Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20].O>C1COCC1>[C:18]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-4-phenyloxazolidin-2-one (65.00 g, 398.3 mmol) in dry THF (612.8 mL) at −78° C. was quickly added n-BuLi (167.3 mL, 418.3 mmol) dropwise, and the mixture was stirred at −78° C. for 0.5 hours. To this cold stirring solution was quickly added dropwise a solution of methacryloyl chloride (40.86 mL, 418.3 mmol) in THF (60 mL), and the mixture was allowed to warm to ambient temperature and stirred for 0.5 hours. Water (300 mL) was added and the suspension was stirred for 1 hour and then filtered to give desired product as a hard solid cake (66 g). The filtrate was concentrated under reduced pressure to a yellow solid residue, which was taken up in Et2O (400 mL) and filtered to give additional pure desired product (9 g). The products were combined to give (R)-3-methacryloyl-4-phenyloxazolidin-2-one (75 g, 81% yield).
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.[NH:23]1[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[N:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@@H:9]2[CH2:10][C@H:6]([N:23]3[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[N:24]3)[CH:7]=[CH:8]2)=[C:16]([Cl:20])[N:15]=1
Reactant: OCc1cn[nH]c1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OCc1cnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture comprising carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate 1) (1.00 g, 2.92 mmol), (1H-pyrazol-4-yl)-methanol (preparation shown below) (0.34 g, 3.50 mmol) and triphenyl phosphine (0.115 g, 0.44 mmol) in deoxygenated THF (10 mL) under an inert atmosphere of argon is treated with tris(dibenzylideneacetone)dipalladium (0) (0.13 g, 0.15 mmol) and stirred at 50° C. for 1 hour. The solvent is removed in vacuo and the crude product is purified by chromatography on silica eluting with MeOH/DCM (1:25) to yield the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:22]([S:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Sc1nnc(-c2ccccc2)o1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CSc2nnc(-c3ccccc3)o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 5-phenyl-[1,3,4]oxadiazole-2-thiol (3.1 g, 17.4 mmol; Aldrich) in ethanol (30 mL) was cooled to 0° C. and treated with diisopropylethylamine (3.1 mL, 17.4 mmol; Aldrich). The suspension cleared. Benzyl bromide (2.08 mL, 17.4 mmol; Aldrich) was then added, and the mixture was allowed to warm to room temperature. After 45 minutes, the resulting precipitate was collected by filtration and dried to afford the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=3)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(C)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-methylbenzoate obtained in Example (172b) (26.3 mg, 0.09 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (15 mg, 0.09 mmol), WSC hydrochloride (49.4 mg, 0.26 mmol) and HOBt (11.6 mg, 0.09 mmol), to obtain 33.0 mg of the title compound as a pale yellow oily substance (88%).
Reaction SMILES: [C:1]([CH:3]([C:7](=[S:25])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[Cl:23])=[C:11]([F:24])[CH:10]=1)[C:4]([NH2:6])=[O:5])#[N:2].BrBr>C(OCC)(=O)C>[Cl:23][C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:7]2[S:25][N:6]=[C:4]([OH:5])[C:3]=2[C:1]#[N:2])=[CH:10][C:11]=1[F:24]
Reactant: N#CC(C(N)=O)C(=S)Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Agent: BrBr
Solvent: CCOC(C)=O
Product: N#Cc1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 25 °C

Procedure:
2-Cyano-2-[4-(2,5-dichloro-phenoxy)-3-fluoro-phenylthiocarbamoyl]-acetamide (1.6 g, 4 mmol) was dissolved in anhydrous ethyl acetate (60 ml) and a solution of bromine (0.2 ml, 4 mmol) in anhydrous ethyl acetate (10 ml) was added dropwise into the mixture with stirring at room temperature. After addition, the reaction mixture was stirred for another 3 hours. The precipitate was filtered and the solid was washed with ethyl ether and suspended in a saturated sodium bicarbonate with stirring for 10 min. The solid was filtered, then washed with water and dried in vacuo to afford a white powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH2:21]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.5 %

Procedure:
4-Fluoro-3-trifluoromethylbenzoic acid (100 g) was dissolved in N,N-dimethylformamide (400 ml), potassium carbonate (199 g) and benzyl bromide (84.0 g) were added under ice-cooling, and the mixture was stirred for 20 min under ice-cooling and at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (144 g) as a pale-yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH:9](O)=[O:10]>>[CH:9]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:10]
Reactant: OCCN1CCCC1
Reactant: O=CO
Product: O=COCCN1CCCC1
Temperature: 80 °C

