Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[O:32]1[CH2:34][C@@H:33]1[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.Cl([O-])(=O)(=O)=O.[Li+]>CC#N>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][CH2:34][C@H:33]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[OH:32])[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: c1cncc([C@H]2CO2)c1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](NC[C@@H](O)c2cccnc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (124 mg, 0.28 mmol), (S)-3-oxiranyl-pyridine (34 mg, 0.28 mmol) and lithium perchlorate (60 mg, 0.56 mmol) in CH3CN was heated to 100° C. in a sealed tube and stirred for 1 h. The reaction mixture was concentrated and diluted with ethyl acetate. The solution was then treated with 1M Na2CO3 and the organic phase was separated. The aqueous phase was re-extracted with ethyl acetate (×2). The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 10:1:0.05 CH2Cl2:MeOH:NH4OH as an eluent to afford 15 mg of the title compound as an off-white solid (10%), m/z 562.7 [M+1]+.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C([Li])CCC.[CH2:15]([CH:18]([C:22]1[N:27]2[N:28]=[C:29]([CH3:32])[C:30](I)=[C:26]2[N:25]=[C:24]([CH3:33])[CH:23]=1)[CH2:19][CH2:20][CH3:21])[CH2:16][CH3:17]>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:32][C:29]1[C:30]([C:5]2[S:4][CH:3]=[N:7][CH:6]=2)=[C:26]2[N:25]=[C:24]([CH3:33])[CH:23]=[C:22]([CH:18]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:16][CH3:17])[N:27]2[N:28]=1
Reactant: C[Si](C)(C)c1nccs1
Reactant: CCCC(CCC)c1cc(C)nc2c(I)c(C)nn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCC(CCC)c1cc(C)nc2c(-c3cncs3)c(C)nn12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Charge an oven dried flask with 2-trimethylsilanylthiazole (1.765 g, 11.24 mmol) dissolved in anhydrous THF (30 mL) and chill under an inert atmosphere to −78° C. Slowly add n-butyl lithium (2.5 M hexane solution, 4.5 mL, 11.24 mmol) and stir 30 min at −78° C. Add anhydrous zinc chloride (2.26 g, 16.58 mmol) in one aliquot and stir 30 min at −78° C. Allow the reaction to rise to room temperature, stir 30 min, and add 7-(1-propyl-butyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.624 g, 5.18 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (0.423 g, 0.518 mmol). Reflux overnight in an oil bath (90° C.) under an inert atmosphere. Cool the reaction to room temperature, quench with saturated sodium bicarbonate, and dilute with ethyl acetate (150 mL). Separate and extract the aqueous with ethyl acetate (75 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (30% THF/hexane) to 0% hexane/100% (30% THF/hexane) in a step gradient of 10% increments to give a white solid (0.720 g, 42%). ES/MS m/z 329.0 (M+1)+.
