1468, 1448, 1433, 1406, 1380, 1370, 1347, 1323, 1293, 1226, 1166, 1064, 771 cm1; MS (EI) m/z 398 (M+), 344, 342, 270, 268, 258, 256, 63, 57, 56. Anal. Calcd for C19H24Cl2N2O3: C, 57.15; H, 6.06; N, 7.01; found: C, 57.20; H, 6.11; N, 6.95.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][C:30]1[N:35]=[CH:34][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][N:31]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.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>[CH3:29][C:30]1[N:35]=[CH:34][C:33]([C:17]2[N:18]=[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:14]3[CH:13]=[C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]4)[S:28][C:15]=3[N:16]=2)=[CH:32][N:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C)nc1
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CSC
Solvent: CCOC(C)=O
Product: Cc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (104 mg) in 1,2-dimethoxyethane (10 mL) was added 2-methyl-5-tributylstannanyl-pyrimidine (180 mg) and copper(I)bromide-dimethyl sulfide (96 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (14 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 409. NMR: (CDCl3): 2.67-2.70 (4 H, m), 2.82 (3 H, s, Me), 2.84 (3 H, s, Me), 3.30-3.32 (4 H, m), 3.85 (2 H, s, CH2), 3.91-3.92 (4 H, m), 3.98-4.01 (4 H, m), 7.01 (1 H, s, Ar) and 9.58 (2 H, s, Ar). MS: (ESI+): MH+=490.14
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].O=[CH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CO.C(OCC)(=O)C>[CH2:10]([N:9]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:8][CH2:7][O:6][C:5]1[CH:22]=[CH:23][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)CCC=O
Reactant: CCCCCCCCCCCCNCCOc1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(I)cc1
Temperature: 22 °C
Reaction time: 24 h
Yield: 88.7 %

Procedure:
To a mixture of N-2-[4-iodophenoxy]ethyldodecylamine ( 4.0 g, 9.3 mmol) and sodium cyanoborohydride (1.45 g, 23 mmol) in methanol (80 ml) was added dropwise a solution of ethyl 4-oxobutyrate (Fournet, G. ; Balme, G.; Barieux, J. J. and Gore, J. Tetrahedron, 1988, 44, 5821) (2.4 g, 18 mmol) in methanol (20 ml) over a period of 10 min. The resulting mixture was stirred at 22° C. for 24 h, and then diluted with ethyl acetate (600 ml), washed with brine (3×250 ml). The aqueous phase was extracted with ethyl acetate (150 ml), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 8:1 to 6:1) to afford the title compound (4.5 g, 89%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])=[CH:4][C:5]([CH3:14])=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8].C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].C(=O)([O-])O.[Na+]>ClCCl.O>[C:28]([NH:1][C:2]1[C:3]([S:15]([F:20])([F:16])([F:17])([F:18])[F:19])=[CH:4][C:5]([CH3:14])=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])(=[O:30])[CH3:29]
Reactant: CON(C)C(=O)c1cc(N)c(S(F)(F)(F)(F)F)cc1C
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(NC(C)=O)c(S(F)(F)(F)(F)F)cc1C
Reaction time: 2 h

