Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:5]([N:28]2[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[NH:30][C:29]2=[O:36])[O:4]1.N1C(C)=CC=CC=1C.[C:45]([S:49][S:50][CH2:51][CH:52]([NH:66][C:67](=[O:73])[O:68][CH2:69][CH:70]([CH3:72])[CH3:71])[C:53]([NH:55][CH:56]1[CH2:61][CH2:60][N:59]([P:62](Cl)([Cl:64])=[O:63])[CH2:58][CH2:57]1)=[O:54])([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:45]([S:49][S:50][CH2:51][CH:52]([NH:66][C:67](=[O:73])[O:68][CH2:69][CH:70]([CH3:71])[CH3:72])[C:53]([NH:55][CH:56]1[CH2:57][CH2:58][N:59]([P:62]([Cl:64])([O:1][CH2:2][C@H:3]2[O:4][C@@H:5]([N:28]3[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[NH:30][C:29]3=[O:36])[CH2:6][N:7]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:8]2)=[O:63])[CH2:60][CH2:61]1)=[O:54])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)NC1CCN(P(=O)(Cl)Cl)CC1
Reactant: Cc1cn([C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1cn([C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](COP(=O)(Cl)N3CCC(NC(=O)C(CSSC(C)(C)C)NC(=O)OCC(C)C)CC3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 1-((2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (moT(Tr)) (5.576 g, 10.98 mmol) in DCM (100 ml) at 0° C., was added lutidine (1.92 ml, 16.47 mmol) and DMAP (669 mg, 5.5 mmol), followed by the addition of the compound from Example 62 (6.13 g, 12.08 mmol). The reaction was left stirring at RT for 18 h. The title compound was obtained after ISCO purification (50% EtAc/Hexane).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:19])[CH3:4].C(Cl)Cl.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[C:23]([O:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:19])[CH3:4])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(1-hydroxypropan-2-yl)-6-methyl-5-nitroisoquinolin-1 (2H)-one (4.8 g, 0.018 mol) in methylene chloride (100 mL, 2 mol) was added acetic anhydride (7 g, 0.07 mol), triethylamine (10 g, 0.1 mol) and 4-Dimethylaminopyridine (20 mg, 0.0002 mol). The mixture was stirred at room temperature for 1 hour, washed with 1N hydrochloric acid and brine, and dried. The volatiles were removed under reduced pressure and the residue was purified by column chromatography to afford a yellow-brown oil.
Reaction SMILES: N[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:25]=[CH:24][C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2([C:42](F)=[O:43])[CH2:41][CH2:40]2)=[O:38])=[CH:32][CH:31]=1.C(#[N:47])C>>[F:28][C:4]1[CH:3]=[C:2]([N:36]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=2)[C:37]([C:39]2([C:42]([NH2:47])=[O:43])[CH2:41][CH2:40]2)=[O:38])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20](=[O:21])[NH:22][CH3:23])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: O=C(F)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Reactant: CC#N
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)cc1
Temperature: 50 °C
Yield: 64 %

Procedure:
A 20 mL sealable tube was charged with 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-N-methylbenzamide (Example 95, Step A, 0.240 g, 0.610 mmol), 1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride (0.172 g, 0.763 mmol), and acetonitrile (5 mL). The mixture was heated under nitrogen to 50° C. for 12 hours. The reaction was then cooled to room temperature and concentrated to dryness. The crude residue was purified by 3 triturations with hot acetonitrile to obtain product (202 mg, 64%) and as a white solid. LRMS (esi+) 599 m/z (M+1) detected. 1H NMR (d6-DMSO, 400 MHz) δ 10.41 (s, 1H), 10 (s, 1H), 8.55 (m, 2H), 8.20 (s, 1H), 8.00 (m, 5H), 7.64 (m, 2H), 7.52 (m, 2H), 7.16 (m, 2H), 6.65 (m, 1H), 2.82 (d, J=4 Hz, 3H), 1.48 (br s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[N:15]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cccnc1Nc1cccc(Cl)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A mixture of N2-(3-chlorophenyl)pyridine-2,3-diamine (29 mg, 0.13 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (27 mg, 0.15 mmol), HOAt (20 mg, 0.15 mmol), 4-methylmorpholine (32 μL, 0.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) in DCM (5 mL) was stirred at RT for 1 h then left standing at RT for 64 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting {(S)-1-[2-(3-chlorophenylamino)pyridin-3-ylcarbamoyl]ethyl}carbamic acid tert-butyl ester, as a brown oil (44 mg), was dissolved in AcOH (3 mL) and heated at 70° C. for 4 h. After cooling to RT, the volatiles were removed in vacuo. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as an orange/brown oil (35 mg, 72% over two steps). LCMS (Method C): RT 3.34 min [M+H]+ 373.2.
