Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([CH:35]1[CH2:40][CH2:39][CH:38]([CH2:41]O)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:41][CH:38]4[CH2:39][CH2:40][CH:35]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:36][CH2:37]4)=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCc1ccc(O)cc1
Reactant: CCCCCC1CCC(CO)CC1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(OCc4ccccc4)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
To a solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol (970 mg, 2.53 mmol), 4-pentylcyclohexylmethanol (699 mg, 3.79 mmol) and triphenylphosphine (994 mg, 3.79 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (956 mg, 3.79 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as a solid. 1.11 g (yield: 79.9%)
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:22](O)=[O:23])[CH2:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[C:40]1([S:46]([NH2:49])(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[H][H]>CN(C)C1C=CN=CC=1.C(Cl)Cl.[Pd].CO>[C:2]([O:5][C:6]([NH:8][C@H:9]([C:22](=[O:23])[NH:49][S:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:48])=[O:47])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: NS(=O)(=O)c1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)NS(=O)(=O)c1ccccc1

Procedure:
1.7 g (5.0 mmol) of Boc-Glu (OBzl)-OH, 1.03 g (5.0 mmol) of dicyclohexylcarbodiimide and 611 mg (5.0 mmol) of 4-(dimethylamino)pyridine were suspended in 20 ml of methylene chloride, to which 866 mg (5.0 mmol) of benzenesulfonamide was added. Following agitation at room temperature overnight, extraction was performed with ethyl acetate/1N hydrochloric acid. The organic layer was washed with saturated saline and then added with sodium sulfate for drying. The organic layer was subjected to vacuum condensation. To the resulting residue, 100 mg of 10% Pd/C and 20 ml of methanol were added and stirred overnight in a hydrogen atmosphere under a normal pressure. After filtrating the catalyst away, the solvent was distilled away and purification step A was used to obtain a crude product of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ccccc4s3)cc2)cc1

Procedure:
To 2-(4-aminophenyl)-benzothiazole (0.5 g, 2.2 mmol) in pyridine (6 mL) was added para-toluenesulphonyl chloride (0.506 g, 2.7 mmol, 1.5 equiv.) in pyridine (4 mL). The reaction mixture was heated at reflux for 10 mins, then cooled and water (10 mL) added. The white precipitate formed was collected on a filter, washed with water and dried under vacuum to give N-[(4-benzothiazol-2-yl)phenyl]-4-methylbenzenesulfonamide as a white solid. The yield was 0.807 g (96%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[CH:11][C:12]1[C:13](=[O:21])[NH:14][C:15]([CH3:20])=[C:16]([CH2:18][CH3:19])[CH:17]=1>CO.C(O)C.C1COCC1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=[O:21])[NH:14][C:15]([CH3:20])=[C:16]([CH2:18][CH3:19])[CH:17]=1
Reactant: CCc1cc(C=Cc2nc3ccccc3o2)c(=O)[nH]c1C
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc(CCc2nc3ccccc3o2)c(=O)[nH]c1C

