Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[C:11]2[C:6]([C:7]([C:21]([F:24])([F:23])[F:22])=[CH:8][CH:9]=[CH:10]2)=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:11]2[C:6]([C:7]([C:21]([F:24])([F:23])[F:22])=[CH:8][CH:9]=[CH:10]2)=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(O)cc1
Yield: 110 %

Procedure:
Prepared according to Method D step C from 2-allyl-3-(4-methoxyphenyl)-7-trifluoromethyl-2H-indazole (0.007 g, 0.02 mmol), boron tribromide (0.10 mL, 1.05 mmol) and 0.3 mL of cyclohexene to give the product (0.007 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C:12]([CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][CH:40]=1)[C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]=1)=[O:20])=[O:13])(C)[CH3:9].[CH2:41](NC)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:11]([CH3:41])[C:12]([CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][CH:40]=1)[C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]=1)=[O:20])=[O:13])[CH3:9]
Reactant: CCNC
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)NC(C)C)c3)c2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)C(=O)COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resin bound activated ester (intermediate in the preparation of 1-[3-(Isopropylcarbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37)) (225 mg, 0.19 mmol) was combined with 3 ml of methylene chloride and 0.035 ml of ethylmethylamine (0.4 mmol). The mixture was shaken for 15 minutes under argon at room temperature. The mixture was filtered and the filter cake was washed with methylene chloride. The filtrate was evaporated to dryness. The residue was saponified by dissolving in 1 ml of methanol containing 0.5 ml of 1N sodium hydroxide solution and several drops of tetrahydrofuran. The mixture was stirred at room temperature for 4 hrs and then evaporated to dryness. The residue was purified through a reverse phase preparative HPLC to give 1-{3-[(Ethyl-methyl-carbamoyl)-methoxy]-benzoyl}-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid, as a fluffy solid (27 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:18])=[C:9](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OC(=O)CO[C:25]1[CH:30]=CC=C(O)[C:26]=1C(=O)C)C>>[CH2:30]([O:1][C:2]1[C:7]2[C:8]([CH3:18])=[C:9](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH:25]=[CH2:26]
Reactant: CCOC(=O)COc1cccc(O)c1C(C)=O
Reactant: CCOC(=O)/C=C/c1oc2cccc(O)c2c1C
Product: C=CCOc1cccc2oc(/C=C/C(=O)OCC)c(C)c12

Procedure:
Following the procedure of Example 116 but substituting an equivalent amount of ethyl E-3-(4-hydroxy-3-methylbenzofuran-2-yl)propenoate for the compound of Example 1, there was obtained the title compound, m.p. 79°-80° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]2[O:29][CH:30]=[C:31]([CH2:33]Cl)[N:32]=2)=[C:22]([F:35])[CH:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]2[O:29][CH:30]=[C:31]([CH2:33][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:32]=2)=[C:22]([F:35])[CH:21]=1
Reactant: Fc1cc(Cl)ccc1C=Cc1nc(CCl)co1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Cl)ccc1/C=C/c1nc(COc2ccc(COCCn3ccnn3)cc2)co1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
380 mg (15 mmol) of 95% sodium hydride were given to a solution of 3.00 g (13.7 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 70 ml N,N-dimethylformamide and stirred for 30 min at room temperature. Then 3.73 g (13.7 mmol) 2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-4-chloromethyl-oxazole were added and stirring continued over night. The mixture was quenched with water, stirred for 1 h and the precipitate isolated by filtration. After washing with water, little methanol, ethyl acetate/heptane 2:1 and ether, and drying at 40° C. in vacuo, 3.34 g (54%) 1-[2-(4-{2-[2-(E)-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzyloxy)-ethyl]-1H-[1,2,3]triazole were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:22]([O:33][C@H:34]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:35][C:36]([OH:38])=O)(=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CI.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)CCl>[C:22]([O:33][C@H:34]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:35][C:36]([NH:1][CH2:2][CH2:3][OH:4])=[O:38])(=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Reactant: CC(C)(C)[Si](OCCN)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCCl
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@H](CC(=O)NCCO)OC(=O)CCCCCCCCC
Yield: 73.7 %

Procedure:
In the same manner as described in Example 20-(1), 2-amino-1-(t-butyldiphenylsilyloxy)ethane (450 mg, 1.5 mmol) was acylated with (R)-3-decanoyloxytetradecanoic acid (600 mg, 1.5 mmol) in the presence of EDC.MeI (594 mg, 2.0 mmol) and then deprotected with TBAF (1.0 M in THF, 2.5 mL, 2.5 mmol) in THF (10 mL) to afford 488 mg (81%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethanol as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([NH:16]C(=O)C)[CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([NH2:16])[CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: CC(=O)Nc1cc2c(cn1)COc1cc(Cl)ccc1-2
Agent: Cl
Product: Nc1cc2c(cn1)COc1cc(Cl)ccc1-2
Temperature: 25 °C

