Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.I[C:34]1SC2C(C#N)=CC=CC=2[N:38]=1>>[NH2:28][C:12]1[C:11]([C:8]2[S:9][C:10]3[C:2]([C:34]#[N:38])=[CH:3][CH:4]=[CH:5][C:6]=3[N:7]=2)=[CH:16][C:15]([C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:21]=2)=[CH:14][N:13]=1
Reactant: N#Cc1cccc2nc(I)sc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Product: N#Cc1cccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc12

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-1,3-benzothiazole-7-carbonitrile and conducting the Suzuki coupling at 55° C. for 3 h, the title compound was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 3.05-3.18 (m, 2H), 3.37-3.44 (m, 2H), 3.77 (brs, 2H), 4.45-4.54 (m, 1H), 7.51 (brs, 1H), 7.75-7.78 (m, 1H), 8.07 (d, J=7.2 Hz, 1H), 8.10 (s, 1H), 8.44-8.48 (m, 3H), 8.58 (brs, 1H), 8.88 (brs, 1H), 9.10 (brs, 1H). MS(ES+): m/z=402.13 (100) [MH+]. HPLC: tR=2.06 min (ZQ3, polar—5 min).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(Cl)c3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and 3-chloro-phenylhydrazine according to the method described for example 43. MS: M=427.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13](C(C4C=CC=CC=4)=O)[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:24]=1.C(OCC)(=O)C.[ClH:31]>C(O)(=O)C>[ClH:31].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)=[CH:8][S:7][C:6]=2[CH:24]=1
Reactant: O=C(c1ccccc1)N1CCC(c2csc3cc(F)ccc23)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(C3CCNCC3)csc2c1
Yield: 89 %

Procedure:
A solution of (4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl) phenylmethanone (6.5 g, 19 mmol) in acetic acid (100 mL) and concentrated hydrochloric acid (100 mL) was stirred at 90° C. for 10 h. To a solution of reaction mixture was added ethyl acetate. The precipitated crystals were collected by filtration and washed with ethyl acetate to give 4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride (4.8 g, 89%) as yellow crystals.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:61])[CH2:7][N:8]([CH2:55][C:56]([O:58]CC)=[O:57])[C:9](=[O:54])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[CH:12][C:11]=1[O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:42][CH:41]=1)C>>[C:56]([CH2:55][N:8]([C:9](=[O:54])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[CH:12][C:11]=1[O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:42][CH:41]=1)[CH2:7][C:6]([OH:61])=[O:5])([OH:58])=[O:57]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCOc2ccc(OCc3ccccc3)cc2)c(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCOc2ccc(OCc3ccccc3)cc2)c(C(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 79 %

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[5-(octadecyloxy)-2-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoyl] glycine ethyl ester under conditions described in Example 81 gave N-(carboxymethyl)-N-[5-(octadecyloxy)-2-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoyl]glycine (79% yield, mp 70°-74° ).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:16])([CH3:15])[C:10]1[O:11][CH:12]=[CH:13][N:14]=1)([CH3:6])([CH3:5])[CH3:4].C([Li])(C)(C)C.CN(C)[C:24](=[O:26])[CH3:25].[NH4+].[Cl-]>C1COCC1.CCCCC.O>[C:3]([SiH2:7][O:8][C:9]([CH3:16])([CH3:15])[C:10]1[O:11][C:12]([C:24](=[O:26])[CH3:25])=[CH:13][N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ncco1
Reactant: CC(=O)N(C)C
Agent: N#N
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(=O)c1cnc(C(C)(C)O[SiH2]C(C)(C)C)o1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazole (480 mg, 2.25 mmol) in dry THF (11.0 mL) was treated at −78° C. with a solution of t-butyllithium (1.83 mL of a 1.6M solution in pentane, 2.93 mmol) while keeping the temperature below −70° C. The reaction mixture was then stirred for 1 h at −40° C. N,N-Dimethyl-acetamide (0.42 mL, 4.50 mmol) was added dropwise to the reaction mixture at −78° C. and the reaction mixture was allowed to warm to rt and stirred for 2 h at rt. Water (20 mL) followed by sat. aq. NH4Cl (15 mL) were added. The aq. layer was extracted with EA (2×20 mL) and the combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (4:1 hept-EA)=0.25. LC-MS-conditions 02: tR=1.05 min; [M+H]+=256.47.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:16][CH:14]1[CH2:15][N:12]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:13]1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OC1CNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cncc(N2CC(O)C2)c1
Temperature: 85 °C
Yield: 13 %