Procedure:
A solution of 80% pure 3-[2-(benzoxazol-2-yl)ethenyl]-5-ethyl-6-methyl-2-(1H)-pyridinone 200 mg) in methanol/ethanol/THF (25 mL, 1:1:1) was hydrogenated at atmospheric pressure over 5% palladium/charcoal for four hours. After filtering off the catalyst, the solvents were evaporated and the residue flash chromatographed over silica gel. Elution with 2% methanol-98% chloroform gave 75 mg of analytically pure product, mp 155°-156.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](I)=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.CCOCC.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.[Cu]I>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:9][C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: Oc1cc(Br)cnc1I
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(Br)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
A sample of 5-bromo-2-iodo-3-pyridinol (0.60 g, 2.0 mmol), from above, was dissolved in DMF (3 mL), and Pd(PPh3)2Cl2 (0.07 g, 0.1 mmol), CuI (0.077 g, 0.4 mmol) and triethylamine (0.33 mL, 2.4 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1-BOC-2-(S)-ethynylpyrrolidine (0.429 g, 2.2 mmol), from Example 1c above, dissolved in DMF (1 mL), was added carefully. The reaction mixture was stirred at 60° C. for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether, then washed with 10% NaOH and brine. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 2:1) to give the title compound (0.32 g, 43%): 1H NMR (CDCl3, 300 MHz) δ 1.32, 1.46 (2 s, 9H), 1.91-2.40 (m, 4H), 3.37-3.70 (m, 2H), 4.93-5.15 (m, 1H), 6.66 (s, 1H), 7.85 (s, 1H), 8.55 (s, 1H); MS (CI/NH3) m/z: 367, 369 (M+H)+.
Reaction SMILES: C([Si](C)(C)O[Si](C)(C)C=C)=C.[CH3:12][SiH:13]([CH3:15])[Cl:14].[C:16]1([O:22][CH2:23][CH2:24][O:25][CH2:26][CH:27]=[CH2:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Pt]>[O:22]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][Si:13]([CH3:15])([CH3:12])[Cl:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[SiH](C)Cl
Reactant: C=CCOCCOc1ccccc1
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Product: C[Si](C)(Cl)CCCOCCOc1ccccc1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
6 mg of platinum in the form of a solution of the complex with 1,3-divinyltetramethyldisiloxane are added to 290 ml (2.6 mol) of dimethylchlorosilane and the mixture is heated at reflux under a nitrogen atmosphere. 356 g of the 2-allyloxyethyl phenyl ether whose preparation is described above under a) are added dropwise over the course of about 2 hours, the temperature of the mixture being adjusted to 80° C. After 2 hours the reflux comes virtually to an end. The crude product is fractionated in vacuo, the main fraction being taken off at 95°-110° C. (2 hPa). 437 g of 3-(2-phenoxyethoxy)propyldimethylchlorosilane are obtained with an acid number of 207 (theoretically 205). The 1H NMR spectrum shows that the product contains neither starting material nor its 1-propeneoxy isomer.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[C:13]([O:16][CH2:17][CH2:18][SH:19])(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CO>>[C:13]([O:16][CH2:17][CH2:18][S:19][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4])(=[O:15])[CH3:14]
Reactant: CC(=O)OCCS
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)OCCSCC(=O)c1ccc(F)cc1F
Yield: 65.6 %

Procedure:
Using 2-chloro-2',4'-difluoroacetophenone (2.0 g, 0.010 mol), 2-acetoxyethanethiol (J. Chem. Soc., 1952, 817.) (1.5 g, 0.013 mol), potassium carbonate (1.8 g, 0.013 mol) and methanol (50 mol), 2-(2-acetoxyethyl)thio-2',4'-difluoroacetophenone (1.8 g, yield: 62.0%) was obtained as a colorless oil by similar procedures to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[C:21]([C:28]4[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=4)[N:20]=[CH:19]3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(Cl)cc4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-chloro-phenyl)-6-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-pyridine (example E.19) (1.35 g, 3.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.792 g, 3.6 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.750 g, 60%). MS (ISP) 416.3 [(M+H)+] and 418 [(M+2+H)+]; mp 196° C. (dec.).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:5]2([CH2:10][CH2:9][N:8](C(C(NC(=O)C(N)(C)C)CC3C4C(=CC=CC=4)NC=3)=O)[CH2:7][CH2:6]2)[CH2:4]1.[F:37][C:38]([F:43])([F:42])[C:39](O)=[O:40].C1(OC)C=CC=CC=1>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([NH2:8])=[O:40].[NH:8]1[CH2:9][CH2:10][C:5]2([C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:3](=[O:2])[CH2:4]2)[CH2:6][CH2:7]1
Reactant: CC(C)(N)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: COc1ccccc1
Product: NC(=O)C(F)(F)F
Product: O=C1CC2(CCNCC2)c2ccccc21
Reaction time: 1 h

