Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:37]B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH3:37])=[CH:10][CH:9]=2)=[O:4]
Reactant: CB(O)O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(C)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 86.2 %

Procedure:
A mixture of 6-bromo-2-(4-tert-butoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (500 mg), methylboronic acid (270 mg), tetrakis(triphenylphosphine)palladium(0) (110 mg), potassium carbonate (380 mg), toluene (6 ml) and THF (4 ml) was stirred at 100° C. for 6 hrs. under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (380 mg).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)[N:14]=[N:13][C:12]=1[C:27]([NH:29][CH:30]1[CH2:32][CH2:31]1)=[O:28])C1C=CC=CC=1>CO.C(O)(=O)C.[C].[Pd]>[CH:30]1([NH:29][C:27]([C:12]2[N:13]=[N:14][N:15]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=3)[C:11]=2[CH2:10][CH2:9][OH:8])=[O:28])[CH2:31][CH2:32]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCO)cc1
Yield: 82.4 %

Procedure:
5-[2-(Benzyloxy)ethyl]-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (737 mg, 1.70 mmol) obtained in Example 107 was dissolved in methanol-acetic acid (25:1, 26 ml), and the mixture was stirred at room temperature for 63 hr in the presence of 10% palladium carbon (wet, purity 50%, 150 mg) under a hydrogen atmosphere. The reaction mixture was filtered to remove the catalyst, the filtrate was concentrated to dryness, and ethyl acetate-diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (480 mg, 1.40 mmol, 82.2%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:25]1[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-trifluoromethyl-phenylboronic acid to give [6-methoxy-1-(4-trifluoromethyl-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 385(MH+).
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[O:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]2[CH:44]=[CH:45][CH:46]=[CH:47][C:2]1=2.[O:48]1[CH:53]=[CH:52][CH2:51][CH2:50][CH2:49]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[S:1]1[C:5]([C@H:6]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[O:14])[CH2:12][C@H:11]([O:15][CH:49]3[CH2:50][CH2:51][CH2:52][CH2:53][O:48]3)[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]2[CH:44]=[CH:45][CH:46]=[CH:47][C:2]1=2
Reactant: C1=COCCC1
Reactant: COC(=O)CCC/C=C\C[C@H]1[C@@H](O)CC(=O)[C@@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC/C=C\C[C@H]1[C@@H](OC2CCCCO2)CC(=O)[C@@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
(Z)-Methyl 7-((1R,2R,5S)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-5-hydroxy-3-oxocyclopentyl)hept-5-enoate (11a, limiting reagent) is dissolved in DCM (0.1 M) under a nitrogen atmosphere. Dihydropyran (1.1 molar equivalent) is added, followed by a catalytic amount of p-toluenesulfonic acid. The reaction is stirred at room temperature under a nitrogen atmosphere and the reaction progress is monitored by TLC. Upon completion, brine is added to the reaction mixture and the layers are separated. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 15a.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Br[C:13]1[CH:22]=[N:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH2:3][NH:2][C:19]2[CH:20]=[N:21][CH:22]=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:6]=1)#[N:9]
Reactant: COC(=O)c1ccncc1Br
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccncc1NCc1ccc(C#N)cc1
Yield: 4 %

Procedure:
The title compound was prepared in 4% yield from 4-(aminomethyl)-benzonitrile hydrochloride and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (500 MHz, CDCl3): δ 8.07 (s, 1H), 7.97 (d, 2H, J=5.0 Hz), 7.63-7.70 (m, 3H), 7.46 (d, 2H, J=8.3 Hz), 4.61 (d, 2H, J=6.1 Hz), 3.94 (s, 3H). [M+H] calc'd for C15H13N3O2, 268. found 268.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[NH2:33]C1C(C#N)=C(Cl)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:33])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C=O)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbaldehyde using 4-amino-6-chloropyrimidine-5-carbonitrile instead of 4-amino-6-chloropyrimidine-5-carbaldehyde. LC-MS: (M+1=446, obsd.=446).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:3]1.[C:18]([O:22][C:23]([NH:25][C:26]1[S:30][C:29]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])=[N:28][C:27]=1[C:39](O)=[O:40])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:29]1[S:30][C:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:27]([C:39](=[O:40])[NH:14][C:9]2[CH:10]=[N:11][N:12]([CH3:13])[C:8]=2[N:4]2[CH2:5][CH2:6][CH2:7][C:2]([F:17])([F:1])[CH2:3]2)[N:28]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)C1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC(F)(F)C1
Yield: 20 %

