Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][N:25]([CH2:27][C:28](O)=[O:29])[CH3:26]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:28](=[O:29])[CH2:27][N:25]([CH3:26])[CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CN(C)CC(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CN(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and dimethylamino acetic acid to yield (3aR,4S,7aR)-4-(2-dimethylamino-acetoxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); Rt 4.592 min; LC-MS Method II
Reaction SMILES: NC1N=CC([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=CC=1OCC1C(F)=CC=C(F)C=1Cl.Br[C:29]1[CH:30]=[C:31]([O:36][CH:37]([C:39]2[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:46])[CH3:38])[C:32]([NH2:35])=[N:33][CH:34]=1.COC(C1C=CC(B(O)O)=CC=1)=O>>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:30][C:31]=1[O:36][CH:37]([C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:46])[CH3:38]
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)cccc1Cl
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(F)ccc(F)c1Cl
Agent: COC(=O)c1ccc(B(O)O)cc1
Product: CC(Oc1cc(-c2ccc(C(=O)O)cc2)cnc1N)c1c(Cl)cccc1Cl

Procedure:
4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid was prepared using the same procedure as 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid from 5-bromo-3-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-2-ylamine and 4-methoxycarbonylbenzeneboronic acid
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:24]2[C:23](=[O:29])[CH2:28][CH2:27][CH2:26][CH:25]=2)=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(-c2cnc(Cl)c(C=O)c2)cc1
Reactant: O=C1C=CCCC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cnc(Cl)c(C(O)C3=CCCCC3=O)c2)cc1
Yield: 91 %

Procedure:
The clear solution of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAc in hexane as eluent, gave pure Baylis-Hillman adduct in 91% yield (3.13 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[O:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1.Cl.CO>CN(C)C=O.C(OCC)(=O)C.CO>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[O:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1ccc(C(F)(F)F)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 2-(bromomethyl)-5-(trifluoromethyl)furan (0.30 g), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate. The obtained crystals were dissolved in aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was treated by silica gel chromatography (ethyl acetate 100%→ethyl acetate:methanol=5:1) to give a yellow solid. The obtained solid was dissolved in methanol, and 2N hydrochloric acid-methanol solution (0.3 ml) was added. The solvent was concentrated under reduced pressure and the residue was crystallized from methanol-ethyl acetate to give the title compound (45 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:27])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([B:18]4[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]4)[CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31].O1CCCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([B:18]4[O:19][C:20]([CH3:25])([CH3:26])[C:21]([CH3:23])([CH3:24])[O:22]4)[CH:16]=3)[NH:11][CH:10]=2)=[O:27])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:31])=[O:32]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a reaction flask, propane-1-sulfonic acid (2,4-difluoro-3-{hydroxy-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methyl}-phenyl)-amide (29, 0.155 g, 0.306 mmol) is combined with 10 mL of tetrahydrofuran and 3 mL of dichloromethane. Dess-Martin periodinane (0.648 g, 1.53 mmol) is added and the reaction is stirred at room temperature for 20 minutes. The reaction is mixed with 1N sodium thiosulfate, extracted with ethyl acetate and the organic layer dried and purified by silica gel column chromatography, eluting with a gradient of 20-100% ethyl acetate in hexanes. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=506.29.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[N:8]=2)[N:3]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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]>[OH:32][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:17]2[S:16][C:15]([NH:14][C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[N:8]=4)[N:3]=3)=[C:19]([C:20]([NH2:22])=[O:21])[CH:18]=2)=[CH:28][CH:27]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Reactant: COc1ccc2nc(Br)ccc2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc2nc(Nc3sc(-c4ccc(C(C)(C)O)cc4)cc3C(N)=O)ccc2n1

