Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:28][N:25]1[CH2:24][CH2:23][CH:22]([O:21][CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[CH:15]=2)[C:29]2[NH:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)[CH2:27][CH2:26]1
Reactant: CN1CCC(OC(c2cccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2)c2nc3ccccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(OC(c2cccc(C3=CCNCC3)c2)c2nc3ccccc3[nH]2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (407 mg) in dichloromethane (2 mL) is added trifluoroacetic acid (1 mL). After 2 hours at room temperature, volatiles are removed under reduced pressure. The mixture is diluted with water, basified to pH 10 by adding of an aqueous saturated solution of sodium carbonate and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 85/15/1.5) to afford 2-{(1-methylpiperidin-4-yloxy)[3-(1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1H-benzimidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1.[N+]([C:28]1[CH:29]=[CH:30][C:31]([O:34]C2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:32][CH:33]=1)([O-])=O>>[N:32]1[CH:33]=[CH:28][CH:29]=[CH:30][C:31]=1[O:34][C:23]1[CH:24]=[C:19]([CH:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][C:5]4[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=4)[CH:10]=3)[O:15]2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(Oc4ccccn4)c2)O3)nc1

Procedure:
Using the same procedure described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine but replacing 5-nitro-2-(2-phenylchroman-6-yloxy)-pyridine by:
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2([C:26](=[O:28])[NH2:27])[CH2:25][CH2:24]2)[CH2:10][CH2:9]1)=[O:7])C.Cl>C(O)C.O>[C:26]([C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]2)[CH2:24][CH2:25]1)(=[O:28])[NH2:27]
Reactant: CCOC(=O)C1(CCCCCCCCCCCCC2(C(N)=O)CC2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)C1(CCCCCCCCCCCCC2(C(=O)O)CC2)CC1
Reaction time: 8.5 h
Yield: 73.3 %

Procedure:
To a solution of KOH (0.9 g, 16.0 mmol) in 90% ethanol (25 mL) was added product of Example 11 (0.7 g, 1.9 mmol) at 80° C. and stirred at same temperature for 8.5 h. The crude product obtained upon evaporation of the solvent was diluted with water (2.0 mL), acidified to pH=2 (1N HCl), and extracted with ethyl acetate (100 mL×2). The organic layer was dried over sodium sulphate and concentrated. The residue obtained was washed with n-hexane (20.0 mL×2) and dried under high vacuum to give product as white solid 470 mg (73%); mp: 116.6-118.1° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[N:14](C(OC(C)(C)C)=O)[C:13]1=[O:26].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:42])(=O)=O)=CC=1>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:42])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1,3-dioxo-2-(1-tert.-butoxycarbonyl-2,6-dioxopiperidin-3-yl)isoindoline (1.0 g, 2.8 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (1.2 mL, 3.0 mmol, 2.5 M) at -78° C. After 20 minutes, N-fluorobenzenesulfonimide (0-8 g, 3.2 mmol) is added to the mixture. The mixture is allowed to reach room temperature and the solvent then removed in vacuo. The residue is stirred with ethyl acetate (10 mL) and 1N hydrochloric acid (10 mL) for one hour. The organic layer is separated and the solvent removed in vacuo to yield 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which can be further purified through chromatography.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[CH:6]=1.[Cl-].[NH4+].C(OCC)(=O)C.O1CCCC1.CCCCCC>C(O)C.O.C(OCC)C.[Fe]>[NH2:21][C:19]1[CH:18]=[CH:17][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[CH:6]=2)=[C:2]([F:1])[CH:20]=1
Reactant: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Nc1cc(Oc2ccc(N)cc2F)ncn1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-yl]-1,1-dimethylurea (227 mg) was dissolved in ethanol (15 ml)-water (3 ml), and then electrolytic iron powder (230 mg) and ammonium chloride (460 mg) were added thereto, followed by heating under reflux for 30 min. The reaction mixture was cooled down to room temperature, and ethyl acetate-tetrahydrofuran (1:1) was then added thereto, followed by stirring. The reaction mixture was filtered through celite to remove an insoluble portion, which was washed with ethyl acetate and water. The organic layer of the filtrate was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:3). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was suspended in diethyl ether (4 ml)-hexane (4 ml). The solid was filtered and dried under aeration to provide the titled compound (172 mg, 83.4%) as a pale yellow solid.
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[F:16])/[C:5]([C:7]1[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:15])=[N:9][CH:8]=1)=O.[C:18]([N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[CH:30][CH:29]=2)[C@@H:23]([CH3:38])[CH2:22]1)(=[O:20])[CH3:19]>>[C:18]([N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]3[N:37]=[C:5]([C:7]4[N:11]([CH:12]([CH3:13])[CH3:14])[C:10]([CH3:15])=[N:9][CH:8]=4)[C:4]([F:16])=[CH:3][N:36]=3)=[CH:30][CH:29]=2)[C@@H:23]([CH3:38])[CH2:22]1)(=[O:20])[CH3:19]
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Reactant: CC(=O)N1C[C@H](C)N(c2ccc(NC(=N)N)cc2)C[C@H]1C
Product: CC(=O)N1C[C@H](C)N(c2ccc(Nc3ncc(F)c(-c4cnc(C)n4C(C)C)n3)cc2)C[C@H]1C

