Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=1)[CH3:7])(=O)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.O>[N:15]([CH:6]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=1)[CH3:7])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)c1cc(Br)ccn1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 1-(4-bromopyridin-2-yl)ethyl methanesulfonate (4.68 g, 16.71 mmol) in anhydrous DMF (45 mL) DMF was added sodium azide (2.17 g, 33.41 mmol) and stirred at room temperature for 2 hours. The reaction was then diluted with 80 mL of water, then extracted with EtOAc (2×75 mL). The organic extracts were combined, washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to give the crude product which was used directly without further purification. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=5.2 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 4.65 (q, J=6.8 Hz, 1H), 1.60 (dd, J=6.8, 0.8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=1[Cl:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(Cl)ccc1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 38.4 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2,5-dichlorophenylboronic acid (Aldrich; 1.28 g, 6.7 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (0.96 mL, 6.8 mmol) in 1,2-dichloroethane (7 mL) was heated in an oil bath at 50° C. overnight. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 20-25% ethyl acetate/hexanes, to give N′-(2,5-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (750 mg, 38%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]=[CH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.Cl.[CH2:13]([NH:16][OH:17])[CH2:14][CH3:15]>CO>[OH:17][N:16]([CH2:13][CH2:14][CH3:15])[CH:8]1[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccnc2c1CCC=C2
Reactant: CCCNO
Agent: Cl
Solvent: CO
Product: CCCN(O)C1CCc2c(C)ccnc2C1
Yield: 73.4 %

Procedure:
This compound was prepared from the product of Step 6 (4.5 g, 30 mmol), 1-propylhydroxylamine hydrochloride (6 g, 55 mmol), and methanol (20 ml) by the method outlined in Example 10. The crude material was recrystallised from cyclohexane to give the product (4.85 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH2:21])=[CH:16][CH:15]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1.C(Cl)Cl>[C:22]1([C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([I:11])[CH:10]=[C:2]([I:1])[C:3]=3[OH:12])=[CH:19][CH:18]=2)=[CH2:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cc(I)cc(I)c1O
Reactant: C=C(c1ccccc1)c1ccc(N)cc1
Solvent: Clc1ccccc1
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: C=C(c1ccccc1)c1ccc(NC(=O)c2cc(I)cc(I)c2O)cc1
Yield: 43.2 %

Procedure:
To a refluxing solution of 7.9 g (0.02 mole) of 3,5-diiodosalicylic acid and 4.6 g (0.02 mole) of 1-(4-aminophenyl)-1-phenylethylene in 125 ml of chlorobenzene was added 3 g (0.022 mole) of phosphorus trichloride over a 1 hour period. The resulting mixture was refluxed for 2 hours, cooled, diluted with 100 ml of methylene chloride. The organic phase was washed with 250 ml of water and dried. The extract was evaporated to dryness. After redissolving the residue in minimum amount of methylene chloride, the solution was flash-chromatographed on a silica gel column. The desired component was eluted with 2 liters of methylene chloride/n-hexane. Evaporation of its solvent gave 4.9 g of N-[4-(1-phenylethenyl)phenyl] -2-hydroxy-3,5-diiodobenzamide. Recrystallization from aqueous ethanol gave 4.2 g of purified product, m.p. 173°-174°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Reactant: C1CCNCC1
Product: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1N1CCCCC1)C(=O)OC(C)(C)C
Yield: 98 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using piperidine as a reagent in the absence of a solvent, the same procedure of Example 264 gave 1.524 g of the titled compound (yield, 98%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:15]=[CH:14][CH:13]=[CH:12][C:4]=1[C:5](OC(C)(C)C)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[OH:6][CH2:5][C:4]1[C:3]([NH:2][CH3:1])=[N:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNc1ncccc1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1ncccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of t-butyl 2-(methylamino)nicotinate (45.0 g, 0.216 mol) in dry THF (500 mL) cooled in an ice-bath was added LiAlH4 (9.84 g, 0.259 mol) portionwise over a period of 30 min. After stiring for 1 h at 0° C., the mixture was warmed to room temperature and stirred for 2 h. After cooling in an ice-bath, the excess LiAlH4 was decomposed completely by the careful addition of H2O (10 mL) and 1N NaOH aqueous solution (10 mL). Na2SO4 (100 g) was added and the mixture was filtered through a pad of celite. The filtrate was evaporated under reduced pressure and the resulting residue was purified by column chromatography (400 g of silica gel, eluent: DCM/MeOH=20/1−10/1) to give the desire product which was further purified by recrystallization from DCM-hexane to give 3-hydroxymethyl-2-(N-methylamino)pyridine (m) (22.7 g, 76%); 1H NMR (CDCl3): δ 2.30 (brs, 1H), 3.01 (d, J=4.6 Hz, 3H), 4.58 (s, 2H), 5.40 (brs, 1H), 6.50 (dd, J=5.1 and 7.3 Hz, 1H), 7.21 (dd, J=1.7 and 7.3 Hz, 1H), 8.08 (dd, J=1.7 and 5.1 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C@H:5]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.COC(=O)[C@H](NS(C1C=CC(Br)=CC=1)(=O)=O)[C@H](OCC1C=CC(C)=CC=1)C1SC=CN=1.COC1C=CC(B(O)O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.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.O.CCO>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([S:21]([NH:20][C@H:4]([C@H:5]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:6]3[S:7][CH:8]=[CH:9][N:10]=3)[C:3]([OH:38])=[O:2])(=[O:23])=[O:22])=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)[C@H](OCc1ccc(C)cc1)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)[C@H](NS(=O)(=O)c1ccc(Br)cc1)[C@H](OCc1ccc(C)cc1)c1nccs1
Agent: COc1ccc(B(O)O)cc1
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(S(=O)(=O)N[C@@H](C(=O)O)[C@H](OCc3ccc(C)cc3)c3nccs3)cc2)cc1
Temperature: 25 °C