Procedure:
Following the procedure for Example 55, starting with 3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25, gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (57 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.67 (s, 1H), 7.71 (s, 1H), 7.41-7.32 (m, 1H), 7.11-7.01 (m, 2H), 3.76 (s, 3H), 3.32 (t, J=11.0 Hz, 2H), 3.19-3.13 (m, 2H), 2.10-1.97 (m, 2H), 1.94-1.85 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: [F-].[K+].CN1C(=O)CCC1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[N:17]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:18]=[C:19](I)[C:12]=12.C[Si](C)(C)[C:33]([F:36])([F:35])[F:34]>[Cu]I.C(OC)(C)(C)C.CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[N:17]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:18]=[C:19]([C:33]([F:36])([F:35])[F:34])[C:12]=12
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ccnc32)cc1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2cc(C(F)(F)F)c3c(Cl)ccnc32)cc1
Temperature: 220 °C
Yield: 67.3 %

Procedure:
Under protective gas atmosphere (argon), 23.1 g (0.398 mol) of dry potassium fluoride and 75.7 g (0.398 mol) of copper(I) iodide were titrated together and heated to 220° C. under high vacuum with agitation for 10 minutes until a slightly greenish colouration appeared. A reaction flask was initially charged under protective gas atmosphere (argon) with the calcined mixture of potassium fluoride and copper(I) iodide together with 170 ml of absolute NMP and 170 ml of absolute DMF, and 86 g (0.199 mol) of 4-chloro-1-(toluene-4-sulphonyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine were subsequently introduced in portions at 20° C. with stirring to form a light grey suspension. 62.1 g (0.437 mol) of trimethyltrifluoromethylsilane were added dropwise to the reaction mixture within 20 minutes and the mixture was left to stir at 20° C. for 18 h. On completion of conversion (GC monitoring of conversion), the reaction mixture was added to 2000 ml of methyl tert-butyl ether, the organic phase was decanted and the residue was dispersed once more with 1000 ml of methyl tert-butyl ether. The combined organic phases were washed three times with 2000 ml each time of water and subsequently dried over MgSO4. Filtration and removal of the volatile constituents in a water-jet vacuum resulted in 50.1 g (0.134 mol; 67%) of 4-chloro-1-(toluene-4-sulphonyl)-3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine as a beige solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]#[N:21])[CH:14]=1>>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](/[C:19](=[CH:11]/[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)/[C:20]#[N:21])[CH:14]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: N#CCc1cccnc1
Product: N#C/C(=C\c1ccnc2ccccc12)c1cccnc1
Yield: 29.6 %

Procedure:
4-Quinolinecarboxaldehyde (157 mg) was condensed with 3-pyridineacetonitrile (118 mg) through Method B (production step 3), to thereby yield the target product (yield: 76 mg, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4](C)[CH:3]=1.BrC1C=CC(I)=C([Cl:19])C=1.C[Si](C)(C)C=C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([Cl:19])[CH:3]=1
Reactant: Clc1cc(Br)ccc1I
Reactant: C=Cc1ccc(Br)cc1C
Agent: C=C[Si](C)(C)C
Product: C=Cc1ccc(Br)cc1Cl
Yield: 96 %

Procedure:
Using a procedure analogous to that used to prepare 30A, 4-bromo-2-chloro-1-iodobenzene (8 g, 25 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 160° C. for 1 h and worked up in a manner similar as in 30A to yield 61A (5.2 g, 96%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.41 (d, J=11.86 Hz, 1 H) 7.02 (dd, J=17.36, 11.21 Hz, 1 H) 7.35 (dd, 1 H) 7.41 (d, 1 H) 7.52 (d, J=1.76 Hz, 1 H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS(C)=O.[N+:29]([C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([N+:41]([O-:43])=[O:42])[CH:40]=1)[C:35](Cl)=[O:36])([O-:31])=[O:30]>O>[N+:29]([C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([N+:41]([O-:43])=[O:42])[CH:40]=1)[C:35]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:2][CH2:3]1)=[O:36])([O-:31])=[O:30]
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCc2cc(N3CCN(C(=O)c4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)CC3)ccc2N1
Temperature: 25 °C
Yield: 6.3 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2.34 ml of triethylamine was added to 40 ml of dimethyl sulfoxide and the mixture was stirred at room temperature while slowly adding dropwise 10 ml of dimethyl sulfoxide solution containing 3.3 g of 3,5-dinitrobenzoyl chloride. After completion of addition the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate, chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 0.3 g of 6-[4-(3,5-dinitrobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 262°-264° C., reddish black needles.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([NH:11][C:7]([CH:3]2[C:2]([CH3:10])([CH3:1])[C:4]2([CH3:6])[CH3:5])=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Solvent: ClCCl
Product: CC1(C)C(C(=O)Nc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.7 %

