Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.CN1C=CN=C1.[F:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O.[NH2:28][C:29]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:34]([CH2:40][CH3:41])[C:30]=1[C:31](O)=[O:32]>C(Cl)Cl>[CH2:40]([C:34]1[C:30]2[C:31](=[O:32])[O:23][C:21]([C:20]3[C:19]([F:18])=[N:27][CH:26]=[CH:25][CH:24]=3)=[N:28][C:29]=2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=1)[CH3:41]
Reactant: CCc1cc(OC)cc(N)c1C(=O)O
Reactant: O=C(O)c1cccnc1F
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CCc1cc(OC)cc2nc(-c3cccnc3F)oc(=O)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
TsCl (275 mg, 1.44 mmol) and N-methylimidazole (285 uL, 3.60 mmol) were added at 0° C. to a suspension of 2-fluoro-nicotinic acid (169 mg, 1.20 mmol) in CH2Cl2 (3 mL) under Ar atmosphere. The mixture was stirred at 0° C. for 1 hour. Compound R (195 mg, 1.00 mmol) was added to the mixture at 0° C. over 5 minutes and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. N-methylimidazole (47.5 uL, 0.60 mmol) and TsCl (114 mg, 0.60 mmol) were added at 0° C. to the mixture, and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with saturated NaHCO3 (aq.), water (5 times) and brine. The organic phase was then dried over anhydrous Na2SO4 and concentrated in vacuo to afford compound S (300 mg, 1.00 mmol) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([OH:16])=[O:15])#[N:2].C(N/C(=N/C(C)C)/O[C:23]([CH3:26])([CH3:25])[CH3:24])(C)C>C1COCC1.CCOCC>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:15])#[N:2]
Reactant: N#Cc1cc2c(cc1F)OCCC2C(=O)O
Reactant: CC(C)/N=C(/NC(C)C)OC(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCOc2cc(F)c(C#N)cc21
Reaction time: 3 h
Yield: 64 %

Procedure:
6-Cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylic acid was dissolved in 10 mL of THF and treated with (Z)-tert-butyl N,N′-diisopropylcarbamimidate. After stirring for 3 hours, an additional 2 mL of (Z)-tert-butyl N,N′-diisopropylcarbamimidate was added and the reaction was stirred overnight. The reaction was diluted with ether, filtered, concentrated onto silica gel and flashed with 8:1 hexanes/ethyl acetate to provide the desired product (1.4 g, 64% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[CH2:20]([O-:22])[CH3:21].[Na+]>O>[CH2:20]([O:22][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1)[CH3:21]
Reactant: CC[O-]
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: [Na+]
Solvent: O
Product: CCOc1cc(-c2ccccn2)nc(-c2ccccn2)c1

Procedure:
In a nitrogen atmosphere, 900 mg (3.4 mmol) of 4′-chloro-[2,2′;6′,2″]terpyridine are added to 15 ml of a 0.7M ethanolic sodium ethanolate solution. The mixture is heated at reflux for 20 hours. The mixture is allowed to cool and 20 ml of water are added, and 4′-ethoxy-[2,2′;6′,2″]terpyridine is filtered off in the form of a white solid. 1H-NMR (360 MHz, DMSO-d6): 1.40 (t, 3 H, 6.8 Hz); 4.28 (q, 2 H. 6.8 Hz); 7.42–7.53 (m, 2H); 7.93 (s, 2H); 7.95–8.02 (m, 2H); 8.58 (d, 2H, J=8.1 Hz); 8.69 (d, 2H, J=4 Hz).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[C:3]1=[O:14].Cl.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[C:3]1=[O:14]
Reactant: COc1ccc2c(c1)CCC(C)C2=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1CCc2cc(O)ccc2C1=O
Reaction time: 2 h
Yield: 84 %

Procedure:
2-Methyl-6-Methoxy-1-Tetralone (19 g, 0.1 mole) and pyridine hydrochloride (53.1 g, 0.46 mole) were heated neet, under a nitrogen sweep at about 220° for about 2 hours. The melt was cooled, acidified with 1N HCl and dissolved in ethyl acetate. The organic layers were dried (brine, MgSO4) and concentrated in vacuo. Purification by flash chromatography [gradient 7:1 to 5:1 EtOAc:Hexanes] yielded the title compound as a light yellow solid (14.8 g, 0.084 mole, 84% yield), [Lit. Buchta et al., Ann. 576, 7-19 (1952)].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of methyl 4-hydroxyphenylacetate (10.0 g) in acetic acid (55 ml) was added nitric acid (22.1 ml) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. After warmed to 20° C., the reaction mixture was diluted with water (200 ml) and precipitated crystals were collected. The crystals were dissolved in chloroform, and the solution was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of chloroform and hexane to give methyl 4-hydroxy-3-nitrophenylacetate (9.3 g) as yellow crystals.
Reaction SMILES: [C:1]1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH2:15]([NH:19][CH:20]([C:23]1[CH:28]=[CH:27][C:26](OCC)=[CH:25][CH:24]=1)[CH2:21][NH2:22])CCC>>[CH3:15][NH:19][CH:20]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:1])[CH:28]=1)[CH2:21][NH2:22]
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: CCCCNC(CN)c1ccc(OCC)cc1
Agent: Cl
Product: CNC(CN)c1cccc(C)c1