Procedure:
(2R,3S)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propionic acid methyl ester. The (2R,3S)-2-(4-bromo-benzenesulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propionic acid methyl ester 1e (590 mg, 1.12 mmol) and 4-methoxyphenylboronic acid (260 mg, 1.68 mmol) are taken up in 10 mL of benzene, 1.5 mL of EtOH and 1.5 mL of water in the presence of Pd(PPh3)4 (40 mg, 0.03 mmol) and 237 mg of Na2CO3 and brought to reflux for 18 hours. The mixture is cooled to room temperature, poured into water, and extracted with methylene chloride. The organic layer is dried over Na2SO4, filtered and evaporated. The crude product is purified by silica gel chromatography using 6/4 hexane/EtOAc to give the desired product as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16](=[O:28])[CH:17]([CH3:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)C>>[Cl:26][C:21]1[CH:20]=[C:19]([CH2:18][CH:17]([CH3:27])[C:16]([OH:28])=[O:15])[CH:24]=[CH:23][C:22]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CC(C)Sc1cccc(CCl)n1
Reactant: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Product: CC(C)Sc1cccc(COc2ccc(CC(C)C(=O)O)cc2Cl)n1
Yield: 77.4 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (35 mg, 0.17 mmol) obtained in Step C of Preparation Example 16 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (47 mg, 0.19 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (50 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14](OC(C)(C)C)=[O:15])[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.C(N(CC)CC)C.C(OC([NH:41][C@H:42](C(O)=O)[C:43]([CH3:46])([CH3:45])[CH3:44])=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:42]([NH2:41])[C:43]([CH3:46])([CH3:45])[CH3:44])=[O:15])[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 400 mg, 1.12 mmol, 1 equiv) in a 4:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred for 30 minutes, then concentrated. The residue was dried via toluene azeotrope (2×10 mL), then dissolved in DMF (5 mL). Triethylamine (0.780 mL, 5.60 mmol, 5.00 equiv), N-(tert-butoxycarbonyl)-3-methyl-L-valine (388 mg, 1.68 mmol, 1.50 equiv), and PYBOP (874 mg, 1.68 mmol, 1.50 equiv) were added, and the resulting mixture was stirred at 23° C. for 24 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 40% ethyl acetate in hexanes) to yield the desired coupled, N-Boc-protected intermediate, which was dissolved in a 2:1 mixture of dichloromethane and trifluoroacetic acid. The resulting solution was allowed to stand for 30 minutes, then concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL), then the combined organic layers were dried over sodium sulfate and concentrated to provide (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylamine (16-1) as a white solid. 1H NMR (500 MD, CDCl3) major rotamer: δ 7.40 (t, 2H, J=7.6 Hz), 7.31 (m, 1H), 7.26 (d, 2H, J=7.8 Hz), 7.11-6.93 (m, 3H), 6.38 (s, 1H), 5.81 (m, 1H), 4.88 (m, 2H), 3.03 (s, 1H), 1.00 (s, 9H). LRMS m/z (M+H) 371.0 found, 371.2 required.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:8]2[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:24]1([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:33][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])=[O:17])=[CH:13][CH:12]=2)[C:8]2[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nc2ccccc2n1Cc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
4-[(2-Butyl-1H-benzimidazol-1-yl)methyl]benzoic acid (150 mg) was added to a solution of benzenesulphonamide (79 mg), dimethylaminopyridine (60 mg) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (91 mg) in dry dichloromethane (5 ml). The mixture was stirred overnight and then diluted with dichloromethane (20 ml). The solution was washed successively with 1M hydrochloric acid (20 ml), water (20 ml) and saturated brine (20 ml), and then dried (MgSO4). The solvent was removed by evaporation and the residue triturated with ether to give 4-[(2-butyl-1H-benzimidazol-1-yl)methyl]-N-phenylsulphonylbenzamide as a white solid, m.p. 241°-242° C.; NMR (d6 -DMSO): 0.9(t,3H), 1.35(m,2H), 1.7(m,2H), 2.85(t,2H), 5.6(s,2H), 7.2(m,3H), 7.4(m,1H), 7.6(m,4H). 7.8(d,2H), 8.0(d,2H); mass spectrum (-ve FAB, DMSO/m-nitrobenzyl alcohol): 446(M-H)- ; microanalysis found: C,66.7; H,5.6; N,9.1; C25H25N3O3S requires: C,67.1; H,5.6; N,9.4%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:12][OH:13])[NH:6]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:12]=[O:13])[NH:6]2
Reactant: OCc1cc2c(Br)cc(F)cc2[nH]1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1cc2c(Br)cc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of (4-bromo-6-fluoro-1H-indol-2-yl)methanol (2.6 g, 11 mmol) in CH2Cl2 (100 mL) at r.t. was added Dess-Martin periodinane (6.4 g, 15 mmol). The mixture was stirred for 30 minutes at r.t. and saturated aqueous NaHCO3 was added. The mixture was filtered through a celite pad and the filtrate was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 30% EtOAc to give 2 g of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[OH:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:20][CH2:21]1
Reactant: NCCCN1CCN(CCO)CC1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)NCCCN1CCN(CCO)CC1
Temperature: 0 °C

