Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:18][O:19]C(OC)N(C)C>C1COCC1>[O:19]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:3][CH:4]=2)[C:9](=[O:10])[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:18]1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2)coc2ccccc12
Temperature: 120 °C
Yield: 16 %

Procedure:
To an oven-dried microwave vial was added 4-methoxydeoxybenzoin (73 mg, 2.83 mmol), dimethyl formamide dimethyl acetal (0.188 mL, 1.41 mmol) and THF (0.100 mL). The reaction was heated to 120° C. for 2 min. The product was recrystallized from methanol and a few drops of water to afford 12 (50 mg, 66%) as a pink powder. Analytical data for isoflavone 12: 1H NMR (500 MHz, DMSO) δ 9.56 (s, 1H), 8.38 (s, 1H), 8.03 (d, J=9 Hz, 1H), 7.40 (d, J=9 Hz, 2H), 7.16 (s, 1H), 7.08 (d, J=9 Hz, 1H), 6.81 (d, J=9 Hz, 2H), 3.91 (s, 3H); 13C NMR (125 MHz, DMSO) δ 175.4, 164.3, 158.1, 157.9, 153.9, 130.8, 127.6, 124.4, 123.0, 118.3, 115.7, 115.4, 101.2, 56.8; LCMS: Mass calculated for C16H12O4, [M+H]+, 269. Found 269.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:20])=[C:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)(=[O:23])C.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:20]=[O:23])=[C:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)c2ccccc2)c1C
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1[nH]c(C=O)c(C(=O)c2ccccc2)c1C
Yield: 75 %

Procedure:
A mixture of 4-benzoyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (4.13 g, 15.2 mmol) and ceric ammonium nitrate (33 g, 4 equiv.) in 50 mL of tetrahydrofuran (THF):acetic acid (HOAc):H2O 1:1:1 was refluxed overnight. The reaction mixture was then cooled, extracted with EtOAc and then basified to pH 9 with sodium carbonate. The organic layer was then washed with brine, dried (MgSO4) and concentrated followed by column chromatography to give 3.25 g (75%) of 4-benzoyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: [C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:17][O-:18].[Na+]>CO>[C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[O:18][CH2:17]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(=O)NC=Cc1ccc(OC(C)=O)cc1
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC=Cc1ccc(OCC2CO2)cc1
Temperature: 50 °C

Procedure:
13.0 g (0.05 mol) of p-(2-acetylaminovinyl)-acetoxy-benzene are suspended in 100 ml of absolute methanol, a solution of 2.8 g (0.05 mol) of sodium methoxide in 20 ml of absolute methanol is added and thereafter the mixture is warmed to 50°C for 15 minutes. It is then evaporated to dryness in vacuo. The resulting crude phenolate of p-(2-acetylaminovinyl)-phenol is heated with 65 ml of epichlorohydrin to the boil for 18 hours, under a reflux condenser and whilst stirring. Thereafter, the excess epichlorohydrin is removed by vacuum distillation. The residue is partitioned between water and ethyl acetate and the organic phase is siphoned off, dried over sodium sulphate and evaporated. After crystallisation of the crude product, thus obtained, from acetone-ether, 1-[p-(2-acetylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 135°-137°C is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].[C:16]([O:20][C:21](=[O:44])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[S:42][C:41]3[C:36](=[N:37][CH:38]=[CH:39][C:40]=3Cl)[CH:35]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:18])[CH3:17]>CS(C)=O.O>[C:16]([O:20][C:21](=[O:44])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[S:42][C:41]3[C:36](=[N:37][CH:38]=[CH:39][C:40]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=3[F:9])[CH:35]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of 4-amino-2-fluorophenol (4) (1.933 g, 15.21 mmol) in DMSO (30 mL) was added potassium tert-butoxide (2.017 g, 17.97 mmol). After 30 min, intermediate 11 (6 g, 13.83 mmol) was added and the reaction mixture was heated at 100° C. for 45 min. The reaction mixture was then cooled down, poured in water (250 mL) at 40-45° C. and the resultant suspension was stirred for 30 min. The precipitate was collected by filtration, washed with water (2×30 mL) and dried overnight. The dry solid was triturated with Et2O (50 mL), to afford intermediate 13 (4.18 g, 58% yield) as a brown solid. MS (m/z): 525.2 (M+H).
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][OH:21])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>ClCCl>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][O:21][C:25](=[O:26])[NH:24][CH2:22][CH3:23])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CO)cn12
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)OCc1ccccc1Sc1ccc2nnc(C(C)C)n2c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of [2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-phenyl]-methanol (45.0 mg, 0.15 mmol) in dichloromethane (1.5 mL) under nitrogen at ambient temperature was added ethyl isocyanate (12.0 μL, 0.15 mmol). The reaction was heated to 50° C. for 1 hour. The reaction was cooled, ethyl isocyanate added (30 μL, 0.38 mmol), and stirred at ambient temperature for 16 hours. The reaction was concentrated in vacuo to an oil. The residue was triturated from ether to give the title compound (45 mg, 82%). MS (M+1)=371.4.
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.Cl.[F:13][CH2:14][CH2:15][NH:16][CH3:17].C(N(C(C)C)CC)(C)C>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:16]([CH2:15][CH2:14][F:13])[CH3:17])[N:11]=[C:5]2[CH:6]=1
Reactant: CNCCF
Reactant: Brc1ccn2nc(Br)nc2c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCF)c1nc2cc(Br)ccn2n1
Temperature: 130 °C
Yield: 34.5 %

