Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[CH:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:13](=[O:27])[CH:12]([CH3:28])[CH2:11]1.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=2)[C:13](=[O:27])[CH:12]([CH3:28])[CH2:11]1
Reactant: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Product: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A cooled (−78° C.) solution of 5-(2-fluoro-6-methoxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (518 mg; 1.30 mmol) in anh. DCM (7 ml) was treated dropwise with a solution of boron tribromide BBr3 (1.0 M in DCM; 6.52 ml; 6.52 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Water was added dropwise, and the separated aq. layer was extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered and concentrated to dryness under reduced pressure affording 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 383.89 g/mol.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:30])=[C:26]([N+:27]([O-])=O)[C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:3][CH2:2]1.[Cl-].[NH4+]>CO.O1CCCC1.O.[Fe]>[NH2:27][C:26]1[C:20]2[S:19](=[O:31])(=[O:32])[N:18]=[C:17]([C:8]3[C:7](=[O:33])[N:6]([NH:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:22][C:21]=2[CH:23]=[CH:24][C:25]=1[OH:30]
Reactant: O=c1c(C2=NS(=O)(=O)c3c(ccc(O)c3[N+](=O)[O-])N2)c(O)c2ccccc2n1NCC1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1c(O)ccc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 60 °C
Yield: 53.9 %

Procedure:
A mixture of the product of Example 381 (10 mg, 0.021 mmol), iron powder (5.9 mg, 0.105 mmol), and ammonium chloride (1.3 mg, 0.024 mmol) in methanol:tetrahydrofuran:water (2:2:1, 2 mL) was heated at 60° C. for 1 hour. The solution filtered through Celite® and washed with tetrahydrofuran. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered and washed with water and dried to give title compound (5 mg, 53%). 1H NMR (300 MHz, DMSO-d6) δ 0.13 (d, J=3.68 Hz, 2 H) 0.40 (d, J=7.72 Hz, 2 H) 1.02 (m, 1 H) 2.85 (d, J=5.52 Hz, 2 H) 5.40 (s, 2 H) 6.46 (s, 1 H) 6.65 (d, J=8.46 Hz, 1 H) 7.00 (d, J=8.09 Hz, 1 H) 7.45 (t, J=7.35 Hz, 1 H) 7.89 (t, J=7.17 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.17 (d, J=8.82 Hz, 1 H) 10.13 (s, 1 H) 13.82 (s, 1 H) 15.17 (s, 1 H). MS (ESI−) m/z 440 (M−H)−.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>[Cu]I.CN(C=O)C>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:46]=[CH:45][C:44]([N:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[CH:43][CH:42]=2)=[CH:39][CH:40]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1

Procedure:
5.0 g of 9H-carbazole (3.0 10−2 mol), 0.67 g of CuI (3.2 10−3 mol), 10.0 g of K2CO3 (7.2 10−2 mol), 1.16 g of 1,10 phenanthroline (6.4 10−3 mol), and 9.36 g of 4,4′-dibromobiphenyl (3.0 10−2 mol) are initially introduced. After addition of 200 ml of DMF, the reaction mixture is stirred under reflux for 12 h. After filtration through Celite with suction, it is precipitated using water and filtered off with suction. The solid is dissolved in hot THF and precipitated using ethanol, giving 7.7 g (64%) of clean substance.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].[CH2:37](Br)[CH:38]=[CH2:39]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([CH2:16][CH2:17][C:18]1([CH3:23])[O:19][CH2:20][CH2:21][O:22]1)[CH2:39][CH:38]=[CH2:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CCCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)OCCO1
Reactant: C=CCBr
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@H](CCC1(C)OCCO1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-9 (19.3 g, 57.9 mmol) in tetrahydrofuran (400 mL) at −78° C. under argon was added a solution of lithium bis(trimethylsilylamide) (75.2 mL of a 1.0 M solution in tetrahydrofuran) over 20 min. After an additional 20 min., allyl bromide (14.0 g, 116 mmol) was added in one portion. After 20 min., the reaction mixture was allowed to warm to 0° C. After 3.5 h, the reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography (silica gel, 25 to 35% ethyl acetate/hexanes) to give 1-10 as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:25])[C:10]([C@H:12]1[CH2:16][CH:15]([F:17])[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:17][CH:15]1[CH2:14][NH:13][C@@H:12]([C:10]([N:9]([CH3:25])[CH3:8])=[O:11])[CH2:16]1
Reactant: CN(C)C(=O)[C@H]1CC(F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@H]1CC(F)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added under ice cooling to a 30 mL chloroform solution of 2.09 g of the compound obtained in step 6-2, after which the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, which gave 3.42 g of residue (pale yellow oily substance). This compound was used in the following reaction without being purified.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:23][C:24]1C=CC(OC2C=CC(C(C=CC(O)=O)=O)=CC=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([O:18][CH2:23][CH3:24])=[O:17])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccc(OC)cc2)cc1

