Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH:6]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH3:4].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[CH2:1]([O:5][CH:6]([C:10]([F:11])([F:12])[F:13])[C:7]([O:9][CH2:15][CH3:16])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(C(=O)O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCCCOC(C(=O)OCC)C(F)(F)F
Reaction time: 12 h
Yield: 750.2 %

Procedure:
A mixed solution of (+)-2-butoxy-3,3,3-trifluoropropionic acid (1.2 g) obtained in Example 6, ethanol (40 ml) and p-toluenesulfonic acid monohydrate (0.1 g) was heated with stirring for 12 hours, followed by distilling off the solvent under normal pressure, extracting the residue with ether, neutralizing, washing with water and concentrating to obtain (+)-ethyl 2-butoxy-3,3,3-trifluoropropionate (0.9 g). [α] +24.1 (cl. 06, CHCl3).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:30])[CH:9]=1>C1COCC1>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([C:1](=[O:3])[CH3:2])[CH2:34][CH2:33]2)=[O:30])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC2CCNCC2)C(COc2cccnc2)C1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(OC(=O)N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)CC1
Reaction time: 16 h

Procedure:
Acetic anhydride (0.0207 mL, 0.219 mmol) was added to a solution of 4-tert-butyl 1-piperidin-4-yl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (83.7 mg, 0.199 mmol) in THF (4 mL). After 16 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 112.5 mg (98%) of the TFA salt of the desired product as a white solid. LC-MS: RT=6.40 min, [M+H]+=463.2.
Reaction SMILES: BrC1C(C2C=CC(SC)=CC=2)=C([C:12]([O:14][CH3:15])=[O:13])C2C=1C=CC=CC=2.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:43]=[C:42]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=[CH:41]3)[C:35]=2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([C:34]2[C:35]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[C:36]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=[CH:37]3)[C:43]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: COC(=O)c1c2cccccc-2c(Br)c1-c1ccc(SC)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c2cccccc-2c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1

Procedure:
Methyl 3 -bromo-2-(4-methylthiophenyl)azulene-1-carboxylate: To a solution of 2-(4-methylsulfonylphenyl)-1-phenylazulene (2.00 g) in CCl4 (20.0 ml) was added N-bromosuccinimide (1.26 g) and α,α'-azobis(isobutyronitrile) (0.01 g), and the reaction mixture was heated under reflux for 1 hr. The mixture was filtered, and concentrated. The crude product was purified by SiO2 column chromatography (benzene/Et2O, 100:1) to give the title compound (2.40 g) as violet crystals; mp 98°-100° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[N:4][N:3]=1.[CH2:22](O)[CH3:23].C(O)(=O)C>CCOC(C)=O>[CH2:22]([O:6][C:2]1[NH:1][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[N:4][N:3]=1)[CH3:23]
Reactant: CCO
Reactant: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1nnc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1
Yield: 27.9 %

Procedure:
To a solution of [4-(5-Amino-[1,3,4]oxadiazol-2-yl)-pyridin-3-yl]-(2-floro-4-iodo-phenyl)-amine (150 mg, 0.38 mmol) in ethanol (10 mL) KOH 9212 mg, 3.78 mmol) was added. The reaction mixture was refluxed for 3 hrs. Then, added acetic acid was added to bring the pH to 5. The volatives were stripped and the residue was dissolved in EtOAc, and washed with 5% Na2CO3, and brine, and then dried over anhydrous MgSO4. After filtration and solvent removal the remaining crude product was subjected to silica gel column chromatography (eluent:Hex:ane EtOAc=1:1) to afford the desired product (45 mg). [5.08 min; 394(M+1)]
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[S:16]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:18])(=[O:17])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCCOS(C)(=O)=O
Reaction time: 2 h

