Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH:19]([OH:21])[CH2:18][CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:3][CH2:2]1.Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26].CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH:19]([O:21][CH2:24][C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])[CH2:18][CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:2][CH2:3]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: OC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(COC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1)N1CCOCC1
Reaction time: 1 h

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-6-ol (1.58 g) and 4-(chloroacetyl)morpholine (1.36 mL) in THF (30 mL) was added potassium tert-butoxide (1.17 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (1.68 g).
Reaction SMILES: [N:1]1([N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=O)=[CH:14][CH:15]=3)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:35]([Si:39]([CH3:47])([CH3:46])[O:40][CH2:41][C:42]#[C:43][CH2:44][NH2:45])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([Si:39]([CH3:47])([CH3:46])[O:40][CH2:41][C:42]#[C:43][CH2:44][NH:45][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[NH:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([CH:7]=[N:6][N:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)=[N:9][N:10]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[CH:15][CH:14]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCC#CCN
Reactant: C[Si](C)(C)CCOCn1nc(C=Nn2cccc2)c2ccc(Nc3ccccc3C(=O)O)cc21
Product: CC(C)(C)[Si](C)(C)OCC#CCNC(=O)c1ccccc1Nc1ccc2c(C=Nn3cccc3)nn(COCC[Si](C)(C)C)c2c1

Procedure:
Prepared in a similar manner to that described for Example 6 above except using 2-[3-(Pyrrol-1-yliminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzoic acid and 4-(tert-Butyl-dimethyl-silanyloxy)-but-2-ynylamine. 1H NMR (DMSO-d6) δ 10.04 (1H, s 9.16 (1H, t, J=5.3 Hz), 9.10 (1H,s), 8.31 (1H, d, J=8.7 Hz), 7.78 (1H, d, J=7.9 Hz), 7.67 (4H, m), 7.49 (1H, t, J=8.5 Hz), 7.24 (1H, dd, J=1.7, 8.7 Hz), 7.03 (1H, t, J=7.4 Hz), 6.33 (2H, t, J=2.3 Hz), 5.85 (2H, s), 4.83 (2H, s), 4.19 (2H, d, J=5.5 Hz), 3.66 (2H, t, J=7.9 Hz), 0.94 (2H, m), 0.89 (9H, s), 0.13 (6H, s), 0.00 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]5[CH2:25][CH2:24][CH2:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:39]([C:44]1C=CC=C[CH:45]=1)(=O)[CH2:40][CH2:41]C>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[S:19][C:20]([CH2:25][CH3:24])=[C:21]([C:23]5[CH:45]=[CH:44][CH:39]=[CH:40][CH:41]=5)[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CCCC(=O)c1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6c(s5)CCC6)cc4)c4c(N)ncnc43)CC2)CC1
Product: CCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccccc1

Procedure:
The procedure for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine was used to convert butyrophenone (436 μL, 3.00 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 8.9-11.1 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-phenyl-1,3-thiazol-2-amine as a white powder (0.022 g, 0.037 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 9.27 min;
Reaction SMILES: OC1C(C(N[C@H](C2C=CC=CC=2P(C)(=O)OCC)C2C=CC=CC=2)=O)=CN=C(N2C=CC=N2)N=1.[OH:35][C:36]1[C:41]([C:42]([NH:44][C@@H:45]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:46]2[CH:47]=[C:48]([P:52]([CH3:57])(=[O:56])[O:53]CC)[CH:49]=[CH:50][CH:51]=2)=[O:43])=[CH:40][N:39]=[C:38]([N:64]2[CH:68]=[CH:67][CH:66]=[N:65]2)[N:37]=1.[OH-].[Na+]>O1CCOCC1>[OH:35][C:36]1[C:41]([C:42]([NH:44][C@@H:45]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:46]2[CH:47]=[C:48]([P:52]([CH3:57])(=[O:53])[OH:56])[CH:49]=[CH:50][CH:51]=2)=[O:43])=[CH:40][N:39]=[C:38]([N:64]2[CH:68]=[CH:67][CH:66]=[N:65]2)[N:37]=1
Reactant: CCOP(C)(=O)c1cccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)c1
Agent: CCOP(C)(=O)c1ccccc1[C@@H](NC(=O)c1cnc(-n2cccn2)nc1O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1cccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)c1
Temperature: 80 °C