Procedure:
A solution of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (1.60 g, 10 mmole) in CH2Cl2 (5 ml) was added dropwise to a solution of aniline (2.8 g, 30 mmole) in CH2Cl2 (10 ml), while maintaining the temperature at 10°-20° C. The reaction mixture was stirred for 6 hours at room temperature, diluted with CH2Cl2 (15 ml) and washed successively with H2O (2×10 ml), 1N HCl (2×10 ml), H2O (20 ml) saturated NaCl (2×15 ml). The organic layer was separated, dried over MgSO4, and evaporated to dryness under reduced pressure. The residue was crystallized from EtOAc/hexane to afford 1.1 g (5.07 mmole, 51%) of a white crystalline solid), m.p. 149° C.
Reaction SMILES: N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@H](OC2C=CC=CN=2)CN1C(C1C=CC=CC=1)C1C=CC=CC=1)O.[NH2:39][C@@H:40]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@@H:41]([C@H:43]1[CH2:47][C@@H:46]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:45][N:44]1C(C1C=CC=CC=1)C1C=CC=CC=1)[OH:42].FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](OC3C=CC=CC=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.[C:117]([NH:120][C@:121]1([C@@H:170]([CH2:172][CH3:173])[CH3:171])[CH2:125][CH2:124][N:123]([C@@H:126]([CH2:161][CH2:162][C:163]2[CH:168]=[CH:167][CH:166]=[CH:165][CH:164]=2)[C:127](N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:128])[C:122]1=[O:169])(=[O:119])[CH3:118].[Li+].[OH-]>CCO.O>[C:117]([NH:120][C@:121]1([C@@H:170]([CH2:172][CH3:173])[CH3:171])[CH2:125][CH2:124][N:123]([C@@H:126]([CH2:161][CH2:162][C:163]2[CH:164]=[CH:165][CH:166]=[CH:167][CH:168]=2)[C:127]([NH:39][C@@H:40]([CH2:68][C:69]2[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=2)[C@H:41]([OH:42])[C@H:43]2[CH2:47][C@@H:46]([O:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:45][NH:44]2)=[O:128])[C:122]1=[O:169])(=[O:119])[CH3:118]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](Oc2ccccc2)CN1C(c1ccccc1)c1ccccc1
Agent: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@H](Oc2ccccn2)CN1C(c1ccccc1)c1ccccc1
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](Oc3ccccc3)CN2C(c2ccccc2)c2ccccc2)O1
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](Oc3ccccc3)CN2)C1=O
Temperature: 25 °C

Procedure:
Step 11 (B): (1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)oxazolidin-2-one (Step 11 (A), (34.7 mg, 0.064 mmol) in EtOH (3 mL) was added a solution of LiOH (31 mg, 1.28 mmol) in H2O (0.75 mL). This reaction mixture was stirred at reflux for 4 h. After cooling down to rt, the mixture was concentrated to remove EtOH and H2O was added followed by 1N HCl solution and pH 7 buffer. The mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-10% MeOH/chloroform) gave 29 mg of the title compound: 1H NMR (CDCl3, 300 MHz) δ 2.16-2.29 (2H, m), 2.49-2.59 (2H, m), 2.78-3.42 (8H, m), 4.68 (1H, s), 4.95 (1H, s), 6.63-6.74 (3H, m), 6.88-6.93 (2H, m), 6.95-6.98 (1H, m), 7.09-7.36 (11H, m), 7.46-7.48 (1H, m). HPLC retention time: 1.59 min (method A). MS (ESI) (M+H)+ 515.19.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[S:13]1[CH:17]=[CH:16][C:15]2[CH:18]=[C:19]([CH:22]=[CH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][C:14]1=2.[OH-].[K+].Cl>C(O)C>[OH:4][C:3]1[CH2:2][CH:22]([C:19]2[CH:20]=[CH:21][C:14]3[S:13][CH:17]=[CH:16][C:15]=3[CH:18]=2)[CH2:23][C:24](=[O:26])[CH:25]=1
Reactant: CC(=O)C=Cc1ccc2sccc2c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [Na]
Solvent: CCO
Product: O=C1C=C(O)CC(c2ccc3sccc3c2)C1