Procedure:
Alternately, combine 2-isopropoxyethanol (5.0 g, 48 mmol) and dichloromethane (50 mL). Cool in an ice bath. Add triethylamine (10.7 g, 105 mmol). Add dropwise methanesulfonyl chloride (1.43 g, 9.6 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with 1 M hydrochloric acid solution, a saturated aqueous solution of sodium bicarbonate, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Distill the residue at reduced pressure to give 2-(isopropoxy)ethyl mesylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=2)=O)=[CH:4][C:3]=1[O:32][CH3:33].C([O-])(=O)C.[NH4+:38]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:38][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=3)=[CH:10][C:9]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:4][C:3]=1[O:32][CH3:33]
Reactant: [NH4+]
Reactant: COc1cc(C(=O)C(CC(=O)c2ccc(OCCN(C)C)cc2)c2ccncc2)ccc1Cl
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(-c2[nH]c(-c3ccc(OCCN(C)C)cc3)cc2-c2ccncc2)ccc1Cl
Temperature: 25 °C

Procedure:
A solution of the product of Example 1 Step 2 (420 mg, 0.9 mmol) and ammonium acetate (750 mg, 9.7 mmol) in glacial acetic acid (15 ml) was heated under reflux for 16 hours. After cooling to room temperature, the reaction mixture was concentrated and aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with chloroform and the organic phase washed with water and brine, dried and concentrated in vacuo to give the title compound; MS(ES+) m/e 448,450 [+H]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[C:20]([CH3:27])[CH:19]=1.Cl>C(OC)(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:25][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)=[CH:19][C:20]=1[CH3:27])=[O:26]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-c2ccco2)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cc(-c2ccco2)ccc1C(=O)CC(=O)C(F)(F)F
Reaction time: 20 h
Yield: 104.7 %

Procedure:
To a stirred solution of ethyl trifluoroacetate (9.90 g, 6.31 mmol) in t-butylmethylether (3 ml) was added sodium methoxide (28 wt. % solution in methanol, 1.5 ml, 6.23 mmol) over 2 min. A solution of 1-[4-(2-furyl)-2-methylphenyl]ethanone (1.15 g. 5.74 mmol) in t-butylmethylether (4 ml) was added dropwise over 5 min. and the mixture was stirred for 20 hours. 2N HCl (10 ml) was added, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give 1.78 g of brown oil. The compound was used for next reaction without purification.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=1>>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Nc1ncccc1O
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2ncccc2O)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 40 %

Procedure:
4-Hydroxy-N-(3-hydroxy-2-pyridyl)-2-methyl-2H-naphtho[2,1-e]1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-3-hydroxy-pyridine. Yield: 40% of theory; m.p. 255° C (decomp.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])/[CH:12]=C/C(OC)=O)(=[O:7])=[O:6].O=O.[O:30]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:27])[C@@H:11]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH:12]=[O:30])(=[O:6])=[O:7]
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)CCCCl)[C@H](C=O)O[Si](C)(C)C(C)(C)C
Yield: 52 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, methyl (2E)(4S)-6-[(3-chloropropyl)sulfonyloxy]-5,5-dimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)hex-2-enoate (15a) (2.4 g, 5.4 mmol) dissolved in 25 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 2 mL (1.59 g, 27.2 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:3) as eluent to provide 1.1 g (52% yield) of the title compound (15b) as a colorless oil. Rf=0.75 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.07 (s, 3H), 0.10 (s, 3H), 0.96 (s, 9H), 1.06 (s, 3H), 1.09 (s, 3H), 2.30-2.37 (m, 2H), 3.28-3.32 (m, 2H), 3.69-3.73 (m, 3H), 4.01 (d, J=9.6 Hz, 1H), 4.12 (d, J=9.6 Hz, 1H), 9.62 (d, J=2.4 Hz, 1H) ppm. MS (ESI) m/z 409.13 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: CS(C)=O.[CH3:5][N:6]1[C:11]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH3:17])=[CH:10][C:9](=[O:18])[N:8]([CH3:19])[C:7]1=[O:20].[CH3:21][C:22]1[C:27](=[O:28])[C:26]2[C:29]([O:33][CH2:34][CH2:35][CH2:36]Br)=[CH:30][CH:31]=[CH:32][C:25]=2[O:24][CH:23]=1>C(N(CC)CC)C>[CH3:5][N:6]1[C:11]([NH:12][CH2:13][CH2:14][N:15]([CH2:16][CH3:17])[CH2:36][CH2:35][CH2:34][O:33][C:29]2[C:26]3[C:27](=[O:28])[C:22]([CH3:21])=[CH:23][O:24][C:25]=3[CH:32]=[CH:31][CH:30]=2)=[CH:10][C:9](=[O:18])[N:8]([CH3:19])[C:7]1=[O:20]
Reactant: CCNCCNc1cc(=O)n(C)c(=O)n1C
Reactant: Cc1coc2cccc(OCCCBr)c2c1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN(CCCOc1cccc2occ(C)c(=O)c12)CCNc1cc(=O)n(C)c(=O)n1C
Reaction time: 6 h