Procedure:
The title compound was prepared from (2Z)-3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 14; 335 mg, 1.40 mmol) and N-[4-((2S,5R)-4-acetyl-2,5-dimethylpiperazin-1-yl)phenyl]guanidine (Method 35; 737.1 mg, 2.10 mmol) by the procedure of Example 116. The reaction mixture was evaporated under reduced pressure and the residue purified by chromatography on silica gel with MeOH:DCM:EtOAc (1:49.5:49.5 to 6:47:47) to give a solid which required further purification with MeOH:DCM (1:99 to 6:94). After trituration with ether and evaporation of the solvent, the title compound was obtained as a solid which was dried in vac oven overnight at 50° C. (330 mg, 51%). NMR: (500 MHz) 0.95 (d, 3H), 1.33 (d, 3H), 1.40 (d, 6H), 2.03 (s, 3H), 2.50 (s, 3H+DMSO), 3.17 (m, 2H), 3.43 (brs, 1H), 3.83 (brs, 1H), 4.00 (m, 1H), 4.47 (brs, 1H), 5.40 (septet, 1H), 6.83 (d, 2H), 7.32 (d, 1H), 7.37 (d, 2H), 8.35 (d, 1H), 8.7 (s, 1H); 19F NMR (500 MHz MHz) −149.95 (t, 1F); m/z 466.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=CC=[C:12]([C:13]3[CH:18]=CC=CC=3OC)[N:6]2[N:5]=1)=O.CS([C:24]1[N:29]=[CH:28][C:27]2=[CH:30][CH:31]=[C:32]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[N:26]2[N:25]=1)=O>>[CH3:42][S:39]([C:36]1[CH:37]=[CH:38][C:33]([C:32]2[N:26]3[C:27]([CH:28]=[N:29][C:24]([N:5]4[C:18]5[CH:13]=[CH:12][N:6]=[CH:7][C:8]=5[N:9]=[CH:4]4)=[N:25]3)=[CH:30][CH:31]=2)=[CH:34][CH:35]=1)(=[O:41])=[O:40]
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(-n4cnc5cnccc54)nn23)cc1

Procedure:
The compound was made in an analogous fashion to Example 322 replacing 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine to afford 16.33 mg of 1-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-1H-imidazo[4,5-c]pyridine as a lyophilized powder. (M+H)=391.6. 1H NMR (400 MHz, DMSO, d6) δ 9.53 (m, 3H), 8.81 (m, 1H), 8.62 (d, 1H, J=6.32 Hz), 8.54 (m, 2H), 8.18 (m, 2H), 7.81 (d, 1H, J=4.92 Hz), 7.46 (d, 1H, J=4.93 Hz), 2.50 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([CH2:27][CH:28]=[CH2:29])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[OH-:41].[Na+].OO>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([CH2:27][CH2:28][CH2:29][OH:41])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: C=CCc1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCCO)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{2-[6-allyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (400 mg in 7.0 mL of dry tetrahydrofuran) at 0° C. was added 2.18 mL of a 1M solution of borane in tetrahydrofuran dropwise over 10 minutes. After 3 hours, the reaction was treated sequentially with sodium hydroxide (0.84 mL of a 3M solution) and hydrogen peroxide (0.29 mL of a 30% solution) and the mixture allowed to warm to room temperature. After 2 hours the mixture was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 8:2; then 7:3; then 3:2; then 1:1) gave the title compound (253 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([O:18]C)[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[BrH:23]>C(O)(=O)C>[BrH:23].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([OH:18])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:21][CH:22]=1
Reactant: COc1cc2c(cc1O)CCNC2COc1ccc(Cl)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cc2c(cc1O)C(COc1ccc(Cl)cc1)NCC2
Temperature: 100 °C