Procedure:
A mixture of methyl 5-bromonicotinate (2.00 g, 9.26 mmol), azetidin-3-ol (1.01 g, 9.26 mmol), Cs2CO3 (9.06 g, 27.8 mmol), BINAP (1.15 g, 1.85 mmol) and Pd(OAc)2 (0.44 g, 1.85 mmol) in dry dioxane (115 mL) was heated overnight at 85° C. under N2 atmosphere. The resulting mixture was filtrated, concentrated under reduced pressure and purified by prep-HPLC to give compound 11a (250 mg, 13%) of as a yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[CH:30]O)[C:23](=[O:29])[NH:24]2>>[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[CH:30][NH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:17][CH:16]=1)[C:23](=[O:29])[NH:24]2
Reactant: Nc1ccc(OCCCCN2CCCCC2)cc1
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Product: Cc1cccc2c1C(=CNc1ccc(OCCCCN3CCCCC3)cc1)C(=O)N2
Yield: 53.2 %

Procedure:
In a manner similar to that described in Example 231, 4-(4-Piperidin-1-yl-butoxy)-phenylamine (1.19 g, 1.1 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.79 g, 4.5 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (0.97 g, 53%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[OH:17])=[N:8][C:7]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Cl[CH:33]([F:35])[F:34]>O>[F:34][CH:33]([F:35])[O:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:18][C:7]=2[N:8]=1
Reactant: FC(F)Cl
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.50 g of 4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol, 1.23 g of potassium carbonate and 14 ml of DMF was stirred while heating at 70° C. for three hours with chlorodifluoromethane gas injected. By stopping injection of gas, the mixture was cooled to room temperature and allowed to stand overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.11 g of 2-(3-difluoromethoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 126”).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][N:20]4[CH3:23])=[CH:15][C:14]=3[O:24][CH3:25])[CH2:7][CH2:6]2)[O:4]CC1.C(=O)(O)[O-].[Na+]>Cl.O1CCCC1>[CH3:25][O:24][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)[N:20]([CH3:23])[CH2:19][CH2:18][CH2:17]2
Reactant: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)N(C)CCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1CCN1CCC(=O)CC1)N(C)CCC2
Temperature: 70 °C
Reaction time: 7 h
Yield: 99.7 %

Procedure:
100 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 6 ml of 2 N hydrochloric acid-tetrahydrofuran (1:1). The reaction solution was stirred at 70° C. for 7 hours. The reaction solution was cooled to a room temperature. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 87 mg of 1-(2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidin-4-one. This compound was used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:22]([NH2:24])[CH3:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[N:4][CH:3]=1.[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C.O>C(O)CCC>[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30]([NH:24][CH:22]([C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9][C:10]3[C:5]([CH:6]=2)=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH3:23])[N:29]=[CH:28][N:27]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanamine (300 mg, 0.86 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (135 mg, 0.86 mmol) in n-butanol (5.2 mL) was added diisopropylethyl amine (336 mg, 2.6 mmol) at 25° C. The reaction mixture was stirred for overnight at 110° C. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated it. The residue was purified by column chromatography on neutral alumina using 0-5% MeOH in DCM. It was further purified by reversed-phase HPLC to give 4-amino-6-((1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethyl)amino)-5-pyrimidinecarbonitrile: 1H NMR (400 MHz, DMSO-d6): δ 1.380 (d, 3H, J=6.8 Hz), 3.215 (s, 3H), 5.240-5.310 (m, 1H), 7.256 (br s, 2H), 7.718-7.828 (m, 2H), 7.934-7.950 (m, 3H), 8.123 (dd, 1H, J=1.2 Hz, 7.6 Hz), 8.336 (dd, 1H, J=2.4 Hz, 9.6 Hz). 8.678 (s, 1H), 9.117 (d, 1H, J=2.8 Hz); LC-MS (ESI) m/z 464.2 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH2:21]>>[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CN
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)CNC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and glycine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp=152-153.5° C.). The reaction was monitored by tlc (Rf=0.10 in 505% EtOAc/hexanes).
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH-].[NH4+]>C(#N)C.C(OCC)C>[C:15]1([NH:14][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Nc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccccc1)c1cccc2ccccc12
Temperature: 82 °C
Yield: 82 %