Reaction SMILES: BrBr.[F:3][C:4]([F:18])([F:17])[O:5][C:6]1[CH:16]=[CH:15][C:9]([NH:10][CH2:11][CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[S-:19][C:20]#[N:21].[K+].[OH-].[Na+].C(O)(=O)C(O)=O>C(O)(=O)C.CC(C)=O.O>[NH:21]=[C:20]1[N:10]([CH2:11][CH2:12][C:13]#[N:14])[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]([F:17])([F:18])[F:3])=[CH:16][C:15]=2[S:19]1
Reactant: N#CCCNc1ccc(OC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C(O)C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: N#CCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Yield: 146.9 %

Procedure:
Bromine (3.2 g; 1 cc) is added at room temperature to 3-(4-trifluoromethoxyanilino)propionitrile (3 g) and potassium thiocyanate (7.8 g) dissolved in acetic acid (50 cc). Stirring is maintained for 12 hours at this temperature. The mixture is evaporated to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is taken up with water (100 cc) and the pH is brought to 9-10 by adding concentrated sodium hydroxide (10N). After extraction with ethyl acetate (2×50 cc, washing of the combined phases with water (2×20 cc), drying over anhydrous magnesium sulphate and evaporation to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa), a brown oil is isolated. This oil is dissolved in acetone (100 cc) and oxalic acid (2 g) is added. 2-Imino-3-(2-cyanoethyl)-6-trifluoromethoxy-benzothiazoline (5.5 g) is thereby isolated in the form of a monooxylate, m.p. 180° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH:24]3[CH2:26][CH2:25]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH:24]1([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=4)[CH:7]=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1ccc(-c2cc(-c3ccnc(Cl)c3)nc(C3CC3)c2)cc1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2′-chloro-6-cyclopropyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.29) (0.300 g, 0.80 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.230 g, 1.17 mmol) according to the general procedure VI. Obtained as a white solid (0.100 g, 28%). MS (ISP) 434.1 [(M+H)+]; mp 242-245° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.O.[OH-].[Na+].Cl>C(O)C>[C:15]1([C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:5][OH:4])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
34.2 g of 4-acetoxy-l,l,2-triphenyl-1-butene are dissolved in 200 ml of 94%ethanol, after which 20 ml of water and 45 ml of a 20% sodium hydroxide solution are added. The mixture is refluxed for 1 h. The solution is neutralized with 2M hydrochloric acid, after which the ethanol is evaporated. Water is added into the residue. The product is extracted in ethyl acetate, the ethyl acetate solution is dried over sodium sulfate andthe solvent is evaporated. The product is recrystallized from a mixture of water and methanol and then has m.p. 117°-9° C. The yield is23.7 g (79%). 1H-NMR-spectrum (CDCl3): δ 1.34 (1H, s), 2.73 (2H, t), 3.05 (2H, t), 6.90 (5H, s), 7.11 (5H, s), 7.25 (5H, s).
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25]O)=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[N:18][C:19]=2[NH:27][O:28][CH3:29])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[N-:54]=[N+:55]=[N-:56].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[CH:8]([O:7][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][N:54]=[N+:55]=[N-:56])=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:30]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[N:18][C:19]=2[NH:27][O:28][CH3:29])([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:10])[CH3:9]
Reactant: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCO)n2COCP(=O)(OC(C)C)OC(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCN=[N+]=[N-])n2COCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 36 (1.00 g, 1.48 mmol) in pyridine (20 mL) is treated with methanesulphonyl chloride (539 mg, 97%, 3.00 mmol) and the mixture is stirred for 20 h at room temperature. The reaction mixture is diluted with ethyl acetate (200 mL), washed with water (2×) and brine and the organic layer dried over MgSO4 followed by filtration and concentration. The residue containing 37 is dissolved in DMF (9 mL), treated with sodium azide (260 mg, 3.96 mmol) and the mixture stirred for 4 h at 100° C. The reaction mixture is diluted with ethyl acetate (300 mL), washed with water (2×) and brine and the organic layer dried over MgSO4. After filtration, the filtrate is concentrated and the residue was purified on a silica gel column using ethyl acetate:hexanes:methanol (1:1:0 to 1:1:0.2) as eluent to give 458 mg (44%, two steps) of product as a colorless film: 1H NMR (CDCl3): δ 8.04 (s, 1H), 7.89 (s, 1H), 7.40-7.18 (m, 13H), 6.79 (d, J=8.8 Hz, 2H), 4.87-4.76 (m, 1H), 4.73-4.60 (m, 2H), 4.19-3.68 (m, 4H), 3.77 (s, 3H), 3.41-3.32 (m, 1H), 3.22-3.10 (m, 1H), 2.47-2.32 (m, 1H), 2.24-2.12 (m, 1H), 1.29 (d, J=6.0 Hz, 6H), 1.24 (d, J=6.7 Hz, 6H). IR (neat, cm−1) 3017, 2103, 1605 and 1216. HRMS Calcd for C36H43N8O5P (M+H)+ 699.3172. Found: 699.3152.
