Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(O)=O.[Na+]>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[O:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)OC[C@@H](c2cc(F)cc(F)c2)NC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(C)(C)OC[C@H]1c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (5R)-5-(3,5-difluorophenyl)-2,2-dimethylmorpholin-3-one from Step G (150 mg, 0.62 mmol) in DMF (2 mL) at 0° C. was added NaH (27 mg of a 60% dispersion in oil, 0.68 mmol). After 10 min, ethyl bromoacetate (104 mg, 0.62 mmol) was added and the mixture was stirred at 0° C. for 30 min. Saturated aqueous NaHCO3 (5 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 70:30, to give the title compound. MS: m/z=328 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1>COCCOCCOC>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=3)=[CH:7][CH:6]=2)=[O:9])=[CH:15][CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCCCc1ccc(C(=O)c2ccc(O)cc2)cc1
Solvent: COCCOCCOC
Product: CCCCc1ccc(C(=O)c2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 180 °C
Yield: 31.7 %

Procedure:
Under argon, 4-n-butylphenyl 4-hydroxyphenyl ketone (727 mg) obtained in Example 148 and 4-chloro-6,7-dimethoxyquinoline (639 mg) were dissolved in diethylene glycol dimethyl ether (10 ml), and the solution was then refluxed with heat at 180° C. for 10 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then with chloroform, followed by chromatography on silica gel eluting with hexane/acetone to obtain 400 mg of the title compound (yield: 32%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](OP(C(=[N+]=[N-])C(=O)C)(=O)OCC)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]#[CH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(OCC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
To 1.23 g (6.17 mmol) 3-Formyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 30 mL dry MeOH was added at room temperature 1.42 g (7.41 mmol) (1-Diazo-2-oxo-propyl)-phosphonic acid diethyl ester and 1.71 g (12.4 mmol) K2CO3 and stirring was continued for 2 h. 10 g of silica gel was added to the reaction mixture, stirring continued for 20 min and then filtered. After evaporation of the solvent the residue was purified by column chromatography (silica, cyclohexane/EtOAc 1:1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:11]1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)[CH2:8][CH2:9][CH3:10].Cl.[CH:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH:23]1[NH2:32])[CH2:29]2.C(N(C(C)C)C(C)C)C>ClCCl>[CH:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH:23]1[NH:32][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([Cl:20])=[N:19][C:11]=1[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:29]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CCCCc1nc(Cl)ccc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nc(Cl)ccc1C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
A solution of oxalyl chloride (0.105 mL, 1.20 mmol) in dichloromethane (2 mL) was added dropwise to a stirred suspension of 2-butyl-6-chloronicotinic acid (214 mg, 1.00 mmol), in dichloromethane (25 mL) over a period of 2 minutes under nitrogen. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was evaporated to dryness and dissolved in DCM (5 mL). This solution was added dropwise to a stirred solution of 2-adamantanamine hydrochloride (188 mg, 1.00 mmol) and N-ethyldiisopropylamine (0.693 mL, 4.01 mmol) in dichloromethane (20 mL) over a period of 2 minutes under nitrogen. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (20 mL), and washed sequentially with 0.1M HCl (20 mL), saturated NaHCO3 (20 mL), and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford N-adamantan-2-yl-2-butyl-6-chloronicotinamide (290 mg, 83%)
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH3:8].C=O.C1(N)CC1.ClC1C=C(C=CC=1Cl)CN(C)C([C:35]1C[N:37]([CH3:42])[C:38](=O)[C:39]=1O)=O>>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][N:7]([CH3:8])[C:6]([C:5]1[CH2:42][N:37]([CH:38]2[CH2:39][CH2:35]2)[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Agent: C=O
Agent: NC1CC1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(C2CC2)C1
Yield: 30 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and cyclopropylamine as described in the preparation of Compound 12. The title compound was extracted with EtOAc and the organic layer was washed with H2O, and dried over Na2SO4. After concentration, the resulting residue was triturated with EtOAc/Hexane (1:1) to give a white solid (52.7 mg, 30% yield). Mp=163–164° C. 1H NMR (300 MHz, CDCl3) δ: 9.97 (bs, 1H), 7.42, (d, 1H, J=8.42), 7.35 (s, 1H), 7.10 (dd, 1H, J=8.42, J=1.47), 4.60 (s, 2H), 4.09 (s, 2H), 3.02 (s, 3H), 2.81 (m, 1H), 0.86 (m, 4H). HRMS (M+H) calcd for C16H17N2Cl2O3: 355.0616. found: 355.0618.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[S:8][CH:7]=[N:6][C:5]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Cc1cc2scnc2cc1-c1ccc(N)nc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2scnc2cc1-c1ccc(NC(=O)c2c(F)cccc2F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 5-(6-methylbenzothiazol-5-yl)-2-pyridylamine (55) (24 mg, 0.1 mmol) in 2 ml DCM was added 2,6-difluorobenzoyl chloride (25 μl, 0.2 mmol) followed by addition of DIEA (105 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (200 μl) at r.t. for 1 h and then at 50° C. for 2 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(6-methylbenzothiazol-5-yl)(2-pyridyl)]carboxamide (56) (29.6 mg, yield: 77.6%, purity>95%) as white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27](Cl)[C:28](OCC)=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][C:8]2=[O:34])(=[O:3])[CH3:2].[NH2:36][C:37]([NH2:39])=[S:38].S1(CCCC1)(=O)=O>>[C:1]([O:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]3[S:38][C:37](=[NH:36])[NH:39][C:28]3=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][C:8]2=[O:34])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reactant: NC(N)=S
Solvent: O=S1(=O)CCCC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)O2