Procedure:
N-(8-chloro-5H-chromeno[3,4-c]pyridin-2-yl)acetamide (0.05 g, 0.182 mmol) was taken up in 50% aqueous HCl (3 mL, 99 mmol) and refluxed for 3 h. The reaction mixture was cooled to room temperature and the volatiles were evaporated under reduced pressure. The residue was treated with water (3 mL) and extracted with dichloromethane (2×6 mL). The aqueous layer was collected and concentrated under reduced pressure to afford a 8-chloro-5H-chromeno[3,4-c]pyridin-2-amine, hydrochloride (50 mg, 0.185 mmol, quantitatively) as a yellow oil. LCMS (ESI) m/e 233.3 [(M+H)+, calcd for C12H10ClN2O 233.0]; LC/MS retention time (method G); tR=0.89 min
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH:18]=[C:17]([C:19](OCC)=[O:20])[N:16]=[CH:15]2)[CH2:10][CH2:9]1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[CH3:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]2[CH:18]=[C:17]([CH:19]=[O:20])[N:16]=[CH:15]2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1cn([C@H]2CC[C@@H](C)CC2)cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@@H](n2cnc(C=O)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
Lithium aluminum hydride (0.35 g) was suspended in tetrahydrofuran (10 mL). To the suspension, a solution of the compound (1.67 g) obtained in Step 1 of this Reference Example in tetrahydrofuran (10 mL) was added dropwise under ice cooling. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours and 40 minutes, and water (2 mL), 5 N aqueous sodium hydroxide (2 mL), and water (6 mL) were added thereto in this order under cooling. The mixture was stirred at room temperature for 2 hours. Then, anhydrous sodium sulfate was added thereto, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in methylene chloride (20 mL). To the solution, manganese dioxide (21.6 g) was added, and the mixture was stirred at room temperature for 17 hours and then filtered through celite. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=50/50-20/80) to obtain the title compound (0.79 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CC([O-])=O.[Na+].[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH:46]=[CH2:47]>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:50]([O:49][C:45](=[O:48])[CH:46]=[CH:47][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15])[CH3:51]
Reactant: O=C1CC[C@@H](c2ccc(Br)c(C(F)(F)F)c2)C1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc([C@@H]2CCC(=O)C2)cc1C(F)(F)F
Temperature: 130 °C

Procedure:
To a mixture of (R)-3-(4-bromo-3-trifluoromethyl-phenyl)-cyclopentanone (Preparation 6, 1.96 g), tri(o-tolyl)phosphine (120 mg), Pd(OAc)2 (43 mg) and NaOAc (0.79 g) in DMF (13 mL) was added ethyl acrylate (0.79 g), and the reaction mixture was heated to 130° C. for 3 h. The mixture was diluted with EtOAc and washed with water. The organic phase was dried and concentrated in vacuo, and the residue was purified by flash chromatography using a gradient of heptane and EtOAc to obtain the title compound. 1H NMR (300 MHz, CDCl3) δ 8.09-7.97 (m, 1H), 7.70 (d, 1H), 7.58 (d, 1H), 7.53-7.38 (m, 1H), 6.40 (d, 1H), 4.28 (q, 2H), 3.58-3.40 (m, 1H), 2.72 (dd, 1H), 2.58-2.26 (m, 4H), 2.10-1.92 (m, 1H), 1.34 (t, 3H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH2:10][NH:11][C:12](=[O:15])[CH2:13][Br:14])=O)(C)(C)C.Cl>C(OCC)(=O)C>[Br:14][CH2:13][C:12]([NH:11][CH2:10][C@@H:9]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[NH2:8])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CBr)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CNC(=O)CBr)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 42.7 %