Procedure:
Ethyl ((S)-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(methyl)phosphinate, 25-e, (33 g, 69 mmol) was dissolved in 400 ml of dioxane and treated with 100 ml of 3N NaOH. The mixture was heated at 80° C. for one hour. The mixture was then concentrated under vacuum and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with conc. HCl to pH=1 and the expected product crashed out, 25-1, (11 g of crude). The product can be further purified via prep-HPLC. 1H NMR (300 MHz, DMSO-d6): δ 10.39 (br, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 8.07 (s, 1H), 7.37 (m, 9H), 6.73 (s, 1H), 6.33 (d, 1H), 1.52 (d, 3H). (2M+H)+=899.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[O:16][C:17]=1[CH3:18])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[O:16][C:17]=1[CH3:18]
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2cccc([N+](=O)[O-])c2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1OCc1nc(-c2cccc([N+](=O)[O-])c2)oc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a solution of 3-methoxy-4-{[5-methyl-2-(3-nitrophenyl)-1,3-oxazol-4-yl]methoxy}benzaldehyde (7.51 g) in tetrahydrofuran (100 mL)-ethanol (15 mL) was gradually added sodium borohydride (397 mg) at 0° C. After stirring at room temperature for 6 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (3-methoxy-4-{[5-methyl-2-(3-nitrophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)methanol as colorless crystals (5.92 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [Na].[C:2]([C:4]1[C:5](=[O:22])[NH:6][N:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:3].[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26].O>CN(C)C=O>[CH3:23][N:24]([CH3:28])[C:25]([N:6]1[C:5](=[O:22])[C:4]([C:2]#[N:3])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:7]1)=[O:26]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)n1nc(-c2ccccc2)c(-c2ccccc2)c(C#N)c1=O
Temperature: 110 °C

Procedure:
5.0 grams (0.016 mole) of the sodium salt of 4-cyano-5,6-diphenyl-3-(2H)-pyridazinone was reacted with 1.83 grams (0.017 mole) of dimethylcarbamyl chloride in 50 mls of dimethylformamide. This solution was heated 110° C. for 3 hours, cooled, and poured into excess water. The precipitant solid was filtered, washed with water and air dried. This solid was taken up in chloroform, dried over sodium sulfate and the solvent distilled at reduced pressure. The residual solid was recrystallized from ethyl alcohol to give 3.0 grams of a solid which melted at 231° C. The infrared spectrum showed the methyl group at 3.5μ, the nitrile band at 4.5μ, and two carbonyl bands at 5.8 and 6.0μ.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC(O)=O>CCO.[Pd]>[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:11]1
Reactant: COC(=O)c1cncc(C)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1CNCC(C)C1
Reaction time: 48 h

