Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:7]([NH2:9])=[O:8])([O-])=O.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([NH2:13])[CH:12]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(N)cc(N)c1

Procedure:
A solution of 20.5 gm. (0.097 mole) of 3,5-dinitrobenzamide in 450 ml. of an ethyl acetate-ethanol mixture (2:1) is hydrogenated at 3 atmospheres of hydrogen using 1 gm. of 10% palladium on charcoal as catalyst. When absorption of hydrogen is complete, the catalyst is removed by filtration and the filtrate is concentrated to dryness under reduced pressure and the residue recrystallized from water. There is obtained 11.65 gm. (79%) of long yellow needles melting at 108°-9° .
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([I:14])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:6]=[N:7][C:8]=2[C:13]=1[I:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2c(nnn2CC2CC2)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1c(OCc2ccccc2)ccc2c1nnn2CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(Cyclopropylmethyl)-4-iodo-1H-benzotriazol-5-ol (9.01 g, 28.6 mmol) was suspended in degassed N,N-dimethylformamide (75 mL) and treated with benzylbromide (3.74 mL, 31.5 mmol, 1.1 equiv) and potassium carbonate (19.8 g, 143 mmol, 5 equiv). The mixture was placed into a preheated oil bath at 50° C. for 30 minutes, cooled to ambient temperature, and diluted with water (500 mL). The mixture was extracted with dichloromethane (2×500 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:46]=[CH:47][CH:48]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([N:26]5[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]#[N:35])[CH2:28][CH2:27]5)[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:46]=[CH:47][CH:48]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([N:26]5[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][C:34]#[N:35])[CH2:30][CH2:31]5)[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCN(CCC#N)CC5)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#CCCN1CCN(c2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)c2)CC1
Yield: 7.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(4-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl) propanenitrile (86 mg, 0.13 mmol) was hydrolyzed by lithium hydroxide (27 mg, 6.525 mmol), THF/Methanol/water (15/4/4 ml) to yield 5 mg (5.6% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.481 (s, 1H), 8.407-8.402 (d, 1H), 8.198 (s, 1H), 7.955 (s, 1H), 7.674 (s, 1H), 7.48-7.292 (m, 4H), 7.123-6.98 (m, 4H), 5.439 (s, 2H), 3.8-3.4 (m, 4H), 3.2-3.0 (t, 2H). MS: m/z=506.4 (M+1); HPLC: 98.91% in method A.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:23]([NH:22][C:16]3[C:15]([Cl:14])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:21])=[N:12][C:7]=2[CH:6]=1)=[O:13])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
Prepared analogously to example 1c from 3,4-diamino-benzoic acid ethyl ester and 1,3-dichloro-2-thioisocyanato-benzene with DIC in DMF.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1

Procedure:
25 g (0.13 mmol) of (E)-4-hydroxy-3-methoxycinnamic acid was dissolved in 180 ml of methanol, and 5 ml of concentrated sulfuric acid was added thereto. The solution was heated at reflux for 2 hours. The majority of the methanol (about 150 ml) was removed by distillation and the remaining residue was poured into 500 ml of ice-water thereby to effect precipitation of the ester, which was then purified by suction filtration and washed firstly with cold water, then with a small amount of cold saturated sodium bicarbonate solution and finally with cold water and dried at 50° C. under a water-jet vacuum. The product was then purified by chromatography using silica gel (250 g) using dichloromethane:diethyl ether (19:1) as eluant to give 21.78 g of (E)-4-hydroxy-3-methoxycinnamic acid methyl ester in the form of a light-yellow oil.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][S:6][C:7]([CH3:17])([CH3:16])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:15])[CH2:12][CH:13]=O.[CH2:18]([O:20][C:21]([CH:23]=[C:24]([CH3:34])[CH2:25]P(=O)(OCC)OCC)=[O:22])[CH3:19]>CN(C)C=O>[CH3:5][S:6][C:7]([CH3:17])([CH3:16])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:15])[CH2:12][CH:13]=[CH:25][C:24]([CH3:34])=[CH:23][C:21]([O:20][CH2:18][CH3:19])=[O:22]
Reactant: CSC(C)(C)CCCC(C)CC=O
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)SC
Reaction time: 1.5 h

Procedure:
Sodium ethoxide (prepared from 0.2 g. of sodium and 12 ml. of ethanol) is slowly added to a mixture of 1.1 g. of 7-methylthio-3,7-dimethyloctan-1-al, diethyl 3-ethoxycarbonyl-2-methyl-prop-2-enyl-phosphonate (1.6 g.) and 50 ml. of dimethylformamide, with stirring, under nitrogen, at 0°. The reaction is stirred for 1.5 hours after addition is complete and then worked up by extraction with ether to yield ethyl 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]([O:16][CH2:17]C)=[O:15])[CH2:9]1.C[O-].[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]([O:16][CH3:17])=[O:15])[CH2:9]1
Reactant: CCOC(=O)C1C2CC(OC3CCCCO3)CC21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C2CC(OC3CCCCO3)CC21

