Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][C:14]=1[NH2:25]>>[CH2:9]([O:8][C:1](=[O:7])[C:2]([NH:25][C:14]1[CH:15]=[C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[CH:17]=[CH:18][C:13]=1[O:12][CH3:11])=[O:4])[CH3:10]
Reactant: COc1ccc(N2CCOCC2)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Nc1cc(N2CCOCC2)ccc1OC
Temperature: 180 °C

Procedure:
139 ml (1015 mmol) Diethyl oxalate were heated to 120° C. 30.3 g (145 mmol) 2-methoxy-5-morpholin-4-yl-phenylamine were added very cautiously in small quantities and the mixture was heated for 90 minutes at 180° C. After cooling to room temperature and filtration 1.5 l n-hexane were added. The resulting precipitate was collected by filtration. After washing with hexane and drying 34.4 g (77%) N-(2-methoxy-5-morpholin-4-yl-phenyl)-oxalamic acid ethyl ester was obtained as greenish crystals, mp.: 95-97° C., MS m/e (%): 309 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:20][CH2:19][C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:21]
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=Cc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CNCc1ccccc1Br)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirring solution of 2-bromobenzaldehyde in dichloromethane (0.2 M) was added glycine benzyl ester (1.2 eq), sodium triacetoxyborohydride (2 eq) and acetic acid (4 eq). After stirring overnight, the solution was washed with 10% sodium carbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica; 30%-40% EtOAc/Hexanes) to afford a pale yellow oil. EI-MS m/z 334, 336 (M+H)+
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[C:25]([C:32]5[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][CH:33]=5)=[CH:26][C:27]([CH:30]=[O:31])=[CH:28][CH:29]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].[BH4-].[Na+]>CCO.C1COCC1>[CH3:3][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[C:25]([C:32]5[CH:33]=[CH:34][C:35]([S:38][CH3:39])=[CH:36][CH:37]=5)=[CH:26][C:27]([CH2:30][OH:31])=[CH:28][CH:29]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: CSc1ccc(-c2cc(C=O)ccc2-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1ccc(-c2cc(CO)ccc2-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of aldehyde from step 2 in EtOH: THF (4:1, 0.05M) at 0° C. was added NaBH4 (1 eq). The reaction mixture was stirred 1 h at 0° C., quenched with a solution of NH4Cl and diluted with ether. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (hexane:EtOAc, 1:1 to 1:9) to afforded the title compound.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:50][CH2:51][C@@H:52]([NH2:55])[CH2:53][CH3:54])([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:29])[NH:55][C@H:52]([CH2:51][O:50][Si:33]([C:46]([CH3:47])([CH3:49])[CH3:48])([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:53][CH3:54])[N:27]=2)[CH2:22]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (2.00 g, 4.29 mmol) (obtained as described in Reference Example 2(1)) in benzene (100 ml) was added a solution of 0.67M (1S)-1-(t-butyldiphenylsilyloxymethyl)propylamine-trimethylaluminium in benzene (12.9 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux overnight. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (200 ml) were added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→2:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-1-(t-butyldiphenylsilyloxymethyl)-propylcarbamoyl]-1,3-thiazol-2-yl}azetidine (2.52 g, yield 79%) as a pale brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>CO.O1CCOCC1>[ClH:31].[CH3:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:17]2[N:18]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:15][CH:16]=2)=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(OCc2csc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (Example 91, 430 mg, 0.95 mmol) in methanol (5 mL) was added 4 N HCl in dioxane (5 mL). The resulting solution was stirred for 30 minutes at room temperature. The mixture was then evaporated to dryness in vacuo to afford the desired product as a pale yellow solid.