Procedure:
Diethyl malonate (7.16 g) was added to a solution of sodium metal (1 equiv) in anhydrous absolute ethanol (40 ml). 1-(Benzo[b]thien-5-yl)but-1-en-3-one (8.7 g) was added to the solution and the mixture was heated under reflux for 2 hr. An aqueous solution of potassium hydroxide (5.3 g in 50 ml water) was added and the mixture was heated under reflux for a further 5 hr. The hot mixture was acidified by dropwise addition of a dilute aqueous hydrochloric acid solution. After cooling, the product was filtered off and dried by azeotropic distillation with toluene to give 3-hydroxy-5-(benzo[b]thien-5-yl)cyclohex-2-en-1-one as a yellow solid, mp 192° C.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O:5][CH3:6])=[O:4].[F:15][C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22]Br)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22][CH:7]([P:3]([O:5][CH3:6])([O:2][CH3:1])=[O:4])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:18][CH:17]=1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: Fc1ccc(OCCBr)cc1
Product: COP(=O)(OC)C(CCOc1ccc(F)cc1)C(=O)OC(C)(C)C
Yield: 61.6 %

Procedure:
20.5 g of tert-butyl dimethylphosphonoacetate were reacted with 25 g of 4-fluorophenoxyethyl bromide by the method described in Example 5 A). The reaction mixture was worked up as described in Example 5 A). 20.4 g of tert-butyl 4-(4-fluorophenoxy)-2-(dimethylphosphono)-n-butyrate were obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][CH:8]([F:19])[C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=1.O.[OH-].[Na+]>O1CCCC1>[F:7][CH:8]([F:19])[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(C(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(C(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (2.86 g, 75.3 mmol) in tetrahydrofuran (50 ml) was dropwise added a solution of methyl 4-(difluoromethyl)benzoate (9.341 g, 50.18 mmol) in tetrahydrofuran (50 ml) under ice-cooling and the mixture was stirred at room temperature for 1 hr. The reaction solution was ice-cooled and water (3 ml), 15% aqueous sodium hydroxide solution (3 ml) and water (8 ml) were dropwise added successively to decompose excess lithium aluminum hydride. The mixture was stirred as it was at room temperature for 2 hrs. The resulting precipitate was removed by filtration and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1-1/1) to give the objective-substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C:24]([CH3:27])([O:23][C:19](=[O:22])/[CH:20]=[CH:21]/[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1)[CH3:26]
Reactant: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 75 °C
Yield: 60 %

Procedure:
A solution of benzyl 2-(4-bromophenyl)acetate (33.5 g. 0.11 mol), t-butyl acrylate (31.6 mL, 0.22 mol) and triethylamine (85 mL. 0.64 mol) in DMF (1000 mL) was deoxygenated with argon, whereupon bis(triphenylphosphine)palladium dichloride (5.1 g. 8.3 mmol) was added. After heating at 75° C. for 12 hours the solvent was removed in vacuo providing a brown residue that was purified by chromatography on silica gel using a mixture of hexanes and ethyl acetate (9:1) to give benzyl (E)-2-[4-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]acetate as a pale yellow oil (23.3 g. 0.07 mol) in 60% yield.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[C:13](OC)[C:12](OC)=[C:11](OC)[CH:10]=2)[CH:4]=1.CC(C1C=CC([C:30]([F:33])([F:32])[F:31])=CC=1)=O>>[Cl:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:30]([F:33])([F:32])[F:31])=[CH:11][CH:10]=2)[CH:4]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(-c2cc(CCl)n(C)n2)cc(OC)c1OC
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCl

Procedure:
5-chloromethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole was prepared in analogy to the preparation of 5-chloromethyl-1-methyl-3-(3,4,5-trimethoxy-phenyl)-1H-pyrazole described by Kodama et al. (U.S. Pat. No. 6,472,386), but starting from 4-trifluoromethylacetophenone instead of 3′4′5′-trimethoxyacetophenone.