Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH:16][C:17](=[O:39])[N:18]([C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][C:27]=2[OH:38])[CH:23]=[CH:24][CH:25]=1)[CH3:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:38][C:27]1[CH:28]=[C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:30]=[CH:31][C:26]=1[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([N:18]([CH3:19])[C:17]([NH:16][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:39])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCc2ccccc2)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 300 μL (2.5 mmol, 2.7 eq) of benzyl bromide and 400 mg (0.93 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 3.9 eq) of potassium carbonate at 90° C. for 3 hours, methyl 3-[2-benzyloxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([N:16]2[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]2)=[O:15])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:9]1[CH:8]=[C:7]([C:6]2[O:5][C:4]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]3)=[O:15])=[CH:3][C:2]=2[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CCN1
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cc(C(=O)N3CCNC(=O)C3)oc2-c2cccc(Cl)c2)c1
Temperature: 120 °C

Procedure:
50.0 mg (0.13 mmol) of the compound from Example 27A are provided in 5 ml of 1,2-dimethoxyethane/water (4:1), 19.8 mg (0.13 mmol) of 3-methoxyphenylboronic acid, 4.4 mg (0.009 mmol) of dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane, 0.9 mg (0.004 mmol) of palladium(II) acetate and 127 mg (0.39 mmol) of cesium carbonate are added and the mixture is heated in a closed glass vessel under microwave irradiation at 120° C. for one hour. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 30.0 mg (56% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]([NH:11][C:12](=O)OC(C)(C)C)([CH3:10])[C:3](=O)[N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>C1COCC1.CCOCC>[CH3:12][NH:11][C:2]([CH3:10])([CH3:1])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNC(C)(C)CN1CCCC1
Temperature: 40 °C

Procedure:
To a solution of tert-butyl 2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-ylcarbamate (Compound F5) (2.696 g, 10.52 mmol) in THF (20 mL) was a 1M LAH in THF (42.1 mL, 42.07 mmol) solution dropwise added (over approximately 10 min) at 0° C. under a nitrogen atmosphere. The resultant mixture was stirred at rt for 1 h and heated at 40° C. over night. The reaction was cooled to 0° C. and Na2SO4×10H2O followed by NaOH (2M, 2 mL) was added. The mixture was diluted with Et2O (100 mL) and the resultant mixture was filtered. The solids were washed with Et2O (3×50 mL). To the filtrate was HCl (1.25 N aq. solution, 15 mL) in EtOH added. The filtrate was concentrated and the residue mixed with EtOH (60 mL). The EtOH was removed under reduced pressure. IPA (30 mL) was added and the mixture sonicated for 2 min. After filtration was the title compound (1.89 g, 96%) obtained as a HCl salt. 1H NMR (400 MHz, CDCl3) δ 1.00, 1.71, 2.29, 2.41, 2.63. Total no of protons: 19.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].O.NN.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>C1(C)C=CC=CC=1>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[NH2:3][C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Agent: O=C(O)/C=C\C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
Crude cis-tert-butyl 2-(1,3-dioxoisoindolin-2-yl)cyclohexylcarbamate (3.90 g) was dissolved in toluene (20 mL) and charged to a round bottom flask. Hydrazine hydrate (0.70 mL) was added and the mixture was heated to 80° C. for 2 h whereupon TLC analysis indicated the reaction was complete. The reaction was cooled to RT and the solids were filtered and washed with toluene (2×5 mL). The filtrates were washed with 2 N NaOH aq (10 mL) and phase separated. The aqueous phase was extracted with toluene (2×5 mL) and the combined organic extracts were washed with 10% HOAc aq (2×10 mL). The combined aqueous washes were basified with 2 N NaOH aq (13 mL). The product was extracted with IPAc (2×10 mL) and the combined organic extracts were washed with water (5 mL). The organic phase was concentrated to dryness to give 0.78 g of crude product. The oil was re-dissolved in IPAc (12 mL), heated to about 75° C., and maleic acid (423 mg) was added. Precipitation of solids occurred immediately and the thick mixture was diluted with IPAc (5 mL). The slurry was cooled to RT and allowed to stand for 20 min. The solids were filtered, washed with IPAc (10 mL), and dried to give a maleic acid salt of the title compound as white crystalline solid (730 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34-1.42 (m, 2H), 1.50 (s, 9H), 1.50-1.64 (m, 6H), 3.22 (m, 1H), 3.83 (br s, 1H), 6.02 (s, 2H), 6.86 (d, J=7.5 Hz, 1H), 7.68 (br s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH2:3]1>N.CO.[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:10]=[C:11]([CH2:12][NH2:13])[CH:14]=[CH:15][CH:16]=2)[CH2:3]1
Reactant: CN1CCCC(Oc2cccc(C#N)c2)C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN1CCCC(Oc2cccc(CN)c2)C1