Reaction SMILES: C([C:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][N:6]2[CH2:15][CH2:16][CH2:17][C:5]=12)(O)=O.[Br:18]N1C(=O)CCC1=O>CC(N(C)C)=O.CCOC(C)=O>[Br:18][C:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][N:6]2[CH2:15][CH2:16][CH2:17][C:5]=12
Reactant: O=C(O)c1c(-c2ccccc2)nn2c1CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Brc1c(-c2ccccc2)nn2c1CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-carboxy-2-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (820 mg, 3.59 mmol) in dry DMA (15 mL) previously degassed add N-bromosuccinimide (NBS) (702.8 mg, 3.95 mmol) and stir at room temperature for 18 hours. Then, dilute with EtOAc (80 mL) and wash with cooled water (5×10 mL). Dry the organic phase (MgSO4), and concentrate in vacuo to obtain a yellow solid, 1.0 g. MS(ES+): m/z=263.0 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[CH3:9][C:10](C)=[O:11].C(=O)=O.C1OC1>CO>[CH3:1][C:2]1([CH3:8])[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:9][CH2:10][OH:11]
Reactant: CC1(C)COCCN1
Reactant: CC(C)=O
Agent: O=C=O
Solvent: C1CO1
Solvent: CO
Product: CC1(C)COCCN1CCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
In a pressure vessel containing 3,3-dimethylmorpholine (12.15 g, 106 mmol) in MeOH (17 mL) at −78° C. (external temperature, acetone/CO2(s)) was added ethylene oxide (6.2 mL, 125 mmol, 1.2 equiv., condensed at −78° C.). The solution was sealed and stirred over 20 hours, during which time the temperature warmed to room temperature. The reaction mixture was concentrated in vacuo and the crude product was distilled (75° C., 0.5 torr) to provide 2-(3,3-dimethyl-morpholin-4-yl)-ethanol (14 g, 82%) as a colorless oil contaminated with ˜15% of 3,3-dimethyl-morpholine. LC/MS found 160.10 (M++H, C8H18NO2 requires 160.13).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[S:14]>C(#N)C>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[S:14])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc(-c2ccccc2)s1
Solvent: CC#N
Product: S=C(Nc1ncc(-c2ccccc2)s1)n1ccnc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To 5-phenylthiazol-2-amine (0.52 g, 2.9 mmol) in acetonitrile (6 mL) was added 1,1′-thiocarbonyldiimidazole (0.68 g, 3.8 mmol). The reaction mixture was stirred at 65° C. for 2 hours. The precipitate was filtered and washed with acetonitrile (2×20 mL) to yield intermediate N-(5-phenylthiazol-2-yl)-1H-imidazole-1-carbothioamide. The intermediate was taken up in N,N-dimethylformamide (30 mL) and treated with (3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate (0.5 g, 2.9 mmol). The reaction mixture was stirred for 5 hours at 65° C. The reaction was concentrated in vacuo and purified via silica gel chromatography (30-100% ethyl acetate/hexane). The product fractions were combined and concentrated in vacuo to yield (3-hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate (0.85 g, 2.19 mmol, 74.4% yield) as a white powder. LC/MS confirmed product with loss of BH3 in the LC/MS conditions: retention time 3.26 (M+1-BH3=375.33).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:20]=[C:19]3[C:11]([N:12]4[C:17](=[CH:18]3)[C:16](=[O:21])[NH:15][CH2:14][CH2:13]4)=[N:10][CH:9]=2)[CH2:3][CH2:2]1.O.[CH:23]1([CH:26]=O)[CH2:25][CH2:24]1.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:23]1([CH2:26][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8]3[CH:20]=[C:19]4[C:11]([N:12]5[C:17](=[CH:18]4)[C:16](=[O:21])[NH:15][CH2:14][CH2:13]5)=[N:10][CH:9]=3)[CH2:5][CH2:6]2)[CH2:25][CH2:24]1
Reactant: O=CC1CC1
Reactant: O=C1NCCn2c1cc1cc(OC3CCNCC3)cnc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NCCn2c1cc1cc(OC3CCN(CC4CC4)CC3)cnc12
Temperature: 55 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
To a solution of 0.40 g (1.40 mmol) 7-(piperidin-4-yloxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one in 8 mL tetrahydrofuran, 30 μL (30 μg, 1.67 mmol) water, 0.16 mL (0.15 g, 2.11 mmol) cyclopropanecarboxaldehyde, 0.24 mL (0.25 g, 4.2 mmol) acetic acid and 2.1 mL (1.93 g, 2.1 mmol) sodium cyanoborohydride (1M solution in tetrahydrofuran) were added successively and the reaction mixture was stirred for 18 hours at 55° C. After cooling to room temperature the reaction was poured on 10% aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with dichloromethane: methanol:ammonia (9:1:0.1 v/v) as eluant to give 0.19 g (40%) of the desired compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][C:19]([O:21]CC)=[O:20])[C:12]=2[N:11]([CH:24]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=1.[Li+].[OH-]>O1CCOCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][C:19]([OH:21])=[O:20])[C:12]=2[N:11]([CH:24]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:35][CH:34]=2)[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=1