Procedure:
To the solution of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (5 g, 18.05 mmol) and (2-fluoro-ethyl)-methyl-amine hydrochloride (20 g, 180.5 mmol) in ethanol (30 ml) was added di-isopropylethylamine (47 ml, 270.75 mmol) and the reaction mixture was heated at 130° C. in a sealed tube for 84 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was diluted with dichloromethane (100 ml). The organic layer was washed with water (2×75 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography over silicagel using 0.5% methanol/dichloromethane as eluent affording (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-fluoro-ethyl)-methyl-amine (1.7 g, 34.5%) as an off white solid. MS: m/z=275.2 (M+H+).
Reaction SMILES: C(OC([NH:8][C:9]([NH:25]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([C:23]#[N:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[ClH:33].[C:23]([C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:25])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2C#N)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1cccnc1-c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-cyanopyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (20 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-cyanopyridin-2-yl)phenylguanidine dihydrochloride (90 mg).
Reaction SMILES: [C-:1]#[N:2].[Na+].COS([O-])(=O)=O.CO[N+:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1>O>[C:1]([C:13]1[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[CH:17][N:12]=1)#[N:2]
Reactant: [C-]#N
Reactant: CO[n+]1cc(C)cc(C)c1
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc(C#N)c(C)c1
Yield: 91.7 %

Procedure:
Cool a solution of sodium cyanide (49.0 g, 0.999 mol, 3.0 eq.) in 135 mL of water to 0° C., (air free) and drip 1-methoxy-3,5-dimethyl pyridinium methyl sulfate (83.0 g, 0.33 mol) in 100 mL water (air free) over 11/4 hr., keeping the temperature below 3° C. Filter the mixture and wash with water to give 40 g of the title compound which may be recrystallized from isopropyl ether and pentane (4:1) (m.p. 61°-62° C.).
Reaction SMILES: [F:1][CH:2]([F:14])[N:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([C:10]([O:12]C)=[O:11])=[CH:4]1.O.[OH-].[Li+]>CO.O>[F:14][CH:2]([F:1])[N:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([C:10]([OH:12])=[O:11])=[CH:4]1
Reactant: COC(=O)c1ccc(=O)n(C(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(=O)n(C(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (0.500 g, 2.461 mmol) in MeOH (12 mL) and water (4 mL) was added lithium hydroxide hydrate (0.207 g, 4.92 mmol, Aldrich). The resulting mixture was then stirred at room temperature for 4 h. Solvent (MeOH) was removed in vacuok, and the remaining aqueous solution was adjusted to pH=5-6 by addition of concentrated HCl. The mixture was then extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4), and the solvent removed to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 190 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].[CH3:18][S:19]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)(=[O:21])=[O:20].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([N:14]([CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:23][CH2:24]3)[CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CS(=O)(=O)N1CCC(C=O)CC1
Reactant: CCCNC1CCc2ccc(OCC)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(OCC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of afford (7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (200 μL of a 0.25M solution in 1,2-dichloroethane, 50 μmole) was added 220 μL of a solution of 1-(methylsulfonyl)-4-piperidinecarboxaldehyde (0.25 M in 1,2-dichloroethane) followed by 30 μL DIEA and 300 μL of a 0.25 M slurry of sodium triacetoxyborohydride in 1,2-dichloroethane. The solution was shaken at 25° C. for 48 h under N2. The reaction was quenched with 1 mL 2% NaOH and the mixture was transferred along with 0.5 mL H2O and EtOAc to workup flasks. The flask was shaken, allowed to settle and the aqueous phase was removed and discarded. The organic phase was washed with water, transferred into a tube and concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford (7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amine (8 mg) 104[M+H]+=409.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[CH:13]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:17]=[C:18]([NH2:20])[S:19][CH:2]=2)=[C:6]([CH3:16])[CH:7]=1)([CH3:15])[CH3:14]
Reactant: Cc1cc(OC(C)C)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(OC(C)C)cc(C)c1-c1csc(N)n1
Yield: 72 %