Procedure:
To 5 ml of dimethyl sulfoxide were added 0.52 g of the previously obtained N-[1,3-dimethyl-2,4-dioxopyrimidine-6-yl]-N'-ethylethylenediamine (Compound 13), 0.7 g of 3-(3-methyl-4-oxo-4H-1-benzopyran-5-yl)oxypropyl bromide (Compound 2) and 0.5 ml of triethylamine, and reaction was carried out at 100° C. for 6 hours. The resultant reaction solution was cooled, and the formed white crystals were collected by filtration, washed with water, and then dried, thereby obtaining 0.56 g of 1,3-dimethyl-6-(2-[N-ethyl-N-[3-(3-methyl-4-oxo-4H-1-benzopyran-5-yl)oxypropyl]amino]ethylamino)-2,4(1H,3H)-pyrimidinedione (the non-oxalate of Compound 14).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C(O)CC(C)C>[N:22]1[CH:23]=[CH:24][C:19]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]2)=[CH:20][CH:21]=1
Reactant: Clc1ccncc1
Reactant: NS(=O)(=O)c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Product: NS(=O)(=O)c1ccc(C2CCN(c3ccncc3)CC2)cc1

Procedure:
A mixture of the product of part (iii) above (3.75 g), 4-chloropyridine hydrochloride (2.34 g), sodium bicarbonate (3.93 g) and isoamyl alcohol (60 ml) was heated under reflux for 30 hours and then evaporated. The residue was triturated with water and the mixture was filtered. The solid was washed well with water and crystallised from methanol/water to give the title compound (0.43 g), m.p. 295° (with decomp).
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]([OH:10])=O)[C:6](=[O:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[S:3]1(=[O:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>O1CCCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:8]([CH:7]1[C:6](=[O:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[S:3](=[O:17])(=[O:16])[N:2]1[CH3:1])=[O:10]
Reactant: Nc1ccccn1
Reactant: CN1C(C(=O)O)C(=O)c2ccccc2S1(=O)=O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: CN1C(C(=O)Nc2ccccn2)C(=O)c2ccccc2S1(=O)=O

Procedure:
To a solution of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide (127 mg.) and 2-aminopyridine (52 mg.) in tetrahydrofuran (5 ml.) is added, with stirring, a solution of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (148 mg.) in tetrahydrofuran (1 ml.). The mixture is stirred at room temperature (23°-25° C.) for four hours and is then concentrated under reduced pressure to an oil. Thin layer chromatography on silica gel plates in the system - benzene:acetic acid (95:5) and visualization of the plate under a 366 mμ lamp showed, by comparison with an authentic sample, the title compound is present.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[C:9]1([CH2:18][CH3:19])[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17].Br.N>ClCCl.C(O)(=O)C>[CH2:18]([C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[CH:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17])[CH3:19]
Reactant: CCC1(C2=C(Cl)C(=O)CCC2)CCCCN(C)C1=O
Agent: Br
Agent: N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1(c2cccc(O)c2)CCCCN(C)C1=O