Procedure:
The title compound was prepared according to the general procedure in Example 30 (Method B) using 2-bromo-6-methoxy-1,5-naphthyridine (54 mg, 0.22 mmol), 2-amino-5-[4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (60 mg, 0.20 mmol), potassium carbonate (31 mg, 0.22 mmol), X-Phos (49 mg, 0.10 mmol), and tris(dibenzylideneacetone)dipalladium (16 mg, 0.02 mmol) as the starting materials.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[Cl:51][C:52]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:53]=1[O:54][CH:55]1[CH2:56][CH2:57][N:58]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:59][CH2:60]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.038 g, 0.00013 mol) in DMF (2 mL) was added DIPEA (0.0872 g, 0.00067 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0325 g, 0.00017 mol) at ambient temperature. After 2 minutes 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (0.036 g, 0.0001349 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.056 g (91%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 457.14 (M+1)+, 98.34%, 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.44 (m, 2H), 7.38 (m, 1H), 7.24 (m, 1H), 7.1 (s, 1H), 6.8 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])[CH2:25][C:26]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)=O)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:43][OH:44].C([O-])(O)=O.[Na+]>>[C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])[CH2:25][C:26](=[N:43][OH:44])[C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)N[C@H](C)c4ccccc4)cc3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(C[C@@H](c2ccc(-c3ccc(C(=O)N[C@H](C)c4ccccc4)cc3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example example 74, step 7, from 4′-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid ((R)-1-phenyl-ethyl)-amide and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.4:1) as a colorless oil, MS (ESI+): m/z=553.702 ([M+H]+).
Reaction SMILES: [C:1]([N:5]1[CH:9]2[CH:10]=[CH:11][CH:6]1[C:7]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[N:25][CH:26]=1)=[C:8]2[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])([O:3][CH3:4])=[O:2].[C:28](N1C2CCC1C(C1C=CC(Cl)=NC=1)C2S(C1C=CC=CC=1)(=O)=O)(OC)=O.C([Li])CCC.CI>CO.O1CCCC1.O>[C:1]([N:5]1[CH:9]2[CH2:10][CH2:11][CH:6]1[CH:7]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[N:25][CH:26]=1)[C:8]2([CH3:28])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)N1C2CCC1C(S(=O)(=O)c1ccccc1)C2c1ccc(Cl)nc1
Reactant: COC(=O)N1C2C=CC1C(S(=O)(=O)c1ccccc1)=C2c1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N1C2CCC1C(C)(S(=O)(=O)c1ccccc1)C2c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
7-Carbomethoxy-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hept-2,5-diene (23) is hydrogenated in methanol containing 10% Pd-C until both double bonds are saturated. The product, 7-carbomethoxy-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-aza-bicyclo[2.2.1]heptane 39, is dissolved in dry tetrahydrofuran and treated with n-butyl lithium (1.1 eq) at -30 to 0° C., followed by methyl iodide (1-1 eq) in tetrahydrofuran. The reaction mixture is then stirred at room temperature and poured into iced water. The product is extracted with ether and washed with water. After drying and evaporation of the ether solution, the crude product is chromatographed on a silica gel column, using a mixture of petroleum ether and ethyl acetate (3:1 by volume) to yield stereoisomers of 7-carbomethoxy-2-(2-chloro-5-pyridyl)-3-methyl-3-phenylsulfonyl-7-aza-bicyclo[2.2.1]heptane (40). The alkylation products are each treated with sodium amalgam as in Example 30 to remove the phenylsulfonyl group, followed by acid cleavage of the 7-carbomethoxy group as in Example 32 to yield isomeric 3-methyl analogs of compound 8 and 8'.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[CH:11].CCCCCC.C([Li])CCC.Br[CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33]
Reactant: CC/C=C\C/C=C\CCCBr
Reactant: C#CCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\CCCC#CCCOC1CCCCO1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A solution of 1-(tetrahydropyran-2-yloxy)-3-butyne (2.25 g, 14 mmol) in dry THF (15 ml) was treated at -50° C. with n-butyllithium hexane solution (11 ml, 17.5 mmol). After 15 min at -30° C., the mixture was kept at room temperature for 30 min. The mixture was then treated at 0° C. with 5 (3.0 g, 13.8 mmol) dissolved in 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidine (DMPU) (15 mL) during 30 min. The reaction mixture was stirred 12 hr. at room temperature and quenched with saturated NH4Cl solution (30 ml). The product (6) was removed with ether (3×50 ml) and purified by silica-gel flash chromatography (2.2 g, 55% yield). 1H NMR (200 MHz) δ5.36 (m, 4H, CH=CH), 4.64 (m, 1H, CH-2'), 3.81 (m, 2H, CH2 -6' and 1), 3.54 (m, 2H, CH2 -6' and 1), 2.78 (dd, J=6.0, 6.0 Hz, 2H, =CH--CH2 --CH=), 2.47 (m, 4H, CH2 -2, and -5), 2.15 (m, 4H, CH2 -7, and -13), 1.8-1.4 (m, 8H, CH2 -6, -3', -4', and -5'), 0.96 (t, J=7.5, 7.6 Hz, 3H, CH3). 13C NMR (100.6 MHz) δ: 131.8 (12), 128.9 (9, 11), 127.2 (8), 98.7 (2'), 81.0 (3), 76.6 (4), 66.2 (1), 62.2 (6'), 33.4 (2), 30.6 (3'), 28.9 (7), 26.2 (6), 25.5 (14), 25.4 (4'), 20.5 (5), 20.2 (13), 18.3 (5'), 14.3 (10). MS [EI, m/z (%)] 159 (7), 131 (9), 119 (8), 117 (9), 105 (8), 93 (11), 91 (16), 86 (12), 85 (100), 79 (18), 77 (11), 67 (36), 57 (16), 55 (15), 43 (29), 42 (16), 41 (51), 40 (24).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:27][C@@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Product: COc1ccc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)cc1