Procedure:
A mixture of 2-bromo-1-(4-isopropoxy-2,6-dimethylphenyl)ethanone (5.18 g, 18.2 mmol) and thiourea (1.38 g, 18.2 mmol) in 95% EtOH (26 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-isopropoxy-2,6-dimethylphenyl)thiazol-2-amine (3.44 g) as yellow solids in 72.2% yield: 1H NMR (500 MHz, CDCl3) δ 6.60 (s, 2 H), 6.26 (s, 1 H), 4.97 (bs, 2 H), 4.54 (m, 1 H), 2.13 (s, 6 H), 1.32 (d, J=6.1 Hz, 6 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:51])[C:9]([N:11]2[C:15]3[N:16]=[C:17]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:18]=[C:19]([C:20]4[CH:21]=[N:22][C:23]([N:26](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=[N:24][CH:25]=4)[C:14]=3[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.N1(C2C=C(NC(N3C4N=C(N5CCOCC5)N=C(C5C=NC(N(CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=NC=5)C=4CC3)=O)C=CC=2)CCOCC1>>[CH3:51][N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[CH:3]=1)[C:9]([N:11]1[C:15]2[N:16]=[C:17]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[N:18]=[C:19]([C:20]3[CH:21]=[N:22][C:23]([NH2:26])=[N:24][CH:25]=3)[C:14]=2[CH2:13][CH2:12]1)=[O:10]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3cccc(Br)c3)cn2)cc1
Reactant: C1COCCN1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccc(N4CCOCC4)c3)cn2)cc1
Product: CN(C(=O)N1CCc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21)c1cccc(N2CCOCC2)c1
Yield: 61.3 %

Procedure:
Using 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-bromo-phenyl)-methyl-amide (112 mg) and morpholine (15.5 mg) instead of 2-piperazin-1-yl-ethanol, in the same manner as Step C in Example 1-D-153, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-morpholin-4-yl-phenyl)-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 3, to obtain the desired compound (1-D-226) as a yellow solid (47.3 mg, 61%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cu][C:16]#[N:17].C(Cl)Cl>CN(C)C=O>[C:16]([C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)#[N:17]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1ccc(Br)c2ncccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc([N+](=O)[O-])c2cccnc12

Procedure:
5.80 g of 8-bromo-5-nitroquinoline and 2.00 g of copper(I) cyanide in 15 ml of dimethylformamide were heated to 150° C. for 5 hours. After cooling, methylene chloride was added, insoluble particles were filtered off and the filtrate was concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Difluoronitrobenzene (3.7 g, 23.2 mmol)was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (4 mL, 23 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was used without further purification.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[N:5]1)([CH3:3])[CH3:2].[I:15]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:15][C:7]1[C:6]([C:9]2[S:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1csc(-c2ccn(C(C)C)n2)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1csc(-c2nn(C(C)C)cc2I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 1-isopropyl-3-(4-methyl-2-thienyl)-1H-pyrazole (5.6 mmol) in 16 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (5.8 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:dichloromethane 100:0 to 0:100) to afford 1.54 g 4-iodo-1-isopropyl-3-(4-methyl-2-thienyl)-1H-pyrazole (82% yield).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH2:50][OH:51])[CH2:48][OH:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:52]1([CH3:62])[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH2:48][O:49][S:58]([C:55]1[CH:56]=[CH:57][C:52]([CH3:62])=[CH:53][CH:54]=1)(=[O:60])=[O:59])[CH2:50][OH:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2cc([C@@H]3OC(CO)(COS(=O)(=O)c4ccc(C)cc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 319.9 %