Procedure:
To a reaction vessel containing methyl 5-methylnicotinate (Alfa Aesar, 1 g, 6.62 mmol) in EtOH (12.03 mL) was added AcOH (1.203 mL). The reaction vessel was purged with nitrogen gas (3×) and 10 weight percent palladium on carbon (0.5 g, 4.70 mmol) was added. The reaction vessel was then purged with hydrogen (balloon, 1 atm) (3×) and maintained under hydrogen while stirring. After 48 hours, the reaction was filtered over Celite® brand filter aid and concentrated under reduced pressure to give methyl 5-methylpiperidine-3-carboxylate. ESI-MS M+H 158.0.
Reaction SMILES: O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:20]([N:22]([CH2:54][CH2:55][O:56][Si](CC)(CC)CC)[C:23](=[O:53])[C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([N:37]2[CH2:42][C@@H:41]([CH3:43])[N:40]([CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=3)[CH2:39][C@@H:38]2[CH3:52])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[CH3:21]>C1COCC1>[CH2:20]([N:22]([CH2:54][CH2:55][OH:56])[C:23](=[O:53])[C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([N:37]2[CH2:42][C@@H:41]([CH3:43])[N:40]([CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=3)[CH2:39][C@@H:38]2[CH3:52])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][CH:25]=1)[CH3:21]
Reactant: CCN(CCO[Si](CC)(CC)CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CCO)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
Tetrabutylammonium fluoride hydrate (1.83 g) was added to the solution of N-Ethyl-4-{(S)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-phenyl-methyl}-N-(2-triethylsilanyloxy-ethyl)-benzamide (3.6 g) in THF (30 mL). The reaction was stirred at room temperature for 90 minutes. The reaction mixture was concentrated. The residual was dissolved in EtOAc (60 mL). The EtOAc solution was washed by H2O (30 mL×3) and brine (30 mL×1), dried by Na2SO4 and concentrated to give crude product (3.3 g), which was purified to give pure N-Ethyl-4-{(S)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-phenyl-methyl}-N-(2-hydroxy-ethyl)-benzamide (2.76 g; 94%). 1H NMR (300 MHz, CDCl3) □ 7.49 (m, 2H), 7.37-7.19 (m, 8H), 7.04 (m, 2H), 6.90 (ddd, 1H, J=8.5, 8.5, 2.0 Hz), 5.16 (s, 1H), 3.87 (m, 3H), 3.69 (m, 2H), 3.36 (m, 2H), 3.18 (d, 1H, J=13.5 Hz), 2.67 (m, 2H), 2.56 (m, 2H), 1.97 (m, 2H), 1.67 (s, 1H), 1.16 (m, 3H), 1.12 (d, 3H, J=6.0 Hz), 1.06 (d, 3H, J=6.5 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][CH:17]2[CH2:16][CH2:15][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([N:13]([CH3:27])[CH3:12])[CH2:19][CH2:18]2)=[CH:2]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(NCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.5 %

Procedure:
292 mg C-(1H-indol-3-yl)methylamine were dissolved in dry 1,2-dichloroethane (15 ml) and THF (5 ml) under argon to give an almost clear solution. After addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg), glacial acetic acid (4 mmol) and sodium triacetoxyborohydride (550 mg), a suspension was present, which was stirred for 72 hours at RT. For working up, water (20 ml) was added to the reaction mixture and the mixture was stirred vigorously for one hour. The organic phase was separated off and the aqueous phase was extracted twice with ether (10 ml) and then rendered strongly alkaline with five molar sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (4×10 ml). A solid, which dissolved in ethyl acetate (50 ml) with warming, thereby precipitated out. The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (382 mg) was recrystallized from a mixture of ethanol (1 ml) and ethyl acetate (5 ml). The precipitate was filtered off with suction and washed with a little cold ethyl acetate. 156 mg N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a cis/trans mixture.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([Br:15])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:18][Mg+].[Br-]>C1COCC1>[Br:15][C:14]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4](=[O:5])[CH3:18])[C:11]=2[S:12][C:13]=1[CH3:16]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cccc2c(Br)c(C)sc12
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c(Br)c(C)sc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
A solution of 3-bromo-2-methyl-benzo[b]thiophene-7-carboxylic acid methoxy-methyl-amide (2.02 g, 6.43 mmol) in THF (65 mL) is cooled to 0° C., treated with CH3MgBr (3.0 M, 2.4 mL, 7.1 mmol). The reaction is stirred at 0° C. for 10 min, then at rt for 10 min. It is cooled to 0° C., quenched with sat. NH4C (10 mL); diluted with H2O (20 mL); treated with 0.1 M HCl (20 mL); extracted with EtOAc (2×40 mL). The combined organic layers are dried with Na2SO4, filtered and concentrated. Purification of the crude material by chromatography gives the title compound (1.39 g, 5.18 mmol, 81%). 1H NMR (CDCl3): δ. 2.58 (s, 3H), 2.75 (s, 3H), 7.53 (t, J=7.9 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H) ppm. ES-MS (m/z): calcd for C11H9BrOS (M+1)+: 270.2. found: 270.0.
Reaction SMILES: [C:1]([C:5]1C=C(C2N=C(C)C3C(C=2)=C[C:17]([O:21]C)=[C:16](OC)C=3)[CH:8]=[CH:9][CH:10]=1)(C)(C)[CH3:2].[CH2:26]1[C:31](=[O:32])N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:16][CH2:17][O:21][C:31]([CH3:26])=[O:32].[CH3:2][CH2:1][CH2:5][CH2:10][CH2:9][CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2cc(-c3cccc(C(C)(C)C)c3)nc(C)c2cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Yield: 168.4 %