Procedure:
A mixture of 115 9 of 1-(2-hydroxyethyl)pyrrolidine and 500 g of formic acid was heated at 80° C. for 10 hours. The reaction mixture was concentrated in vacuum, diluted with ethyl acetate, and neutralized with saturated sodium bicarbonate in water. This was followed by separation, water washing, drying over anhydrous sodium sulfate, and vacuum concentration. Purification by vacuum distillation yielded 2-(1-pyrrolidinyl)ethyl formate, designated (B-10].
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][C@H:15]([CH3:17])[C@@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:13]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[C:39]([C:41]([OH:44])([CH3:43])[CH3:42])[CH:38]=[C:37]([F:45])[C:36]=1[C:46]1[N:51]=[C:50]([C:52](O)=[O:53])[CH:49]=[CH:48][C:47]=1[F:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:19]([O:18][C@@H:14]1[C@@H:15]([CH3:17])[CH2:16][N:11]([C:3]2[C:2]([NH:1][C:52]([C:50]3[CH:49]=[CH:48][C:47]([F:55])=[C:46]([C:36]4[C:35]([F:34])=[CH:40][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:38][C:37]=4[F:45])[N:51]=3)=[O:53])=[CH:7][N:6]=[C:5]3[O:8][CH2:9][CH2:10][C:4]=23)[CH2:12][C@H:13]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:20])[CH3:21]
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)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: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(C(C)(C)O)cc4F)n3)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (200 mg, 0.418 mmol), 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (130 mg, 0.418 mmol), HATU (318 mg, 0.836 mmol) in DMF (1.5 mL) and DIPEA (218 μL, 1.25 mmol) was stirred at room temperature for 2 h. After quenched with water, the mixture was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%), to yield an amide intermediate, tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{5-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-2,3-dihydrofuro[2,3-b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 4 from above was coupled with 4-aminomethyl-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 442.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH:21]=[O:22])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cncs2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ncc(-c2ccc(F)cc2)s1
Reaction time: 0.33 h
Yield: 69 %

Procedure:
A solution of 5-(4-fluorophenyl)thiazole (0.5 g, 2.78 mmol) and THF (40 mL) was cooled to −78° C., 1.6 M n-BuLi in hexanes (0.7 mL, 8.36 mmol) was slowly added, the solution was stirred for 20 min and DMF in THF (20 mL) was added. The reaction mixture was stirred at −78° C. for 2 h, quenched with saturated ammonium chloride solution and diluted with ethyl acetate (150 mL). The organic layer was separated, washed with ammonium chloride (3×150 mL) and followed by brine solution (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200μ silica gel and 18% ethyl acetate in hexane) to obtain 5-(4-fluorophenyl)thiazole-2-carbaldehyde as off-white solid (0.4 g, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.63 (s, 1H), 7.88-7.91 (m, 2H), 7.35 (t, 2H), LC-MS m/z calculated for [M+H]+ 208.02 found 208.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[CH3:21][C:22]([CH3:24])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH:22]([CH3:24])[CH3:21])[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Product: CC(C)N1CCc2nn(C(C)C)c(-c3ccc(F)cc3)c2CC1

Procedure:
The title compound (92 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and acetone as in Example 35. MS (ESI): exact mass calculated for C19H26FN3, 315.21. found, m/z 316.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.39 (m, 2H), 7.33-7.30 (m, 2H), 4.40 (m, 1H), 3.78-3.74 (m, 2H), 3.68-3.63 (m, 1H), 3.36-3.21 (m, 4H), 2.99-2.94 (m, 1H), 2.80-2.76 (m, 1H), 1.54-1.37 (m, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:6]2=[CH:7][C:8]=1[OH:9].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:15][CH:17]2[CH2:18][O:19]2)=[CH:7][C:6]2[O:10][C:11](=[O:12])[CH:13]=[CH:14][C:5]=2[CH:4]=1
Reactant: ClCC1CO1
Reactant: COc1cc2ccc(=O)oc2cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ccc(=O)oc2cc1OCC1CO1