Procedure:
5-Amino-N-methoxy-2,N-dimethyl-4-(pentafluorosulfanyl)benzamide (200 mg) was dissolved in dichloromethane (10 ml) and then triethylamine (100 μl) and acetyl chloride (50 μl) were added while stirring. After 2 h, further acetyl chloride was added (50 μl) and the mixture was stirred for 4 h. Then the reaction mixture was admixed with water and saturated sodium hydrogencarbonate solution, and the organic phase was removed and washed three times with water. After drying over magnesium sulfate, the organic phase was filtered and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 170 mg of the desired compound were obtained.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.C[Si](Cl)(C)C.[CH:25]([O:28][C:29]1[CH:48]=[CH:47][C:32]([C:33]([N:35]2[CH2:40][CH2:39][C:38]3([O:45][CH:44]=[CH:43][C:42](=[O:46])[CH2:41]3)[CH2:37][CH2:36]2)=[O:34])=[CH:31][C:30]=1[O:49][CH3:50])([CH3:27])[CH3:26]>C1COCC1.[Cu](I)I>[CH:25]([O:28][C:29]1[CH:48]=[CH:47][C:32]([C:33]([N:35]2[CH2:40][CH2:39][C:38]3([O:45][CH:44]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:43][C:42](=[O:46])[CH2:41]3)[CH2:37][CH2:36]2)=[O:34])=[CH:31][C:30]=1[O:49][CH3:50])([CH3:27])[CH3:26]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)C=CO3)ccc1OC(C)C
Reactant: Br[Mg]c1ccccc1
Agent: I[Cu]I
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)CC(c2ccccc2)O3)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
A round bottom flask was heated with a heat-gun under vacuum followed by being flushed with Ar. The process was repeated three times. To the flask, copper iodide (2.32 g, 12.2 mmol) was placed followed by the addition of THF (5 mL). The suspension was purged with argon for 2 minutes and then cooled to −78° C. Phenylmagnesium bromide (122 mL of 1 M, 122 mmol) in THF was added dropwise at −78° C. under argon. The mixture was stirred at −78° C. for 20 minutes. HMPA (44.0 g, 244 mmol) was added. The mixture was stirred at −78° C. for 30 min. TMSCl (26.5 g, 244 mmol) was added to a solution of 3-(4-isopropoxy-3-methoxy-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (7.30 g, 20.3 mmol) in THF (25 mL). The above solution was added to the reaction mixture dropwise. The mixture was slowly warmed to room temperature and was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution, repartitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (40-60% ethyl acetate-Hex) to provide 3-(4-isopropoxy-3-methoxy-benzoyl)-10-phenyl-11-oxa-3-azaspiro[5.5]undecan-8-one (6 g). ESI-MS m/z calc. 437.22, found 438.0 (M+1)+; Retention time: 1.69 minutes (3 minute run).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH:13](OC)OC)[C:5]([O:7][CH3:8])=[O:6].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([N:1]2[C:2]3[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=3)[CH:12]=[CH:13]2)[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)c1ccc(CC(OC)OC)c(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
44.3 g of methyl 3-amino-4-(2,2-dimethoxyethyl)benzoate synthesized according to the publication (Tetrahedron Letters, Vol. 37, No. 34, pp. 6045-6048) and 64.9 g of benzyl 4-oxo-1-piperidinecarboxylate were dissolved in 485 ml of acetic acid, followed by stirring at room temperature. Approximately 20 minutes later, 58.9 g of sodium triacetoxyborohydride was added to the reaction solution. Then, the reaction solution was further stirred for 2 hours. Thereafter, 485 ml of water was added to the reaction solution, and the obtained mixture was heated to a temperature between 100° C. and 115° C. Approximately 3 hours later, the reaction solution was cooled, and then concentrated under a reduced pressure. Thereafter, water and ethyl acetate were added thereto, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by NH silica gel column chromatography (hexane/ethyl acetate). The obtained solid was suspended in a mixed solvent consisting of hexane and t-butylmethyl ether, followed by filtration, so as to obtain 64.6 g of the subject compound.
Reaction SMILES: [OH:1][C:2]([CH3:25])([CH2:20][CH2:21][O:22][CH2:23][CH3:24])[CH:3]=[CH:4][CH:5]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][CH2:6]1.[OH-].[Na+].[CH3:28]I>CN(P(N(C)C)(N(C)C)=O)C>[OH:1][C:2]([CH3:25])([CH2:20][CH2:21][O:22][CH2:23][CH3:24])[CH:3]=[CH:4][CH:5]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:28])=[O:17])[C:8](=[O:19])[CH2:7][CH2:6]1
Reactant: CI
Reactant: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-[5-(3-Hydroxy-3-methyl-5-ethoxypent-1-enyl)-2-oxocyclopentyl]heptanoic acid (0.24 g.) was diluted with hexamethylphosphotriamide (1.8 ml.) and treated with aqueous sodium hydroxide solution (25% w/v; 0.163 ml.). After stirring for two hours at room temperature, methyl iodide (0.177 ml.) was added and stirring continued for a further 24 hours. The reaction mixture was extracted twice with diethyl ether and the combined ethereal extracts were washed twice with water and dried over anhydrous sodium sulphate. Evaporation gave crude methyl 7-[5-(3-hydroxy-3-methyl-5-ethoxypent-1-enyl)-2-oxocyclopentyl]heptanoate (0.17 g.) as the residue. This was purified by preparative thin-layer chromatography on silica gel, using mixture of toluene, dioxan and acetic acid (65:15:1 by volume) as eluant, to give methyl 7-[5-(3-hydroxy-3-methyl-5-ethoxypent-1-enyl)-2-oxocyclopentyl]-heptanoate (30 mg.). Elemental analysis: found: C, 68.3; H, 10.1%; C21H36O5 requires: C, 68.5; H, 9.9%. N.M.R. (approximately 10% solution in deuterochloroform): triplet at 1.2δ (J=7 cycles/sec.), singlet at 1.3δ, multiplets at 1.0-2.0δ, 2.0-2.5δ, 3.2-3.75δ, singlet at 3.6δ, and multiplet at 5.6-5.8δ.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[NH:8][CH2:7][C:6]=2[CH:20]=1.[Br:21][CH2:22][CH2:23][CH2:24]O>>[Br:21][CH2:22][CH2:23][CH2:24][N:8]1[CH2:7][C:6]2[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[S:9]1(=[O:19])=[O:18]
Reactant: OCCCBr
Reactant: O=S1(=O)NCc2cc(F)ccc2N1c1ccccc1F
Product: O=S1(=O)N(CCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 71.9 %