Procedure:
To a stirred solution of {(3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-hydroxymethyl-tetrahydro-pyran-2-yl}-methanol (Example 9, 500 mg, 0.70 mmol) in pyridine (15 mL) was added p-toluene sulfonyl chloride (670 mg, 0.21 mmol). After stirring for overnight at room temperature, reaction mixture was heated to 80° C. for another 18 h. The volatiles were evaporated, resulting residue was taken in ethyl acetate and washed with 1N HCl, brine, concentrated to furnish toluene-4-sulfonic acid (3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-hydroxymethyl-tetrahydro-pyran-2-ylmethyl ester (580 mg). The crude product was used as such for next step without purification which also contains small amount of bis-tosylate.
Reaction SMILES: [CH:1]1([PH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C1(C)C=CC=CC=1>[CH:8]1([P:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[Cl:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: C1CCC(PC2CCCCC2)CC1
Solvent: Cc1ccccc1
Product: ClP(C1CCCCC1)C1CCCCC1
Reaction time: 1 h

Procedure:
A solution of 19 g (0.1 mol) dicyclohexylphosphine in 50 ml toluene was dropped into a suspension of 21 g (0.1 mol) PCl5 in 100 ml toluene. The reaction temperature was maintained at less than 30° C. After all had been dropped in, the whole was boiled for 1 hour under reflux. A slight precipitate was removed by means of a reverse frit and the reaction mixture was freed from all low boilers at 60° C. under 0.1 mbar. Yield: 23.3 g; 31P-NMR: δ P=126 ppm, (c-C6H11)2PCl, 96 mol %; δ P=54 ppm, (c-C6H11)2P(O)Cl, 3.7 mol %.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:2]=[CH2:3].[OH:13]NC(=O)OC(C)(C)C.[H-].[Na+].C(Br)C=C.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[O:13]1[CH2:3][CH:2]1[CH2:1][O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C=CCONC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NO
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NOCC1CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
According to (16-1) described in Reference Example 16, 659 mg (3.80 mmol) of tert-butyl N-(allyloxy)carbamate prepared from tert-butyl N-hydroxycarbamate, sodium hydride and allyl bromide was dissolved in 10 ml of dichloromethane, and the thus prepared solution was mixed with 886 mg (4.67 mmol) of m-chloroperbenzoic acid and stirred at room temperature for 24 hours. The reaction solution was filtered, mixed with a 1 N sodium hydroxide aqueous solution and extracted with chloroform. The chloroform layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 447 mg (yield, 62%) of tert-butyl N-(2,3-epoxypropoxy)carbamate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>C1(C)C=CC=CC=1.C(O)C>[C:2]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: O=C(O)C(Cc1cccc(Br)c1)CS(=O)(=O)Cc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)C(Cc1cccc(-c2ccccc2)c1)CS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
3-(3-Bromo-phenyl)-2-benzylsulfonylmethyl-propionic acid (0.5 g, 1.26 mmol) was dissolved in toluene (20 mL) and ethanol (5 mL). Tetrakistriphenylphosphine palladium (146 mg, 0.126 mmol) was added and the mixture was stirred at ambient temperature under nitrogen for 30 minutes. Powdered potassium carbonate (870 mg, 6.3 mmol) and phenylboronic acid (200 mg, 1.64 mmol) were added, and the reaction mixture was heated at 75° C. for 2 hours. After cooling, the mixture was acidified with 1N aqueous HCl and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and evaporated. The acid was purified by flash chromatography on silica gel (ethyl acetate/hexane; 1:1) to yield 3-biphenyl-3-yl-2-benzylsulfonylmethyl-propionic acid (0.40 g).