Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([C@H:15]([S:28][CH2:29][C:30]2([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:31]2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:27])([CH3:26])[CH3:25])[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([C@H:15]([S:28][CH2:29][C:30]2([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:31]2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:27])([CH3:26])[CH3:25])[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(COC3CCCCO3)c2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(CO)c2)CC1
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 0.1 %

Procedure:
To the hydroxy ester from Step 15 (9.02 g, 17.1 mol) in anhydrous MeOH (60 mL) under nitrogen was added pyridine (50 μL) followed by PPTS (1.1 g, 4.3 mmol). The reaction mixture was stirred 3.5 hr at 55° C., then at r.t. overnight before concentrating in vacuo. The residue was diluted with EtOAc (500 mL) and washed with H2O, saturated aq. NaHCO3, NaH2PO4 buffer (pH=4.5) and with brine. After drying over MgSO4 and evaporation of the solvents, the residue was purified by flash chromatography (40% to 60% EtOAc in hexanes) giving 6.85 g (91%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16].[F-].[K+]>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4])[CH:15]=[CH2:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1cc(OC(F)(F)F)ccc1N
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-4-(trifluoromethoxy)aniline (75 g, 293 mmol) in DMF (1000 ml) was added Pd(PPh3)4 (13.5 g, 11.7 mmol) and allyltributyltin (116 g, 351 mmol) and the reaction mixture was stirred at 80° C. for 16 h. The mixture was cooled to room temperature and saturated aqueous KF solution was added. The mixture was diluted with ethyl acetate (1500 mL) and washed with 1:1 H2O: saturated aqueous NaCl solution (2×750 mL) and saturated aqueous KF (1×). The aqueous layers were combined and extracted with ethyl acetate (250 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product, which was absorbed onto silica and purified by chromatography eluting with 1% ethyl acetate in petroleum ether to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][C:13]([CH3:21])=[N:12]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([CH3:21])=[N:12]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc2onc(N)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)n(-c2ccc3onc(N)c3c2)n1
Temperature: 600 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of ethyl 1-(3-aminobenzisoxazole-5-yl)-3-methyl-5-pyrazole carboxylate (0.14 g) in THF (5 mL) was added NaOH (10% in water, 5 mL). The reaction was stirred at 600° C. for 2 h, THF was evaporated, HCl (10% in water) was added dropwisely until the pH was between 4-5, partitioned between ethylacetate and water, washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-(3-aminobenzisoxazole-5-yl)-3-methyl-5-pyrazole carboxylic acid (0.11 g). ESI mass spectrum z (rel. intensity) 259 (M+H, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2].[C:26]1([NH:32][NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:33][N:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CC(C(=O)c1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Reactant: NNc1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1-c1ccc(Cl)cc1
Yield: 91 %

Procedure:
12.0 grams 3,3-bis-(p-chlorobenzoyl)-propionic acid ethyl ester, 3.9 grams phenylhydrazine and 2.7 grams glacial acetic acid were mixed and the mixture was heated in a nitrogen atmosphere to the boiling temperature under reflux for 6 hours. To the reaction mixture were then added benzene, and the pH was adjusted to 2-3, followed by extraction with water. The benzene was evaporated from the benzene phase and the dry, crystalline residue was recrystallized from a mixture of cyclohexane and petroleum ether boiling in a range from 50°-70° C. 13.0 grams 1-phenyl-3,5-bis-(p-chlorophenyl)-pyrazol-4-acetic acid ethyl ester, melting at 120°-122° C., were obtained, representing a yield of 91%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][CH:7]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][CH:7]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:18]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1COC(c2cccs2)c2cc(Br)ccc2N1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C1COC(c2cccs2)c2cc(-c3cccc(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chlorobenzeneboronic acid generally according to the procedure described in example 1. 1H-NMR (CDCl3) δ 8.26 (br s, 1H), 7.51 (dd, J=8.3, 2.1 Hz, 1H), 7.45 (d, J=0.9 Hz, 1H), 7.42 (dd, J=5.1, 0.9 Hz, 1H), 7.36 (m, 3H), 7.24 (d, J=2.0 Hz, 1H), 7.05 (m, 2H), 6.93 (d, J=3.5 Hz, 1H), 6.24 (s, 1H), 4.56 (d, J=Hz, 1H), 4.47 (d, J=17.0 Hz, 1H); MS (ES) m/z 356 (M+H)+; Anal. Calc. For C19H14ClNO2S: C, 64.13; H, 3.97; N, 3.94. Found: C, 64.1; H, 3.83; N, 3.99.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:3])[CH3:2].[CH:32]1N=CN(C(N2C=NC=C2)=O)C=1.CO>CN(C=O)C>[CH3:32][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH:7]=1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(OC(C)C)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To 0.3 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid in 2 ml DMF was added 0.4 mmol CDI, and the mixture heated at 50° C. for 30 min. 5.2 mmol methanol was then added, and the mixture was stirred at RT for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/e): 451.2 (M+H+, 100%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[CH3:22])[NH2:18])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:19]=[CH:20][C:21]=1[CH3:22])([O-:14])=[O:13]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1ccc(Nc2ccccc2CC(=O)O)cc1[N+](=O)[O-]

