Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:21])[C:12]3[C:17]([S:18][C:19]=2[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C(N(CC)CC)C.[Cl:29][CH2:30]Cl>O>[Cl:29][CH2:30][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:21])[C:12]3[C:17]([S:18][C:19]=2[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CN1c2ccccc2Sc2cc(O)ccc21
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CN1c2ccccc2Sc2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
With ice-cooling, methanesulfonyl chloride (3.9 ml, 50 mmol) was added dropwise to a mixture of 3-hydroxy-10-methylphenothiazine (10.9 g, 45 mmol), triethylamine (8.2 ml, 59 mmol) and dichloromethane (80 ml), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the reaction product was extracted with chloroform. The extract was washed with a saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to give the title compound (8.09 g, 30.9 mmol, 69%) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]([CH2:8][CH3:9])=[CH:3][C:4](OC)=[O:5].[C:10]([O:18]CC)(=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C[O-].[Na+].ClC1C=CC=CC=1Cl>CO.C(O)C>[C:12]([C:11]1[C:10](=[O:18])[NH:1][C:2]([CH2:8][CH3:9])=[CH:3][C:4]=1[OH:5])([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC(N)=CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1c(O)cc(CC)[nH]c1=O
Temperature: 160 °C

Procedure:
113.6 g (0.88 mol) of methyl 3-amino-2-pentenoate and 128 g (0.8 mol) of diethyl malonate are added to a solution of 259.2 g (0.8 mol) of 21% strength sodium methoxide solution in methanol and 130 g of ethanol. After addition of 800 ml of 1,2-dichlorobenzene, a mixture of methanol and ethanol is removed by distillation in the course of one hour and the remaining suspension is heated to 160° C. for two hours. After cooling, 600 ml of water are added, and the organic phase is separated off, extracted using water and then discarded. The combined aqueous phases are washed with ether, and the aqueous phase is separated off, acidified using hydrochloric acid and filtered off with suction.
Reaction SMILES: C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O.O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].[C:22]([O:26][C:27]([N:29]1[CH2:36][CH2:35][C:32]2([CH2:34][CH2:33]2)[C:31](=[O:37])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH-].[Na+]>C1N(CCS(O)(=O)=O)CCOC1.CCCCCCC>[C:22]([O:26][C:27]([N:29]1[CH2:36][CH2:35][C:32]2([CH2:34][CH2:33]2)[C@H:31]([OH:37])[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C(=O)C1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)CCN1CCOCC1
Agent: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CCCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@H](O)C1
Temperature: 35 °C
Yield: 93 %

Procedure:
D(+)-glucose monoydrate (300 g) and magnesium chloride hexahydrate (1.0 g) were dissolved in 10 mM MES buffer pH 6.5 (2.4 L; Sigma M3671). After addition of 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (300 g; 1.33 mmol) and 8-NAD (3.0 g; free acid; Roche Diagnostics Cat. No. 10 004 626) the pH was re-adjusted and the suspension heated to 35° C. The reaction was started by adding ketoreductase KRED-NADH-117 (3.0 g; former Biocatalytics, now Codexis) and glucose dehydrogenase GDH-102 (300 mg; Biocatalytics). The suspension was vigorously stirred at 35° C. keeping the pH constant at 6.5 by the controlled addition (pH-stat) of 1.0 M aq. sodium hydroxide solution. After a consumption of 1.307 L (corresponding to 98% conversion; after 17 h) the reaction mixture was extracted with ethyl acetate (10 L). The organic phase was dried over sodium sulfate and concentrated in vacuo (200 mbar/45° C.) until evaporation fell off. Upon cooling the oily residue (411 g) started to crystallize and was stirred with heptane (1 L) for 2 h. The crystals were filtered off and the filtrate evaporated to dryness, redissolved in ethyl acetate (150 ml) and concentrated in vacuo as described above. The crystal suspension formed again upon cooling was stirred with heptane (200 ml; 2 h) and the crystals filtered off. Both crops of crystals were washed with heptane and dried under high vacuum to yield the titled compound in 93% yield (250.77 g and 34.60 g white crystals), each having a purity of >98.5% GC and 99.8% ee. [α]D=−44.97° (c=1.00, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:24]=[C:25]([NH2:27])[CH3:26].O>CN(C=O)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:7]2[O:9][N:27]=[C:25]([CH3:26])[N:24]=2)[CH:10]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1noc(-c2cncc(Br)c2)n1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A mixture of 5-bromo nicotinic acid(1.0 eq.) and CDI (1.1 eq) in DMF (0.25M) was stirred at 20° C. for 5 min and then N′-hydroxy ethanimidamide (1.1 eq) in pyridine (0.6 M) was added. The reaction mixture was stirred at 110° C. for 15 h, cooled to rt and poured into water. The title compound was isolated by filtration as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])[N:7]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cccc(Cl)n1
Product: Cc1ccc(C)n1-c1cccc(Cl)n1
Yield: 54.9 %