Reaction SMILES: COC([C:5]1[CH2:10][C:9]([C:18]#[N:19])([C:11]2[CH:12]=[N:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:8][CH2:7][C:6]=1[OH:20])=O.[Na+].[Cl-].O>CS(C)=O>[F:17][C:14]1[N:13]=[CH:12][C:11]([C:9]2([C:18]#[N:19])[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:10]2)=[CH:16][CH:15]=1
Reactant: COC(=O)C1=C(O)CCC(C#N)(c2ccc(F)nc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(F)nc2)CCC(=O)CC1
Temperature: 160 °C
Yield: 49989.7 %

Procedure:
To a solution of 5-Cyano-5-(6-fluoro-pyridin-3-yl)-2-hydroxy-cyclohex-1-enecarboxylic acid methyl ester (32 g crude, 0.11 mmol) in DMSO (110 mL) was added NaCl (7.78 g, 0.133 mol) and water (6.5 mL). The reaction mixture was heated at 160° C. for 3 h. It was cooled to room temperature and poured into water (300 mL). The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine (300 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with a gradient elution of between 10-25% EtOAc in petroleum ether) to give the title compound (12 g, 50% over two steps). 1H NMR (CDCl3 400 MHz): ppm 8.34 (d, J=2.4 Hz, 1H), 7.95-7.82 (m, 1H), 7.00-6.92 (m, 1H), 2.95-2.87 (m, 2H), 2.60-2.2. (m, 2H), 2.50-2.40 (m, 2H), 2.28-2.20 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH2:10])[CH2:7][CH:8]=[CH2:9].C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][C:3]([NH:10][CH2:6][CH2:7][CH:8]=[CH2:9])=[O:4]
Reactant: C=CCCN
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCNC(=O)CBr
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
A solution of bromoacetyl bromide (5.21 g, 25.8 mmol) in dichloromethane (5 ml) was added dropwise at −78° C. to a solution of 3-butene-1-amine (2.00 g, 25.8 mmol) and triethylamine (2.56 g, 25.8 mmol) in dichloromethane (20 ml). After 10 min at −78° C., the reaction mixture was allowed to reach room temperature over 2 h, then washed with water. The organic layer was washed with brine, dried (MgSO4), and evaporated to produce the title compound (4.59 g, 94%). Yellow liquid, 1H-NMR (300 MHz, CDCl3): 6.53 (br. s, 1H), 5.85-5.7 (m, 1H), 5.2-5.1 (m, 2H), 3.89 (s, 2H), 3.38 (q, J=6.3, 2H), 2.31 (q, J=6.3, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH3:15]>CN(C=O)C>[CH3:15][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[CH:8]=2)[CH:4]=[CH:5]1
Reactant: Cc1cc(C)c2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2ccn(C)c2c1
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
A solution of the 4,6-dimethylindole (750 mg, 5.2 mmol) in DMF (20 mL) was cooled to 0° C. under nitrogen and treated with 60% sodium hydride in mineral oil (413 mg, 10.3 mmol). After stirring for 15 minutes, iodomethane (0.4 mL, 6.2 mmol) was introduced and the cooling bath was removed (reaction became light purple). After 30 minutes the solution was subsequently quenched with water (5 ml) and then concentrated to reduce the volume of DMF. The reaction was poured into water (200 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×200 mL). The combined organics were washed with water (3×) and then dried (MgSO4), filtered and concentrated. The residue was purified by silica gel flash column chromatography with 10% EtOAc in Hexane as the eluent to afford the title compound (700 mg, 80%) as a white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C:2]([C:5]([NH:7][C@@H:8]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6])([CH3:4])[CH3:3].[CH2:36]([N-:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH:37]([CH3:39])[CH3:38].CSC.C(S)CS.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]([C:5]([NH:7][C@@H:8]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6])([CH3:3])[CH3:4].[CH2:36]([N-:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Agent: CC(C)C[N-]CC(C)C