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-nitro-4-methylaniline to yield 2-[(3-nitro-4-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[C:18]([O:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:20])[CH3:19]>>[C:18]([O:21][C:22]1[CH:27]=[C:26]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:20])[CH3:19]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CC(=O)Oc1cc(I)ccc1OCc1ccccc1
Product: CC(=O)Oc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1OCc1ccccc1

Procedure:
This compound was obtained by coupling rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 5-iodo-2-(phenylmethoxy)phenyl acetate under the conditions described in Example 26. The crude product was chromatographed over the 50 fold amount of silica gel using methylene chloride. The combined fractions were evaporated and the residue was crystallized from methanol after treatment with charcoal and was recrystallized from ether/hexane for analysis to give colorless crystals with m.p. 117°-120°.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17][CH2:18][CH3:19])=[C:6]([C:12]([CH3:16])=[C:13]([Cl:15])[CH:14]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[Cl:15][C:13]1[C:12]([CH3:16])=[C:6]([C:5]([O:17][CH2:18][CH3:19])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:14]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8]
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)=O)c1OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)O)c1OCC

Procedure:
3-Acetyl-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide (0.2 g, 0.7 mmol) was treated with sodium tetrahydroborate (0.032 g, 0.84 mmol) in methanol (6 mL) at room temperature for 1 h. The mixture was diluted with water, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and filtered, concentrated to give the desired product. LCMS calculated for C14H21ClNO3 (M+H)+: m/z=286.1; Found: 286.1.
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]([C:14]([NH:16][C@H:17]([C:24]([O:26][CH3:27])=[O:25])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[N:5][C:4]2=[N:30][C:31]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:32][C:3]=12>CO.C(Cl)Cl.[Pd]>[OH:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:16][C@H:17]([C:24]([O:26][CH3:27])=[O:25])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:15])=[CH:28][CH:29]=2)[CH:6]=[N:5][C:4]2=[N:30][C:31]([NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:32][C:3]=12
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC[C@H](NC(=O)c1ccc(CCn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OC
Reaction time: 3 h
Yield: 71.5 %