Procedure:
4.77 g of 1-naphthoyl chloride (TCI America) was dissolved in 100 ml of anhydrous acetonitrile. To the solution so formed, 2.28 ml of aniline (Sigma-Aldrich) was added in a dropwise fashion over a period of c.a. 20 min. The reaction was then refluxed for 2 h at 82° C. 100 ml of distilled water and 5 ml of concentrated ammonium hydroxide were added along with 100 ml of diethyl ether in a separatory funnel. The phases were separated and the aqueous phase was washed with 100 ml of dichloromethane. The organic fractions were collected and dried with magnesium sulfate, filtered and the solvent was then removed under reduced pressure to yield a white solid 5.07 g (82%; 20.5 mmol).
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(OC([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=2[NH2:44])[CH2:31][CH2:30]1)=O)(C)(C)C.CCO.CC(O)=O>O>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH:32]2[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]2)=[C:37]([NH:44][C:2]2[C:3]([NH:12][S:13]([C:16]3[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:38]=1
Reactant: COc1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: Cn1cnc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CC2CCNCC2)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cn(C)cn2)c1
Temperature: 90 °C
Yield: 34.6 %

Procedure:
N-(3-chloroquinoxalin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide (1 g; 3.1 mmol; 1 eq) and 4-(2-amino-4-methoxy-benzyl)-piperidine-1-carboxylic acid tert-butyl ester (1.1 g; 3.4 mmol; 1.1 eq) are suspended in water (12.5 mL) and EtOH (12.5 mL) then AcOH (2.5 mL) is added. The resulting suspension is heated up to 90° C. for 3 days. Boc deprotection occurs during the reaction. The solvents are evaporated under reduced pressure and the resulting oily brown residue is taken up in water. An excess triethylamine is added until pH=8 to trap the HCl formed during the reaction. The precipitate is filtered off then washed thoroughly with water until neutral. It is dried under vacuum at 40° C. for 2 days, affording 544 mg (35%) of the title compound as a grey solid. 1H NMR (DMSO-d6) δ 9.35 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.50-7.30 (m, 3H), 7.35-6.97 (m, 3H), 6.48 (dd, J=8.3, 2.7 Hz, 1H), 3.89 (s, 2H), 3.78 (s, 3H), 3.63 (s, 3H), 3.45-3.15 (m, 2H), 2.97-2.78 (m, 2H), 2.65-2.53 (m, 2H), 2.05-1.80 (m, 2H), 1.56-1.32 (m, 2H). HPLC (max plot) 89%; Rt 3.08 min. LC/MS: (ES+) 508.1, (ES−) 506.1.
Reaction SMILES: [CH3:1][C@H:2]([NH:12][CH3:13])[C@H:3]([O:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-].[C-:15]1(C[N+](C)(C)C)[CH:19]=[CH:18][CH:17]=[CH:16]1.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30]>C(#N)C>[C-:15]1([CH2:13][N:12]([C@@H:2]([CH3:1])[C@H:3]([O:10][CH3:11])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:25])[CH:19]=[CH:18][CH:17]=[CH:16]1.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30]
Reactant: CN[C@@H](C)[C@H](OC)c1ccccc1
Reactant: C[N+](C)(C)C[c-]1cccc1
Agent: [Fe+2]
Agent: [I-]
Agent: c1cc[cH-]c1
Solvent: CC#N
Product: CO[C@H](c1ccccc1)[C@H](C)N(C)C[c-]1cccc1

Procedure:
Reaction of (1R,2S)-O-methylephedrine with N-ferrocenylmethyl-N,N,N-trimethylammonium iodide (D. Lednicer and C. R. Hauser, J. Org. Chem., 40 (1960), 31) in acetonitrile gives the intermediate (−)-(1R,2S)-N-(ferrocenylmethyl)-N-methyl-1-methoxy-1-phenyl-prop-2-ylamine.
Reaction SMILES: C([N:8]1[CH2:14][C:11]2([CH2:13][CH2:12]2)[C:10]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:9]1)C1C=CC=CC=1>CCO.[Pd]>[CH2:13]1[C:11]2([CH2:14][NH:8][CH2:9][C:10]32[O:15][CH2:16][CH2:17][O:18]3)[CH2:12]1
Reactant: c1ccc(CN2CC3(CC3)C3(C2)OCCO3)cc1
Agent: [Pd]
Solvent: CCO
Product: C1COC2(CNCC23CC3)O1