Procedure:
The product from Example 12a (20 g, 156 mmol) was treated with hexane-2,5-dione (18.3 mL, 156 mmol) for 2 h following the procedure from Example 2a giving the title compound (17.7 g 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][NH2:8])=[O:6].[CH3:13][C:14]([CH3:16])=O.FC(F)(F)C(O)=O>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][N:8]=[C:14]([CH3:16])[CH3:13])=[O:6]
Reactant: Cc1ccc(C(=O)NN)cc1Br
Reactant: CC(C)=O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=NNC(=O)c1ccc(C)c(Br)c1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a mixture of 3-bromo-4-methylbenzohydrazide (2.0 g, 8.72 mmol, 1.0 eq) and acetone (10 mL, 172 mmol, 21 eq) in hexane (10 mL), was added molecular sieves (500 mg) followed by trifluoroacetic acid (2 mL) and the resulting mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was taken in ethyl acetae (100 mL), washed with water (50 mL), aqueous saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to afford the 2.10 g of the 3-bromo-4-methyl-N′-(propan-2-ylidene)benzohydrazide. 1HNMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H, D2O exchangeable), 8.02 (s, 1H), 7.75 (dd, J=1.0, 8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 2.40 (s, 3H), 2.01 (s, 3H), 1.94 (s, 3H); ESI-MS (m/z) 269, 271 [(MH)+, Br79,81].
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][CH2:12][C:13]2[CH:26]=[CH:25][C:16]([C:17]([NH:19][C:20]3[N:21]=[N:22][NH:23][N:24]=3)=[O:18])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[S:27]1[C:31]([C:32](O)=[O:33])=[CH:30][C:29]2[CH:35]=[CH:36][CH:37]=[CH:38][C:28]1=2.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:19][C:20]3[N:21]=[N:22][NH:23][N:24]=3)=[CH:25][CH:26]=2)[C:32]([C:31]2[S:27][C:28]3[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=3[CH:30]=2)=[O:33])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(NCc2ccc(C(=O)Nc3nn[nH]n3)cc2)CC1
Reactant: O=C(O)c1cc2ccccc2s1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)c2cc3ccccc3s2)CC1
Temperature: 25 °C