Procedure:
A mixture of 1.0 g of dimethyl N-[4-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoyl]-L-glutamate in 250 mL of 50% methanol in methylene chloride and 0.8 g of 3% palladium-on-carbon is hydrogenated at 50 p.s.i. for three hours, filtered, and concentrated under reduced pressure. The solid is collected by filtration and dried to yield 0.72 g of dimethyl N-{4-[2-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)ethyl]benzoyl}-L-glutamate- mp 247° C. 1NMR (d6 -DMSO)δ1.21 (s, 9H), 1.90-2.12 (m, 2H), 2.42 (t, J=7.4 Hz, 2H), 2.92 (t, J=4 Hz, 2H), 2.97 (t, J=4 Hz, 2H), 3.55 (s, 3H), 3.61 (s, 3H), 4.38-4.45 (m, 1H), 6.61 (s, 1H), 7.27 (d, J=8.2 Hz, 2 H), 7.75 (d, J=8.2 Hz, 2 H), 8.64 (d, J=7.4 Hz, 1 H), 10.75 (s, 1H), 11.22 (s, 1H) . Anal. Calc. for C27H33N5O7 : C, 60.10; H 6.17; N, 12 . 98. Found: C, 59.94; H, 6.15; N, 12.72 .
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[CH:16]=[CH:17]/[CH2:18][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.C(Cl)(Cl)Cl>CC#N>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:16]([F:31])[CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C/C=C/[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C=C[C@@H](F)[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (4R)-4-benzyl-3-[(2R,3E)-2-benzyl-5-(trimethylsilyl)pent-3-enoyl]-1,3-oxazolidin-2-one (0.88 mmol, 370 mg) in CH3CN (8 mL) was added [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (referred to hereafter as Selectfluor) (0.88 mmol, 310 mg). The reaction was allowed to stir at RT for 48 hr. The solvent was removed in vacuo. The crude product was purified by column chromatography to yield a mixture of diastereoisomers de=10% (250 mg, 95%). 1H NMR (400 MHz, CDCl3): δ=6.98-7.3 (m, 10H), 6.0 (m, 1H), 5.5 (dm, J=17, 1H), 5.42 (d, J=10.6, 1H), 5.1 (ddd, J=7.1, 8.1, 47.2, 1H), 4.85 (m, 1H), 4.64 (m, 1H), 3.98-4.12 (m, 2H), 2.84-3.0 (m, 3H), 2.2 (m, 1H); 13C NMR (100 MHz, CDCl3): δ=172.5, 152.9, 137.2, 135.1, 133.7, 133.6, 129.5, 129.3, 128.9, 128.5, 127.2, 126.8, 120.6, 120.5, 94.4 (d, J=175), 65.6, 55.1, 48.1 (d, J=21), 37.3 34.8 (d, J=6); 19F {1H} NMR (376.5 MHz, CDCl3): δ=−175.7; IR (CHCl3): v 3444, 2957, 1645, 1367, 1235, 1205 cm−1; [α]D20=−18.4° (c, 0.5 CHCl3); HMRS required for C22H23NO3F 368.1662 ([M+H+]) found 368.1669.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]2[CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].P(OCC)(OCC)([S-])=[S:18]>O1CCCC1.O>[C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]2[CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:18])[NH2:2]
Reactant: CCOP(=S)([S-])OCC
Reactant: COC(=O)c1cc(C#N)c(C)cc1C1CC1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(N)=S)c(C)cc1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a round-bottom flask, was added a solution of methyl 5-cyano-2-cyclopropyl-4-methylbenzoate (compound 190.3, 220 mg, 0.920 mmol, 1.00 equiv, 90%) in tetrahydrofuran (6 mL). A solution of O,O′-diethyl dithiophosphate (300 mg, 1.61 mmol, 2.00 equiv) in water (1.5 mL) was added to the solution, and the resulting mixture was stirred overnight at 80° C. in an oil bath (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (5:1) as eluent. The collected fractions were combined and concentrated in vacuo to furnish 100 mg (39%) of methyl 5-carbamothioyl-2-cyclopropyl-4-methylbenzoate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>CCOC(C)=O.[Pd]>[NH2:13][C:6]1[CH:5]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[C:3]([O:2][CH3:1])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: COCCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOc1cc(N)c(C(=O)OC)cc1OC
Yield: 94.4 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of methyl 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate (3.19 g, 11.2 mmol) and Pd/C (10%, 0.3 g) in EtOAc (150 mL) was stirred under 1 atmosphere of hydrogen at room temperature for 6 hours, to afford methyl 2-amino-5-methoxy-4-(2-methoxyethoxyl)benzoate as a solid (2.699 g, 95%). 1H NMR (300 MHz, CDCl3) δ 7.30 (s, 1H), 6.17 (s, 1H), 5.55 (br, 2H), 4.14 (t, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79 (t. 2H), 3.44 (s, 3H); LC-MS (ESI) m/z 256 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].C([Si](C)(C)[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[O:32][CH3:33])(C)(C)C.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:26][C:25]=1[O:32][CH3:33]
Reactant: COc1cc(C=O)ccc1OCCO[Si](C)(C)C(C)(C)C
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)c(OC)c3)nc2c1
Temperature: 150 °C
Yield: 7.8 %