Procedure:
A mixture of 1-(4-chlorophenoxy)methyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (100 mg), 47% hydrobromic acid (3 ml) and acetic acid (1.5 ml) was heated at 100°C in an oil bath for 4.5 hours, and to the mixture was further added 47% hydrobromic acid (0.5 ml), and the mixture was continuously heated for 0.5 hour. After the reaction, the solvent was distilled off under reduced pressure. The amorphous residue was dissolved in acetone, and to the solution was added ether, and the mixture was allowed to stand. The precipitated crystals were collected by filtration to give 1-(4-chlorophenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (97 mg), mp 232° to 233°C. The product was identified with a sample by I.R. spectrum and N.M.R. spectrum.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:41])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH:27]([OH:39])[CH2:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH2:25][CH3:26])[C:5]1=[O:40])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([C@@:4]1([CH3:41])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH:27]([OH:39])[CH2:28][CH2:29][CH2:30][OH:31])[CH2:25][CH3:26])[C:5]1=[O:40])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)CCCO[Si](C)(C)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)CCCO)C1=O

Procedure:
A solution of (3S,5R,6S)-3-allyl-1-((3S)-7-(tert-butyldimethylsilyloxy)-4-hydroxyheptan-3-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (127 mg, 0.21 mmol; Example 221, Step A) in THF (1.5 mL) was treated with tetrabutylammonium fluoride (0.62 mL 1M in THF, 0.62 mmol) at ambient temperature for 1.5 hours. The solvent was removed under vacuum. Purification by silica chromatography eluting with ethyl acetate/hexane provided the title compound as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[C@H:16]([N:18]2[CH2:23][CH2:22][C:21]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[C@@H:16]([N:18]2[CH2:23][CH2:22][C:21]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC(O)(c2ccccc2)CC1
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Product: C[C@@H](C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC(O)(c2ccccc2)CC1

Procedure:
(2R)-1-(4-benzyloxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanone may be similarly prepared using di-benzoyl-L-tartaric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:21]#[N:22].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][N:16]=[C:17]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:21]#[N:22]
Reactant: CN(C)CC[O-]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1cc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2cn1
Yield: 59 %

Procedure:
To 250 mg of 4-(2,4-dichloro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 186 mg (59%) of 4-(2,4-dichloro-phenylamino)-6-(2-dimethylamino-ethoxy)-[1,7]naphthyridine-3-carbonitrile as a yellow solid: melting point 75-9° C.; mass spectrum (m/e): M+H 401.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:35]=[CH:34][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19]4([CH:32]=[CH:31][C:30](=[O:33])[CH:29]=[CH:28]4)[N:18]=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]>ClC1C=CC(Cl)=CC=1Cl.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]4[CH:32]=[CH:31][C:30](=[O:33])[CH:29]=[CH:28][C:19]4=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)[CH2:13][CH2:12]2)=[CH:34][CH:35]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CN2CCN(C3=NC4(C=CC(=O)C=C4)C(c4ccccc4)=C3)CC2)cc1
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CN2CCN(c3cc(-c4ccccc4)c4ccc(=O)ccn34)CC2)cc1
Yield: 46 %

Procedure:
A solution of 2-[4-(4-ethoxycarbonylbenzyl)-1-piperazinyl]-4-phenyl-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (12.4 g) in 1,2,4-trichlorobenzene (250 cc) is heated for 11 hours to a temperature of about 210° C. After evaporation to dryness under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C., the residue obtained is dissolved in methylene chloride (250 cc) and the solution is poured into silica (400 g ) contained in a column 6 cm in diameter. Elution is first performed with methylene chloride (2 liters and the corresponding eluates are rejected. Elution is then performed with a mixture of methylene chloride and methanol (99:1 by volume) (5 liters) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. After recrystallization of the residue in ethanol (120 cc), 3-[4-(4-ethoxycarbonylbenzyl)-1-piperazinyl]-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (5.7 g), m.p. 129° C., is obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:12]1[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH2:5]([C:12]1[C:17](=[O:18])[C:16]([N+:1]([O-:4])=[O:2])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCc1c(C)[nH]c(C)cc1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCCCCc1c(C)[nH]c(C)c([N+](=O)[O-])c1=O
Temperature: 80 °C