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: SCCS
Solvent: ClCCl
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 86.2 %

Procedure:
Under N2 atmosphere, the Boc-Aib-DTrp-DPro-diisobutylamide was dissolved in 30 ml of CH2Cl2, 1 ml of methylsulfide and 0.5 ml of 1,2-ethanedithiol were added as scavengers to suppress the indole alkylation of tryptophan. 10 ml of trifluoracetic acid was added dropwise while being stirred. The reaction mixture was stirred for 30 min. Volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH2Cl2 and washed with 10 ml saturated NaHCO3 aqueous solution. The organic layer was removed and the aqueous layer was extracted with CH2Cl2 (3×10 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered and the solvents were removed in vacuum. The residue was further purified by column chromatography (SiO2, CHCl3/MeOH, 85:15) to afford 0.43 mmol (86.2%) of compound (YL-156) which was characterized by TLC and mass spectra M+=497.6.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1Br.BrCC.[Mg].C[O:16][B:17](OC)[O:18]C.Cl>CCOCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[B:17]([OH:18])[OH:16]
Reactant: COB(OC)OC
Reactant: Clc1cc(Cl)c(Cl)c(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CCBr
Product: OB(O)c1cc(Cl)cc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of 2,3,5-trichlorobromobenzene (8.60 g, 0.033 mole) in dry ether (33 ml) and bromoethane (4.73 ml, 7.31 g, 0.067 mole) was added dropwise to a suspension of magnesium turnings (2.80 g, 0.12 mole) in dry ether (21.50 ml) at room temperature. The mixture was refluxed for 0.50 hr and cooled to room temperature. The mixture was then added dropwise under nitrogen to a solution of trimethylborate (5.16 ml, 5.16 g, 0.05 mole) in dry ether (8.60 ml) maintaining the temperature below −60° C. This was warmed to room temperature overnight, then cooled in an ice-bath and treated with 2M hydrochloric acid (10 ml). The ether layer was separated, washed with water (2×20 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 4.57 g (61%), M.p. 257-260° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[CH3:11][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[NH2:1]
Reactant: Nc1ncccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccnc1N
Yield: 78 %

Procedure:
A stirred suspension of 2-amino-nicotinic acid (12.15 g, 87.95 mmol) in a mixture of MeOH (175 mL) and THF (500 mL), under nitrogen at room temperature, was added a solution of trimethylsilyldiazomethane (2M in hexane, 50 mL, 99.5 mmol)) dropwise. After completion of the reaction the volatiles were removed in vacuo and the crude product triturated with disisopropyl ether, filtered and dried to give 2-amino-nicotinic acid methyl ester (10.44 g) as a yellow solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])=[CH:21][N:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:33]1[N:42]=[CH:41][C:40]2[C:35](=[C:36]([F:47])[CH:37]=[C:38]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=2)[C:34]1=[O:48])(=O)C.[OH-].[Na+].C(OCC)(=O)C.O>O1CCOCC1>[C:43]([C:38]1[CH:39]=[C:40]2[C:35](=[C:36]([F:47])[CH:37]=1)[C:34](=[O:48])[N:33]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[O:26])=[CH:21][N:20]=4)[N:15]=[CH:14][N:13]=3)[C:6]=1[CH2:5][OH:4])[N:42]=[CH:41]2)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)ncn2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4cc(Nc5ccc(C(=O)N6CCOCC6)cn5)ncn4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(6-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)pyrimidin-4-yl)benzyl acetate (90 mg, 0.14 mmol) in 1,4-dioxane (5 mL) was added 1N NaOH (10 mL). The mixture was stirred at room temperature for 2 hrs. The mixture was acidified to pH=2, followed by addition of ethyl acetate (50 mL) and H2O (20 mL). The organic phase was washed with H2O (2×20 mL), then brine (2×20 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified by prep-HPLC to afford 6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(6-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)pyrimidin-4-yl)phenyl)-phthalazin-1(2H)-one (30 mg, 36%). 