Procedure:
NaH (0.12 g, 0.0050 mol, 60% in mineral oil) was added to 4-hydroxy-3-methoxylbenzalde (0.636 g, 4.18 mmol) in anhydrous DMF (15 mL) and then (2-bromoethoxy)-tert-butyl-dimethylsilane (1.0 g, 4.18 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water. The mixture was extracted with dichloromethane and the combined organic layers were passed through a column to yield 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-methoxybenzaldehyde (170 mg, 13%). 2-Amino-4,6-dimethoxy-benzamide (101 mg, 0.515 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-methoxybenzaldehyde (160 mg, 0.515 mmol), sodium hydrogen sulfite (100 mg, 58.5%) and p-toluenesulfonic acid monohydrate (10 mg) were mixed with N,N-dimethyl acetamide (15 mL) and heated to 150° C. for 16 h. N,N-dimethyl acetamide was removed under vacuum and the residue was poured into water (50 mL). The solid was filtered off and further purified by column chromatography to yield 2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (15 mg, 7.8%). Selected data: MS (ES) m/z: 373.1; MP 246-248° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:8]=2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>C[O-].[Na+].CO>[OH:27][C:7]1[C:8]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:18][C:9]=2[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:11][C:6]=1[C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5]
Reactant: CCOC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-4-piperidin-1-yl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (39 mg, 0.10 mmole) and glycine (573 mg, 7.63 mmole) in 0.5 M sodium methoxide/methanol (10.2 ml) was refluxed for 25 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (40 ml) and extracted three times with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (6 ml). The suspension was extracted with ethyl acetate (2×40 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (40 mg). MS: (+) m/z 413.30 (M+1), MS: (−) m/z 411.33 (M−1).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH-].[Ca+2].[OH-].C([O-])(=O)C.[Ca+2].C([O-])(=O)C>O>[OH:1][CH2:2][C:3]([C@@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO
Agent: CC(=O)[O-]
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=C(CO)[C@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 2 h
Yield: 44 %

Procedure:
To a 25 ml Erlenmeyer flask, equipped with a magnetic stirrer, was added 0.5 g L-galactose, 5 ml water, 0.2 g calcium hydroxide, and 22 mg calcium acetate. The mixture was stirred. After 2 hours, the solution was filtered to collect the calcium hydroxide-L-tagatose complex that had formed. The sticky complex was resuspended in 5 mL of H2O, and CO2 was bubbled through the slurry until the pH was below 7. The solution, after filtering off the calcium carbonate, was deionized as in Example 1 and concentrated in vacuo to a syrup which, after seeding with a few L-tagatose crystals, provided 0.22 g of pure L - tagatose, a 44 % yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:18].[Na+].OO>C1COCC1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH:13]2[OH:18])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CS(=O)(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(c2ccc(Cl)cc2)C(O)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(4-chlorophenyl)-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridine (654 mg, 2.407 mmol) was dissolved in THF (4.81 mL). Borane-THF complex (2.407 mL, 2.407 mmol) was added dropwise via syringe and the reaction was stirred 72 h at rt. Then sodium hydroxide (1.5 mL, 4.50 mmol) and hydrogen peroxide (1.2 mL, 11.75 mmol, 30% solution) were added. The reaction was stirred 2 h at rt, then diluted with saturated Na2S2O3 and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 25 g column by eluting with 20% to 100% EtOAc:Hexane to provide the desired product. LC-MS: calculated for C12H16ClNO3S 289.05 observed m/e: 289.92 (M+H)+ (Rt 1.35/4 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[C:17]1([CH2:23][N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:27]1[CH2:26][CH2:25][N:24]([CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:29][CH2:28]1)([O-:16])=[O:15]
Reactant: Nc1ccccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-c1ccccc1NC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
To a solution of 30.0 g (0.140 mol) of 2-amino-2′-nitrobiphenyl and 111.5 g (0.630 mol) of 1-(phenylmethyl)-4-piperidone in 1200 mL of dichloromethane were added a total of 140.5 g (0.630 mol) of sodium triacetoxyborohydride in batches whilst maintaining a reaction temperature of 0° C. and the mixture was then stirred for 14 hours at room temperature. It was made alkaline with sodium hydroxide solution, the dichloromethane phase was separated off, dried over sodium sulfate and concentrated by evaporation. The residue was digested with methanol, then filtered. The filtrate was evaporated down, the residue remaining was purified by chromatography on aluminium oxide (activity stage 3) using PE/EE 9/1 (v/v) as eluant. Corresponding fractions were combined, freed from solvent and used in the next step without further purification. Yield: 40.0 g (74% of theory).