Procedure:
To the above resin bound 4-[(4-tert-butylcyclohexylamino)methyl]-N-(2H-tetrazol-5-yl)-benzamide was added a solution of benzo[b]thiophene-2-carboxylic acid (400 μmol) in a mixture of NMP, DCP and diisopropylethylamine (4.5:4.5:1, 1 mL) followed by a solution of PyBrOP (400 μmol) in DCP (500 μL). The mixture was allowed to react 3 hours at 50° C. The resin was cooled to 25° C. while washed with NMP (4×1 mL), and DCM (10×1 mL).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: Cl
Product: Cc1c(-c2cccnc2)n(C(=O)c2ccccc2)c2ccccc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride and benzoyl chloride are processed according to the method described in Example 38 to give (3-methyl-2-pyridin-3-yl-indol-1-yl)-phenyl-methanone. 1H NMR (400 MHz, MeOD) δ ppm 2.33 (s, 3H), 7.26-7.40 (m, 5H), 7.45-7.52 (m, 1H), 7.57 (d, J=1.3 Hz, 1H), 7.59 (s, 1H), 7.63 (dd, J=7.1, 1.3 Hz, 1H), 7.68-7.73 (m, 1H), 7.75 (dt, J=7.8, 1.9 Hz, 1H), 8.33 (dd, J=5.1, 1.5 Hz, 1H), 8.47 (d, J=1.3 Hz, 2H). HRMS (ESI) m/z 313.1337 [(M+H)+ Calcd for C21H17N2O: 313.1341].
Reaction SMILES: C[C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=O)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH3:2][C:3]1[C:4](=[O:5])[CH:6]2[CH:11]([C:12](=[O:13])[C:24]=1[CH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH:14]([CH3:15])[CH3:16])=[CH:22][CH:21]=1)[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Product: CC1=C(Cc2ccc(C(C)C)cc2)C(=O)C2C=CC=CC2C1=O
Yield: 58 %

Procedure:
As starting materials for the coupling reaction menadione and 4-isopropylphenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:1, UV), 395 mg (1.30 mmol, 58% yield) of P_TM100 were isolated as yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:26]1[C:30]2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.CN>C(Cl)Cl>[CH3:30][NH:26][C:22](=[O:24])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a stirred solution of N-(Benzyloxycarbonyl)-O-methyl-L-tyrosine (155 g, 0.471M) in dry CH2Cl2 was added 1-hydroxybenzotriazole (63.6 g, 0.471M) followed by a solution of DCC (97.2 g, 0.0471M) in CH2Cl2 (100 ml) added slowly at 0° C. After warming to room temperature over 1 hr, a solution of methylamine (30 g) in CH2Cl2 (250 ml) was added dropwise to the reaction mixture which was then stirred overnight at room temperature. The reaction was then filtered, washed with saturated aqueous sodium bicarbonate (x2), dried (MgSO4) and concentrated in vacuo to give a solid. Recrystallisation from ethyl acetate/hexane gave the desired amide (142 g); m.p. 167°-170°; (Found: C,66.72; H,6.58; N,8.29. C19H22N2O4 requires C,66.65; H,6.48; N,8.18%)νmax (CHCl3) 3440, 1710 and 1672 cm-1 ; δ (CDCl3) 2.70 (3H,d,J=5 Hz,NCH3); 2.98 (2H,m,CH2C6H4); 3.77 (3H,s,OCH3); 4.30 (1H,dd,J=7.6 and 3 Hz, α--CH); 5.06 (2H,m,OCH2C6H5); 5.43 (1H,m,OCONH); 5.84 (1H,m,CONH); 6.80 (2H,d,J=8.6 Hz, Tyr H-3 and H-5); 7.15 (2H,d,J=8.6 Hz, Tyr H-2 and H-6); 7.32 (5H,m,C6H5); m/e 343 (100%, [m+1]+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])[OH:13]>C(N(CC)CC)C>[C:1]([O:21][CH2:20][C@@H:18]([C@H:16]([C@@H:14]([C@@H:12]([CH2:11][O:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:13][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:15][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:19][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC[C@H](OC(=O)c1ccccc1)[C@@H](OC(=O)c1ccccc1)[C@H](OC(=O)c1ccccc1)[C@@H](COC(=O)c1ccccc1)OC(=O)c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 74 %

