Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C@:4]1([CH3:19])[C@:15]([O:17][CH3:18])([CH3:16])[O:14][C@@H:7]2[CH2:8][NH:9][CH2:10][C@H:11]([CH2:12][OH:13])[C@H:6]2[O:5]1.C([O-])([O-])=O.[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:9]1[CH2:10][C@H:11]([CH2:12][OH:13])[C@H:6]2[O:5][C@@:4]([O:3][CH3:2])([CH3:19])[C@:15]([O:17][CH3:18])([CH3:16])[O:14][C@@H:7]2[CH2:8]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CO[C@@]1(C)O[C@@H]2[C@@H](CO)CNC[C@H]2O[C@]1(C)OC
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CO[C@@]1(C)O[C@@H]2[C@@H](CO)CN(Cc3ccccc3)C[C@H]2O[C@]1(C)OC
Temperature: 40 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a solution of 2 (14.85 g, 50.0 mmol) in DMF (200 mL) was added K2CO3 (17.25 g, 125 mmol) and the mixture was stirred at 40° C. for about 4 hrs. At this point, BnCl (5.7 mL, 50.0 mmol) was added in one portion and the reaction was stirred at 40° C. overnight. The solvent was evaporated in vacuo and the residue was suspended in water (600 mL) and HCl was added to dissolve the residue. The solution was washed with Et2O and then basified with Na2CO3. The solution was extracted with EtOAc (2×) and the combined extracts were washed with water and then brine and then dried over MgSO4. The solution was filtered and the filtrate evaporated in vacuo to give the title compound (17.2 g, >95%) as a colorless to very pale yellow viscous oil which was used without further purification. 1H NMR (CDCl3) 7.3 (m, 5H), 3.6-3.8 (m, 2H), 3.5 (s, 3H), 3.4 (t, 1H), 3.26 (s, 3H), 3.268 (s, 3H), 2.9 (m, 2H), 2.2 (br s, 1H), 2.05 (m, 1H), 1.85 (t, 1H), 1.28 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[CH:11]=1>C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]2[NH:1][CH:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:5])([CH3:4])[S:6]2)[CH:11]=1
Reactant: CC(C)(S)C(N)C(=O)O
Reactant: O=Cc1cccnc1
Solvent: CCO
Product: CC1(C)SC(c2cccnc2)NC1C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.9 %

Procedure:
To a suspension of DL-penicillamine (50 g, 335 mmol) in 1:1 aqueous ethanol (500 mL) was added 3-pyridinecarboxaldehyde (36 g, 335 mmol). The resulting clear-yellow solution was stirred for 17 hours at ambient temperature during which time a white precipitate formed. The white solid was filtered off and rinsed with 3:1 H2O, ethanol and ether to give 2-(3-pyridinyl)-5,5-dimethyl-4-thiazolidinecarboxylic acid (51 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([C:23](O)=[O:24])=[CH:18][CH:17]=[CH:16]4)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:33][C:23]([C:19]1[C:20]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:24]
Reactant: O=C(O)c1cccc2cc(Oc3ccnc4cc(Cl)ccc34)ccc12
Reactant: Nc1ccccc1N
Product: Nc1ccccc1NC(=O)c1cccc2cc(Oc3ccnc4cc(Cl)ccc34)ccc12
Yield: 75.5 %