Procedure:
A solution of the intermediate from Step A in a 1:1:0.5 mixture of trifluoroacetic acid, dichloromethane and anisole was stirred for 1 hour and then concentrated and azeotroped from toluene to give the title compound. 1H NMR (200 MHz, CDCl3): 7.81-7.70 (m, 1H),7.62-7.45 (m, 2H), 7.22-7.15 (m, 1H), 3.72-3.58 (m, 2H), 3.29-3.04 (m, 2H), 2.70 (s, 2H), 2.47 (dt, 2H), 1.85-1.75 (m, 2H).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:9]=[C:8]([C:10]([O:12]CC)=O)[O:7][N:6]=1)([CH3:4])[CH3:3].[NH2:15][CH2:16][C@@H:17]([N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1)[CH3:18]>>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([C@@H:17]([CH3:18])[CH2:16][NH:15][C:10]([C:8]3[O:7][N:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:9]=3)=[O:12])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CCOC(=O)c1nc(C(C)(C)O)no1
Product: C[C@@H](CNC(=O)c1nc(C(C)(C)O)no1)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 52(g) starting from ethyl 3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxylate (1.5 mmol, 300 mg) and (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.5 mmol, 417 mg). Yield 160 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.49 (bs, 9H), 3.57-3.64 (m, 1H), 3.68-3.76 (m, 1H), 4.69-4.75 (m, 1H), 5.69 (s, 1H), 7.02 (d, 1H), 7.89 (d, 1H), 7.94 (d, 1H), 7.99 (s, 1H), 9.46 (t, 1H). LC-MS: [M+1]=433.17.
Reaction SMILES: [NH2:1][C@@H](C1[N:11]2[C:7]([S:8][C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)=[N:10]2)=NN=1)C.[NH2:20][C:21]1[C:22]([C:32]([OH:34])=O)=[N:23][C:24]([C:27]2[CH:31]=[CH:30][O:29][CH:28]=2)=[CH:25][N:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH2:23][CH:22]([C:21]1[N:10]2[C@H:9]([S:8][CH:7]=[N:11]2)[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:20]=1)[CH3:32].[O:29]1[CH:30]=[CH:31][C:27]([C:24]2[N:23]=[C:22]([C:32]([NH2:1])=[O:34])[CH:21]=[N:26][CH:25]=2)=[CH:28]1
Reactant: Nc1ncc(-c2ccoc2)nc1C(=O)O
Reactant: C[C@@H](N)c1nnc2sc(Nc3cccc(Cl)c3)nn12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(N)C1=NN(c2cccc(Cl)c2)[C@H]2SC=NN12
Product: NC(=O)c1cncc(-c2ccoc2)n1
Yield: 118.7 %

Procedure:
(Step 8-v) To a mixture of (R)-3-(1-aminoethyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-amine (0.141 g, 0.483 mmol) in DMF (3 mL) was added 3-amino-6-(furan-3-yl)pyrazine-2-carboxylic acid (0.066 g, 0.322 mmol), HBTU (0.159 g, 0.42 mmol), and TEA (0.135 ml, 0.966 mmol). After two hours the mixture was diluted with water and the resulting solids were collected. The solids were washed sequentially with 20% ethanol/ethyl ether, methylene chloride, and methanol, then dried in vacuo to provide (R)-3-(1-aminoethyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-(furan-3-yl)pyrazine-2-carboxamide (0.09 g): 1H NMR 300 MHz DMSO-d6 10.8 (s, 1H), 9.21 (s, 1H), 8.61 (s, 1H), 8.38 (s, 1H), 7.68 (s, 1H), 7.51 (s, 1H), 7.39 (d, 2H), 7.13 (m, 3H), 7.05 (d, 2H), 5.69 (m, 1H), 1.76 (d, 3H); ESMS MH+=482.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.N1C(C)=CC(C)=CC=1C.S([Cl:33])(C)(=O)=O.[Cl-].[Li+]>CN(C)C=O.O>[Cl:33][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=c1[nH]nc(-c2cccc(CO)c2)c2ccccc12
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: O=c1[nH]nc(-c2cccc(CCl)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound prepared in example 1 (2.52 g) in dimethylformamide (30 ml) were added 2,4,6-collidine (3.96 ml), mesyl chloride (929 μl) and lithium chloride (593 mg). The mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water and the precipitate was collected by filtration. The precipitate was washed with water, methanol and ether to give the title compound (2.50 g) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:9][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][C:14]=3[O:15][C:4]=2[CH:3]=1.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>>[C:23]1([S:29]([C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[CH2:9][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][C:14]=4[O:15][C:4]=3[CH:3]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCc2oc3cc(Br)ccc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCCc2oc3cc(S(=O)(=O)c4ccccc4)ccc3c2C1
Yield: 34 %

Procedure:
The product of step E was coupled with sodium benzenesulfinate following the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 70:30 hexanes/ethyl acetate) provided tert-butyl 8-(phenylsulfonyl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (106 mg, 34%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.04-7.87 (m, 3H), 7.83-7.72 (m, 1H), 7.60-7.41 (m, 4H), 4.64-4.61 (m, 2H), 3.67 (br s, 2H), 3.03 (t, J=6.3 Hz, 2H), 1.99 (br s, 2H), 1.53-1.25 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].CN(C)C=O.[H-].[Na+].I[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCI
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCNc1c(F)c(C)c(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.3 %

