Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]=[CH:9][CH2:10][CH2:11]CCCCCCC)=[O:7].[Mg].BrC=CCCCCCCCCC.CC[O:34]CC>>[O:34]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: CCOCC
Reactant: CCCCCCCCCC=CC(=O)c1ccco1
Agent: CCCCCCCCCC=CBr
Agent: [Mg]
Product: O=C(c1ccco1)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation of 2-Furyl-n-undecenylketone (R=n-C9H18CH═CH2)—Magnesium turnings (2.0 g, 83.3 mmol) were covered with anhydrous Et2O (10 mL) and a solution of 1-bromoundecene (5.0 mL, 23.0 mmol) in anhydrous Et2O (15 mL) was added in small aliquots until the reaction begins. The remaining halide solution was added dropwise, then heated to reflux (1 hour), allowed to cool to rt and then added to a cooled solution of the Weinreb amide (2.82 g, 18.2 mmol in 15 mL anhydrous Et2O, 0° C.) via cannula. The resulting slurry was stirred (3 h) and then quenched with equal amounts of 1 N HCl and H2O. After warming to rt the mixture was separated and the aqueous layer was extracted with Et2O (2×). The combined organics were washed with sat'd. NaHCO3, brine, dried (Na2SO4), filtered, and evaporated to yield crude furyl ketone. 1H NMR: δ 7.58 (dd, 1H, 3JH,H=1.7 Hz, 4JH,H=0.74 Hz, H-2), 7.18 (dd, 1H, 3JH,H=3.6 Hz, 4JH,H=0.74 Hz, H-4), 6.53 (dd, 1H, 3JH,H=1.7 Hz, 3JH,H=3.6 Hz, H-3), 5.82 (m, 1H), 5.00 (m, 1H, vinyl), 4.92 (m, 1H, vinyl), 2.82 (t, 2H, 3JH,H=7.5 Hz, H-7), 2.04 (qd, 2H, 3JH,H=7.5 Hz, H-15), 1.72 (quintet, 2H, 3JH,H=7.5 Hz, H-8), 1.37–1.20 (m, 12H). 13C NMR: δ 189.9, 152.9, 146.2, 139.2, 116.8, 114.1, 112.1, 38.5, 33.8, 29.7, 29.4, 29.3, 29.2, 29.1, 28.9, 24.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C@@H:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([O:14]C(C)(C)C)=[O:13])[C:7]1=[O:23].FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C@@H:11]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:12]([OH:14])=[O:13])[C:7]1=[O:23]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2cccc(O)c2)C1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2cccc(O)c2)C1=O
Yield: 99.7 %

Procedure:
A solution of Example 143B (0.026 g, 0.072 mmol) in dichloromethane (1.5 mL) was treated with trifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography eluting with a gradient of 95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.022 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:16]1[C:20]([C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[N:19][N:18]=[N:17]1>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12]([NH:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]4[NH:19][N:18]=[N:17][N:16]=4)[CH:22]=3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1nc(-c2ccc(S(=O)(=O)Cl)s2)cs1
Product: Cc1nc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)cs1
Yield: 25.7 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-(2-methylthiazol-4-yl)thiophene-2-sulphonylchloride (15 mg, 0.055 mmol) and [3-(1H-tetrazol-5-yl)phenyl]amine (8 mg, 0.05 mmol) giving 5.2 mg (26%) of the title compound. MS (ESI+) calcd for C15H12N6O2S3 404.0184, found 404.0182.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Li]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([OH:15])[CH2:14][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCCCC[C@@H]2CO2)cc1
Reactant: [Li]C
Product: CC[C@H](O)CCCCOCc1ccccc1

Procedure:
(R)-6-Benzyloxyhex-1-ene oxide was prepared by copper catalyzed addition of 3-benzyloxypropyl-1-magnesium bromide to R-epichlorohydrin to form R-1-chloro-6-benzyloxyhexan-2-ol, which was then ring closed under basic conditions to (R)-6-benzyloxyhex-1-ene oxide. This epoxide was then treated with methyl lithium (1.5 M in diethyl ether) in the presence of dilithiotetrachlorocuprate (0.02 molar equivalents, 0.1 M in tetrahydrofuran) to yield (S)-1-benzyloxy-5-hydroxyheptane.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6](=O)[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3]1.[CH3:21][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[CH3:21][C:4]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][C:2]([CH3:20])([CH3:1])[CH2:6][N:5]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CCOC(=O)[C@@H]1CC(C)(C)C(=O)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CC(C)(C)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of (S)-1-tert-butyl 2-ethyl 4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (163D) (10 g, 0.035 mol) in dry THF (60 mL) stirred at −78° C. under nitrogen was added a 1 M solution of lithium hexamethyldisilazide in THF (38.5 mL, 0.038 mol). The mixture was stirred at −78° C. for 30 min, iodomethane (5.4 g, 0.038 mol) in THF (5 mL) was added, and the mixture was then stirred 1 h, warmed up to room temperature and continued stirring for additional 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography (10-20% EtOAc/hexane) to furnish (163E) (8.2 g, 72%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][C:29]([F:30])([F:32])[F:31])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=C(Cl)CS[C@H]23)cs1
Agent: Cl
Solvent: CO
Product: Nc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=C(Cl)CS[C@H]23)cs1
Yield: 98.2 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.7 g.), conc.hydrochloric acid (0.43 ml.) and methanol (16 ml.) were treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.65 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Solvent: c1ccncc1
Product: O=C(c1cccnc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the general procedures for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone 5 g (21.5 mmol) and 4-bromo-benzenesulfonyl chloride 5.78 g (21.5 mmol), in 150 ml anhydrous pyridine, overnight at 80° C., followed by flash column chromatography on silica gel to yield a salmon color solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[S:28]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])(=[O:30])[NH2:29]>>[S:28]([C:32]1[CH:33]=[C:34]([NH:38][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:35]=[CH:36][CH:37]=1)(=[O:30])(=[O:31])[NH2:29]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 542.1 [(M−H)−]; mp 245° C.
Reaction SMILES: [C:1]1([N:7](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][CH2:9][CH2:10][N:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:12][CH2:13][CH2:14][N:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)S(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.[Na].[Cl-].[NH4+]>>[C:1]1([NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:12][CH2:13][CH2:14][NH:15][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCN(CCCN(c2ccccc2)S(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)c2ccccc2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N(CCCNc1ccccc1)CCCNc1ccccc1