Procedure:
In an analogous manner to Example 11 step 4, a solution of 6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.51 g, 1.7 mmol) was reacted with 3-bromopropanol (0.25 mL, 2.8 mmol) to afford 3-(3-bromopropyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.51 g, 71%) as a white solid:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]3[NH:23][CH2:22][CH2:21][CH2:20][C:15]=3[C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-].Cl>O1CCCC1.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]3[NH:23][CH2:22][CH2:21][CH2:20][C:15]=3[C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(Cc2n[nH]c(=O)c3c2NCCC3)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cc2n[nH]c(=O)c3c2NCCC3)ccc1F
Temperature: 25 °C

Procedure:
A solution of EXAMPLE 506E (2.8 g, 8.8 mmol) in tetrahydrofuran (150 mL) was treated with LiOH (253 mg, 10.6 mmol) in water (20 mL) at 50° C. overnight. After cooling to room temperature, the mixture was acidified with dilute HCl to pH 4, and concentrated to about 10 mL. The solid material was collected by filtration, washed with water and dried to provide the title compound. MS (DCI/NH3) m/z 305 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:44])=[O:43])=[CH:38][CH:37]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:44])=[O:43])=[CH:38][CH:37]=2)[C:6]=1[CH3:14]
Reactant: CS(=O)c1ccc(CBr)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)=O)cc2)c2ncccc12
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.512 g, 2.51 mmol) in dry DMF (5.6 ml) at room temperature is treated with BEMP (1.17 ml, 4.01 mmol) dropwise. The reaction mixture is stirred at room temperature for 80 minutes and then treated with 1-bromomethyl-4-methanesulfinyl-benzene (0.934 g, 4.01 mmol). After stirring at room temperature for a further 2 hours, the reaction mixture is partitioned between ethyl acetate/ether (300 ml of a 1:1 mixture) and water (30 ml). The organic portion is separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with DCM/methanol (10:1) to yield the titled product. (MH+ 357)
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)([OH:10])[CH2:8][F:9])=[N:4][CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]2[N:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=2)[CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:9][CH2:8][C:7]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)([OH:10])[C:5]1[S:6][C:2]([C:27]2[CH:26]=[C:25]([NH:38][C:39]3[N:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=3)[CH:24]=[C:23]([CH3:22])[CH:28]=2)=[CH:3][N:4]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(O)(CF)c2ncc(Br)s2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(CF)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 100 °C

Procedure:
Racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-2-fluoro-1-hydroxyethyl]cyclohexane-carboxylate (107 mg, 0.281 mmol), N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (231 mg, 0.610 mmol), X-Phos (56 mg, 0.120 mmol), Pd2(dba)3 (52 mg, 0.056 mmol), cesium carbonate (429 mg, 1.32 mmol), 1,4-dioxane (3.0 ml) and water (0.3 ml) were combined and the vial was evacuated and purged with nitrogen 3 times then heated to 100° C. for 2 h. The mixture was then filtered and diluted with EtOAc. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (0-10% MeOH in DCM) to afford racemic ethyl trans-4-{2-fluoro-1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate which was used without further purification. MS ESI calc'd. for C26H28F4N4O3S [M+H]+ 553. found 553.