Procedure:
3-[(1-Methylpiperidin-3-yl)oxy]benzonitrile (623 mg, 2.90 mmol) was dissolved (0.05 M) in NH3 in MeOH (58 ml). Hydrogenation was performed using a Raney-Ni 30×4 mm CatCart (H-Cube, 50 bar, 50° C., 1 ml/min). Evaporation in vacuo yielded the title compound as a colorless oil. Yield: 633 mg (99%). 1H NMR (400 MHz, CDCl3) δ 7.20 (t, 1H, J=7.9 Hz), 6.89-6.83 (m, 2H), 6.79 (dd, 1H, J=8.2 Hz, J=2.2 Hz), 4.37 (m, 1H, J=4.2 Hz), 3.80 (s, 2H), 2.91 (d, 1H), 2.62-2.54 (m, 1H), 2.28 (s, 3H), 2.13 (m, 2H), 1.97 (m, 1H), 1.86-1.76 (m, 1H), 1.69-1.54 (m, 3H), 1.52-1.40 (m, 1H).
Reaction SMILES: [Si]([O:8][C@H:9]([C:48]1[CH:49]=[CH:50][C:51]([OH:59])=[C:52]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:53]=1)[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([C@@H:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:33][CH2:34][N:35]([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH:26]=2)=[CH:16][CH:15]=1)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C.N>O1CCCC1.[Cl-].[Na+].O>[NH3:11].[CH:39]([N:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][C@@H:32]([C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:48]3[CH:49]=[CH:50][C:51]([OH:59])=[C:52]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:53]=3)[OH:8])=[CH:15][CH:16]=2)[CH:30]=[CH:29][C:28]=1[OH:31])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([CH3:41])[CH3:40]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Agent: F
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C

Procedure:
N-{5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}amino)ethyl]-2-hydroxyphenyl}methanesulfonamide (Preparation 15, 190 mg, 0.22 mmol) was dissolved in tetrahydrofuran (5 ml) and N,N-diethylethanamine trihydrofluoride (0.2 ml, 1 mmol) was added dropwise. After 29 hours a mixture of tetrahydrofuran (5 ml) and 880 ammonia (5 ml) were added and after 15 minutes brine was added, the organic layer was separated, dried (magnesium sulphate), filtered, the solvents were removed in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (981210.2 to 92/8/0.8 by volume) to furnish the title compound as a white foam, 90 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:23])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(C(OC1C(OC(C(C)(C)C)=O)=C(I)C=CC=1)=O)(C)(C)C.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47]>C(OC(C)C)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2([OH:23])[CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(O)CCC4)cc3)cc12
Reactant: CS(N)(=O)=O
Agent: CC(C)(C)C(=O)Oc1cccc(I)c1OC(=O)C(C)(C)C
Solvent: CC(=O)OC(C)C
Product: CS(=O)(=O)NC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(O)CCC4)cc3)cc12
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 12.8 %

Procedure:
To a mixture of 6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carbaldehyde (40 mg, 0.123 mmol), Bis(tert-butylcarbonyloxy)iodobenzene (104 mg, 0.256 mmol) in isopropyl acetate (2 mL) was added methanesulfonamide (12 mg, 0.126 mmol). After stirring 5 minutes, Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] (5 mg, 0.007 mmol) was added and heated to 80° C. overnight. The mixture was concentrated to give a crude residue, which was purified by preparative HPLC to afford the title compound (6.6 mg, 13%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH2:11])=[N:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH3:11])=[N:8][CH:9]=1
Reactant: C=Cc1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(N)cn1

Procedure:
10% Palladium-carbon (50% wet, 90 mg) was added to 5-nitro-2-vinylpyridine (450 mg) in ethanol (30 mL), followed by stirring in a hydrogen atmosphere at room temperature for 15 hours. The catalyst was removed from the reaction mixture by filtration. Subsequently, the solvent was evaporated under reduced pressure, to thereby give the title compound as an oily substance (359 mg, 98%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.O.[H][H]>[Pd].CO>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: CN(C)CCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CN(C)CCNc1ccccc1N
Reaction time: 20 h