Procedure:
The procedure in Example 17(1) was followed, except that 6.00 g of 3-[4-(4-methoxyphenoxy)benzoyl]acrylic acid were used in place of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid, to give 5.06 g of ethyl 3-[4-(4-methoxyphenoxy)benzoyl]-acrylate in the form of an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=N1.C1(N)C(N)=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:39][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[NH:41][C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1NC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
(2S)-2-[(Benzyloxy)-carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (65.3 mg, 0.128 mmol) in DMF (4 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (67.8 mg, 0.153 mmol). After 5 minutes 1,2-benzenediamine (20.7 mg, 0.192 mmol) and N,N-diisopropylethylamine (111 μL, 0.638 mmol) were added and the solution stirred at rt for 2 h. Purification by preparative LCMS afforded product as a white solid (58 mg, 76%). 1H NMR (400 MHz, CD3OD): δ 7.72 (s, 1H), 7.56–7.23 (m, 10H), 6.91–6.85 (m, 1H), 5.67 (t, J=7.7 Hz, 1H), 5.09 (s, 2H), 4.50–4.47 (m, 1H), 3.46 (dd, J=16.5, 8.8 Hz, 1H), 3.34–3.24 (m, 1H), 3.26–3.08 (m, 2H); LCMS found for C26H26BrN4O6S (M+H)+: m/z=601.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:15])[CH3:4].[Na].[C:17]1([C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1)=[O:18]>CO>[CH2:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:15])[CH3:4]
Reactant: CCN1C(=O)Cc2cc(O)ccc21
Reactant: O=C1OCc2ccccc21
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: CCN1C(=O)Cc2cc(OCc3ccccc3C(=O)O)ccc21
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To a solution of 2.24 g. (54.3 mmoles) of sodium hydroxide in 450 ml. of methanol was added 9.63 g. (54.3 mmoles) of 1-ethyl-5-hydroxyoxindole and the resulting solution concentrated in vacuo to dryness at 65° C. The residual sodium salt was mixed with 10.7 g. (79.8 mmoles) of phthalide and the mixture heated one hour at 185° C. An additional 4.0 g. (29.9 mmoles) of phthalide was added and the heating continued at 220° C. for 20 minutes. The reaction was cooled, the solids washed with diethyl ether and the remaining solids partitioned between 1N hydrochloric acid and diethyl ether. The organic phase was separated and extracted with a saturated sodium bicarbonate solution. The bicarbonate solution was separated, acidified with 4N hydrochloric acid and extracted with diethyl ether. The ether layer was separated, dried over magnesium sulfate and concentrated to give a solid. Recrystallization from methanol gave 4.0 g. (24% yield) of the desired product, m.p. 180° -181° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]([OH:26])[CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)(=[O:16])=[O:15])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>O1CCCC1.Cl>[NH2:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH:11]([OH:26])[CH2:10][NH:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCC(O)CNc2nc(Cl)ncc2Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)NCC(O)CNc2nc(Cl)ncc2Br)c1
Reaction time: 2 h