Procedure:
While stirring, 71 parts by weight of benzoyl chloride were dripped over 30 minutes into a mixed solution of 30 parts by weight of sorbitol and 101 parts by weight of triethylamine maintained at 100° C., and the resulting mixture was stirred for an additional 30 minutes. After completion of the reaction, the temperature was lowered to room temperature, and the resulting precipitates were collected by filtration. Thereafter, washing was performed by adding ethyl acetate-pure water. Subsequently, the organic phase was collected and ethyl acetate was distilled out under vacuum, whereby 100 parts by weight (at a yield of 74 percent) of white crystals were obtained. The molecular weight of the resulting compound was 809.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[CH:11]1([CH2:14][NH2:15])[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([NH:15][CH2:14][CH:11]2[CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: NCC1CC1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cn1c(NCC2CC2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g, 0.45 mmol), cyclopropylmethanamine (0.051 mL, 0.58 mmol) and NaHCO3 (0.150 g, 1.79 mmol) in n-BuOH (3 mL) was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.114 g, 98%) as a pale yellow solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.46 (t, J=5.5 Hz, 1H), 3.33 (s, 3H), 3.19 (t, J=6.2 Hz, 2H), 1.12 (m, 1H), 0.43 (m, 2H), 0.24 (m, 2H). LRMS (ESI pos) m/e 258, 260 (M+1, Br pattern).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:25]([OH:27])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O[N:62]=[C:63]([O:65][CH2:66][CH3:67])[NH2:64]>CN(C)C=O>[CH2:66]([O:65][C:63]1[N:64]=[C:25]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]2)[O:27][N:62]=1)[CH3:67]
Reactant: CCOC(N)=NO
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccc(CC(F)(F)F)cc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 459 mg (0.889 mmol, purity 75%, 2:1 cis/trans isomer mixture) of the carboxylic acid from Example 59A in 19 ml of N,N-dimethylformamide were added, at RT, 541 mg (1.42 mmol) of HATU and 0.45 ml (337 mg, 2.61 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 136 mg (1.30 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at room temperature overnight. The reaction solution was purified directly by means of preparative HPLC. The resulting intermediate was taken up in toluene (50 ml), admixed with 4 Å molecular sieve and stirred under reflux overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by means of preparative HPLC. Yield: 124 mg (31% of theory)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=O)[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][S:20]([CH2:23][C:24](=O)[CH3:25])(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:14])[N:15]([CH3:17])[N:16]=[C:24]([CH3:25])[C:23]=1[S:20]([CH3:19])(=[O:22])=[O:21])[CH3:2]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Temperature: 5 °C
Reaction time: 20 h
Yield: 90.3 %

Procedure:
To a 25 mL volume three-necked flask with Dean-Stark, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (1.01 g), 1-methylsulfonyl-2-propanone (7-2-1) (613 mg), and toluene (2.9 ml) were added under a nitrogen atmosphere. Water was removed by azeotropic distillation at 60° C. under 100 mmHg for 4 hours. The mixture was concentrated under reduced pressure. To the residue, toluene (1.73 g) and methanol (1.90 ml) were added, then lithium hydroxide monohydrate (80 mg) was added at 0° C. After the mixture was stirred at 0° C. for 4 hours and at 5° C. for 20 hours, 20 w/w % of sulfuric acid was added to adjust pH to less than 1. To the mixture was added toluene and water, and then the organic layer was removed. The aqueous layer was extracted with toluene 2 times. The organic layers were combined, and concentrated under reduced pressure to give 1.28 g of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C@@H:26]([F:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:32](C1C=NC(C2C=CC(O)=CC=2)=NC=1)[CH2:33]CCCCCCCCCC.CS(OCC[C@H](F)CCCC)(=O)=O>>[CH2:1]([C:11]1[CH:16]=[N:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C@H:26]([F:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[N:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(OCC[C@@H](F)CCCC)cc2)nc1
Agent: CCCC[C@@H](F)CCOS(C)(=O)=O
Product: CCCCCCCCCCCCc1cnc(-c2ccc(OCC[C@H](F)CCCC)cc2)nc1
Yield: 78.4 %