Procedure:
Gas-liquid chromatographic analysis of the ethyl 3-[(tetrahydropyran-2-yl)oxy]bicyclo[3.1.0]hexane-6-carboxylate (VIII) obtained as above shows that the product is a mixture of exo and endo isomers in a 4:1 ratio. A solution of 2.8 g. of the above mixture of isomers and 150 mg. of sodium methoxide in 50 ml. of methanol is heated under reflux for 4 hours. The mixture then is evaporated, the residue extracted with diethyl ether, and the diethyl ether extract evaporated to give the exo isomer of methyl 3-[(tetrahydropyran-2-yl)oxy]bicyclo[3.1.0]-hexane-6-carboxylate as an oil; b.p. 130°-133° at 1.1 mm.; homogenous as to the exo isomer by gas-liquid chromatographic analysis and by thin layer chromatographic analysis (silica, developed with benzene-ether 5:1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:32]([CH2:44][CH:45]([CH3:47])[CH3:46])[S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C@@H:11]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:10].N1(C(N[C@@H](CC2C3C(=CC=CC=3)C=CC=2)C(O)=O)=O)CCOCC1>>[OH:1][CH2:2][C@@H:3]([N:32]([CH2:44][CH:45]([CH3:46])[CH3:47])[S:33]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)(=[O:35])=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C@@H:11]([NH:23][C:24]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[O:25])[CH2:12][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH:22]=1)=[O:10]
Reactant: COc1ccc(S(=O)(=O)N(CC(C)C)[C@H](CO)CCCCNC(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)N2CCOCC2)cc1
Agent: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Product: COc1ccc(S(=O)(=O)N(CC(C)C)[C@H](CO)CCCCNC(=O)[C@H](Cc2cccc3ccccc23)NC(=O)N2CCOCC2)cc1

Procedure:
The title compound was prepared from (1S)-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-4-methoxy-benzenesulfonamide (XII) (example 35, step B) as described in general procedure B using (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid (see example 32, step A). The final product was obtained in 23% yield (27 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][CH:18]1[NH:23][CH:22]([CH3:24])[CH2:21][N:20]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=2)[CH2:19]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([N:20]3[CH2:19][CH:18]([CH3:17])[NH:23][CH:22]([CH3:24])[CH2:21]3)=[CH:26][CH:27]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N:20]3[CH2:19][CH:18]([CH3:17])[NH:23][CH:22]([CH3:24])[CH2:21]3)=[CH:33][CH:32]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: CC1CN(c2ccc(C(=O)[O-])cc2)CC(C)N1
Product: CC1CN(c2ccc(C(=O)Nc3ccc(C(=O)c4ccc(NC(=O)c5ccc(N6CC(C)NC(C)C6)cc5)cc4)cc3)cc2)CC(C)N1

Procedure:
Compound 319 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-(3,5-dimethylpiperazino)benzoate. [M+H]+ calcd for C39H44N6O3: 645.35; found: 645.16.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[OH:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[N:37]1([CH2:43][CH2:44]O)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:44][CH2:43][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: OCCN1CCOCC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCCN1CCOCC1
Yield: 42.8 %

Procedure:
A solution of (2S)-(5-bromo-2-hydroxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (25 mg, 46 μmol, obtained by following similar procedure described for example 34), 2-morpholin-4-yl-ethanol (1.5 eq., 8.3 μL, 69 μmol) and triphenylphosphine (1.5 eq., 18 mg, 69 μmol) in anhydrous THF (1 mL) was treated with DIAD (1.5 eq., 13.5 μl, 69 μmol) as described in Procedure I. Flash column chromatography (4:1 hexanes:EtOAc) provided 13 mg of the title compound. LCMS for C35H35BrN2O6: 659, 661.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]([F:47])([F:46])[O:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][CH2:31][CH2:32][NH:33][C:34](=O)[C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[F:23][C:24]([F:47])([F:46])[O:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][CH2:31][CH2:32][NH:33][C:34](=[S:10])[C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[CH:28][CH:27]=1
Reactant: O=C(NCCOc1ccc(OC(F)(F)F)cc1)c1c(F)cccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1C(=S)NCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lawesson's reagent (1.94 g) was added to a toluene (20 ml) solution of N-[2-(4-trifluoromethoxyphenoxy)ethyl]-2,6-difluorobenzamide (1.44 g) and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]=[C:7]1[C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:11]2[CH2:12][CH:8]1[CH2:9][CH2:10]2.[S-][C:19]#[N:20].[K+].[H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+]>C1(C)C=CC=CC=1.Cl[O-].[Na+]>[CH3:19][NH:20][C:7]1([CH3:6])[C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:11]2[CH2:12][CH:8]1[CH2:9][CH2:10]2
Reactant: C=C1C2CCC(C2)C12CCCC2
Reactant: N#C[S-]
Agent: COCCO[Al+]OCCOC
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: CNC1(C)C2CCC(C2)C12CCCC2
Temperature: 85 °C
Reaction time: 5.5 h
Yield: 53 %