Procedure:
4′-Methoxy[1,1′-biphenyl]-4-carbaldehyde 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:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14]CC1C=CC=CC=1)[CH3:2].C1CC=CCC=1>[Pd].C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:2]
Reactant: CCOC(=O)C[C@H](C=CCCCCCOCc1ccccc1)c1cnc(C)nc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1=CCC=CC1
Product: CCOC(=O)C[C@H](CCCCCCCO)c1cnc(C)nc1
Temperature: 80 °C
Yield: 43 %

Procedure:
A mixture of 11-5 (1.2 g, 4.9 mmol), 10% Pd/C (1.0 g), 1,4-cyclohexadiene (10 mL), and acetic acid (30 mL) was purged with argon, and then heated at 80° C. for 6 hours. Following cooling, filtration and concentration, the mixture was diluted with ethyl acetate, washed with 10%. K2CO3 and brine, and dried over magnesium sulfate. Evaporation of the solvents gave 0.65 g (88%) of 11-6 as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C@H:10]1[NH:15][C:14](=O)[CH2:13][O:12][CH2:11]1)([CH3:9])[CH3:8]>O1CCCC1>[CH:7]([C@@H:10]1[CH2:11][O:12][CH2:13][CH2:14][NH:15]1)([CH3:9])[CH3:8]
Reactant: CC(C)[C@@H]1COCC(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@@H]1COCCN1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
To ice-cold tetrahydrofuran (8.0 mL) was added lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (R)-5-isopropylmorpholin-3-one (1.7 g, 12.0 mmol) in tetrahydrofuran (8 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added water (1.0 mL), then a 15% solution of sodium hydroxide (1.0 mL), and then water (1.0 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solid with ethyl acetate (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (R)-3-isopropylmorpholine (1.4 g, 93%) as a light yellow oil. 1H NMR consistent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=O.CN(C)C=O.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH2:13][C:14]([Cl:25])=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cc(-c2ncco2)ccc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cc(-c2ncco2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the title compound of Step (B) and 0.048 ml dimethylformamide (DMF) in 19 ml CH2Cl2, oxalyl chloride (2M in CH2Cl2, 2.38 ml, 4.75 mmol) was added. The reaction was stirred at room temperature for 1 hour and concentrated to give the title compound of this step as a gum.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH3:21][C:20]1[C:16]([C:13]2[S:12][C:11]([C:9]([N:5]3[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:4]3)=[O:10])=[CH:15][CH:14]=2)=[N:17][O:18][C:19]=1[C:22]([F:25])([F:24])[F:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](N)C3)s2)noc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](NS(C)(=O)=O)C3)s2)noc1C(F)(F)F
Reaction time: 48 h
Yield: 69.7 %