Procedure:
The titled compound was synthesized in a yield of 78.4% in the same manner as for the compound of Example 4, except for using 5-n-dodecyl-2-(4-hydroxyphenyl)pyrimidine and (R)-3-fluoroheptyl methanesulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:30]45[CH2:39][CH:34]6[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]6)[CH2:31]4)[CH2:37]5)=[C:17]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]=3)[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[OH:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:30]45[CH2:37][CH:36]6[CH2:38][CH:32]([CH2:33][CH:34]([CH2:35]6)[CH2:39]4)[CH2:31]5)=[C:17]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]=3)[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1O

Procedure:
930 mg (1.8 mmol) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoate and 100 ml of a 2N methanolic sodium hydroxide solution were introduced into a round-bottomed flask and the reaction mixture was heated at reflux for one hour. The reaction mixture was evaporated to dryness, the residue was taken up in water and acidified to pH 1 with concentrated hydrochloric acid and the solid was filtered. The solid obtained was triturated in ethyl acetate, filtered and dried. 710 mg (79%) of the expected acid were collected, which acid had a melting point of 263°-4° C.
Reaction SMILES: [H-].[Na+].[S:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]1[SH:12].C1(C)C=CC(S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O)=CC=1>CN(C)C=O>[F:25][C:24]([F:27])([F:26])[CH2:23][S:12][C:4]1[S:3][C:11]2[C:6]([N:5]=1)=[N:7][CH:8]=[CH:9][CH:10]=2
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Sc1nc2ncccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)CSc1nc2ncccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
A mixture of sodium hydride (60% suspension in oil, 0.72 g, 0.03 mol) in N,N-dimethylformamide is cooled to 0° C., treated dropwise with a solution of thiazolo[4,5-b]pyridine-2-thiol (5.0 g, 30 mmol) in N,N-dimethylformamide, stirred for 30 minutes, treated with a solution of 2,2,2-trifluoroethyl p-toluenesulfonate (3.81 g, 15 mmol) in N,N-dimethylformamide, heated to and stirred at 110° C. for 6 hours, and poured into an ice/water mixture. The resultant aqueous mixture is extracted with diethyl ether. The organic extract is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Column chromatography of the residue using an ethyl acetate/hexanes solution gives the title product as a light yellow liquid (2.91 g, 39% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1.F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([CH3:25])(=[O:24])=[O:23].C(N(CC)C(C)C)(C)C.ClCCl>CN(C)C=O>[F:21][C:19]1[CH:20]=[CH:15][C:16]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([NH:10][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([Cl:13])[C:5]=2[O:11][CH3:12])[CH3:9])[CH:18]=1
Reactant: COc1c(Cl)cc(F)cc1C(C)N
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(Cl)cc(F)cc1C(C)Nc1cc(F)ccc1S(C)(=O)=O
Yield: 25.6 %

Procedure:
A solution of 1-(5-Fluoro-2-methoxy-3-chlorophenyl)ethanamine (0.38 g, 1.87 mmol), 2,4-difluoro-1-methanesulfonyl-benzene (0.3 g, 1.56 mmol) and N,N-diisopropylethylamine (1.4 mL, 7.81 mmol) in N,N-dimethylformamide (10 mL) was stirred at 110° C. for 18 h. Dichloromethane was added (20 mL) and washed with water (2×20), brine (20 mL), dried, and concentrated under reduced pressure to the crude compound which was purified by silica gel column (20% ethyl acetate in hexanes) to afford 5-fluoro-N-(1-(5-fluoro-2-methoxy-3-chlorophenyl)ethyl)-2-(methylsulfonyl)benzenamine (0.15 g, 26%): 1H NMR (400 MHz, CDCl3): δ 7.76 (dd, 1H), 7.06 (dd, 1H), 6.84 (dd, 1H), 6.79 (bs, 1H), 6.42 (dd, 1H), 6.19 (dd, 1H), 4.82 (m, 1H), 3.97 (s 3H), 3.05 (s, 3H), 1.58 (d, 3H).