1H NMR (300 MHz, CD3OD): δ 8.98 (s, 1H), 8.52-8.48 (m, 2H), 8.39 (s, 1H), 7.99-7.95 (m, 1H), 7.85 (s, 1H), 7.73-7.68 (m, 5H), 4.55 (s, 2H), 3.72 (brs, 8H), 1.46 (s, 9H). LC-MS (ESI): 610.3, [M+1]+ HPLC: 97.17% at 214 nm, 99.01% at 254 nm, tR=5.761 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.C1N=[CH:17][N:16]([C:19](N2C=NC=C2)=[O:20])[CH:15]=1.C1CCN2C(=NCCC2)CC1.CNC>C(#N)C>[CH3:12][C:8]1([CH3:13])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:19](=[O:20])[N:16]([CH3:17])[CH3:15])[S:3][C:4]=2[C:10](=[O:11])[CH2:9]1
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CN(C)C(=O)Nc1nc2c(s1)C(=O)CC(C)(C)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 2-amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one (151 g, 0.768 mol) in acetonitrile (5 L) are added CDI (249 g, 1.53 mol) and DBU (233 g, 1.53 mol). The reaction mixture is stirred overnight at 100° C. Dimethylamine (310 g, 3.83 mol) is added at RT and the stirring is continued overnight at 100° C. After cooling to RT, the reaction mixture is concentrated in vacuo and the residue is poured into ice water. The pH of the mixture is adjusted to pH 5 with HCl (6 M). The aqueous mixture is extracted with ethyl acetate (4×500 mL). The combined organic layers are washed with brine (500 mL) and dried over anhydrous Na2SO4. The solvent is evaporated in vacuo to give crude product. The crude product is washed with water to give 3-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-1,1-dimethyl-urea (169 g, 82% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[CH:10]=[C:9]([CH:12]([OH:24])[C:13]#[C:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:4][CH2:3]1>CCCCC.ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1([CH3:32])[C:11]2[CH:10]=[C:9]([C:12](=[O:24])[C:13]#[C:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:4][CH2:3]1
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(C(O)C#Cc4ccc(C(=O)O)cc4)ccc32)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCCCC
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)C#Cc4ccc(C(=O)O)cc4)ccc32)cc1
Temperature: 37 °C
Yield: 20 %

Procedure:
0.1 g (0.237 mmol) of 4-[3-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthyl)-3-hydroxyprop-1-ynyl]benzoic acid (described in Example 15d) is dissolved in 2 ml of pentane and 2 ml of dichloromethane, 0.31 g (3.55 mmol) of manganese dioxide is then added and the medium is heated at 37° C. for 24 hours. The medium is filtered and concentrated, and the residue obtained is purified by chromatography (eluent: 85/15 heptane/ethyl acetate). A white solid is obtained (0.02 g; yield=20%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]2[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[O:33][N:32]=2)[CH:30]=1)[C:25](O)=[O:26]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]2[N:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[O:33][N:32]=2)[CH:30]=1)[C:25]([NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:26]
Reactant: COc1cc(C(=O)O)cc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Product: COc1cc(C(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)cc(-c2noc(C(F)(F)F)n2)c1