Procedure:
A solution of 258 mg (0.553 mmol) of N-[3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-2-hydroxy-propyl]-3-nitro-benzenesulfonamide in 20 ml of tetrahydrofuran is mixed under argon at room temperature with 2.6 ml of a 15% solution of Ti(III)Cl in approximately 10% hydrochloric acid. After 2 hours, the reaction solution is mixed again with 0.2 ml of Ti(III)Cl solution and stirred for another 60 minutes. The batch is made basic with 1 M NaOH solution and then filtered. The filter cake is rewashed 2× with 50 ml of ethyl acetate/MeOH (30 ml/20 ml) in each case. The filtrate is concentrated by evaporation in a rotary evaporator and then extracted with ethyl acetate (2×). The combined organic phases are washed with NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (dichloromethane/MeOH 95:5, Flashmaster II). 155 mg (0.36 mmol, corresponding to 64% of theory) of the product is obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:9]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[CH2:1]([NH:19][C@@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccccc1
Product: c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
Benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(C1N=C(O)C2C(C=1O)=CC=C(OC1C=CC3OC(N(C)C)=NC=3C=1)C=2)=O)CCC.P(Cl)(Cl)([Cl:67])=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:67])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1nc(O)c2ccc(Oc3ccc4oc(N(C)C)nc4c3)cc2c1O
Agent: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc4oc(N(C)C)nc4c3)ccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc4oc(N(C)C)nc4c3)cc2c1O
Temperature: 120 °C

Procedure:
A solution of the regioisomeric mixture of 6-(2-dimethylamino-benzooxazol-5-yloxy)-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester and 7-(2-dimethylamino-benzooxazol-5-yloxy)-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester obtained as described above (1.05 g, 2.41 mmol), and phosphorus oxychloride (286 μL, 3.13 mmol) in dichloroethane (18 mL) was stirred at 120° C. in a CEM microwave apparatus for thirty minutes. The mixture was stirred with saturated sodium bicarbonate solution for twenty minutes. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo. Purification by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane gave a solid (463 mg). Recrystallization from ethyl acetate (190 mL) furnished the title compound as a yellow solid (219 mg): MS: (+) m/z 456.31 (M+1).
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH2:20][NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][C:14]=1[C@:27]12[CH2:36][O:35][C@@H:34]([CH2:37][F:38])[CH2:33][C@H:32]1[CH2:31][S:30][C:29]([NH:39]C(=O)C1C=CC=CC=1)=[N:28]2>CO>[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH2:20][NH:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[CH:15][C:14]=1[C@:27]12[CH2:36][O:35][C@@H:34]([CH2:37][F:38])[CH2:33][C@H:32]1[CH2:31][S:30][C:29]([NH2:39])=[N:28]2
Reactant: O=C(NC1=N[C@@]2(c3cc(CNCC(F)(F)F)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@@]2(c3cc(CNCC(F)(F)F)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1
Temperature: 70 °C

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.084 mL, 0.534 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C27) (0.4064 g, 0.7650 mmol) in methanol (30 mL). The resulting solution was heated to 70° C. until complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to yield product as an orange oily residue. Purification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) afforded the product as a white solid. Yield: 0.273 g (84%). LCMS m/z 428 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.38 (t, J=8.8 Hz, 1H), 6.98 (dd, J=12.2, 9.7 Hz, 1H), 4.42-4.48 (m, 1H), 4.30-4.37 (m, 1H), 4.09 (dd, J=11.2, 2.0 Hz, 1H), 3.86-3.90 (m, 3H), 3.72 (d, J=11.2 Hz, 1H), 3.13-3.18 (m, 2H), 2.90-2.97 (m, 2H), 2.70 (dd, J=12.4, 2.6 Hz, 1H), 1.76-1.87 (m, 1H), 1.52 (ddd, J=13.1, 4.0, 2.3 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][N:13]3[C:14]4[C:10](=[CH:9][CH:8]=[C:7]([CH2:6][CH:5]([O:16][CH2:17][CH3:18])[C:4]([OH:3])=[O:19])[CH:15]=4)[CH:11]=[CH:12]3)[N:23]=2)[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=1
Reactant: CCOC(=O)C(Cc1ccc2cc[nH]c2c1)OCC
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Product: CCOC(Cc1ccc2ccn(Cc3nc(-c4cc(OC)cc(OC)c4)oc3C)c2c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(1H-indol-6-yl)-propionic acid ethyl ester (preparation 11) was reacted with 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-6-yl}-2-ethoxy-propionic acid as yellow solid.
Reaction SMILES: I/[CH:2]=[CH:3]/[C@@H:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br-].[CH2:25]([Zn+])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1.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>[C:26]1([CH2:25]/[CH:2]=[CH:3]/[C@@H:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C[C@@H](/C=C/I)c1ccc(OC2CCCCO2)cc1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](/C=C/Cc1ccccc1)c1ccc(OC2CCCCO2)cc1