Procedure:
m.p. dihydrochloride 202°-205° C; β-n-butylamino-β-(4-ethoxyphenyl)-ethylamine;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:6]2.[H-].[Na+].F[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1)=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:6]2
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCCCCCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 93 %

Procedure:
6-(Methyloxy)-3-octyl-2-phenyl-1-naphthalenol (193) (0.60 g, 1.66 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.72 g (93%) of the title compound (194) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.84 (t, J=7.0 Hz, 3H), 1.05-1.30 (m, 10H), 1.40-1.50 (m, 2H), 2.54 (t, J=7.9 Hz, 2H), 3.94 (s, 3H), 6.67 (d, J=8.4 Hz, 2H), 7.03-7.14 (m, 3H), 7.16-7.26 (m, 4H), 7.56-7.64 (m, 3H), 7.67 (d, J=9.1 Hz, 1H), 9.79 (s, 1H). LCMS (APCI): m/z 467 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(CCN)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
8.3 g 4-Chlorobenzoyl chloride are added dropwise at 5°-10° C., within the course of 10 minutes, to a solution of 11.0 g ethyl 4-(2-aminoethyl)-phenylacetate in 90 ml anhydrous pyridine. The reaction mixture is then stirred for 90 minutes at 10° C., subsequently allowed to warm up to 20° C. and thereafter warmed to 40°-45° C. for 30 minutes. The reaction mixture is then cooled and stirred into 900 ml ice water, a solid precipitate thereby being obtained. This is filtered off with suction and washed with water. There are obtained 14.5 g (94% of theory) of crude product which is recrystallized from isopropanol to give 10.9 g (70% of theory) ethyl 4-[2-(4-chlorobenzamido)-ethyl]-phenylacetate; m.p. 118°-119° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Br:9]NC(=O)CCC(N)=O>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[C:3]=1[Br:9]
Reactant: Nc1ccnc(Cl)c1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC(=O)O
Product: Nc1ccnc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-amino-2-chloropyridine (50 g, 388 mmol) was dissolved in glacial acetic acid (500 mL). To this solution was added N-bromosuccinamide (75 g, 426 mmol,) portionwise at room temperature (water bath cooling was provided to control the exothermicity). The reaction mixture was stirred at RT for 1 h at which point the reaction was found complete (as monitored by TLC). Solvent was removed under reduced pressure followed by azeotropic distillation with ethanol. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=[CH:19][C:14]=3[CH2:13][CH2:12][C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]2=3)[CH2:5][CH2:4]1.B(F)(F)F.[CH3:31][CH2:32]OCC>C(O)C>[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:15]3[CH:16]=[C:17]([C:20]([O:22][CH2:31][CH3:32])=[O:21])[CH:18]=[CH:19][C:14]=3[CH2:13][CH2:12][C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]2=3)[CH2:5][CH2:4]1
Reactant: CN1CCC(=C2c3ccccc3CCc3ccc(C(=O)O)cc32)CC1
Reactant: CCOCC
Agent: Cl
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)C(=C1CCN(C)CC1)c1ccccc1CC2