Procedure:
Sulfuric acid (1.61 mL, 2.96 g, 30.2 mmol) was slowly added to a suspension of 3-methylenespiro[bicyclo[2.2.1]heptane-2,1′-cyclopentane]. (4.80 g, 29.6 mmol) and potassium thiocyanate. (2.96 g, 30.2 mmol) at 50° C. The reaction mixture was then stirred at 85° C. for 5.5 h, cooled to ambient temperature, diluted with toluene (30 mL) and washed with water (20 mL) followed by with saturated aqueous sodium bicarbonate (10 mL). The toluene layer was dried over anhydrous sodium sulfate and filtered To the filtrate was added sodium bis(methoxyethoxy)aluminum hydride (40% solution in toluene, 2 equivalents) and the reaction was stirred at 85° C. for 2 h. The reaction was cooled to 0° C., and a solution of 3N aqueous sodium hydroxide (20 mL) in 5% aqueous sodium hypochlorite (35 mL) was slowly added (drop-wise at intervals). The toluene layer was separated and washed with water (30 mL). The toluene layer was then extracted with 1N aqueous hydrochloric acid (2×10 mL) and discarded. The aqueous hydrochloric acid layer was made basic (to pH 10) by addition of 10% aqueous sodium hydroxide and extracted with diethyl ether. The diethyl ether extracts were concentrated, and the residue was purified by silica gel column chromatography, using 0-40% CMA (chloroform:methanol:30% aqueous ammonia, 9:1:0.1) in chloroform to obtain N,3-dimethylspiro[bicyclo[2.2.1]heptane-2,1′-cyclopentan]-3-amine (1.2 g, 53%) as oil. 1H NMR (CDCl3, 400 MHz): δ 2.28 (s, 3H), 2.24 (bs, 1H), 1.84-1.76 (m, 2H), 1.73-1.68 (m, 1H), 1.62-1.52 (m, 4H), 1.48-1.24 (m, 7H), 1.09-1.05 (m, 1H), 1.04 (s, 3H); LCMS (m/z): 194 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH2:52][OH:53])[CH:46]=3)=[CH:41][C:40]=2[N:54]2[CH:58]=[CH:57][C:56]([CH3:59])=[N:55]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1>CCOC(C)=O.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][NH:14][C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH2:52][OH:53])[CH:46]=3)=[CH:41][C:40]=2[N:54]2[CH:58]=[CH:57][C:56]([CH3:59])=[N:55]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(CO)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(CO)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1

Procedure:
A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.24 mmol) in EtOAc (5 mL) was hydrogenated using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. Purification on normal phase silica gel (EtOAc/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][Br:15])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(-c2ccc(F)cc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2cc(CBr)ccn2)cc1
Yield: 88.7 %

Procedure:
A mixture of 2-(p-fluorophenyl)-4-methyl-pyridine (0.5 g, 2.67 mmol), N-bromosuccinimide (0.48 g, 2.69 mmol), and a catalytic amount of benzoylperoxide in CCl4 (50 ml) was stirred at reflux temperature and irradiated by means of an ordinary 250-W UV lamp for 4 hrs. Afterwards, the reaction mixture was cooled and subsequently triturated with Et2O/petroleum benzine. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give 2-(p-fluorophenyl)-4-bromomethyl-pyridine (0.63 g, 88%, unstable) as a dark yellow oil.
Reaction SMILES: C([O:8][C:9](=[O:20])[CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[NH:17][N:18]=[CH:19][C:13]=2[CH2:12]1)C1C=CC=CC=1>CCO>[NH:17]1[C:14]2[CH2:15][CH2:16][N:11]([CH2:10][C:9]([OH:20])=[O:8])[CH2:12][C:13]=2[CH:19]=[N:18]1
Reactant: O=C(CN1CCc2[nH]ncc2C1)OCc1ccccc1
Solvent: CCO
Product: O=C(O)CN1CCc2[nH]ncc2C1