Procedure:
The title compound (33.2 mg, 83% yield) was prepared as a brown solid from 6-(7-chloroquinolin-4-yloxy)-1-naphthoic acid (35.0 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.97 (s, 2H, benzene-NH2), 6.65 (t, J=7.4 Hz, Ar—H), 6.77 (d, J=5.5 Hz, 1H, Ar—H), 6.82 (d, J=7.2 Hz, 1H, Ar—H), 7.00 (t, J=7.0 Hz, 1H, Ar—H), 7.38 (d, J=7.2 Hz, 1H, Ar—H), 7.60 (dd, J=2.6 and 9.2 Hz, 1H, Ar—H), 7.67-7.74 (m, 2H, Ar—H), 7.89 (d, J=7.4 Hz, 1H, Ar—H), 7.94 (d, J=2.4 Hz, 1H, Ar—H), 8.09 (d, J=8.2 Hz, 1H, Ar—H), 8.13 (d, J=2.1 Hz, 1H, Ar—H), 8.41 (d, J=9.0 Hz, 1H, Ar—H), 8.46 (d, J=9.6 Hz, 1H, Ar—H), 8.76 (d, J=5.2 Hz, 1H, Ar—H), 9.85 (s, 1H, benzene-NH). LC-MS (m/z) 440 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[C:11]#[CH:12])[CH3:2]>C(OCC)(=O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]=[CH2:12])[CH3:2]
Reactant: C#Cc1ncccc1C(=O)OCC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: C=Cc1ncccc1C(=O)OCC

Procedure:
3.45 g of 2-ethynylnicotinic acid ethyl ester are dissolved in 100 ml of ethyl acetate, 1 g of Lindlar catalyst (5% Pd/CaCO3 lead poisoned) added and stirred under H2 (1 atm) until H2 absorption ceases. The reaction mixture is filtered through celite and the solvent removed by evaporation to yield the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:43](=[O:44])[NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2C(=O)Nc1ccccc1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 8 h

Procedure:
990 mg tert.butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-acetate are dissolved in 10 ml dichloromethane. 598 mg potassium carbonate and 247 μl phenylisocyanate are added. After stirring overnight the solid is filtered off and washed twice with dichloromethane. The combined organic phases are evaporated down in vacuo and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 10:1 to 1:2).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[F:28][C@@H:29]1[CH2:33][NH:32][C@@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:30]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:32]1[CH2:33][C@@H:29]([F:28])[CH2:30][C@@H:31]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@H]1C[C@H](F)CN1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N2C[C@@H](F)C[C@@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 2.36 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 3.30 g of the compound obtained in Step 13-3 as starting materials, respectively 874 mg (Isomer A: colorless solid) and 1.80 g (Isomer B: colorless solid) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:28][N:29](C1C=CC=CN=1)C.C(=O)([O-])[O-].[K+].[K+].CN>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:29][CH3:28])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCBr
Reactant: CN(C)c1ccccn1
Agent: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNCCOc1ccc(CC(=O)NCCCc2ccc(C)c(C)c2)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.10 g (0.23 mmol) of N-{3-(3,4-dimethylphenyl)propyl}-4-(2-bromoethoxy)-3-methoxyphenylacetamide obtained in step 1 of Example 2 and a catalytic amount of dimethylaminopyridine were dissolved in 50 ml of tetrahydrofuran and 0.048 g (0.35 mmol) of potassium carbonate was added thereto. Then, methylamine was passed through the mixture by bubbling at the temperature ranging from -10° to -20° C. The resultant mixture was stirred at a room temperature for 6 hours. After removing the solvent under a reduced pressure, the residue was subjected to silica gel column chromatography(eluent: ethyl acetate:hexane= 1:1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]([C:12]2[O:23][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]=2)[C@@H:24]([OH:26])[CH3:25])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 29 %