Procedure:
A solution of 5.0 g 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene) piperidine hydrochloride in 200 ml of absolute ethanol was treated with 5 ml of boron trifluoride etherate. After stirring and refluxing for 18 hours the ethanol was evaporated in vacuo and the residue was partitioned between saturated aqueous sodium carbonate solution and ether. The ether phase was separated, washed with 3×100 ml of water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue, 5.4 g of 1-methyl-4-(10,11-dihydro-3-ethoxycarbonyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, after recrystallization from acetonitrile had m.p. 85°-87° C.
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:26][N:20]([C@H:21]([C:23](O)=[O:24])[CH2:22]2)[C:19](=[O:27])[C@@H:18]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][S:8]3)=[CH:3][CH:2]=1.[NH2:42][C@:43]1([C:48]([NH:50][S:51]([CH:54]2[CH2:56][CH2:55]2)(=[O:53])=[O:52])=[O:49])[CH2:45][C@H:44]1[CH:46]=[CH2:47].CC1C=CC(S(O)(=O)=O)=CC=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>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:26][N:20]([C@H:21]([C:23](=[O:24])[NH:42][C@:43]4([C:48](=[O:49])[NH:50][S:51]([CH:54]5[CH2:56][CH2:55]5)(=[O:53])=[O:52])[CH2:45][C@H:44]4[CH:46]=[CH2:47])[CH2:22]2)[C:19](=[O:27])[C@@H:18]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][S:8]3)=[CH:3][CH:2]=1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCCC=CCS[C@@]2(c3ccc(-c4ccccc4)cc3)C[C@@H](C(=O)O)N(C2)C1=O
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCCC/C=C/CS2)C(=O)NS(=O)(=O)C1CC1
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCCC/C=C/CS[C@@]2(c3ccc(-c4ccccc4)cc3)C[C@@H](C(=O)O)N(C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCCCC=CCS2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an iced slurry of (3S,14R,16S,E)-14-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadec-10-ene-16-carboxylic acid, (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, pTSA, 0.68H2O (29.6 mg, 0.071 mmol), and HATU (32.5 mg, 0.0855 mmol) in DCM (2 mL) was added N,N-Diisopropylethylamine (0.050 mL, 0.285 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with EtOAc, washed it with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated. The formed residue was purified by Biotage column, eluted with gradient 5%˜40% Acetone-Hexane to afford the desired product tert-butyl (3S,14R,16S,E)-14-(biphenyl-4-yl)-16-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadec-10-en-3-ylcarbamate (31 mg, 0.038 mmol, 66.0% yield) as a white foam. 1H NMR (500 MHz, MeOD) δ ppm 1.09 (s, 1 H) 1.16-1.32 (m, 3 H) 1.33-1.40 (m, 2 H) 1.41-1.63 (m, 16 H) 1.64-1.83 (m, 4 H) 1.87-1.99 (m, 2 H) 2.00-2.11 (m, 1 H) 2.13-2.24 (m, 1 H) 2.24-2.34 (m, 1 H) 2.40 (t, J=11.29 Hz, 1 H) 2.62-2.75 (m, 2 H) 2.87-3.01 (m, 1 H) 3.08 (d, J=14.95 Hz, 1 H) 3.87 (dd, J=10.38, 6.41 Hz, 1 H) 4.01 (d, J=10.68 Hz, 1 H) 4.59-4.80 (m, 2 H) 5.12 (d, J=10.07 Hz, 1 H) 5.29 (d, J=17.09 Hz, 1 H) 5.53-5.63 (m, 2 H) 5.64-5.80 (m, 1 H) 7.37 (t, J=7.48 Hz, 1 H) 7.47 (t, J=7.48 Hz, 2 H) 7.57-7.64 (m, 2 H), 7.68-7.82 (m, 4 H). LC-MS (retention time: 3.48 min, method C), MS ink 792 (M+H), 735 (M-t-Bu), 691 (M-BOC).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([OH:14])=O)[CH2:4]1.[Cl-].[NH4+].C[Si](C)(C)N[Si](C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:39][NH:40][O:41][CH3:42].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O.ClCCl.C(#N)C>[OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([N:40]([O:41][CH3:42])[CH3:39])=[O:14])[CH2:4]1
Reactant: CC1(C)O[C@H](CO)C[C@H](CC(=O)O)O1
Reactant: CNOC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CON(C)C(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 30 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid (50.0 g), acetonitrile (500.0 mL), and ammonium chloride (1.3 g) were added to a reactor. The reaction mixture was cooled to 0˜5° C. and then hexamethyldisilazane (102.1 mL) was slowly added thereto. The reaction mixture was stirred at 30° C. for 1 hour and then concentrated under reduced pressure to remove the solvent. Ethyl acetate (250.0 mL) and water (200.0 mL) were added to the resulting residue. The separated organic layer was dehydrated with anhydrous magnesium sulfate (50.0 g) and then filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain a concentrated residue in a colorless clear oil form. Dichloromethane (250.0 mL) was added to the concentrated residue. The reaction mixture was cooled to 0˜5° C. and then 1,1′-carbonyldiimidazole (43.7 g) was slowly added thereto. The temperature of the reaction mixture was raised to 20˜25° C. The reaction mixture was stirred at the same temperature for 3 hours and then N,O-dimethylhydroxyamine hydrochloride (26.4 g) and sodium bicarbonate (22.6 g) were added thereto. The reaction mixture was stirred for over 10 hours, while maintaining the temperature of 20˜25° C. Water (250.0 mL) was added to the reaction mixture and then the resulting organic layer was separated. The water layer was extracted with dichloromethane (150.0 mL) to obtain an organic layer. The combined organic layer was dehydrated with anhydrous sodium sulfate (50.0 g) and then filtered under reduced pressure. The filtrate was concentrated under reduced pressure to remove the solvent, and then purified with silica gel column chromatography (ethyl acetate/n-hexane=1:4) to obtain 2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide in a colorless gel form (49.7 g, yield 82%).
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[OH:1][CH:2]([C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1)[CH:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-hydroxy-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (9.36 g, 26.5 mmol) in methanol (40 ml) was added 2N aqueous sodium hydroxide solution (26 ml, 52 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 6, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (2RS,3RS)-3-hydroxy-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (7.8 g, 90%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>>[F:24][C:23]([F:26])([F:25])[CH2:22][N:7]1[C:8]2[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2CC(F)(F)F)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2,2,2-trifluoroethyl trifluoromethanesulfonate: MS (ES) m/z 293 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16](O)=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.S(Cl)([Cl:26])=O>>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([Cl:26])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reaction time: 3 h