Procedure:
10-benzyl-5,8-Dioxa-10-azadispiro[2.0.4.3]undecane (A) (1.0 g, similar prepared according to JMC 37, 3344) was mixed with Pd—C (10%, 600 mg) in EtOH (40 ml) and hydrogenated under H2 at 50 psi for 5 hour. The reaction was filtered through Celite and evaporated to give 5,8-Dioxa-10-azadispiro[2.0.4.3]undecane (B).
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[F:7][C:8]([F:57])([F:56])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:55])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C(N(CC)CC)C>C1COCC1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28]([N:5]4[CH2:6][CH:3]([F:2])[CH2:4]4)[N:27]=3)[C@H:20]2[CH3:55])[CH:10]=[C:9]([C:8]([F:7])([F:57])[F:56])[CH:14]=1
Reactant: FC1CNC1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
3-Fluoroazetidine hydrochloride (159 mg, 1.422 mmol), methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (INTERMEDIATE 46, 350 mg, 0.474 mmol), THF (2.4 mL) and triethylamine (330 μl, 2.369 mmol) were stirred at 100° C. for 10 minutes in the microwave reactor. Once complete, the reaction was partitioned between water and ethyl acetate. The organic was then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by silica gel chromatography, eluting with 25-100% ethyl acetate/hexanes to give the title compound. 1H NMR (CDCl3, 500 MHz): δ 8.21 (d, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.92 (d, 1H), 7.88 (s, 1H), 7.73 (s, 2H), 7.47 (d, 1H), 7.31 (d, 1H), 5.68 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.72 (d, 1H), 4.47 (m, 3H), 4.30 (m, 2H), 4.00 (d, s, 4H), 3.93 (s, 3H), 2.37 (s, 3H), 0.74 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:39])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:21]=2[N:20]([CH3:37])[C:19]1=[O:38])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:39])[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:22]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:21]=3[N:20]([CH3:37])[C:19]2=[O:38])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-F), the title compound was prepared as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21])(O)=[O:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:16]=[C:15]1[C:18]2[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[O:21]1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)c1ccc(NC2OC(=O)c3ccccc32)cc1

Procedure:
The mixture of 17.7 g of ethyl α-(4-aminophenyl)-propionate, 15 g of 2-carboxy-benzaldehyde, 50 mg of p-toluenesulfonic acid and 400 ml of toluene is refluxed for two days on a water trap. After collection of the theoretical amount of water (1.9 ml), it is concentrated and the precipitate formed recrystallized from ethanol, to yield the ethyl α-[4-(3-oxo-isobenzofuran-1-ylamino)-phenyl]-propionate, melting at 136°-139°.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[N:14][N:15]=[C:8]1[CH:7]=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].I([O-])(=O)(=O)=[O:26].[Na+]>[Ru](=O)=O>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:12]=[CH:11][C:10]([N:9]2[CH:13]=[N:14][N:15]=[C:8]2[CH3:7])=[C:5]([CH:4]=1)[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:26]
Reactant: FC(F)(F)c1ccc2c(c1)c(-c1ccccc1Cl)cc1nncn12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-(trifluoromethyl)-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5-(trifluoromethyl)-2'-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: O[C:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].CC[OH:19]>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[O:6][C:2]([CH3:16])([CH3:15])[C:3](=[O:19])[CH:4]=2)=[CH:8][CH:9]=1
Reactant: CCO
Reactant: COc1ccc(C(=O)C#CC(C)(C)O)cc1
Product: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1
Reaction time: 4 h
Yield: 92 %

Procedure:
To a stirred solution of 4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one (6 g, 0.027 mol) in ethanol (100 mL) diethyl amine (2.86 g, 0.027 mol) in EtOH (15 mL) was added dropwise at RT and the reaction mixture was stirred for additional 4 h. The EtOH was then removed and the mixture diluted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (5.5 g, 92%).