Procedure:
A solution of 3-(2-chloro-3-oxocyclohex-1-enyl)-3-ethyl-hexahydro-1-methylazepin-2-one (5.68 g) in dichloromethane (60 ml) was treated with 48% HBr in acetic acid (2 ml). After 12 hours the mixture was treated with excess aqueous ammonia, the organic solvent removed under reduced pressure and the resulting solid removed by filtration to give the title compound, m.p. 178°-80° C. (EtOAc).
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[N:4]=1)[NH2:2].[C:13]([CH:16]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[C:17](OCC)=[O:18])(=O)[CH3:14]>>[CH3:14][C:13]1[C:16]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[C:17]([OH:18])[N:1]([C:3]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=3[N:4]=2)[N:2]=1
Reactant: CCOC(=O)C(Cc1ccc2ccccc2c1)C(C)=O
Reactant: Cc1ccc2[nH]c(NN)nc2c1
Product: Cc1ccc2[nH]c(-n3nc(C)c(Cc4ccc5ccccc5c4)c3O)nc2c1

Procedure:
Using 2-hydrazino-5-methyl-1H-benzimidazole (4) obtained in Example 1, step 3 and ethyl 2-acetyl-3-(2-naphthyl)propanoate (39), and by a method similar to that in Example 1, step 4, 3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-4-(2-naphthylmethyl)-1H-pyrazol-5-ol (40) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[I-].[K+].[Cl:16][C:17]1[N:22]=[C:21]([S:23][CH3:24])[N:20]2[CH:25]=[C:26]([CH2:28]Cl)[N:27]=[C:19]2[CH:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([S:23][CH3:24])[N:20]2[CH:25]=[C:26]([CH2:28][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:27]=[C:19]2[CH:18]=1
Reactant: CSc1nc(Cl)cc2nc(CCl)cn12
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc2nc(CN3CCOCC3)cn12
Reaction time: 16 h