Procedure:
The crude material of N′-((2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 12b) (509 mg, 1.36 mmol) was added to THF (100 mL) stirred at room temperature. PS-BEMP (1.86 g, 4.09 mmol base) was added to the solution followed by slow addition of p-TSCl (286 mg, 1.50 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction, the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to provide the title compound (140 mg). 1H NMR(500 MHz, CDCl3, δ in ppm) 7.93 (d, J=9 Hz, 2H), 7.54 (m, 1H), 7.46 (m, 3H), 6.83 (s, 1H), 6.65 (d, J=9 Hz, 1H), 5.35 (d, J=9 Hz, 1H), 4.70 (d, J=9 Hz, 1H), 4.62 (m, 1H), 3.30 (d, J=5 Hz, 1H), 1.42 (d, J=6 Hz, 3H).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O.CCOC(C)=O>N1C=CC=CC=1>[F:1][CH2:2][CH2:3][O:4][S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCF
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCF)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a stirred solution of 2-fluoroethanol (1.92 g, 29.97 mmol) in dry pyridine (15 ml) under an atmosphere of argon at 0° C. was added p-toluenesulphonyl chloride over 15 min, maintaining the temperature below 5° C. The reaction mixture was then stirred at 0° C. for 4 h, then at room temperature for 12 h. The reaction mixture was cooled to 0° C. and ice (15 g) was added followed by water (40 ml) and EtOAc (50 ml). The organic extract was washed with water (30 ml), 1 M HCl (until aqueous extracts were acidic), 10% sodium carbonate (2×30 ml), brine (40 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give the title compound (5.10 g, 78%) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)=[C:4]([N+:21]([O-])=O)[CH:3]=1.BrC1C(OC)=CC(NCC2C=CC3N=C(SC)SC=3C=2)=C([N+]([O-])=O)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)=[CH:19][CH:20]=1
Reactant: CSc1nc2ccc(CNc3ccc(Br)cc3[N+](=O)[O-])cc2s1
Agent: COc1cc(NCc2ccc3nc(SC)sc3c2)c([N+](=O)[O-])cc1Br
Product: CSc1nc2ccc(CNc3ccc(Br)cc3N)cc2s1

Procedure:
4-Bromo-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine was synthesized as an oil (1 g) using a procedure analogous to that described in Step 2 of Example 41, substituting 4-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline from Step 2 of this Example for 4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline used in Example 41. LCMS (ESI) m/z 379 and 381 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:18].[Na+]>O.[N+]([O-])([O-])=O.[Ag+]>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:18])=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(NCc2ccc(F)cc2)cn1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(NCc2ccc(F)cc2)cn1

Procedure:
4.62 g of 5-(p-fluorobenzylamino)-pyridine-2-carboxaldehyde are added in small portions to the cold stirring mixture consisting of 70.4 g of silver nitrate in 150 ml of water and 33.1 g of sodium hydroxide in 150 ml of water. The mixture is stirred 10 minutes after the last of the aldehyde is added and filtered. The filtrate is cooled, acidified with 12 N hydrochloric acid to a pH=4, filtered and the residue washed with water to yield the 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid melting at 197°-200°. The starting material is prepared as follows:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]1[CH2:24][NH:23][CH2:22][CH:21]([C:25]([F:28])([F:27])[F:26])[CH2:20]1>>[F:26][C:25]([F:28])([F:27])[CH:21]1[CH2:20][CH2:19][CH2:24][N:23]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:22]1
Reactant: FC(F)(F)C1CCCNC1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCCC(C(F)(F)F)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and DL-3-(trifluoromethyl)piperidine (9.2 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (11.8 mg). Calcd for C17H14F6N2O2: 392.0959, found 392.0959.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][C:21]([C:25]([OH:27])=[O:26])=[CH:22]3)=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Si](C=[N+]=[N-])(C)C.CCCCCC>CO.C1(C)C=CC=CC=1>[CH3:28][O:26][C:25]([C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[CH:16][C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:13]=3)=[CH:24]2)=[CH:19][CH:20]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3ccc(C(=O)O)cc3c2)ccn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2ccc(Oc3ccnc(C(=O)OC(C)(C)C)c3)cc2c1
Reaction time: 5 h
Yield: 58.4 %