Procedure:
13.1 g (0.04 mol) of 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid (prepared according to example 3 a)) are reacted with 31.4 g (0.25 mol, about 20 ml) of thionyl chloride by boiling under reflux while continuously introducing nitrogen and constantly stirring for 3 hours. After distilling off the excess thionyl chloride with exclusion of moisture under reduced pressure, a distillation residue is obtained which can be directly used for further transformation.
Reaction SMILES: [Na].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[C:13]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:12][S:11][N:10]=1.[CH3:21][O:22][CH2:23][CH2:24][OH:25]>>[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[CH3:21][O:22][CH2:23][CH2:24][O:25][C:9]1[C:13]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:12][S:11][N:10]=1
Reactant: CN1CCC=C(c2nsnc2Cl)C1
Reactant: COCCO
Agent: O=C(O)C(=O)O
Agent: [Na]
Product: COCCOc1nsnc1C1=CCCN(C)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of sodium (120 mg, 5 mmol) in 2-methoxyethanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate (310 mg, 1 mmol). The mixture was stirred at 50° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The title compound was crystallized as the oxalate salt from acetone to yield 270 mg. (M.p. 152.1° C.; M+ : 253; Compound 15).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:36])=[O:35])=[O:26])=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Prepared from the coupling of 3d and benzene sulfonamide by the method described in Procedure 1, Method A. Yield (46%); ESI m/z: 492 (M−H−, 100%)
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][C:14]([O:16]CC)=[O:15].O>C1(C)C=CC=CC=1.C(OCC)(=O)C.CO.[OH-].[Na+]>[CH2:3]([O:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCBr
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
In small portions, add sodium hydride (2.22 g, 60% dispersion in mineral oil, 55.4 mmol) to a cold (0° C.) solution of benzyl alcohol (4.0 g, 37 mmol) in toluene (100 mL). Add ethyl 3-bromopropionate (8.0 g, 44 mmol) dropwise to the mixture, allow the resulting solution to warm to room temperature and stir for 1 hour. Quench the reaction with the addition of water until all bubbling ceases. Dilute the mixture with ethyl acetate (100 mL) and extract with water (100 mL) and brine (100 mL). Dry the organic extract over Na2SO4 and remove the solvent under reduced pressure to yield the crude ester as a clear oil. Dissolve the oil in methanol (20 mL) and 6 N NaOH (20 mL), and stir for 1 hour. Concentrate the mixture (approximately 20 mL) and dilute with water (20 mL). Extract the aqueous mixture once with CH2Cl2 (40 mL). Acidify the aqueous phase with conc. HCl and extract with EtOAc (3×50 mL). Dry the combined EtOAc extracts over Na2SO4. Remove the solvent under reduced pressure to yield the title compound as a clear oil (2.28 g; 34.0%) that solidifies upon standing.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([Cl:36])[CH:23]=1)(C)(C)C.Cl.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCCC1>[NH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([Cl:36])[CH:23]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CNC(=O)OC(C)(C)C)cc34)cc2Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CN)cc34)cc2Cl)cn1
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a solution of 4.42 g of E-(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-carbamic acid tert-butyl ester in 21 mL of tetrahydrofuran was added 21 mL of 2 N hydrochloric acid. The mixture was heated at 60° C. for 3 hours, cooled to room temperature and basified with 10% aqueous potassium carbonate. Methylene chloride was added to the aqueous mixture and a solid precipitated. The solid was filtered and dried to yield 2.98 g of E-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine. 1H NMR (d6 DMSO): δ 8.62 (s, 1), 8.53 (m, 1), 8.26 (m, 2), 7.99 (m, 1), 7.89 (m, 1), 7.77 (m, 1), 7.30 (m, 3), 6.67 (m, 2), 3.44 (m, 2), 2.47 (s, 3).