Reaction SMILES: [C:1]([C:11]1[CH:35]=[CH:34][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:36]1([CH2:41][CH2:42][C:43](Cl)=[O:44])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([CH2:41][CH2:42][C:43]([N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:15][C:14]2[CH:34]=[CH:35][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=2)=[O:44])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)c(C(=O)OC)c2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)c(C(=O)OC)c2)C(=O)CCC2CCCC2)cc1

Procedure:
The title compound was prepared following the procedure G using the hydrochloride salt of methyl 5-{[(4-dec-1-ynylbenzyl)amino]methyl}-2-(2-methoxy-2-oxoethoxy)benzoate and 3-cyclopentylpropanoyl chloride (purification by flash chromatography on SiO2, chloroform/MeOH 99:1) as a colorless oil (70%). M+ (ESI): 604.0. HPLC, Rt: 6.2 min purity: 100%). 1H NMR (CDCl3) δ: 7.61 (m, 1H), 7.41-7.05 (m, 5H), 6.85 (m, 1H), 4.75 (s, 1H), 4.72 (s, 1H), 4.56 (m, 2H), 4.42 (m, 2H), 3.92 (s, 1.5H), 3.90 (s, 1.5H), 3.82 (s, 1.5H), 3.81 (s, 1.5H), 2.41 (m, 4H), 1.74-1.09 (m, 23H), 0.90 (t, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(Cl)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Cl)ccc1CBr

Procedure:
Bromination of 4-chloro-2-methoxytoluene by means of N-bromosuccinimide in boiling carbon tetrachloride in the presence of dibenzoyl peroxide produces 4-chloro-2-methoxybenzyl bromide as a colourless liquid which has a boiling point of 140°-145° C./13 mm Hg. Reaction of this compound with triethyl phosphite in boiling xylene turns it into diethyl 4-chloro-2-methoxybenzylphosphonate; this is a colourless, viscous liquid which has a boiling point of 132° C./0.1 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([C:12]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][C:15]2(OCC[O:16]2)[CH2:14][CH2:13]1)[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([C:12]1([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]1)[CH2:9][CH2:10][CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(NC(=O)OC(C)(C)C)C1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCC(NC(=O)OC(C)(C)C)C1(c2ccc(F)cc2)CCC(=O)CC1
Temperature: 25 °C

Procedure:
1.22 g of {1-[8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-butyl}-carbamic acid tert-butyl ester (16) were dissolved in 42 mL of acetone and 3 mL of 1N hydrochloric acid were added. The mixture was stirred at room temperature until conversion was complete. 40 mL of saturated aqueous sodium bicarbonate solution were added and the reaction mixture was extracted with ethyl acetate three times. The combined organic layer was extracted with brine, dried over sodium sulphate and evaporated to dryness to give 966 mg of crude (17), that was sufficiently pure for further conversion. Rt=1.72 min (Method 5). Detected mass: 308.2 (M-Isobutene+H+).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]([C:21]3[C:26]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[CH:25][N:24]=[C:23]([Cl:35])[N:22]=3)[CH3:20])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.C(O)C.O.O[Li].O>C1COCC1>[Cl:35][C:23]1[N:22]=[C:21]([N:19]([CH3:20])[CH2:18][CH2:17][CH2:16][O:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[C@H:6]([CH2:5][C:4]([OH:36])=[O:3])[CH2:7][CH2:8]3)[C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:25][N:24]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3-c3ccc(OC)cc3)ccc21
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cnc(Cl)nc2N(C)CCCOc2ccc3c(c2)CC[C@H]3CC(=O)O)cc1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a solution of ethyl((1S)-5-{3-[[2-chloro-5-(4-methoxyphenyl)-4-pyrimidinyl](methyl)amino]propoxy}2,3-dihydro-1H-inden-1-yl)acetate (Example 443, 70 mg, 0.137 mmol) in a mixture of THF (2 mL), ethanol (1 mL), and water (2 mL) was added LiOH.H2O (13 mg, 0.55 mmol). The mixture was maintained at rt in an orbital shaker for 16 h after which the reaction mixture was washed with Et2O. To the remaining aqueous solution was added HCl (1 N aqueous solution) dropwise until pH 5 was reached. The aqueous solution was then extracted with EtOAc, the combined organic layers dried (Na2SO4), filtered, and concentrated under reduced pressure to give 20 mg (30%) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.75-1.79 (m, 1H), 2.18-2.21 (m, 2H), 2.24-2.49 (m, 2H), 2.77-2.90 (m, 3H), 3.31 (s, 3H), 3.52-3.74 (m, 1H), 3.92 (s, 3H), 3.99 (t, 2H), 4.05 (t, 2H), 6.67 (d, 1H), 6.75 (s, 1H), 6.94 (d, 2H), 7.08 (s, 1H), 8.15 (s, 1H), 8.27 (d, 2H); LC-MS: RT=2.91 min, (M+H)+ 482.2.