Procedure:
The final compound was prepared using a method analogous to that of Example 14 step 14.2, (1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)acetic acid benzyl ester replacing intermediate 14.1 and using EtOH instead of MeOH/AcOH. LC-MS (B): tR=0.15 min; [M+H]+: 182.30.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].C(N(CC)CC)C.[C:25]([C:27]1[S:31][C:30]([CH2:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:29][CH:28]=1)#[N:26]>C(#N)C>[C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][CH2:32][C:30]2[S:31][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)[CH2:36][CH2:37]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1ccc(C#N)s1
Reactant: N#Cc1ccc(CCCN2CCNCC2)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)C(C#N)(CCCN1CCN(CCCc2ccc(C#N)s2)CC1)c1ccc(C#N)s1
Temperature: 55 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
In acetonitrile (3 ml) was dissolved 200 mg (0.56 mmol) of 4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl iodide. To the mixture were added 78.0 μl (0.56 mmol) of triethylamine and 178 mg (0.76 mmol) of 1-[3-(5-cyano-2-thieny)propyl]piperazine, followed by stirring at 55° C. After 5 hours, the reaction solution was concentrated, and the residue was subjected to Cromatorex NH silica gel (ethyl acetate/hexane=1/2), to give 243 mg (0.52 mmol, 92.8%) of the title compound as a yellow syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:18]1(=[O:30])=[O:29])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][C:16]=1[N:17]1[S:18](=[O:30])(=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:20](=[O:22])[CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=O)cc2OCc2ccccc2)S1(=O)=O
Agent: CC[SiH](CC)CC
Solvent: c1ccccc1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CO)cc2OCc2ccccc2)S1(=O)=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzaldehyde (1.6 g, 3.6 mmol) in benzene (20 mL), in a pressure vessel, is added triethylsilane (688 μL, 4.3 mmol) and (PPh3)2Re(O)2I (63 mg, 0.072 mmol). The vessel is sealed and the reaction is stirred at 60° C. for 18 h. The reaction is allowed to cool to RT and the solvent is removed under reduced pressure. The crude triethylsilyl ether is immediately dissolved in MeOH (20 mL), treated with TFA (approximately 0.15 mL) and stirred for 1 h. The solvent is removed under reduced pressure and the crude alcohol is purified by silica gel chromatography using a gradient of 0-50% EtOAc/hexane as eluent to afford the title compound as a light grey solid: (M+H)+=466.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.[CH2:18]([S:25][C:26]1[CH:27]=[C:28](/[CH:33]=[CH:34]/[C:35](OCC)=[O:36])[C:29](Cl)=[N:30][CH:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[CH2:18]([S:25][C:26]1[CH:27]=[C:28]2[C:29](=[N:30][CH:31]=1)[N:8]([C:6]1[C:5]([O:9][CH3:10])=[CH:4][C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)=[C:2]([Cl:1])[CH:7]=1)[C:35](=[O:36])[CH:34]=[CH:33]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1N
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)cnc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-n1c(=O)ccc2cc(SCc3ccccc3)cnc21
Temperature: 100 °C
Yield: 68 %

Procedure:
A vial was charged with 2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-amine (302 mg, 1.198 mmol), (E)-ethyl 3-(5-(benzylthio)-2-chloropyridin-3-yl)acrylate (400 mg, 1.198 mmol), Xantphos (69.3 mg, 0.120 mmol), Pd2 dba3 (54.9 mg, 0.060 mmol), cesium carbonate (781 mg, 2.396 mmol) and 1,4-dioxane (4793 pp. The mixture was purged with argon, the vial was sealed, and the reaction was heated at 100° C. for 5 h. Upon cooling to RT, 10 mL methanol was added, and the mixture was heated at 80° C. for 2 h. Upon cooling to RT the mixture was loaded onto silica gel and purified using 0-50% EtOAc/heptane to provide 6-(benzylthio)-1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,8-naphthyridin-2(1H)-one (410 mg, 0.815 mmol, 68.0% yield) as a light orange foamy solid. m/z (ESI) 503.0 (M+H)+.
Reaction SMILES: [C:1]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]([OH:23])=[O:22])=[O:15])([OH:3])=[O:2]>C(O)CCC>[CH2:1]([O:22][C:21]([C@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:4]1[C:1]([O:3][CH2:9][CH2:10][CH2:11][CH3:12])=[O:2])=[O:24])=[O:23])[CH2:4][CH2:8][CH3:7]
Reactant: O=C(O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)O
Solvent: CCCCO
Product: CCCCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
A mixture of 170 mg (0.5 mmol) (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid and 54 mg Amberlite® IR120 in 10 ml butanol were stirred at room temperature for 48 hours. After filtration the solvent was distilled off, the residue was taken up in dichloroethane and extracted with 2% aqueous sodium bicarbonate. The organic extract was dried with sodium sulfate and the solvent was distilled off to yield 70 mg (31%) (R)-1-{6-[(R)-2-butoxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl}-pyrrolidine-2-carboxylic acid butyl ester as alight yellow oil, MS m/e (%): 453 (M+H+, 100).