Reactant: CCOC(=O)CC1CCCc2c(-c3ccc(Cl)cc3Cl)cn(C(CCc3ccccc3)c3ccc(C(F)(F)F)cc3)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CC1CCCc2c(-c3ccc(Cl)cc3Cl)cn(C(CCc3ccccc3)c3ccc(C(F)(F)F)cc3)c21
Temperature: 60 °C

Procedure:
The ester from the foregoing step (0.03 g, 0.05 mmol) was dissolved in a mixture of dioxane (7 ml)/water (2 ml). Then LiOH (12 mg, 0.5 mmol) was added and the solution heated to 60° C. for 14 h. The reaction mixture was then diluted with AcOEt (20 ml), washed with 2.0N HCl (20 ml), brine (20 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 20% AcOEt/Hexane and consequently by HPLC (gradient 60-98% CH3CN/0.1% TFA-H20) to afford 1.2 mg of the title compound; m/z (ES+) 586 (MH+); m/z (ES−) 584 (M−H+).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([O:10][CH:11]([CH2:15][CH2:16][CH2:17][Cl:18])[C:12](O)=[O:13])(=[O:9])[CH3:8]>>[C:7]([O:10][CH:11]([CH2:15][CH2:16][CH2:17][Cl:18])[C:12]([Cl:4])=[O:13])(=[O:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OC(CCCCl)C(=O)O
Product: CC(=O)OC(CCCCl)C(=O)Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
Oxalyl chloride (114 g, 0.90 mol) was added to 2-acetoxy-5-chloropentanoic acid g, 0.37 mol). The mixture was stirred at room temperature for 15 h. The volatiles were evaporated and the oily residue was distilled in vacuo to give 75 g (96%) of product. B.p. 93-95° C. (2 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2.C(OC(=O)C)(=O)C.[S:32](=O)(=[O:35])([OH:34])[OH:33]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:32]([OH:35])(=[O:34])=[O:33]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(S(=O)(=O)O)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 5-chloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate (5.56 g, 15.3 mmol) in 50 mL of dichloromethane at 0° C. was added acetic anhydride (7.23 mL, 76.6 mmol), followed by dropwise addition of concentrated sulfuric acid. The solution was warmed to room temperature, stirred for 3 hours, and partitioned between 0.5 L of EtOAc and 0.5 L of 3N HCl solution. The organic phase was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The product was reconcentrated from benzene in vacuo to give the titled product as a yellow solid. Proton NMR for the product was consistent with the titled compound of the formula C17H14ClNO7S2.0.5 CH3CO2H. ESI+MS: 444.0 [M+H+, 466.0 [M+Na]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH3:12][O:13][C:14](=[O:17])[CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(C)c(C=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-2,6-dimethylbenzaldehyde (1.3 g, 8.6 mmol) and bromoacetic acid methyl ester (0.98 ml, 10.3 mmol) in DMF (20 mL) was added K2CO3 (1.8 g, 12.9 mmol). The suspension was stirred at ambient temperature overnight then the reaction mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the organic layer was dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (5:1) as eluent gave (4-formyl-3,5-dimethylphenoxy)-acetic acid methyl ester as a yellow solid.
Reaction SMILES: C([S:4][CH2:5][CH:6]([O:16][CH3:17])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C.C[O-].[Na+].CS(O)(=O)=[O:23].O>CO.C(OCC)(=O)C>[CH2:9]([O:8][CH2:7][CH:6]([O:16][CH3:17])[CH2:5][S:4][OH:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(COCc1ccccc1)CSC(C)=O
Reactant: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(COCc1ccccc1)CSO
Reaction time: 2 h

Procedure:
To a solution of 14.028 g (55 mM) of acetylthio-3-benzyloxy-2-methoxypropane VII 6 in 300 ml of methanol is added dropwise 11.24 ml (58.3 mM) of 28 weight % solution of sodium methoxide in methanol at -10° C. After the mixture is stirred at -10° C. to 0° C. for 2 hours, 3.58 ml of methanesulfonic acid is added. The reaction mixture is poured into water and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with water, dried, and evaporated. The oily residue is purified by column chromatography on silica gel using an ether-n-hexane (3:97) mixture as an eluent to give 8.85 g (41.7 mM) of the titled compound, 3-benzyloxy-2-methoxypropylthioalcohol VII 6 as an oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[OH:33])=[C:20](C3C=CC=CC=3C(C)C)[CH:21]=[N:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])(C(C)(C)C)(C)C.[F:43][C:44]([F:56])([F:55])[O:45][C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1.[C:57]([O-:60])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH:32]([OH:33])[C:19]2[C:16]3[C:17](=[O:18])[N:12]([CH2:11][CH2:10][CH2:9][O:8][CH:20]4[CH2:19][CH2:16][CH2:15][CH2:57][O:60]4)[C:13](=[O:42])[N:14]([CH3:41])[C:15]=3[N:22]=[CH:21][C:20]=2[C:50]2[CH:49]=[CH:48][CH:47]=[C:46]([O:45][C:44]([F:56])([F:55])[F:43])[CH:51]=2)=[CH:39][CH:38]=1