Procedure:
To a stirred solution of 84.4 (321.9 mg, 0.748 mmol, 1 eq., MW 430.29) in THF (19 mL) at 23° C. was added Pd(PPh3)4 (86.8 mg, 0.075 mmol, 0.1 eq., MW 1155.58) followed by dropwise addition of benzyl zinc bromide solution (1.8 mL, 0.90 mmol, 1.2 eq., 0.5 M) After 3 hours, water (10 mL) was added to quench the reaction. The mixture was extracted with EtOAc (2×50 mL), dried with MgSO4, and filtered. The organic layer was concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0 to 20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated providing the product as a colorless oil that was used without further purification.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:21]1CCN2C(=NCCC2)CC1.C=O>C1COCC1.C(OCC)(=O)C>[CH2:17]([C:11](=[CH2:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(CC(C)C)P(=O)(OCC)OCC
Reactant: C1CCC2=NCCCN2CC1
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(CC(C)C)C(=O)OCC

Procedure:
333 mg of lithium chloride was suspended in 14 ml of dry THF. Then, 2.0 g of ethyl 2-diethylphosphono-4-methylpentanoate was added thereto under stirring. Then, 1.41 g of. DBU was added thereto in the form of a dry THF solution. Then, a suspension of 348 mg of paraformaldehyde in dry THF was added thereto. The mixture was stirred at room temperature overnight. The reaction solution was subjected to filtration, and the collected substance was washed with a small amount of benzene. The filtrate and the washing solution were put together and concentrated under reduced pressure. The syrup thereby obtained was dissolved in 60 ml of ethyl acetate. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, solvent was distilled off to obtain 700 mg of ethyl 2-isobutyl-2-propenoate as colorless oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].O=[C:12]1[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH:12]2[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1ccc(NC2CCN([C@H](C)CC#N)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Following General Procedure A, a solution of 4-ethoxyaniline (0.48 g, 3.5 mmol) and (R)-3-(4-oxo-piperidin-1-yl)butyronitrile (0.49 g, 3.0 mmol) in CH2Cl2 (10 mL), was treated with glacial AcOH (3 drops) and NaBH(OAc)3 (0.93 g, 4.4 mmol), stirring for 16 h at room temperature. Saturated aqueous NaHCO3 solution (15 mL) and 1N NaOH (2 mL) was added and the phases were separated and the aqueous extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was then purified by flash column chromatography on silica gel (1:1 EtOAc/CH2Cl2) to afford (R)-3-[4-(4-ethoxy-phenylamino)-piperidin-1-yl]-butyronitrile as a pale brown solid (90%). 1H NMR (CDCl3) δ 1.20 (d, 3H, J=6.6 Hz), 1.37 (t, 2H, J=7.2 Hz), 1.39 (m, 2H), 2.05 (br d, 2H), 2.36 (m, 3H), 2.47 (m, 1H), 2.81 (m, 2H), 3.07 (sex, 1H, J=7.2 Hz), 3.28 (m, 2H), 3.96 (q, 2H, J=7.5 Hz), 6.55 (d, 2H, J=9.0 Hz), 6.76 (d, 2H, J=9.0 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14]3)[N:10]=1)([CH3:5])[CH3:4].[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(OCC)(=O)C>ClCCl>[CH3:4][C:3]([C:6]1[NH:10][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14]3)=[C:8]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[N:7]=1)([CH3:5])[CH2:2][NH:1][S:28]([CH3:27])(=[O:30])=[O:29]
Reactant: CC(C)(CN)c1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(CNS(C)(=O)=O)c1nc(-c2ccncc2)c(-c2ccc3c(c2)CCC3=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of the product of Example 1, Step 6 (0.1 g, 0.29 mmol) and methane sulphonyl chloride (0.023 ml, 0.3 mmol) in dichloromethane (3 ml) was stirred at room temperature for 2 hours. The reaction was then poured into ethyl acetate, washed with water and aqueous sodium hydrogen carbonate solution, dried (MgSO4) and concentrated in vacuo. The crude residue was then purified by silica gel chromatography eluting with a 1:9:90 mixture of 0.88 ammonia solution:methanol:dichloromethane to give the title compound (0.075 g, 61%) as a yellow solid; MS(AP+) m/e 425 [M+H]+.