Procedure:
A mixture of 2.0 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate (prepared as described in Preparation 45), 0.62 g of thiourea, and 3.1 g of sulfolane was heated at 120°-125° C. for 7 hours under a nitrogen stream. The reaction mixture was extracted with benzene and then the benzene was distilled off from the extract. Water was then added to the residue and the oily layer was separated. The oily layer was subjected to silica gel column chromatography [successively with an eluent of (1) a 2:1 by volume mixture of n-hexane and ethyl acetate, (2) ethyl acetate, and (3) a 1:1 by volume mixture of ethyl acetate and ethanol] to yield 5-[4-(6-acetoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2-iminothiazolidin-4-one in a yield of 0.74 g. This was further purified by recrystallization from ethyl acetate, to give the purified title compound melting at was 218°-222° C.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[C:19]([F:22])([F:21])[F:20])(=O)=O.[CH3:23][C:24]1[C:29]([CH3:30])=[C:28](O)[CH:27]=[CH:26][C:25]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:7]([CH2:6][O:5][C:28]3[CH:27]=[CH:26][C:25]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:24]([CH3:23])[C:29]=3[CH3:30])=[C:8]([C:19]([F:22])([F:21])[F:20])[S:9][CH:10]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CS(=O)(=O)OCc1c(-c2ccc(F)cc2)csc1C(F)(F)F
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(F)cc3)csc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(4-fluorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(4-fluoro-phenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl) propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.44 (m, 2H), 7.37 (s, 1H), 7.08 (t, J=8.0 Hz, 2H), 6.95 (d, J=7.0 Hz, 1H), 6.62 (d, J=7.0 Hz, 1H), 4.88 (s, 2H), 2.95 (t, J=6.8 Hz, 2H), 2.62 (t, J=6.8 Hz, 2H), 2.22 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[C:26](I)=[C:25]([O:28][CH3:29])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>>[F:18][C:19]1[C:26]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[CH3:17])=[C:25]([O:28][CH3:29])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Reactant: COc1ccc(C=O)c(F)c1I
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3c(OC)ccc(C=O)c3F)cc21
Yield: 59 %

Procedure:
The intermediate 2-Fluoro-4-methoxy-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde was prepared in a similar manner to example 7a using 7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example 2b) and 2-Fluoro-3-iodo-4-methoxy benzaldehyde (example 7b). 59% yield. 1H NMR (300 MHz; CDCl3): 1.21 (t, J=6.9 Hz, 3 H), 1.31 (s, 3 H), 1.34 (s, 3 H), 1.60 (s, 2 H), 2.10 (s, 3 H), 2.52 (s, 2 H), 3.88 (s, 3 H), 4.02 (q, J=7.2 Hz, 1 H), 6.82 (s, 1 H), 6.93 (d, J=9.0 Hz, 1 H), 7.22 (s, 1 H), 7.95 (t, J=8.1 Hz, 1 H), 10.26 (s, 1 H).
Reaction SMILES: CN(C=O)C.[CH:6]1([C:9]([NH:11][C:12]2[N:29]=[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=4)[N:14]3[N:13]=2)=[O:10])[CH2:8][CH2:7]1.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH:6]1([C:9]([NH:11][C:12]2[N:29]=[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:28]=[CH:27][C:23]([C:24]([Cl:33])=[O:25])=[CH:22][CH:21]=4)[N:14]3[N:13]=2)=[O:10])[CH2:8][CH2:7]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 Drops of DMF are added to a solution of 4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A using 4-carboxyphenylboronic acid in DCM under N2 atmosphere. Then oxalyl chloride (2 eq) is added dropwise to this resulting solution (gas release). The mixture is stirred at room temperature for 2 hours. After completion of the reaction by LCMS, the solvent is removed. The crude acid chloride is used without further purification in next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:11])=[N:6][C:5]=1[C:12]1[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=1.[H-].[Na+].[CH3:25][S:26]([CH3:28])=O>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:25][S:26][CH3:28])[C:7]([CH3:11])=[N:6][C:5]=1[C:12]1[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=1
Reactant: COC(=O)c1cc(O)c(C)nc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(OCSC)c(C)nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 0 °C