Reaction SMILES: C(N)(=O)C=C.[CH3:6][C:7]1[C:38]2[O:39][C:34]3([CH3:40])[C:35]([C:37]=2[C:10]2[C:11]([O:54]CC(NC4C=CC(I)=CC=4)=O)=[CH:12][C:13]([NH:16][C:17]([C:19]([CH3:53])=[CH:20][CH:21]=[CH:22][CH:23]([CH3:52])[CH:24]([OH:51])[CH:25]([CH3:50])[CH:26]([OH:49])[CH:27]([CH3:48])[CH:28]([O:44][C:45]([CH3:47])=[O:46])[CH:29]([CH3:43])[CH:30]([O:41][CH3:42])[CH:31]=[CH:32][O:33]3)=[O:18])=[C:14]([OH:15])[C:9]=2[C:8]=1[OH:66])=[O:36]>>[CH3:6][C:7]1[C:38]2[O:39][C@@:34]3([CH3:40])[C:35]([C:37]=2[C:10]2[C:11]([OH:54])=[CH:12][C:13]([NH:16][C:17]([C:19]([CH3:53])=[CH:20][CH:21]=[CH:22][C@H:23]([CH3:52])[C@H:24]([OH:51])[C@@H:25]([CH3:50])[C@@H:26]([OH:49])[C@@H:27]([CH3:48])[C@H:28]([O:44][C:45]([CH3:47])=[O:46])[C@H:29]([CH3:43])[C@@H:30]([O:41][CH3:42])[CH:31]=[CH:32][O:33]3)=[O:18])=[C:14]([OH:15])[C:9]=2[C:8]=1[OH:66])=[O:36]
Reactant: COC1C=COC2(C)Oc3c(C)c(O)c4c(O)c(cc(OCC(=O)Nc5ccc(I)cc5)c4c3C2=O)NC(=O)C(C)=CC=CC(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C1C
Agent: C=CC(N)=O
Agent: COC1/C=C/OC2(C)Oc3c(C)c(O)c4c(O)c(cc(OCC(=O)Nc5ccc(I)cc5)c4c3C2=O)NC(=O)/C(C)=C\C=C\C(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(cc(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(cc(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Temperature: 4 °C

Procedure:
Fifty grams (wet weight) of acrylamide gel entrapped cell of Monocillium spp. (ATCC 20621), prepared through the procedures described in Example 4, were added to 2 l of centrifuged rifamycin B fermentation broth (6100 mgr rifamycin B/l). After reaction at 45° C. for 25 hours were aeration and agitation, the immobilized enzyme pellets were recovered through filtration on a sintered glass. It was extensively washed with 500 ml of acetone. The residual precipitates were completely solubilized by addition of another 500 ml of acetone. Thereto, 100 ml of ascrobic acid solution (10% in water) were added dropwisely while gently stirring. After confirming complete reduction to rifamycin SV, the pH was adjusted to 3.5 and the acetone was removed by evaporation with suction at 40° C. The solution was chilled to 4° C. for one day and the yellowish precipitate thus formed was recovered through filtration and dried. By this procedure, 12.5 gr of crude rifamycin SV were obtained (Purity=84%, Yield=93.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[O:18][C:17]([B:19]([OH:21])[OH:20])=[CH:16][CH:15]=1)=O.N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[O:18][C:17]([B:19]([OH:21])[OH:20])=[CH:16][CH:15]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=Cc1ccc(B(O)O)o1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(B(O)O)o1
Yield: 20.4 %

Procedure:
A solution of 5-chlorooxindole (999 mg, 5.98 mmol), 5-formylfuran-2-boronic acid (832 mg, 5.98 mmol) and piperidine (0.59 mL, 5.98 mmol) in EtOH (5.0 mL) was stirred at rt 90 min. The resulting precipitate was collected by filtration to yield the desired compound (354 mg). LCMS (ES): m/z 290 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:13]/[CH:14]=[CH:15]/[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]([O:5]CC1C=CC=CC=1)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)C/C=C/CC(C)(C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)CCCCC(C)(C(=O)O)c1ccccc1