Procedure:
Mix 1,9-bis[(phenyl)]-1,9-bis[(4-methylphenyl)sulfonyl]-5-(t-butyloxycarbonyl)-1,5,9-triazanonane (691 mg, 1 mmol) in dry liquid ammonia (25 mL) at -40° C. Add small pieces of sodium until a permanent blue color remains. Discharge the excess sodium with saturated ammonium chloride. Allow the ammonia to evaporate spontaneously and partition the residue between ethyl acetate and water. Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:37])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[CH:20]([C:29](O)=[O:30])[NH:19][CH:18]3[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:62][C:63]1[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[CH:65][CH:64]=1>>[C:67]([C:66]1[CH:69]=[CH:70][C:63]([NH:62][C:29]([CH:20]2[NH:19][CH:18]([CH2:32][C:33]([CH3:34])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:37])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:30])=[CH:64][CH:65]=1)#[N:68]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 53.7 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 63 (0.95 g, 1.7 mmol), was reacted with diisopropylethylamine (1.8 g, 14 mmol), diphenylphosphinic chloride (1.6 g, 6.8 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.8 g, 6.8 mmol) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white solid (Yield 0.5 g, 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2C=N[CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].ClC1[N:23]=[C:22]([O:24][CH3:25])C=CN=1>>[CH3:25][O:24][C:22]1[CH:14]=[CH:13][N:12]=[C:11]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[N:23]=1
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Reactant: COc1ccnc(Cl)n1
Product: COc1ccnc(-c2ccc(C)cc2C(=O)O)n1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-chloro-4-methoxypyrimidine. ESI-MS (m/z): 245 [M+1]+.
Reaction SMILES: [N:1]#[N:2].C(OC([NH:13][C@@H:14]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:15]([OH:37])[CH2:16][C@@:17]1([C:34]([NH2:36])=[O:35])[CH2:21][C@@H:20]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][N:18]1[C:30]([CH3:33])([CH3:32])[CH3:31])=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:1]#[N:2].[NH2:13][C@@H:14]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@H:15]([OH:37])[CH2:16][C@@:17]1([C:34]([NH2:36])=[O:35])[CH2:21][C@@H:20]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][N:18]1[C:30]([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(C)(C)C)[C@](C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)(C(N)=O)C1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(C)(C)C)[C@](C[C@@H](O)[C@@H](N)Cc2ccccc2)(C(N)=O)C1
Yield: 99 %

Procedure:
0.22 g of N2 -[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-4(R)-(tert.butoxyformamido)-N1 -tert.butyl-L-prolinamide was dissolved in 10 ml of ethanol and hydrogenated over 0.05 g of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 2 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.17 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-4(R)-(tert.butoxyformamido)-N1 -tert.butyl-L-prolinamide as a gum which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#N)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:25]([O:29]C(N1CCC(NC2N=CC(O)=CN=2)CC1)=O)(C)(C)C.BrCCCOC1CCCCO1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.N1CCC(NC2N=CC(OCC#N)=CN=2)CC1>CN(C=O)C.ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:25][OH:29])=[CH:19][N:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(O)cn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(OCC#N)cn2)CC1
Agent: BrCCCOC1CCCCO1
Agent: N#CCOc1cnc(NC2CCNCC2)nc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: OCCCOc1cnc(NC2CCNCC2)nc1