Procedure:
A 50 mL chloroform solution of 2.45 g. (0.0112 mol) of dodecanoyl chloride was added dropwise under argon to an ice cold 50 mL chloroform solution of 2.12 g. (0.0113 mol) of N-(3-aminopropyl)-N'-(2-hydroxyethyl) piperazine and stirred for one hour maintaining the temperature between 2°-4° C. This reaction mixture was then treated with 100 mL of aqueous sodium bicarbonate and extracted with chloroform (2×50 mL). The combined chloroform layers were washed with aqueous sodium bicarbonate (2×50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The remaining solid was crystallized in ethyl acetate/hexane to yield 1.69 g. (40.8%)of the subject product.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2]>CO.O1CCCC1.[OH-].[Na+].C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)OC)cc3)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)O)cc3)c2)c(C)c1
Yield: 74.6 %

Procedure:
Methyl 3-[4-[[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy]phenyl]propanoate (0.12 g, 0.26 mmol) was dissolved in a mixed solution of methanol (2 mL) and tetrahydrofuran (4 mL), and 1 N aqueous sodium hydroxide solution (0.52 mL) was added at room temperature with stirring. The mixture was stirred at the same temperature for 2 hrs. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, water and saturated brine, dried and concentrated under reduced pressure. The residue was crystallized from hexane/ethyl acetate=4/1 to give the title compound (0.087 g, yield 75%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=[O:17])[N:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:21][CH3:22].[CH3:23][Mg]Br>C1COCC1.CCOCC>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]([OH:17])[CH3:23])[N:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(CNC(=O)c2cc(C=O)nc(C)n2)ccc1F
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(CNC(=O)c2cc(C(C)O)nc(C)n2)ccc1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
A solution of N-(4-fluoro-3-methoxybenzyl)-6-formyl-2-methylpyrimidine-4-carboxamide (2 g, 6.59 mmol, Preparation #8) in THF (200 mL) was cooled to about −78° C. and methyl magnesium bromide was added drop wise (8.79 mL, 26.4 mmol, 3M in ether). Upon completion of addition, the reaction mixture stirred for about 4 h at −78° C. The reaction mixture was quenched with aqueous ammoniumchloride (20 mL) and the product extracted with EtOAc (2×100 mL). The organic layer was washed successively with water (1×50 mL), brine (1×50 mL), dried over sodium sulphate and concentrated under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-6-(1-hydroxyethyl)-2-methylpyrimidine-4-carboxamide (1 g, 47.6% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO): δ 9.40 (bs, 1H) 7.95 (s, 1H) 7.17-7.11 (m, 2H) 6.89-6.88 (m, 1H) 5.75-5.71 (m, 1H) 4.49-4.47 (m, 2H) 3.81 (s, 3H) 2.68 (s, 3H) MS m/z=320 (m+H)+.
Reaction SMILES: O.[OH-].[Li+].[F:4][CH:5]([F:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)[C:14]([O:16]C)=[O:15])[CH3:9]>O.C1COCC1>[F:4][CH:5]([F:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])[CH3:9]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)COC(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.6 %