Reaction time: 72 h
Yield: 99.8 %

Procedure:
A solution of Example 35C (3.32 g, 9.47 mmol) in ethyl acetate (50 mL) was treated with 10% palladium on carbon (0.332 g, 10 weight percent) and stirred under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (2.48 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 0.84 (m, 9 H) 1.19 (m, 6 H) 1.57 (m, 3H) 1.98 (m, 2 H) 7.34 (m, 5 H).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[C:16]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.C(OCC)(=O)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[O:1]1[CH:5]=[C:4]([C:6]2[C:16]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cnoc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(-c3cnoc3)c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
A mixture of tert-butyl 9-isoxazol-4-yl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (120 mg, 0.379 mmol), ethyl acetate (2 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (13.3 mg, 13.9%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=3)=[CH:17][CH:16]=1)=[N:8]2.[H][H]>CCO.CC(O)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:25][CH2:26]3)=[CH:17][CH:16]=1)=[N:8]2
Reactant: [H][H]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2c1
Yield: 101.1 %

Procedure:
A solution of tert-butyl 4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.160 g, 0.34 mmol) in EtOH (10 mL) and HOAc (5 mL) was purged with nitrogen, and 10% Pd/C (0.016 g) was added. The mixture was stirred under 1 atmosphere of hydrogen overnight. Then, the solution was filtered through Celite, with MeOH washings, and the filtrate was concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 30% to 70% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.160 g, 100%). 1H NMR (300 MHz, DMSO-d6): δ 11.91 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 4.00-4.22 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 2.65-2.97 (m, 3H), 1.68-1.88 (m, 2H), 1.48-1.68 (m, 2H), 1.42 (s, 9H). ESI MS m/z 466 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:10]([OH:24])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:32]([Si:36]([CH3:39])([CH3:38])Cl)([CH3:35])([CH3:34])[CH3:33].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.C1COCC1.O.CCCCCC.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@@H:10]([O:24][Si:36]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:39])[CH3:38])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1cccc(F)c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1cccc(F)c1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
Analogously to Example 1j), 2.7 g (6.25 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(m-fluorophenylmethyl)-hexanoic acid in 30 ml of DMF are silylated with 4.33 g (28.8 mmol) of tert-butyldimethylchlorosilane and 3.51 g (51.3 mmol) of imidazole. Hydrolysis of the silyl ester function with 5.1 g of potassium carbonate in 100 ml of methanol/THF/water 4:1:1 yields the title compound after column chromatography (SiO2, hexane/ethyl acetate 2:1): tRet (I)=20.8 min.