Procedure:
N-(2-(dimethylamino)ethyl)-2-nitrobenzenamine (2.0 g, 14 mmol) and 10% palladium on carbon, wet, 50% water (3.0 g) were combined under nitrogen. 30 mL MeOH was added via syringe, and the atmosphere was replaced with hydrogen from a balloon. The reaction was stirred rapidly for 20 h, at which point the reaction was flushed with nitrogen, and filtered through a pad of Celite®, and concentrated in vacuo to give N1-(2-(dimethylamino)ethyl)benzene-1,2-diamine as a red-brown solid. This material was used without further purification. MS m/z=180 [M+H]+. Calc'd for C10H17N3: 179.3.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](Cl)=[O:6])[CH3:3].C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:16]=1)(C)(C)C.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]2[CH2:26][CH2:25][N:24]([C:5](=[O:6])[CH2:4][N:2]([CH3:3])[CH3:1])[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CN(C)CC(=O)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCC(c2cccc(N)c2)CC1
Reaction time: 6 h
Yield: 47.8 %

Procedure:
Dimethylamino-acetyl chloride (0.14 g, 0.86 mmol) and (3-piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol) were combined in CH2Cl2 (5 mL) and triethylamine (0.21 g, 2.2 mmol) was added. After 6 h, water (5 mL) was added. The reaction mixture was extracted with CH2Cl2 (3×5 mL) and the combined organic extracts were dried (MgSO4) and concentrated. The compound was found to be unstable on silica and therefore carried on without further purification. (3-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.090 g) (48%) of 1-[4-(3-amino-phenyl)-piperidin-1-yl]-2-dimethylamino-ethanone.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[NH:42][CH2:41][CH2:40][N:39]2[C:43](=[O:46])[CH2:44][CH2:45][C@@H:38]12.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[CH2:41][CH2:40][N:39]4[C:43](=[O:46])[CH2:44][CH2:45][C@@H:38]4[CH2:37]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1CC[C@H]2CNCCN12
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3C(=O)CC[C@@H]3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 19.3 %