Procedure:
To an ice-cooled solution of (1R)-N1 -(tert-butoxycarbonyl)-N2 -(bromoacetyl)-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (9.32 g) in ethyl acetate (90 ml) was added 4N hydrogen chloride in ethyl acetate solution (90 ml). The mixture was stirred at the same temperature for 50 minutes and then evaporated under reduced pressure. Dichloromethane and aqueous saturated sodium bicarbonate solution were added to the residue. The organic layer was separated. The aqueous layer was extracted six times with dichloromethane. The extracts were combined and dried over magnesium sulfate, and concentrated under reduced pressure to give (1R)-N2 -(bromoacetyl)-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (3.01 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])#[CH:28].O>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][Si:29]([C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])=[CH:4][CH:3]=1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of tert-butyl 2-[(4-bromophenyl)acetyl]hydrazinecarboxylate (10 g, 30.4 mmol), copper (I) iodide (579 mg, 3.04 mmol), dichlorobis(triphenylphosphine)palladium (II) (2.13 g, 3.03 mmol) and triethylamine (8.5 ml, 61.0 mmol) in anhydrous N,N-dimethylformamide (50 ml) was added ethynyltrimethylsilane (6.3 ml, 45.5 mmol). After stirring overnight at 50° C., water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70→35:65) to give tert-butyl 2-({4-[(trimethylsilyl)ethynyl]phenyl}acetyl)hydrazinecarboxylate (7.1 g, yield 68%) as a greeny brown solid.
Reaction SMILES: P(O[CH2:14][C@H:15]1O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)[C@H:17](O)[C@@H:16]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.C(NC1NC(=O)NC(=O)C=1N)[C@H](O)[C@H](O)[C@H](O)CO.[CH3:52][C:53]1[N:64]=[C:63]2[C:56](=[N:57][C:58]([NH:60][C:61]2=[O:62])=[O:59])[N:55]([CH2:65][C@H:66]([OH:73])[C@H:67]([OH:72])[C@H:68]([OH:71])[CH2:69][OH:70])[C:54]=1[CH3:74]>>[CH3:14][C:15]1[CH:52]=[C:53]2[N:64]=[C:63]3[C:56](=[N:57][C:58]([NH:60][C:61]3=[O:62])=[O:59])[N:55]([CH2:65][C@H:66]([OH:73])[C@H:67]([OH:72])[C@H:68]([OH:71])[CH2:69][OH:70])[C:54]2=[CH:74][C:16]=1[CH3:17]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: Cc1nc2c(=O)[nH]c(=O)nc-2n(C[C@H](O)[C@H](O)[C@H](O)CO)c1C
Agent: Nc1c(NC[C@H](O)[C@H](O)[C@H](O)CO)[nH]c(=O)[nH]c1=O
Product: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C

Procedure:
Guanosine triphosphate (GTP) is converted by GTP cyclohydrolase II (rib 1 gene product) into 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5-phosphate. This compound is subsequently reduced by the rib 7 gene product to 2,5-diaminoribitylamino-2,4(1H,3H)-pyrimidine 5-phosphate and then deaminated by the rib 2 gene product to 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione. Subsequently, in a reaction catalyzed by the rib 4 gene product, the C4 compound DBP is added on to result in 6,7-dimethyl-8-ribitvllumazine (DMRL), from which riboflavin is produced in the reaction catalyzed by the rib 5 gene product. The C4 compound DBP (L-3,4-dihydroxy-2-butanone 4-phosphate) is formed from D-ribulose 5-phosphate in a reaction catalyzed by the rib 3 gene product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C@@H:22]([N:24]1[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]1[CH3:30])[CH3:23].C(Br)(Br)(Br)[Br:32]>C(#N)C>[Br:32][CH2:21][C@@H:22]([N:24]1[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]1[CH3:30])[CH3:23]
Reactant: Cc1ccc(C)n1[C@@H](C)CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1ccc(C)n1[C@@H](C)CBr
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
Triphenylphosphine (2.24 g, 8.50 mmol) was added in four portions over 10 minutes to an ice cooled mixture of (S)-1-(2-hydroxy-1-methylethyl)-2,5-dimethylpyrrole (1.0 g, 6.54 mmol) and carbon tetrabromide (3.03 g, 9.15 mmol) in 50 mL of acetonitrile. The mixture was stirred at 0° C. for 1.5 h, room temperature for 18 h, and 50° C. for 6 h. The solvent was removed in vacuo. The residue was purified by flash column chromatography on 70 g of silica gel, eluting with 1 L of 15% dichloromethane in hexane to give 1.22 g (85% yield) of (S)-1-(2-bromo-1-methylethyl)-2,5-dimethylpyrrole as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:34]([NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:35])=[N:4][C:5]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][O:30][CH2:31][O:32]C)=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[N:6][C:7]=1[CH3:8].Cl.O1CCOC[CH2:45]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:31]([O:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:12][CH2:11][CH:10]([CH2:9][C:5]4[N:4]=[C:3]([C:34]([NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:35])[C:2]([OH:1])=[C:7]([CH3:8])[N:6]=4)[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)=[CH:24][CH:25]=1)(=[O:32])[CH3:45]
Reactant: C1COCCO1
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(Cc4ccc(COCOC)cc4)cc3)CC2)nc(C)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(Cc4ccc(COC(C)=O)cc4)cc3)CC2)nc(C)c1O
Reaction time: 12 h
Yield: 68.4 %