Procedure:
To a solution of 7-{[2-(tert-butoxycarbonyl)pyridin-4-yl]oxy}-2-naphthoic acid (5.25 g, 14.3 mmol) in MeOH (50 mL) and toluene (50 mL), was added a solution of 2.0M trimethylsilyldiazomethane in hexane (14.3 mL, 28.7 mmol) dropwise. The reaction was allowed to stir for 5 h, after which time 2.0M trimethylsilyldiazomethane in hexane (7.17 mL, 14.3 mmol) was added. Stirring continued for an additional 1 h. The solvents were evaporated and the residue was dissolved in EtOAc and washed with saturated NaHCO3 and brine. The organic solution was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography to give tert-butyl 4-{[7-(methoxycarbonyl)-2-naphthyl]oxy}pyridine-2-carboxylate as an off-white solid (3.18 g, 58.4%). LCMS: (FA) ES+ 380.2.
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:30])=[C:19]([C@@:21]2([CH3:29])[NH:27][C:26](=[O:28])[CH2:25][CH2:24][O:23][CH2:22]2)[CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:31]>O1CCOCC1>[ClH:31].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:30])=[C:19]([C@@:21]2([CH3:29])[NH:27][C:26](=[O:28])[CH2:25][CH2:24][O:23][CH2:22]2)[CH:20]=1
Reactant: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCCC(=O)N1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(N)ccc2F)COCCC(=O)N1

Procedure:
A solution of (R)-3-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-3-methyl-[1,4]oxazepan-5-one (338 mg, 0.84 mmol) in dioxane (5 ml) was treated with hydrochloric acid (1 N, 1.01 ml) at room temperature for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure, the resulting residue suspended in hydrochloric acid (1 N, 3 ml) and extracted with diethylether (2×10 ml). The combined organic layers were washed again with hydrochloric acid (1 N, 3 ml), then the aqueous layers were combined and evaporated at reduced pressure to yield the (R)-3-(5-amino-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one hydrochloride (intermediate C13A) as a light brown foam (225 mg, 97% of theory) which was engaged in the next step without further purification. MS (ISP): m/z=239.3 [M+H]+.
Reaction SMILES: [NH:1]([C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:12]=2[CH2:11]1)=[S:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:24][S:9]/[C:8](=[N:1]\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)/[N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:12]=2[CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nc2c(s1)CN(C(=S)Nc1ccccc1)CC2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1nc2c(s1)CN(/C(=N/c1ccccc1)SC)CC2
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 5-(anilinocarbonothioyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate obtained in step I (1 eq) in acetone, K2CO3 (1.2 eq) was added and the reaction mixture was stirred for 15 min. To this, iodomethane (1.2 eq) was added and the reaction was continued at room temperature for 5 h. Solvent was evaporated and the residue was diluted dichloromethane. It was then washed with water and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the ethyl 5-[(Z)(methylthio)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate.
Reaction SMILES: [H][H].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd]>[CH:3]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: c1ccc(C2CCCCC2)cc1
Temperature: 300 °C
Yield: 79 %

Procedure:
2 g of a hydroalkylation catalyst comprising 0.15 wt % Pd on alumina/MCM49 20/80 wt/wt was sized and loaded into the reactor as described above. The catalyst was activated by ramping its temperature at 60° C./hour heating rate to 300° C. and holding it there for 2 hours in 2028 GHSV of flowing hydrogen at 3.44 bar (50 psig, 344 kPag) total pressure. Other details of the experimental procedure and the reactor were as described above. This reference case was established by running two experiments (A and B) parallel at identical conditions. As the results in Table 1 indicate, the catalyst yielded 35%-37% benzene conversion with 79% cyclohexylbenzene selectivity.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C1(N)CCCCC1.[Cu]I>[CH:3]1([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NC1CCCCC1
Product: O=[N+]([O-])c1ccccc1NC1CCCCC1
Temperature: 25 °C
Yield: 164.1 %