Procedure:
Lithium hydroxide monohydrate (19 mg, 0.45 mmol) in water (2 mL) was added to methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-phenylmethoxy-benzoate (0.11 g, 0.3 mmol) in THF (4 mL) and the mixture stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer adjusted to pH 3 with citric acid then extracted into ethyl actetate (2×30 mL). The organics were washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound (0.1 g).
Reaction SMILES: [NH3:1].[OH:2][CH:3]1[O:7][CH:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([N:17]4[CH2:21][CH:20]([CH2:22][O:23][CH3:24])[O:19][C:18]4=[O:25])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:5][CH2:4]1>>[OH:7][C@H:6]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([N:17]3[CH2:21][C@H:20]([CH2:22][O:23][CH3:24])[O:19][C:18]3=[O:25])[CH:14]=[CH:13][C:11]=2[N:12]=1)[CH2:5][CH2:4][C:3](=[O:2])[NH2:1]
Reactant: COCC1CN(c2ccc3nc(C4CCC(O)O4)sc3c2)C(=O)O1
Reactant: N
Product: COC[C@H]1CN(c2ccc3nc([C@@H](O)CCC(N)=O)sc3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
50 ml of liquid ammonia was put in a sealed tube at -78° C. and 2.9 g of 3-[2-(5-hydroxytetrahydrofuran-2-yl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone was added thereto. After sealing followed by stirring at room temperature for 3 h, ammonia was slowly evaporated. Acetone was added to the residue and the precipitated crystals were separated by filtration and dried to give 2.6 g of the titled compound.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[OH:18].C(N(C(C)C)C(C)C)C.[CH3:28][O:29][CH2:30]Cl.C(N(CC)CC)C>ClCCl.O>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[O:18][CH2:28][O:29][CH3:30]
Reactant: CCCCCC1CCc2cc(O)c(F)c(F)c2O1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCCCCC1CCc2cc(OCOC)c(F)c(F)c2O1
Reaction time: 0.08 h

Procedure:
16.9 g (65.9 mmol) of 7,8-difluoro-2-pentylchroman-6-ol are dissolved in 110 ml of dichloromethane, and 13.5 ml (77.1 mmol) of N-ethyldiisopropylamine are added with ice-cooling. After 5 min, 6.0 ml (79.0 mmol) of chloromethyl methyl ether are metered in the temperature range from 15 to 30° C. After 16 h at room temperature, 50 ml of triethylamine are added, and the batch is stirred again for 24 h. Water is added to the reaction mixture, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed successively with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, 1-chlorobutane), giving 7,8-difluoro-6-methoxymethoxy-2-pentylchroman as a yellowish oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16](=[O:18])[CH3:17])([CH3:14])([CH3:13])[CH3:12].Br[CH2:20][C:21]1[C:22]([Cl:37])=[N:23][C:24]([S:35][CH3:36])=[N:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].CO>C1COCC1>[Cl:37][C:22]1[C:21]([CH2:20][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:18])=[C:26]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[N:25]=[C:24]([S:35][CH3:36])[N:23]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: CSc1nc(Cl)c(CBr)c(-c2ccc(F)cc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(CCC(=O)OC(C)(C)C)c(-c2ccc(F)cc2F)n1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of LiHMDS (4.1 mL) in 3 mL of THF was added t-butylacetate (0.6 mL). After stirring for 10 min, 1.0 g of 5-(bromomethyl)-4-chloro-6-(2,4-difluorophenyl)-2-(methylthio)pyrimidine (COMPOUND VV-3) in 4 mL of THF was added dropwise. The mixture was stirred at −78° C. for 1.5 h, then warmed to −50° C. The reaction mixture was recooled to −78° C. and 3 mL of methanol was added. The solution stirred for 24 h at rt. The crude mixture was purified by flash chromatography, eluting with 2% diethyl ether/hexanes. Mass spectrum m/z (ESI) 401.5 (M+1).