Procedure:
Premixed nitric acid (d 1.5, 0.15 g) and sulfuric acid (0.05 g) was added dropwise at 5-10° C. to 3 (94 mg) in sulfuric acid (d 1.64, 0.5 g). The mixture was heated at 80° C. for 1 hr then cooled and added to ice. Saturated aqueous sodium carbonate was added until effervescence ceased. The mixture was extracted with portions of ethyl ether. The combined organic phase was dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue. Elution with hexane/ethyl acetate gave 3-heptyl-2,6-dimethyl-5-nitropyridin-4(1H)-one (13) as a yellow oil: yield 76 mg (67%); silica gel TLC Rf 0.45 (1:1 hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.77-0.81 (m, 3H), 1.19-1.27 (m, 10H), 2.29 (s, 3H), 2.35 (s, 3H) and 2.44-2.47 (m, 2H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.N1C=CC=CC=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:2]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Oc2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
A mixture of m-tolylboronic acid (0.164 g; 1.20 mmol), copper acetate (0.219 g; 1.20 mmol), pyridine (0.097 mL; 1.20 mmol) and ethyl 3-hydroxybenzoate (0.100 g; 0.602 mmol) in dichloromethane (5 mL) was stirred at room temperature under nitrogen for 24 hours. The reaction mixture was filtered through celite, concentrated under reduced pressure and the residue purified by column chromatography on silica (eluent 2 to 20% ethyl acetate in heptane) to yield 0.084 g (54%) of the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([C:4]1([NH2:18])[CH2:9][CH2:8][CH:7]([O:10][Si](C(C)(C)C)(C)C)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].Cl>C(OCC)C>[CH2:1]([C:4]1([NH2:18])[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(N)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Product: C=CCC1(N)CCC(O)CC1
Reaction time: 0.5 h

Procedure:
The crude 1-allyl-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamine (16, step a) was dissolved in 100 mL of diethyl ether. Then, 100 mL of 1N aqueous HCl were added dropwise and the resultant biphasic mixture was stirred for 30 min. The layers were separated, the aqueous layer was washed with diethyl ether and the pH adjusted to pH8 by the addition of solid sodium hydroxide. The suspension was then extracted with a 3:1 mixture of dichloromethane and 2-propanol and the combined organic extracts were concentrated in vacuo to afford 0.54 g of the title compound as mixture of diastereomers (1.5:1). Rt=0.15 min, 0.27 min (Method C). Detected mass: 156.2 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=O)[C:12]([O-:14])=[O:13])=[CH:2]1.[As](=O)([O-])([O-])[O-].[Na+].[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)C[N:26](CC(O)=O)CC(O)=O.B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>>[NH2:26][C@@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: O=C([O-])C(=O)Cc1c[nH]c2ccccc12
Agent: O=[As]([O-])([O-])[O-]
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Product: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
The extent of reaction was followed by measuring the amount of indole-3-pyruvate formed using the following assay: to 5 μl, 10 μl and 20 μl of reaction mix, 200 μl of the following solution was added: 0.5 mM sodium arsenate; 0.5 mM EDTA; and 50 mM sodium tetraborate (pH 8.5). Absorbance of the indole-3-pyruvate enol-borate complex at 325 nm was compared to a standard curve of indole-3-pyruvate prepared in the same solution.
Reaction SMILES: C([O:5][C:6]([CH2:8][S:9][C:10]1[N:11]=[C:12]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]3[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=3)[CH:27]=[CH:26][N:13]2[C:14](=[O:25])[C:15]=1/[CH:16]=[CH:17]/[C:18]([O:20]C(C)(C)C)=[O:19])=[O:7])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]([CH2:8][S:9][C:10]1[N:11]=[C:12]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]3[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=3)[CH:27]=[CH:26][N:13]2[C:14](=[O:25])[C:15]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])([OH:7])=[O:5]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(SCC(=O)OC(C)(C)C)nc3c2)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(SCC(=O)O)nc3c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.2 %

Procedure:
The tert-butyl (E)-3-{2-(tert-butoxycarbonylmethylthio)-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (19 mg) obtained in (B) was dissolved in methylene chloride (2 ml), added with triethylsilane (0.5 ml) and trifluoroacetic acid (0.5 ml), and then the mixture was stirred at room temperature for 5 hours. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (4 mg) as yellow powder.