Procedure:
653 mg (1.62 mmol) of the above 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one was dissolved ion 20 mL of dimethylformamide under argon atmosphere, 200 mg (5.00 mmol) of sodium hydride (60% oil dispersion) and 0.48 mL (3.2 mmol) of 1-iodohexane were added under ice-cooling and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by medium pressure liquid chromatography to give 422 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(1-hexylamino)-7-methyl-4H-1-benzopyran-4-one (yield: 54%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2C(C(O)=O)=[CH:18]1>ClCCl>[ClH:4].[Cl:4][C:2]([C:1]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:17]([C:8]2[CH:9]=[CH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]=2)[CH:18]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn(-c2ccc3ccccc3n2)c2ncccc12
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1cn(-c2ccc3ccccc3n2)c2ncccc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.606 cm3 (6.91 mmol) of oxalyl chloride was added, at a temperature in the region of 20° C., to 1.0 g (3.46 mmol) of 1-(quinolin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid in suspension in 30 cm3 of dichloromethane. After stirring at a temperature in the region of 20° C. for 2 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was used directly in the following stage.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4]>[Pt].O>[OH:1][CH2:2][C:3]([C@H:5]([C@H:2]([CH2:3][OH:4])[OH:1])[OH:6])=[O:4]
Reactant: OCC(O)CO
Agent: [Pt]
Solvent: O
Product: O=C(CO)[C@@H](O)[C@@H](O)CO
Reaction time: 48 h

Procedure:
One hundred ml aliquots of a nutrient culture medium, consisting of 2 w/v % trypton soya broth, one w/v % glycerol and deionized water, were distributed to ten 500-ml shaking flasks, followed by autoclaving the flasks at 120° C. for 20 min. Thereafter, the flasks were cooled and inoculated with a seed culture of Gluconobacter frateurii (IFO 3254) using a platinum loop, followed by incubation at 30° C. for 2 days under shaking conditions. After completion of the culture, the cells were collected by centrifugation, and about 10 g wet alive cells was mixed with 100 ml of 0.05 M Tris-HCl buffer (pH 7.0) containing 5 w/v % ribitol. The mixture solution in a volume of 100 ml was placed in a 500-ml shaking flask, and incubated at 30° C. for 20 hours under shaking conditions to convert ribitol into L-ribulose. Thereafter, the culture was centrifuged to remove cells, and the resulting supernatant was in a conventional manner decolored with activated charcoal, desalted with "DIAION SK1B (H-form)" and "DIAION WA30 (OH-form)", both of which are cation exchangers of Mitsubishi Chemical Corporation, Tokyo, Japan, and concentrated in vacuo to obtain a transparent syrup with a concentration of about 60 w/w %. The syrup was fractionated by column chromatography using "DOWEX 50W-X4", a cation exchanger in Ca++ -form commercialized by The Dow Chemical Co., Midland, Mich., USA, to obtain high L-ribulose content fractions which were then concentrated into an about 70 w/w % syrup. High-performance liquid chromatographic (HPLC) analysis using a column, 8×300 mm, packed with "MCIGEL CK-08EC", a gel in Ca++ -form commercialized by Mitsubishi Chemical Corporation, Tokyo, Japan, revealed that the product contained at least 97 w/w % L-ribulose, d.s.b. The yield of L-ribulose to the material ribitol was about 90%, d.s.b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].C(N(C(C)C)C(C)C)C.Cl.[C:34]([O:38][C:39](=[O:43])[C@H:40]([CH3:42])[NH2:41])([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:41][C@H:40]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:43])[CH3:42])=[O:19])=[C:5]2[OH:23]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 66.5 %

Procedure:
Ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (610 mg, 1811 μmol, prepared in Example 1 A-C) was dissolved in 1,4-dioxane (1811 μL) and N-ethyl-N-isopropylpropan-2-amine (947 μL, 5434 μmol). L-Alanine t-butyl ester hydrochloride (494 mg, 2717 μmol) was added, and the reaction mixture was heated to 80° C. for 24 hours. The reaction mixture was then cooled to ambient temperature, diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (525 mg) as an oil after flash chromatography. MS (m/z)=436 (M+H)+.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][CH:11]([SH:13])[CH3:12].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:13][CH:11]([CH3:12])[CH3:10])([CH3:9])[CH3:8])[CH3:7]
Reactant: CC(C)S
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC(C)C
Yield: 61.7 %

Procedure:
Ethyl 2-bromoisobutyrate (100 g, 0.513 mole), 2-propanethiol (42.95 g, 0.564 mole), potassium hydroxide (36.0 g, 0.564 mole), ethyl alcohol (200 g) were combined and reaction mixture was refluxed for three hours prior to quenching. Crude yield: 74.7%, distilled yield: 61.7%.