Procedure:
A mixture of 2-chloronitrobenzene (20 g), potassium carbonate (35 g) and copper (I) iodide (1.21 g)in cyclohexylamine (43.6 ml) was heated at 150° under nitrogen for 18 h. The mixture was allowed to cool to room temperature and was adsorbed onto silica. This was chromatographed with hexane-EA (98:2) as eluent to give the title compound (22.94 g) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12](OCC)=[O:13])=[CH:7][C:6]=2[C:5]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:4]=2[N:3]=1.[Li+].[B-](CC)(CC)CC>C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][OH:13])=[CH:7][C:6]=2[C:5]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1cnc2c(N)nc3cc(C)ccc3c2c1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CO)cc12

Procedure:
To a stirred solution of ethyl 5-amino-8-methylbenzo[f][1,7]naphthyridine-2-carboxylate (from the previous step) in THF (0.2 M) cooled in an ice-water bath was added 1 N solution of super hydride in THF (10 eq.). Upon completion of the reaction the reaction was quenched with 1 N HCl, and extracted with EtOAc. Combined organic extracts were concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give (5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)methanol as a white solid. 1H NMR (CDCl3): δ 8.68 (d, 1H), 8.52 (d, 1H), 8.04 (d, 1H), 7.44 (s, 1H), 7.12 (dd, 1H), 6.00 (bs, 2H), 4.90 (s, 2H), 2.45 (s, 3H). LRMS [M+H]=240.1
Reaction SMILES: [ClH:1].C([O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][CH2:19][C:20]2[O:24][C:23]([C:25]([O:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[C:33]([C:38](=[NH:40])[NH2:39])[CH:34]=4)[CH:29]=3)=[O:26])=[CH:22][CH:21]=2)=[O:17])=[CH:11][CH:10]=1)=[O:8])(C)(C)C.C(O)(=O)C.Cl>O>[ClH:1].[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:18][CH2:19][C:20]2[O:24][C:23]([C:25]([O:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[C:33]([C:38](=[NH:39])[NH2:40])[CH:34]=4)[CH:29]=3)=[O:26])=[CH:22][CH:21]=2)=[O:17])=[CH:13][CH:14]=1)([OH:8])=[O:6]
Reactant: CC(C)(C)OC(=O)c1ccc(CC(=O)NCc2ccc(C(=O)Oc3ccc4cc(C(=N)N)ccc4c3)o2)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)Cc4ccc(C(=O)O)cc4)o3)ccc2c1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To 5.4 g of 6-amidino-2-naphthyl 5-(4-t-butoxycarbonylphenylacetylaminomethyl)furan-2-carboxylate hydrochloride was added 8 ml of acetic acid, and hydrogen chloride gas was passed into the mixture for 2 hours while stirring and cooling with ice. The mixture was further stirred for 2.5 hours with water-cooling, the precipitate was collected by filtration and washed twice with 20 ml of acetone. The crystals were dissolved in 20 ml of DMF, then 1 g of active carbon was added to the solution and stirred for 30 minutes while cooling with ice. The insolubles were removed by filtration, the filtrate was added to 250 ml of acetone and stirred for 2 hours at room temperature. The precipitate was collected by filtration to obtain 3.2 g of the intended product.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[N:5]=[C:4]([NH2:13])[N:3]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[N:5]=[C:4]([NH2:13])[N:3]=1
Reactant: Nc1nc(O)cc(-c2nccs2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)cc(-c2nccs2)n1
Temperature: 120 °C
Yield: 60 %

Procedure:
A suspension of the 4-hydroxy-6-(2-thiazolyl)pyrimidine-2-amine (2.64 g, 13.6 mmol) in POCl3 (30 mL) was heated at 120° C. for 3 h, cooled and concentrated in vacuo. The resulting brown solid was added to ice/water (200 g), basified with NH4OH (8 mL), filtered and purified by chromatography [SiO2; EtOAc:isohexane (2:3-1:0)] to give the title compound (1.73 g, 60%) as a pale yellow solid; NMR δH (400 MHz, DMSO) 7.22 (1H, s), 7.40 (2H, br s), 8.01 (1H, d, J 3.2 Hz) and 8.07 (1H, d, J 3.2 Hz); M/Z 213, 215 (M+H)+