Procedure:
Ethyl {[(5-hydroxy-2-{[1-(4-{4-[(methoxymethoxy)methyl]benzyl}phenyl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetate (1.1 g, 1.9 mmol) was dissolved in ethyl acetate (14 mL), and a solution of hydrogen chloride in dioxane (4 M, 7 mL, 28 mmol) was added at room temperature, followed by stirring at the same temperature for 12 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.60 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.74 g, 1.3 mmol) as a yellow oil (yield 69%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:17]([C:14]3[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=3)(=[O:19])=[O:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Reference: Gerster, John F.; Hinshaw, Barbara C.; Robins, Roland K.; Townsend, Leroy B. Study of electrophylic substitution in the pyrrolo[2,3-d]pyrimidine ring. J. Heterocycl. Chem. (1969), -(2), 207-213) (20 g) and para-toluene sulfonylchloride (28.6 g) in toluene (1L) was treated with a solution of sodium hydroxide (50 g) in water (800 mL), and tetrabutyl ammonium sulfate (462 mg). The solution was stirred vigorously at room temperature for 2 hours and partitioned between ethyl acetate and brine. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a gradient of ethyl acetate and cyclohexane (50:50 to 80:20, v/v) to give the title compound (2.5 g) as a solid m.p.=143° C. LCMS (Method B) RT=2.78 minutes.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[CH2:14]([C:18]1[CH:19]=[C:20]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=O)[C:21]2[O:25][CH2:24][C:23]([CH3:27])([CH3:26])[C:22]=2[CH:28]=1)[CH:15]([CH3:17])[CH3:16].[S:42]1[CH2:46][C:45](=[O:47])[NH:44][C:43]1=[O:48]>C(OCC)(=O)C.C(O)(=O)C>[CH2:14]([C:18]1[CH:19]=[C:20]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][C:38]([F:41])([F:39])[F:40])[CH:32]=[C:46]2[S:42][C:43](=[O:48])[NH:44][C:45]2=[O:47])[C:21]2[O:25][CH2:24][C:23]([CH3:26])([CH3:27])[C:22]=2[CH:28]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)Cc1cc(-c2cc(C=O)ccc2OC(F)(F)F)c2c(c1)C(C)(C)CO2
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C)Cc1cc(-c2cc(C=C3SC(=O)NC3=O)ccc2OC(F)(F)F)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A mixture of toluene (35 mL), piperidine (145 μL), acetic acid (145 μL), 3-(5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde (5.7 g, 14.53 mmol) and 2,4-thiazolidinedione (1.7 g, 14.53 mmol) was heated at reflux for 20 hrs. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (0 to 20% ethylacetate in hexane) and further recrystallised from ethanol/water to afford 5.15 g (72%) of 5-[3-(5-Isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione. mp 142–146° C. 1H-NMR (300 MHz, DMSO-d-6): 0.87 (d, J=6.9 Hz, 6H), 1.31 (s, 6H), 1.81 (m, 1H), 2.44 (d, J=6.9 Hz, 2H), 4.19 (s, 2H), 6.91 (d, J=1.5 Hz, 1H), 7.07 (d, J=1.5 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.70 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.75 (d, J=2.1 Hz, 1H), 7.86 (s, 1H), 12.70 (br s, 1. The intermediate 3-(5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde was prepared as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].[CH3:11][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]([OH:9])[CH3:11]
Reactant: O=Cc1c(Cl)cncc1Br
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)cncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 3-Bromo-5-chloro-pyridine-4-carbaldehyde (440 mg, 2 mmol) in THF (8 mL) was added methylmagnesium bromide (3M solution in THF, 2 mL, 6 mmol) at −36° C. After 1 h, the resulting mixture was warmed to 0° C., and saturated NH4Cl solution was added. The mixture was extracted with ethyl acetate, and washed with brine. The combined extracts were separated, dried over MgSO4 and concentrated. The residue was passed though a pad of silica gel and eluted with EtOAc/Heptane (v/v, 1:1). After concentration, 370 mg of title compound was obtained without further purification. ESI-MS m/z: 237.8 [M+1]+, Retention time 1.20 min. 1H-NMR (CDCl3, 400 MHz) δ 1.56 (d, J=6.8 Hz, 3H), 5.43 (q, J=6.8 Hz, 1H), 8.40 (1H), 8.52 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 3-trifluoromethyl-phenyl boronic acid to give the title compound as colorless amorphous solid. MS: 461.3 (MH+).