Reactant: CC(C)c1ccccc1-c1cnc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)cnc21
Temperature: 100 °C
Yield: 22 %

Procedure:
To a mixture of 6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 5, 120 mg, 0.22 mmol) and 3-(trifluoromethoxy)phenylboronic acid (60 mg, 0.33 mmol) in dioxane (3.2 ml) and water (0.8 mL) was added K2CO3 (92 mg, 0.67 mmol) and Pd(PPh3)4 (20 mg). The reaction was degassed with nitrogen (3×), heated at 100° C. for 18 h, cooled to RT, diluted with water (10 mL) then extracted with EA (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (3:1) to give the intermediate 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg) as a white solid. The intermediate was dissolved in EtOH (3 mL) and acetyl chloride (0.3 mL) was added. The reaction was stirred at RT for 30 min then concentrated to a residue which was purified by Prep HPLC to give 5-((4-chlorophenyl)(hydroxy)methyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3 mg, 3% yield over 2 steps) as a white solid. 1H NMR (CDCl3) δ: 8.64 (s, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.21-7.17 (m, 3H), 7.05 (d, J=8.0 Hz, 2H), 6.25 (s, 1H), 4.11-4.05 (m, 2H), 3.77 (s, 3H), 3.51 (t, J=6.4 Hz, 2H), 1.79-1.74 (m, 2H). LCMS: [M++Na] 558 and TR=3.048 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][F:13])[CH2:10][F:11].CCN(C(C)C)C(C)C.[CH2:24](Cl)[O:25][CH3:26].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14][CH2:24][O:25][CH3:26])([CH2:10][F:11])[CH2:12][F:13]
Reactant: Cc1ccc(C(O)(CF)CF)c(Br)c1
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(CF)(CF)c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 11 h
Yield: 79.2 %

Procedure:
To a stirring solution of 2-(2-bromo-4-methylphenyl)-1,3-difluoropropan-2-ol (1.3 g, 4.9 mmol) in DCM (10 mL) at rt were successively added DIPEA (3.4 mL, 19.6 mol) and MOMCl (0.6 mL, 7.4 mmol) over a 10 min period. The solution was stirred 11 h at rt followed by addition of a saturated aqueous NH4Cl solution (20 mL). The aqueous phase was segregated, and the organic one was washed with water (20 mL), brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated to give pure 2-bromo-1-(1,3-difluoro-2-(methoxymethoxy)propan-2-yl)-4-methylbenzene (1.2 g, yield 80%) 1H NMR (400 MHz, CDCl3): δ 7.50 (s, 1 H), 7.38 (d, 1 H), 7.15 (d, 1 H), 5.15-5.12 (m, 1 H),5.03-5.00 (m, 2 H), 4.91-4.88 (m, 1 H), 4.62 (s, 2 H), 3.43 (s, 3 H), 2.32 (s, 3 H) ppm.
Reaction SMILES: [N+](=[C:3]([C:9](=[O:15])[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].Cl>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH3:13][C:12]1([CH3:14])[CH2:11][CH2:10][C:9](=[O:15])[CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)CCC(C)C
Agent: [Rh+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)CCC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 1737.3 %

Procedure:
Rhodium acetate (170 mg) was added to a solution of ethyl 2-diazo-6-methyl-3-oxoheptanoate (0.5 g) in DCM (80 mL). A solution of ethyl 2-diazo-6-methyl-3-oxoheptanoate (7.652 g) in DCM (50 mL) was added in portions. The mixture was stirred at room temperature for 1 hour. 1N HCl (100 mL) was added. The organic phase was separated. The aqueous phase was extracted with DCM (100 mL). The combined DCM solutions were dried (Na2SO4). After filtration and concentration, the crude material was purified with flash chromatography to give ethyl 2,2-dimethyl-5-oxocyclopentanecarboxylate (7.54 g). 1H NMR (CDCl3, 400 MHz) δ (ppm): 4.25-4.09 (m, 2H), 2.52-2.37 (m, 2H), 2.03-1.99 (m, 2H), 1.80-1.67 (m, 1H), 1.33-1.26 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][OH:14])=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:15])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][O:14][C:21]3[CH:22]=[CH:23][C:18]([S:17][CH3:16])=[CH:19][CH:20]=3)=[CH:12][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2ccc(CO)cc2OC1
Reactant: CSc1ccc(O)cc1
Product: CSc1ccc(OCc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
According to the method described in example 23, the title compound is prepared from (3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-methanol (31) and 4-(methylthio)phenol. MS (ESI) 331.3 (M+H)+.