Yield: 46 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (70 mg, yield 46%): 1H NMR (400 MHz, CDCl3) δ 8.75 (t, J=6.3 Hz, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=7.0 Hz, 2H), 7.63 (m, 1H), 7.57 (m, 1H), 7.38-7.35 (m, 2H), 7.30-7.26 (m, 1H), 3.85 (s, 3H), 3.83 (m, 2H), 3.56 (d, J=6.5 Hz, 2H), 3.41-3.36 (m, 2H), 2.23 (d, J=13.5 Hz, 2H), 2.01-1.94 (m, 2H). MS (ESI) m/z: Calculated for C26H23F3N4O4S: 544.14. found: 545.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C[N:18]([CH:20]=[O:21])C>>[N:1]1([C:20]([NH2:18])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CN(C)C=O
Agent: On1nnc2ccccc21
Product: NC(=O)N1CCCCC1
Reaction time: 5 h

Procedure:
Combine N-(t-butoxycarbonyl)-S-methionine (1.50 g, 6.0 mmol), piperidine (0.51 g, 6.0 mmol) and HOBT (0.91 g, 6.0 mmol) in DMF (40 ml). Add DEC (1.15 g, 6.0 mmol). Stir 5 hours, concentrate in vacuo, and partition between EtOAc and H2O. Wash with aqueous NaHCO3, dry, and concentrate to obtain the piperidine amide as a colorless oil (TLC single spot Rf =0.6 in 5% MeOH/CH2Cl2).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1>C(N)CN.C(O)(C)C>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:3][CH2:4][CH2:5][NH2:6]
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CC(C)O
Solvent: NCCN
Product: NCCNc1nc2ccccc2[nH]1
Yield: 37.4 %

Procedure:
A mixture of 2-chloro-1H-benzoimidazole (1 g) in 4 mL of ethane-1,2-diamine was heated to 100 C for several hours until complete by HPLC. The reaction was allowed to cool and diluted with a mixture of chlororform and isopropanol (3:1). The organic phase was washed with water then dried and concentrated to give 216 mg of product as a solid which was used in the next step without further purification. MS(ES): m/e (El*) 177.1 [M+H]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([N+:12]#[C-:13])([CH3:11])([CH3:10])[CH3:9].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>Cl(O)(=O)(=O)=O>[C:8]([NH:12][C:13]1[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:18]=1[C:17]1[CH:16]=[C:15]([OH:14])[CH:22]=[CH:21][CH:20]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=Cc1cccc(O)c1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1ccccn1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2cccc(O)c2)nc2ccccn12

Procedure:
Compound (10) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml tert-butylisonitrile solution (0.2 M, MC), 0.500 ml 3-hydroxybenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[N:5]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][C:48]([Cl:51])=[CH:49][CH:50]=1>O1CCOCC1>[Cl:51][C:48]1[N:47]=[CH:46][C:45]([CH2:44][NH:43][C:2]2[N:3]=[C:4]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:5]=[C:6]([NH:8][N:9]=[CH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=3)[N:7]=2)=[CH:50][CH:49]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Reactant: NCc1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Nc2nc(NCc3ccc(Cl)nc3)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
{4-Chloro-6-[N′-(4-trifluoromethoxybenzylidene)hydrazino]-1,3,5-triazin-2-yl}-(4-fluoro-3-trifluoromethylphenyl)amine (XXI) (2.54 g, 5.14 mmol) was dissolved in dioxane (25 mL). To this solution was added diisopropylethylamine (1.8 mL, 10.3 mL) followed by 3-aminomethyl-6-chloropyridine (0.52 mL, 5.17 mmol). The reaction was allowed to stir overnight at room temperature. The solvent was removed under vacuum and the residue dissolved in ethyl ether (40 mL). This solution was rinsed with brine, dried over magnesium sulfate, filtered and concentrated to give a dark yellow oil which was purified by column chromatography (silica, gel, hexane/EtOAc), to afford desired product 2 (0.93 g, 32% yield).