Procedure:
25.0 g (130 mmol) of scopoletine, 15.3 ml (196 mmol) epichlorohydrin, 36.0 g (260 mmol) potassium carbonate and 2.5 g of potassium iodide are agitated in 500 ml DMF under nitrogen for 3 h at 80° C. After vacuum evaporation and repeated extraction with hot ethanol re-evaporation was performed. 21.2 g (66%); fusion point 143°-145° C. (from ethanol).
Reaction SMILES: [BH4-].[Li+].CO[C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][C:13]2[CH:15]=[C:16]([CH:19]([OH:27])[CH2:20][CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=[CH:18][C:12]=2[O:11]1.CC[O:31]CC>>[OH:27][CH:19]([C:16]1[CH:17]=[CH:18][C:12]2[O:11][CH:10]([CH:9]([OH:31])[CH2:8][CH2:7][CH2:6][CH3:5])[O:14][C:13]=2[CH:15]=1)[CH2:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCCCC1Oc2ccc(C(O)CCc3cccs3)cc2O1
Reactant: CCOCC
Agent: [BH4-]
Agent: [Li+]
Product: CCCCC(O)C1Oc2ccc(C(O)CCc3cccs3)cc2O1
Reaction time: 1 h
Yield: 98 %

Procedure:
Lithium borohydride (2.1 mg, 0.096 mmol) was added to a solution of (±)-methyl-5-[[6-(1-hydroxy-3-(2-thienyl)propyl]-1,3-benzodioxolyl]pentanoate (Compound F, 36.0 mg, 0.096 mmol) in Et2O (2.0 mL) at 23° C. After 12 hours the reaction was quenched with 1N NaOH, stirred 1 hour, and extracted with EtOAc. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 2:1 hex/EtOAc) provided 32.6 mg (98%) of the title compound. 1H NMR (300 MHz, CDCl3) δ7.14 (d, J=5.5 Hz, 1H), 7.01 (s, 1H), 6.93 (dd J=3.3, 5.5 Hz, 1H), 6.84 (d, J=3.3 Hz, 1H), 6.61 (s, 1H), 5.92 (s, 2H), 4.88-4.92 (m, 1H), 3.63 (t, J=5.7 Hz, 2H), 2.97-3.03 (m, 2H), 2.43-2.49 (m, 2H), 1.84-2.20 (m, 3H), 1.26-1.59 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure BF above, and using 3,5-dichlorophenylacetic acid (from Example BC above) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 115°-116° C. The reaction was monitored by tlc on silica gel (Rf=0.40 in 3% methanou/dichloromethane) and purification was by flash chromatography on silica gel using 3% methanol/dichloromethane as the eluant.
Reaction SMILES: [C:1](=O)(O)[O-:2].[Na+].C=O.[C:8]1([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)C(O)=O>CS(C)=O>[C:15]([O:17][CH3:18])(=[O:16])[CH:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:1][OH:2]
Reactant: COC(=O)Cc1ccccc1
Reactant: O=C([O-])O
Agent: C=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccccc1
Reaction time: 0.67 h

Procedure:
A nitrogen purged 500 mL three-neck flask was charged with sodium bicarbonate (1.05 g; 0.013 mole), paraformaldehyde (17.37 g; 0.55 mole) and dimethyl sulfoxide (100 mL). Methyl phenylacetate (75.09 g; 0.5 mole) was added and rinsed in with dimethylsulfoxide (50 mL). The slurry was stirred magnetically and the temperature rose from 22° C. to 34° C. over 40 minutes. The temperature remained at 33°-34° C. for about one hour, after which the temperature was raised to 45°-46° C. and held for 12 hours. The reaction mixture was allowed to cool with stirring for about seven hours. A solution of anhydrous oxalic acid (1.13 g; 0.013 mole) in dimethylsulfoxide (6 mL) was added, and the solvent was distilled at pot temperature 45° C. to 100° C. at 0.05 mm Hg. The distillate (153.6 g) was retained. The pale yellow oily residue of crude methyl tropate (112.82 g) contained a small amount of white solid (sodium hydrogen oxalate).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]#[N:24])[CH:17]=1>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:22](/[C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)\[C:23]#[N:24])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: N#CCc1cccnc1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3cccnc3)cc2c1
Yield: 78.1 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (222 mg) was condensed with 3-pyridineacetonitrile (118 mg) through Method B (production step 3), to thereby yield the target product (yield: 251 mg, 78%).
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)[CH2:3]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:37]I>CC#N.C1(C)C=CC=CC=1>[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)([F:12])[CH2:3][I:37]
Reactant: II
Reactant: Cc1ccc(C(F)(F)CO)nc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1ccc(C(F)(F)CI)nc1
Temperature: 90 °C
Yield: 32 %