Procedure:
A solution of 2.5 g (8.19 mmol) 5-hydroxy-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-6-methyl-nicotinic acid methyl ester in 25 ml dimethyl sulfoxide is reacted with 0.26 g (8.19 mmol) sodium hydride (80%) and after 10 minutes' stirring, 0.87 g (9.01 mmol) chlorodimethylsulfide is added. It is stirred overnight, then added to 500 ml ice water. The product is extracted with ethyl acetate, the extract is dried over magnesium sulfate, and compressed. The residue is chromatographed over silica gel with ethyl acetate/hexane 1:1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:27]([CH2:30][CH2:31][CH2:32][CH3:33])([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>>[N+:27]([CH:30]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:31][CH2:32][CH3:33])([O-:29])=[O:28]
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: CCCC[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]

Procedure:
6-Phenylhexanoic acid (0.100 g, 0.52 mmol) and CDI (0.169 g, 1.04 mmol) were added together and then reacted with nitrobutane (0.080 g, 0.78 mmol) and DBU (0.198 g, 1.30 mmol) according to the general procedure. Purification by column chromatography gave 0.084 g (59%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 2H), 7.20 (m, 3H), 5.17 (dd, J=4.4, 10.0 Hz, 1H), 2.63 (m, 4H), 1.65 (m, 6H), 1.36 (m, 4H) 1.00 (t, J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 199.5, 142.6, 128.7, 128.6, 126.0, 94.3, 39.5, 35.9, 31.8, 31.4, 28.7, 23.3, 19.5, 13.6 ppm; IR νmax (cm−1) 3027, 2935, 2858, 1730, 1560, 1454, 1373, 1031, 749, 700; HRMS (FAB) calcd for C16H23NO3 (MNa+) 300.1570, found 300.1575.
Reaction SMILES: F[C:2]1C=C(OC2N=CC=C3C=CN(C)C=23)C=CC=1N.[NH:20]1[C:24]2=[C:25]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40](=[O:48])[CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[S:38])=[CH:32][C:31]=3[F:49])[N:26]=[CH:27][CH:28]=[C:23]2[CH:22]=[CH:21]1>>[F:49][C:31]1[CH:32]=[C:33]([NH:36][C:37]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[S:38])[CH:34]=[CH:35][C:30]=1[O:29][C:25]1[N:26]=[CH:27][CH:28]=[C:23]2[CH:22]=[CH:21][N:20]([CH3:2])[C:24]=12
Reactant: Cn1ccc2ccnc(Oc3ccc(N)c(F)c3)c21
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Product: Cn1ccc2ccnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Yield: 87 %

Procedure:
Starting from the compound 265 and following the procedure described above for the synthesis of compound 262a (scheme 59, step 4, example 218), title compound 262b was obtained in 87% yield as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.40(s, 1H), 11.78(s, 1H), 7.83(dd, 1H, J1=10.95 Hz, J2=1.9 Hz), 7.56(d, 1H, 2.7 Hz), 7.49(d, 1H, J=5.5 Hz), 7.43-7.39(m, 2H), 7.37-7.33(m, 4H), 7.31-7.26(m, 2H), 6.52(d, 1H, J2=2.9 Hz), 4.11(s, 3H), 3.84(s, 2H), MS (m/z): 435.1(M+H) (found).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].ClC1C=C(N)C=CC=1OC[CH2:37][CH2:38][N:39]([CH2:42]C)[CH2:40][CH3:41]>>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][CH2:42][N:39]([CH2:40][CH3:41])[CH2:38][CH3:37]
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Reactant: CCN(CC)CCCOc1ccc(N)cc1Cl
Product: CCN(CC)CCCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 3-chloro-4-(3-diethylamino-propoxy)-phenylamine (Z29b).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1>>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[CH2:10][O:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: CNc1nc(Cl)nc2c1COC2c1ccc(F)cc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1COC2c1ccc(F)cc1