Procedure:
The compound was prepared in analogy to the synthesis of 4-(5-cyanomethoxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C32/step 1) from 4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C31/step 2) by reaction with rac-2-(3-bromopropoxy)tetrahydro-2H-pyran (commercially available) and potassium carbonate in DMF at 100° C., followed by BOC and THP cleavage with 90% trifluoroacetic acid in dichloromethane at rt for 16 h in analogy to the procedure described for [2-(piperidin-4-ylamino)-pyrimidin-5-yloxy]-acetonitrile (intermediate C32/step 2). MS (ISP): 253.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:23][C:22]3([F:25])[F:24])[C:17]([OH:19])=O)[C:10](=[O:26])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:23][C:22]3([F:25])[F:24])[C:17]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=3)=[O:19])[C:10](=[O:26])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2CC2(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CC2CC2(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
88.0 mg (215 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoic acid (mixture of two racemic diastereomers), 41.6 mg (215 μmol) of tert-butyl 4-aminobenzoate, 30.6 mg (215 μmol) of Oxima and 34.0 μl (215 μmol) of DIC in 2.1 ml of dimethylformamide were reacted according to General Method 5B. Yield: 101 mg (66% of theory)
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:30][CH:29]=[N:28][C:27]=1[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncsc1-c1ccccc1F
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncsc3-c3ccccc3F)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(2-fluoro-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1([OH:40])[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)#[CH:32]>>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3([OH:40])[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:27])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC1(O)CCN(C)CC1
Product: Cc1cc2ccc(C#CC3(O)CCN(C)CC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (79) was prepared by the method of Example 68 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 4-ethynyl-1-methylpiperidin-4-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.77 (d, J=9 Hz, 1H), 7.70 (br s, 1H), 7.58 (m, 3H), 7.41 (d, J=8 Hz, 1H), 7.30 (m, 2H), 5.16 (s, 1H), 3.35 (m, 4H), 2.89 (s, 3H), 2.60 (s, 3H), 2.15 (m, 4H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H35ClNO4: 520.2; found: 520.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:28](B(O)O)=[C:27]([CH3:32])[O:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[C:24]([CH3:23])=[N:25][O:26][C:27]=3[CH3:32])=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 114.7 %

Procedure:
The procedure described for 202 was followed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28 mmol), PdCl2(PPh3)2, (0.020 g, 0.028 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (0.079 g, 0.56 mmol), Na2CO3 (0.060 g, 0.56 mmol), and THF/H2O (5 mL, 4:1). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 0.120 g (78%) of the title compound 206 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 9.28 (s, 1H), 7.28 (d, J=6.00 Hz, 2H), 7.18 (d, J=6.0 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.67 (d, J=6.3 Hz, 2H), 2.37 (s, 3H), 2.23-2.22 (br, m, s, 4H), 1.52 (br s, 8H). LCMS (ESI): m/z 372 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:18][C:19]([OH:21])=[O:20].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:10][CH:9]=2)[C:5]([CH2:18][C:19]([OH:21])=[O:20])=[CH:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1cn(Cc2ccccc2)c2ccc(Br)cc12
Reactant: OB(O)c1ccccc1
Product: O=C(O)Cc1cn(Cc2ccccc2)c2ccc(-c3ccccc3)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 78 except that 2-[5-bromo-1-benzyl-1H-indol-3-yl]acetic acid and phenylboronic acid were used.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1>>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[N:17]=1
Reactant: Cc1cccc(Br)n1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1cccc(C#Cc2c(-c3ccccc3)noc2C)n1
Yield: 60 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-6-methylpyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 83 mg, 60%) which was obtained as a yellow oil. MS: m/e=275.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH:12]=O>CO.[Pd]>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2]
Reactant: COC(C=O)OC
Reactant: CCN(CC)CCN
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCNCC(OC)OC
Temperature: 15 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
A solution of N,N-diethyl-ethylenediamine (150 g) in methanol (500 mL) was treated dropwise rapidly with glyoxal dimethylacetal (60 wt % soln. in water, 225 g) at 10-15° C. After the addition was complete the solution was warmed to 15° C., then to 22° C. and left at this temperature for 16 hr. The reaction mixture was treated with 5% palladium on carbon (Johnson-Matthey type 38H paste, 15 g) and hydrogenated at 6 bar until reaction was complete as judged by GC/MS. The catalyst was removed by filtration and the filtrate evaporated to dryness (toluene azeotrope, 2.5 L), affording 196.2 g of the sub-titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]=O)[CH2:14][O:13][C:12]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:22]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]2[OH:30])[CH2:23]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][N:27]2[CH2:28][CH2:29][C:24]3([CH2:22][CH2:23]3)[C@H:25]([OH:30])[CH2:26]2)[CH2:14][O:13][C:12]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CC=O)N1C(=O)OCc1ccccc1
Reactant: O[C@@H]1CNCCC12CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC[C@H](CCN2CCC3(CC3)[C@H](O)C2)N1C(=O)OCc1ccccc1
Yield: 97.3 %

Procedure:
To a solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid benzyl ester (8.51 g, 30.7 mmol) in dichloromethane (140 mL) were added (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 5.03 g, 30.7 mmol), triethylamine (3.11 g, 30.7 mmol) and sodium triacetoxyborohydride (9.11 g, 43.0 mmol) at room temperature. After 1 h the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane. The aqueous layer was extracted twice with dichloromethane, the combined organic phases were dried (MgSO4), filtered, and evaporated to afford the title compound (11.6 g, 97%). Light yellow gum, MS (ISP)=389.3 (M+H)+.