Procedure:
2,2-Difluoro-2-(5-methyl-pyridin-2-yl)-ethanol (8.5 g, 0.05 mol), as prepared in the previous step, was dissolved into toluene:CH3CN (98 mL, 2:1) and cooled to 0° C. To this solution was added PPh3 (19.3 g, 0.074 mol, 1.5×), imidazole (6.7 g, 0.098 mol, 2×) and I2 (18.7 g, 0.074 mol, 1.5×). The reaction was heated to 90° C., then was cooled to RT and concentrated in vacuo to afford a thick amber oil. Purification via flash chromatography (CH2Cl2) afforded the product as a clear oil (4.6 g, 0.016 mol, 33% yield). 1H NMR (300 Hz, CDCl3) δ 8.48 (s, 1H), 7.61 (m, 1H), 3.92 (t, J=14.7 Hz), 2.41 (s, 3H); LC/MS (m/z) [M+1]+ 284.1 (calculated for C8H9F2IN, 284.07).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Mg].C(Br)C.CN([CH:18]=[O:19])C>C1COCC1>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([Cl:8])[CH:5]=1)[CH:18]=[O:19]
Reactant: COc1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: COc1cc(Cl)cc(C=O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3,5-Dichloroanisol (1.1 g; 6.8 mmol) was added in portions to magnesium chips (0.20 g; 8.2 mmol) in THF (dry, 20 mL). After the first addition, EtBr (0.1 mL) was added to start the reaction. After total addition the reaction mixture was stirred at 60° C. overnight, whereafter the mixture was cooled to 0° C., and DMF was added. After stirring for 1 hour, the mixture was poured onto HCl/aq, concentrated, and extracted with ether (3×50 mL). The combined organic phase was washed with water, dried (Na2SO4), and concentrated, yielding 2.35 g of the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([F:13])[CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[N:3]=1.[Cl:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:23][C:24]1[S:28][C:27]([S:29]([NH:1][C:2]2[C:10]3[C:5](=[C:6]([F:13])[CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[C:17]([C:18]#[N:19])[CH:16]=3)[N:3]=2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: COc1ccc(F)c2c1c(N)nn2Cc1cccc(C#N)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 3-{[3-amino-7-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 44) (665 mg, 2.24 mmol) in dry DCM (10 mL) was added 5-chloro-2-thiophenesulfonyl chloride (0.300 mL, 2.24 mmol), followed with pyridine (2 mL). The resultant dark yellow solution was stirred at room temperature overnight. More 5-chloro-2-thiophenesulfonyl chloride was added (0.100 mL) and the reaction stirred for a further 1 h. The reaction mixture was partitioned between ethyl acetate and 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (×2). The combined organic solutions were washed with water and brine, dried (Na2SO4) and concentrated in vacuo to leave a deep red oil. This residue was loaded in dichloromethane to a silica 100 g cartridge and purified by chromatography on Flashmaster eluting with a 0-100% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (323 mg, 30%) as a pale yellow powder. LCMS (System A) RT=1.2 min, ES+ve m/z 476/478 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]=[O:13])[CH:4]=1.[CH3:14][Mg]Cl>C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]([OH:13])[CH3:14])[CH:4]=1
Reactant: COc1cc(C=O)cc2c1OCO2
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(C)O)cc2c1OCO2
Yield: 45 %

Procedure:
A solution of 7-Methoxy-benzo[1,3]dioxole-5-carbaldehyde (I) (1.8 g, 10 mmol) in THF (20 mL) was cooled to −78° C. A solution of methylmagnesium chloride in THF (5.0 mL of 3M, 15 mmol) was added to the solution of i in THF in a dropwise fashion. The reaction was quenched by the addition of HCl (1N, aqueous) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; 40%-60% ethyl acetate in hexanes) to afford 2 (0.89 g, 45%).
Reaction SMILES: [NH:1]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH3:13][OH:14]>S(=O)(=O)(O)O>[CH3:13][O:14][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[NH2:1]
Reactant: CO
Reactant: O=C1CCCc2ccccc2N1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccccc1N
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1 g, 6.2 mmol) in MeOH (8 mL), concentrated sulfuric acid (0.5 mL) was added and the mixture was stirred at room temperature for 2 hrs and at 70° C. for an additional hr. The solvent was removed and DCM and water were added. The organic layer was removed and the aqueous layer was basified with sat NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to yield 4-(2-amino-phenyl)-butyric acid methyl ester (0.93 g). MS [M+H]+: 194.1; tR=1.49 min. (method 1)