Procedure:
158 mg (1.81 mmol) of morpholine are introduced into 10 ml of DMF at 0° C., and 367 mg (3.63 mmol) of triethylamine and a catalytic amount of potassium iodide are added. A solution of 300 mg of 7-chloro-2-(chloromethyl)-5-(methylthio)imidazo[1,2-c]pyrimidine (Example 26A) in DMF is then slowly added dropwise. The mixture is allowed to reach RT and is stirred at this temperature for a further 16 h. Purification of the crude product by preparative HPLC and drying under high vacuum result in 221.8 mg (41% of theory) of product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BrH:13].O>CS(C)=O>[NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([Br:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: Cc1ccc(C(=O)O)c(N)c1C
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(Br)cc(C(=O)O)c(N)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-3,4-dimethylbenzoic acid (50.0 g) in DMSO (500 mL) was added hydrobromic acid (174 mL) while keeping the internal temperature at 25 to 30° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water (500 mL), and the mixture was stirred for 30 min. The precipitate was collected by filtration, and washed with water to give the title compound (102 g: containing DMSO).
Reaction SMILES: C(NC1C=[C:12]([CH:51]=C(C)C=1)[C:13]([NH:15][C@@H:16]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[C@@H:17]([C@H:26]1[CH2:30][C@@H:29]([O:31][CH2:32][CH2:33][CH3:34])[CH2:28][N:27]1C(OC(C)(C)C)=O)[O:18][Si](C(C)(C)C)(C)C)=[O:14])(=O)C1C=CC=CC=1.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=[C:80]([C:82]2[O:83][CH:84]=[CH:85][N:86]=2)[CH:79]=[C:78]([C:87]([N:89]2[CH2:93][CH2:92][CH2:91][C@@H:90]2[CH2:94][O:95][CH3:96])=[O:88])[CH:77]=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.COC[C@H]1CCCN1C(C1C=C(C=C(C2OC=CN=2)C=1)C(O)=O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:49][C:47]1[CH:48]=[C:43]([CH2:42][C@H:16]([NH:15][C:13](=[O:14])[C:12]2[CH:51]=[C:80]([C:82]3[O:83][CH:84]=[CH:85][N:86]=3)[CH:79]=[C:78]([C:87]([N:89]3[CH2:93][CH2:92][CH2:91][C@@H:90]3[CH2:94][O:95][CH3:96])=[O:88])[CH:77]=2)[C@H:17]([OH:18])[C@H:26]2[CH2:30][C@@H:29]([O:31][CH2:32][CH2:33][CH3:34])[CH2:28][NH:27]2)[CH:44]=[C:45]([F:50])[CH:46]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(NC(=O)c3ccccc3)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC[C@H]1CCCN1C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)C1
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Step 11 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzoic acid (Preparation H, 40 mg, 0.12 mmol) in dichloromethane (3 mL) was added Hunig's base (46 mg, 0.36 mmol) to make a clear solution and HATU (60 mg, 0.156 mmol) was then added. After stirring for 20 min, the reaction mixture was added (2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step 1 (A), 64 mg, 0.12 mmol) and the reaction mixture was stirred at rt for 16 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 70 mg of the title compound (70% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.07 (3H, s), 0.84 (9H, s), 0.87 (3H, m), 1.46-1.50 (11H, m), 1.74 (1H, m), 1.92-2.06 (3H, m), 2.17-2.23 (2H, m), 2.66 (1H, m), 2.77-2.81 (2H, m), 2.92 (1H, m), 3.05 (1H, m), 3.29-3.38 (4H, m), 3.48 (1H, m), 3.58 (1H, m), 3.66 (1H, m), 3.76 (1H, m), 3.98 (1H, m), 4.07-4.09 (1H, m), 4.12-4.14 (1H, m), 4.43 (1H, brd s), 4.61 (1H, m), 6.58 (1H, m), 6.77 (2H, d, J=10 Hz), 7.22 (1H, s), 7.69 (1H, s), 8.10 (1H, s), 8.28 (1H, s), 8.53 (1H, brd s), 8.64 (1H, s). MS (ESI) (M+H)+ 841.61.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([N:24]3[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[C:25]3=[O:32])=[CH:21][CH:22]=2)[CH2:17][O:16]1.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>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:29]([CH:26]1[CH2:27][CH2:28][N:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[CH2:15][O:16][CH2:17]3)[C:25]1=[O:32])=[O:30]
Reactant: O=C(O)C1CCN(c2ccc3c(c2)COC3)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc3c(c2)COC3)C1=O
Yield: 35.6 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(1,3-dihydroisobenzofuran-5-yl)-2-oxopyrrolidine-3-carboxylic acid (0.111 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent 7 to 60% of ethyl acetate in dichloromethane) to give 0.064 g (36%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(1,3-dihydroisobenzofuran-5-yl)-2-oxopyrrolidine-3-carboxamide a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(N/C(=C2\C(=O)Nc3cc(OC)c(OC)cc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and p-anisidine
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([F:13])([F:12])[F:11].CC1(C)C(C)(C)OB([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:9][C:4]1[C:3]([C:10]([F:13])([F:12])[F:11])=[C:2]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)c(C(F)(F)F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(F)cc(F)c2C(F)(F)F)CC1
Temperature: 85 °C
Yield: 117.7 %

Procedure:
A mixture of l-bromo-3,5-difluoro-2-(trifluoromethyl)benzene (25, 0.200 g, 0.76 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.237 g, 0.76 mmol), Pd(dppf) (0.056 g, 0.077 mmol), and 2 N Na2CO3 (2 mL, 4 mmol) in DME (3 mL) was heated to 85° C. for 5 h. The mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (3×75 mL). The combined organics were dried over Na2SO4, concentrated under reduced pressure, and the resulting residue was chromatographed over silica gel (24 g Redisep column, 0-25% EtOAc in hexanes) to afford tert-butyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (26) as a light yellow oil (0.325 g, 90%). 1H NMR (300 MHz, CDCl3) δ 6.92-6.80 (m, 1H), 6.78-6.68 (m, 1H), 5.58 (s, 1H), 4.06-3.94 (m, 2H), 3.69-3.53 (m, 2H), 2.36-1.24 (m, 2H), 1.50 (s, 9H).