Procedure:
3-(3-(tert-Butyl)phenyl)-6,7-dimethoxy-1-methylisoquinoline (400 mg), NBS (223 mg, 1.05 eq.), and AIBN (20 mg, 0.1 eq.) in 7 mL CCl4 were heated at 85° C. for 2 hours. Reaction mixture was then cooled to room temperature and diluted with hexane. Solid precipitate was filtered off and filtrate was concentrated. Chromatography achieved using ISCO max gradient 15% EtOAc/hexane yielding product as a white solid (350 mg, 71% yield). 1H NMR (400 MHz) (CDCl3) δ 8.15-8.14 (m, 1H), 7.94-7.91 (m, 2H), 7.48-7.45 (m, 3H), 7.18 9s, 1H), 5.10 (s, 2H), 4.11 (s, 3H), 4.07 (s, 3H), 1.45 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ 153.03, 152.89, 151.50, 150.11, 149.96, 139.19, 134.59, 128.46, 125.45, 124.18, 123.86, 121.45, 116.56, 105.75, 103.56, 56.16, 56.10, 34.90, 32.97, 31.47.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)=[O:4]>CO.[Pd]>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@@H:6]([C:17]([OH:19])=[O:18])[NH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of material from Example 22A and 10% Pd—C (500 mg) in methanol (250 mL) was stirred under an atmosphere of hydrogen at ambient temperature for 4 hours. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to provide the titled compound. MS (ESI (−)) m/e 237 (M−H)+; 1H NMR (300 MHz, DMSO-d6) 7.32 (d, 1H), 6.88 (d, 2H), 6.45 (d, 2H), 4.05-3.96 (m, 1H), 3.47 (s, 3H), 3.49-3.40 (m, 2H), 2.89-2.80 (m, 1H), 2.67-2.57 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[C:7]([NH2:11])=[N:6][CH:5]=1.O=[C:14]([CH3:18])[C:15]([OH:17])=[O:16].CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[NH:11][C:7]2=[N:6][CH:5]=1)=[O:12]
Reactant: CC(=O)C(=O)O
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2[nH]c(C(=O)O)cc2c1
Reaction time: 1 h

Procedure:
A solution of 5.6 g 6-Amino-5-iodo-nicotinic acid methyl ester, 5.3 g 2-Oxo-propionic acid, 11.1 g NEt3, 4.2 g Triphenylphosphine and 1.1 g Pd(OAc)2 in 100 mL DMF was heated under argon to 100° C. After 10 h the reaction mixture was concentrated under reduced pressure and the residue was strirred with 250 mL water for 1 h. The precipitated product was collected by filtration and washed with water. The crude product was subjected to the next reaction step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1>C(O)C.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CCCc2ccc(N)cc2)cc1
Yield: 91.1 %

Procedure:
To a solution of 4-[3-(4-methylphenyl)-1-propenyl]nitrobenzene (20 g) in ethanol (100 ml), 10% palladium-carbon (10 g) was added, and the resultant mixture was subjected to catalytic reduction under a pressure of 50 atm. After removal of the solvent from the reaction mixture by distillation, the residue was distilled under reduced pressure to give 4-[3-(4-methylphenyl)propyl]aniline (16.2 g). B.P. 135°-145° C./0.15 mmHg.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1[O:9]C1)[CH:2]1[O:4][CH2:3]1.[CH2:10]([OH:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:10]([O:26][CH2:3][CH:2]1[O:4][C:7](=[O:9])[CH2:6][O:5][CH2:1]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][CH2:23][CH2:24][CH3:25]
Reactant: C(OCC1CO1)C1CO1
Reactant: CCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCOCC1COCC(=O)O1