Procedure:
A suspension of ((R)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 27, 79 mg, 0.2 mmol) in THF (2 mL) was treated with triethylamine (63 μL, 0.45 mmol) followed by methanesulfonyl chloride (19 μL, 0.24 mmol). The reaction mixture was allowed to stir 48 h, evaporated, and chromatographed on silica gel with EtOAc as eluant to afford product as a colorless foam (61 mg, 70%). 1H NMR (CDCl3) 1.68 (m, 2 H), 1.88 (m, 2 H), 2.02 (m, 1 H), 2.33 (d, J=1.8, 3 H), 2.98 (s, 3 H), 3.46 (m, 2 H), 3.57 (m, 1 H), 3.84 (m, 1 H), 4.05 (d, J=12.7, 1 H), 5.45 (d, J=7.5, 1 H), 7.39 (d, J=4.0, 1 H), 7.43 (d, J=3.5, 1 H). 13C NMR 7.9, 23.4, 31.6, 41.9, 47 (br), 52 (br), 49.9, 114.8, 118.7 (q, J=271), 128.2, 129.8, 131.8, 139.6, 155.2 (q, 40), 157.9, 163.5. 19F NMR −63.1. LC/MS 5.82 min, [M+1]+ 438.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([C:16]#[N:17])=[C:14]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:13]([C:24]#[N:25])=[C:12]([S:26][CH2:27][C:28]2[N:29]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[S:31][CH:32]=2)[N:11]=1.[ClH:40]>C(#N)C.[Cu](Cl)Cl>[Cl:40][C:10]1[C:15]([C:16]#[N:17])=[C:14]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:13]([C:24]#[N:25])=[C:12]([S:26][CH2:27][C:28]2[N:29]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[S:31][CH:32]=2)[N:11]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3.85 g (29.55 mmol) of isopentyl nitrite and 3.97 g (29.55 mmol) of copper(II) chloride were initially charged in 40 ml of acetonitrile, and 2.30 g (4.93 mmol) of the compound from Example 45A were added. The reaction mixture was stirred at 60° C. for 3 h. 20 ml of 1N hydrochloric acid were added to the reaction solution. The aqueous phase was extracted twice with in each case 40 ml of ethyl acetate. The combined organic phases were washed in each case once with 20 ml of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed on a rotary evaporator. The residue was purified by column chromatography on silica gel 60 (mobile phase gradient cyclohexane:ethyl acetate=10:1→1:4).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][C:13](=O)[CH2:14][CH2:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>C(O)(=O)C>[CH2:14]([C:13]1[NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[N:12]=1)[CH2:15][CH3:16]
Reactant: CCCC(=O)Nc1c(N)cccc1C(=O)OC
Solvent: CC(=O)O
Product: CCCc1nc2c(C(=O)OC)cccc2[nH]1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
[step 1] To methyl 2-aminobenzoate (1.5 g, 9.92 mmol) was added butyric anhydride (4.9 mL, 29.76 mmol), and the mixture was stirred at room temperature for 2 hr. Under ice-cooling, fuming nitric acid (1.6 mL) was added dropwise to the mixture, and the mixture was stirred at 0° C. for 20 min. The mixture was adjusted to pH 7 with water and 4 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate (150 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40) to give methyl 2-butyramido-3-nitrobenzoate (1.26 g, 48%). [step 2] Methyl 2-butyramido-3-nitrobenzoate (1.65 g, 6.2 mmol) obtained in step 1 was dissolved in methanol (34 mL), and the mixture was stirred in the presence of 10% palladium carbon (413 mg) under a hydrogen atmosphere at room temperature for 6 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give methyl 3-amino-2-butyramidobenzoate (1.46 g, 100%). [step 3] To methyl 3-amino-2-butyramidobenzoate (1.46 g, 6.2 mmol) obtained in step 2 was added acetic acid (9.0 mL), and the mixture was stirred at 80° C. for 1.5 hr. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (300 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 50/50) to give the title compound (1.18 g, 87%).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([P:19](=[O:26])([O:23]CC)[O:20][CH2:21][CH3:22])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:27][CH2:28][CH2:29][CH:4]2[NH:3]1.Cl>[OH-].[Na+]>[O:30]=[S:2]1(=[O:1])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([P:19](=[O:23])([OH:26])[O:20][CH2:21][CH3:22])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:27][CH2:28][CH2:29][CH:4]2[NH:3]1
Reactant: CCOP(=O)(OCC)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOP(=O)(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1

Procedure:
0.66 mmol of the product of Example 52 in 3 ml of 1N NaOH is stirred for 8 h at 70° C. The reaction solution is acidified with 1N HCl and the white precipitate is filtered off to yield the expected product.