Procedure:
2-chloro-7-(4-fluorophenyl)-N-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (Preparation Ma) (149 mg, 0.533 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (119 mg, 0.533 mmol) were combined and purified as per Example 75 to give the racemate N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine which was separated by multiple chiral SFC injections (OJ-H 30×250 mm, 5 μM, 35% MeOH (0.1% DEA)/CO2) to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine (first to elute, enantiomer A) (18.3 mg, 0.039 mmol, 7.36% yield) as a white scrapable foam. LC-MS (M+H)+=467.0. 1H NMR (500 MHz, MeOD) δ ppm 7.89-7.94 (1H, m), 7.65-7.69 (1H, m), 7.36-7.42 (2H, m), 7.20-7.24 (1H, m), 7.13-7.18 (1H, m), 7.03-7.12 (3H, m), 5.79 (1H, br. s.), 5.08-5.16 (1H, m), 4.95-5.03 (1H, m), 3.68-3.73 (3H, m), 3.02-3.07 (3H, m). The absolute stereochemistry of Example 79A was not determined.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:8]1[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCc1ccccc1
Product: CCCCN1C(=O)C(NCc2ccccc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and benzylamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (CD3CN) δ 7.47-7.42 (m, 1H), 7.40-7.35 (m, 2H), 7.34-7.29 (m, 2H), 7.23-7.18 (m, 3H), 6.88-6.83 (m, 2H), 6.44-6.35 (m, 1H), 4.16 (d, J=6.6 Hz, 2H), 3.68 (t, J=7.3 Hz, 2H), 1.82-1.71 (m, 2H), 1.49-1.38 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); Mass spectrum: M+H+ 371.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]([S:7]([CH:9]=[CH2:10])=[O:8])=[CH2:6]>O>[OH:2][CH2:1][CH2:3][N:4]1[CH2:10][CH2:9][S:7](=[O:8])[CH2:5][CH2:6]1
Reactant: C=CS(=O)C=C
Reactant: NCCO
Solvent: O
Product: O=S1CCN(CCO)CC1
Yield: 104.2 %

Procedure:
Step 1. To a solution of ethanolamine (0.54 g, 8.82 mmol) in water (20 ml) was added divinylsulfoxide (1.0 g, 9.8 mmol). After the reaction mixture was refluxed for 0.5 h, the mixture was concentrated and dried at 50° C. to afford 4-(2-hydroxyethyl)thiomorpholine 1-oxide (1.50 g, 94%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 2.65 (t, J=5.4 Hz, 2H), 2.75-3.02 (m, 6H), 3.05-3.31 (m, 3H), 3.66 (t, J=5.4 Hz, 2H). Step 2. To a solution of OZ288 (0.50 g, 1.4 mmol), 4-(2-hydroxyethyl)thiomorpholine 1-oxide (0.34 g, 2.1 mmol), triphenylphosphine (0.55 g, 2.1 mmol), and triethylamine (0.29 ml, 2.1 mmol) in dry THF (50 ml) at 0° C. was added dropwise a solution of DIAD (0.43 g, 2.1 mmol) in THF (10 ml). After stirring at rt overnight, the solvent was removed under vacuum. The residue was dissolved in EtOAc (50 ml), washed with water (3×50 ml), dried over MgSO4, and concentrated. The residue was purified by chromatography (silica gel, 50% EtOH in EtOAc) to afford OZ464 free base (0.51 g, 73%) as a colorless solid. To a solution of OZ464 free base (0.51 g, 1.0 mmol) in EtOAc (10 ml) at 0° C. was added dropwise a solution of methanesulfonic acid (0.14 g, 1.4 mmol) in ether (10 ml). The resulting precipitate was filtered, washed with ether (25 ml), and dried in vacuo at 40° C. to afford trioxolane OZ464 (0.51 g, 85%) as a colorless solid. mp 139-141° C.; 1H NMR (500 MHz, DMSO-d6) δ 1.45-1.98 (m, 22H), 2.37 (s, 3H), 2.53-2.64 (m, 1H), 3.08-3.26 (m, 4H), 3.41-3.92 (m, 6H), 4.36 (brs, 2H), 6.95 (J=8.8 Hz, 2H), 7.17 (J=8.3 Hz, 2H), 10.06 (s, 1H); 13C NMR (125.7 MHz, DMSO-d6) δ 26.00, 26.41, 31.47, 34.26, 34.44, 35.97, 36.27, 39.90, 40.90, 42.09, 42.46, 55.80, 62.12, 108.29, 110.72, 114.89, 127.72, 139.13, 155.99. Anal. Calcd for C29H43NO8S2: C, 58.27; H, 7.25; N, 2.34. Found: C, 58.46; H, 7.14; N, 2.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[C:22](=[O:23])[C:21]2[CH:25]=[C:26]([CH3:28])[CH:27]=[C:19]([CH3:18])[CH:20]=2)=[CH:5][CH:4]=1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COc1ccc(-c2coc3ccccc23)cc1
Product: COc1ccc(-c2c(C(=O)c3cc(C)cc(C)c3)oc3ccccc23)cc1

Procedure:
When 3-p-methoxyphenylbenzofuran is acylated with 3,5-dimethylbenzoyl chloride as described in the procedure of Example 1, 3-p-methoxyphenyl-2-(3',5'-dimethylbenzoyl)benzofuran is obtained.