Procedure:
Prepared from the glycidyl ether of hexadecanol.
Reaction SMILES: ClCCCC(Cl)=O.C(C1C=CC=CC=1CC(O)=O)C.C([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[C:24]([C:32](=[O:37])[CH2:33][CH2:34][CH2:35]Cl)[CH:23]=1)C.[Li+].[OH-]>C(Cl)Cl.O.C(O)C>[CH:33]1([C:32]([C:24]2[CH:23]=[CH:22][CH:27]=[CH:26][C:25]=2[CH2:28][C:29]([OH:31])=[O:30])=[O:37])[CH2:34][CH2:35]1
Reactant: CCc1ccc(CC(=O)O)c(C(=O)CCCCl)c1
Agent: CCc1ccccc1CC(=O)O
Agent: O=C(Cl)CCCCl
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccccc1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
To a slurry of AlC3 (210 g, 1.6 mol) in methylene chloride (200 mL) cooled in an ice bath is added 4-chlorobutyryl chloride (121 g) dropwise while maintaining the pot temperature below 10° C. After 10 minutes, ethyl benzeneacetic acid (118 g, 0.72 mol) is added dropwise maintaining the pot temperature below 10° C. The mixture is stirred at room temperature for 1 hour, then heated to 40° C. After 4 hours, the solution is cooled to room temperature and poured onto crushed ice (2 L). Methylene chloride (1 L) is added. The organic phase is separated. The aqueous phase is extracted with two 1 L portions of methylene chloride. The combined organics are dried (MgSO4) and concentrated. Toluene (1 L) is added and the solution is concentrated to ca. 500 mL. Ethanol (500 mL) is added. The solution is heated to 70° C. and HCl (g) is bubbled through for 20 minutes. The solution is sparged with N2 and concentrated. Chromatography through silica gel (2.5 L) using an ethyl acetate/heptane gradient gives a 1:1 mixture of meta, para ethyl (4-chloro-1-oxobutyl)benzene acetic acid (119 g). To a slurry of LiOH (23.5 g, 0.56 mol) in water (100 mL) and ethanol (100 mL) is added the 1:1 mixture of meta, para ethyl (4-chloro-1-oxobutyl)benzene acetic acid (50g, 0.19 mol). The reaction becomes exothermic and is cooled with an ice bath. After 1 hour, the solution is allowed to warm to room temperature. After 18 hours, the mixture is concentrated. Water (400 mL) and conc. HCl are added (until pH 4). Ethyl acetate (600 mL) is added. The organic phase is separated, washed with brine and dried (MgSO4). The solution is heated on a steam bath and charcoal (ca. 3 g) is added. The mixture is filtered through Celite and concentrated. The residue is dissolved in ethyl acetate (300 mL) and heptane (600 mL) with heating. Seed crystals are added. After cooling an organic oil appears. Heptane (500 mL) is added and the mixture is heated to reflux, treated with charcoal (ca. 5 g), filtered and seeded. A solid forms and is collected. 1H NMR shows ca. 4:1 mixture of para:meta isomers. Recrystallization from ethyl acetate/heptane gives 4 (cyclopropylcarbonyl)benzeneacetic acid (4.3 g, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(Cl)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: O=C(O)C1=Cc2cc(-c3ccc(Cl)cc3)ccc2S(=O)(=O)CC1
Temperature: 70 °C
Reaction time: 64 h
Yield: 88.1 %

Procedure:
To a solution of methyl 7-(4-chlorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.95 g) in 1,2-dimethoxyethane (50 ml) was added 6N hydrochloric acid (30 ml), and the mixture was stirred at 70° C. for 64 hours. The mixture was cooled to room temperature, extracted with ethylacetate, saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration, and the crystals was washed with diisopropylether and hexane to give pale yellow crystals of 7-(4-chlorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (804.9 mg).