Procedure:
A 8 ml sealed vial was charged with 100 mg (0.187 mmol) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO2005/002577), 78.6 mg (0.561 mmol) of (8aS) -hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 52 mg (0.374 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 23 mg of the desired compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:12]([CH3:21])[CH:11]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28][OH:29]>>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[CH2:28][OH:29])(=[O:19])=[O:18])=[C:12]([CH3:21])[CH:11]=1
Reactant: OCC1CCCCN1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of triethylamine (2.5 eq) and 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (13.04 mmol, 1 eq) in MC (10 ml) was added dropwise to a solution of piperidin-2-ylmethanol (13.04 mmol) in MC (30 ml) at 0° C. and the mixture was stirred at 0° C. for 30 min. It was then stirred at room temperature for 14 h, MC (50 ml) was subsequently added to the mixture and the mixture was washed with water and sat. sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography. Yield: 3.2 g (79%)
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([C:17]([OH:19])=O)[CH:5]=1)([CH3:3])[CH3:2].[F:20][C:21]([F:32])([F:31])[C:22]1[N:27]=[CH:26][C:25]([C@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([C:17]([NH:30][C@@H:28]([C:25]2[CH:24]=[N:23][C:22]([C:21]([F:32])([F:31])[F:20])=[N:27][CH:26]=2)[CH3:29])=[O:19])[CH:5]=1)([CH3:2])[CH3:3]
Reactant: C[C@@H](N)c1cnc(C(F)(F)F)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(C)C)n2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C(F)(F)F)nc3)cc(C(C)C)n2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
To a solution of 6-isopropyl-5′-methyl-2,2′-bipyridine-4-carboxylic acid (25.0 mg, 0.07 mmol) in DMF (0.3 mL) were added hydrochloride salt of (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine (22.1 mg, 0.08 mmol), HATU (38.2 mg, 0.10 mmol) and diisopropylethylamine (58.5 μL, 0.34 mmol). The mixture was stirred at ambient temperature. After 20 min, the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (24 mg), HRMS 430.1850 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.96 (s, 2H), 8.48 (s, 1H), 8.43 (d, 8.1 Hz, 1H), 8.37 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.63 (s, 1H), 6.96 (d, J=6.7 Hz, 1H), 5.44-5.35 (m, 1H), 3.24-3.14 (m, 1H), 2.42 (s, 3H), 1.74 (d, J=7.2 Hz, 3H), 1.37 (d, J=6.9 Hz, 6H).
Reaction SMILES: C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:17])=CC=1.[C:30]([NH:33][NH:34][C:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([I:42])[CH:37]=1)(=O)[CH3:31].O>C(OCC)(=O)C>[I:42][C:38]1[CH:37]=[C:36]([C:35]2[S:17][C:30]([CH3:31])=[N:33][N:34]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)NNC(=O)c1cccc(I)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nnc(-c2cccc(I)c2)s1
Temperature: 120 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
Toluene (4.1 mL) and Lawesson's reagent (366 mg, 0.904 mmol) were added to N′-acetyl-3-iodobenzohydrazide (250 mg, 0.822 mmol) obtained in Step 1, and the mixture was stirred at 120° C. for 1 hour. After cooling, water and ethyl acetate were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give 2-(3-iodophenyl)-5-methyl-1,3,4-thiadiazole (150 mg, 60%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][OH:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][CH2:15][O:16][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: COCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of p-toluenesulfonyl chloride (205 g, 1.08 mol) and pyridine (150 mL) is stirred under an argon atmosphere. The temperature is maintained below 5° C. (ice-water bath), while ethylene glycol monomethyl ether (80 ml, 1 mol) is added slowly from a dropping funnel. After the addition is complete, the mixture is stirred for 1 h below 5° C. The mixture is poured into ice-water (1 L) and is extracted with dichloromethane (1.2 l). The organic layer is washed with ice-cold 6 M HCl (3×350 ml), and is reduced to a minimum volume by evaporation in vacuo.
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20][N:21](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8])([O:3][CH3:4])=[O:2]>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20][NH2:21])[CH2:6][C:7]([O:9][CH3:10])=[O:8])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CC(Cc1ccc(OC)cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC(Cc1ccc(OC)cc1CN)C(=O)OC
Yield: 139.8 %

Procedure:
A solution of methyl (±)-3-carbomethoxy-4-[2-bis(tert-butoxycarbonyl)aminomethyl-4-methoxyphenyl]butanoate (12 g) in chloroform (100 mL) and trifluoroacetic acid (50 mL) was stirred under argon at room temperature for 4 hr. The solution was then concentrated under vacuum to give the title compound (10 g, 100%) as a viscous oil: MS (ES) m/e 296.2 (M+H)+.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:9](=[O:11])[CH2:8][N:5]2[CH2:4][CH2:3][O:2][CH2:7][CH2:6]2)[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CN1CCOCC1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CN1CCOCC1
Yield: 25.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-morpholinoacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 116, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-morpholinoacetyl)pyrrolidine-2-carboxamide (9.2 mg, 25.4%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.99 (s, 1H), 7.52-7.60 (m, 2H), 7.29-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.95-7.02 (m, 4H), 4.67-4.71 (m, 1H), 3.74 (m, 1H), 3.42-3.50 (m, 1H), 3.28-3.35 (m, 2H), 3.11-3.28 (m, 4H), 2.56-2.73 (m, 3H), 2.33-2.40 (m, 2H), 2.11-2.28 (m, 2H), 1.88-1.97 (m, 2H). MS (EI) for C30H32FN3O4. found 518.5 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=O)[N:14]=2)=[CH:5][CH:4]=1.[S:17]1[CH2:23][C:21](=[O:22])[N:20]([CH2:24][C:25]([OH:27])=[O:26])[C:18]1=[S:19].[Cl-].[NH4+].N>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[C:23]3[S:17][C:18](=[S:19])[N:20]([CH2:24][C:25]([OH:27])=[O:26])[C:21]3=[O:22])[N:14]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: COc1ccc(Nc2nc(C=O)cs2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(Nc2nc(C=C3SC(=S)N(CC(=O)O)C3=O)cs2)cc1

Procedure:
The reaction described in Example 1 was repeated, but using 1 g of 2-(p-anisidino)thiazole-4-carbaldehyde, 0.8 g of rhodanine-3-acetic acid 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia, and 10 ml of ethanol, giving the title compound as an orange powder.