Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](COCC[Si](C)(C)C)[N:13]=2)=[CH:4][CH:3]=1.C(Cl)Cl.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Cc2ccc(Cl)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(Cc2cc(-c3ccncc3)sc2-c2nnc[nH]2)cc1
Yield: 97 %

Procedure:
The 4-[4-(4-chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine (58 mg, 0.12 mmol) and methylene chloride (4.0 mL, 62 mmol) were combined in a round bottomed flask equipped with a stirbar. The mixture was stirred and trifluoroacetic acid (1.1 mL, 14 mmol) was added in one portion. The resulting yellow solution was stirred overnight at rt under an atmosphere of nitrogen. Excess solvent was removed on the rotovap and the residue was digested in a mixture of EtOAc and aqueous sodium bicarbonate solution. The mixture was stirred then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted twice more with EtOAc. The organics were combined, washed with bicarbonate solution, then saline, and then dried over sodium sulfate. The mixture was filtered then evaporated in vacuo and the residue was purified by column chromatography on silica, elution 100% DCM to 100% EtOAc to afford the title compound as an off-white powder. Yield 41 mg (97% yield). LCMS: (FA) ES+, 353, 355. 1H NMR (400 MHz, d6-DMSO) δ: 14.31 (1H, br s), 8.67 (1H, br s), 8.55 (2H, d, J=6.3 Hz), 7.69 (1H, s), 7.63 (2H, d, J=6.3 Hz), 7.36-7.30 (4H, m), 4.47 (2H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])=[CH:2]1>O1CCCC1.[O-2].[O-2].[Mn+4]>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)=[O:7])=[CH:2]1
Reactant: OC(c1ccoc1)c1cc2ccncc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=C(c1ccoc1)c1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
3-Furyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (130 mg, 0.61 mmol) was dissolved in tetrahydrofuran (8 mL). Manganese dioxide (530 mg, 6.10=mmol) was added and the reaction mixture was stirred at room temperature for 8 h. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed thoroughly with ethyl acetate. The organic filtrate was concentrated to a tan solid. Drying under vacuum at 40° C. produced 3-furyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (78 mg, 60%): mp 232-236° C. dec.; 1H NMR (500 MHz, CD3OD) δ 7.00-7.01 (1H, m), 7.42 (1H, s), 7.71-7.77 (2H, m), 8.16 (1H, d, J=5.6 Hz), 8.53 (1H, d, J=0.8 Hz), 8.85 (1H, s); ESI MS m/z=213 [C12H8N2O2+H]+; HPLC (Method A) >99% (AUC), tR=13.8 min.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:24][C@H:25]([CH3:32])[CH2:26]OS(C)(=O)=O)[CH2:18]OS(C)(=O)=O)=[O:15])([CH3:12])([CH3:11])[CH3:10]>COCCOC>[C:9]([O:13][C:14](=[O:15])[NH:16][C@H:17]1[CH2:24][C@H:25]([CH3:32])[CH2:26][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18]1)([CH3:10])([CH3:11])[CH3:12]
Reactant: C[C@H](COS(C)(=O)=O)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Solvent: COCCOC
Product: C[C@H]1C[C@H](NC(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A 50 L reactor is charged with 9.1 Kg of neat benzylamine. The reactor is brought to 55° C. and a solution of intermediate (6) (8.2 Kg) in 1,2-dimethoxyethane (DME) (14.1 Kg) is added to the reactor while maintaining a temperature of 60° C.±5° C. After complete addition of this solution, the reaction is stirred at 60° C.±5° C. for several hours and monitored for completion by TLC or HPLC. The reaction is cooled to ambient temperature and volatiles (DME) are removed by rotary evaporation under vacuum. The residue is diluted with 11.7 Kg of 15% (v/v) ethyl acetate/hexanes solution and treated, while agitating, with 18.7 Kg of 20% (wt) aqueous potassium carbonate solution. A triphasic mixture is obtained upon settling. The bottom aqueous phase is removed and the middle phase is set aside. The upper organic phase is collected and held for combination with extracts from additional extractions. The isolated middle phase is extracted twice again with 11.7 Kg portions of 15% (v/v) ethyl acetate/hexanes solution, each time combining the extracts with original organic phase. The combined organic extracts are transferred into a rotary evaporator and solvent is removed under vacuum until an oily residue remains. The residue is then purified via large-scale preparative chromatography to afford purified intermediate (7) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:23][C:24]=1[CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][C:24]2[S:23][C:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:21][C:20]=2[CH3:19])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccccc2)sc1CO
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccccc3)nc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with (4-methyl-2-phenyl-thiazol-5-yl)-methanol in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-[3-fluoro-4-(4-methyl-2-phenyl-thiazol-5-ylmethoxy)-phenyl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-[3-fluoro-4-(4-methyl-2-phenyl-thiazol-5-ylmethoxy)-phenyl]-propionic acid as a light yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][C:7]([CH3:19])([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH3:8])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[CH3:8][C:7]1([CH3:19])[C:9]2[C:14](=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:4](=[O:3])[NH:5][CH2:6]1
Reactant: CCOC(=O)NCC(C)(C)c1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CNC(=O)c2cc(C(F)(F)F)ccc21
Yield: 38.9 %

Procedure:
Using the same procedure and workup as described in Example 1, step 4, [2-methyl-2-(4-trifluoromethyl-phenyl)-propyl]-carbamic acid ethyl ester (I-20c: 1.1 g, 3.8062 mmol) in POCl3 (8 mL) was reacted with P2O5 (1.08 g, 7.6162 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 360 mg of the product (33.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:45][O:46][C:47]1[C:48]2[N:61]=[C:60]([NH2:62])[S:59][C:49]=2[C:50]([N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)=[N:51][CH:52]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:62][C:60]1[S:59][C:49]2[C:50]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[N:51][CH:52]=[C:47]([O:46][CH3:45])[C:48]=2[N:61]=1)=[O:8]
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1OC

Procedure:
From 3,4-dimethoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 431 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]([C:11]([NH:13][CH3:14])=[O:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)O1>>[NH:33]1[C:34]2[C:30](=[C:29]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[O:10][C:9]([C:11]([NH:13][CH3:14])=[O:12])=[CH:8][C:6]=4[N:7]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CNC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2o1

Procedure:
2-Chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to give, after purification by reverse HPLC, 293. MS (Q1) 379 (M+)
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=2)=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=2)=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)c(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2ccc(F)c(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(3,4-difluorophenoxy)benzoic acid (step 2): 1H-NMR (CDCl3) δ 8.16 (1H, d, J=2.8 Hz), 7.98–7.93 (2H, m), 7.60 (1H, d, J=7.4 Hz), 7.49 (1H, dd, J=8.7, 2.8 Hz), 7.35–7.29 (2H, m), 7.14 (1H, q, J=8.9 Hz), 6.88–6.78 (2H, m), 6.73–6.66 (1H, m), 5.31 (1H, dq, J=7.4, 6.9 Hz), 3.91 (3H, s), 1.51 (3H, d, J=6.9 Hz); MS (ESI) m/z 446 (M+H)+, 444 (M−H)−.
Reaction SMILES: [C:1](#[N:3])C.[F:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:7](F)[N:6]=1.CN>C(Cl)(Cl)Cl>[F:12][C:8]1[C:7]([NH:3][CH3:1])=[N:6][C:5]([F:4])=[C:10]([F:11])[CH:9]=1
Reactant: CC#N
Reactant: Fc1cc(F)c(F)nc1F
Agent: CN
Solvent: ClC(Cl)Cl
Product: CNc1nc(F)c(F)cc1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 10 ml of acetonitrile were added 4.5 g of 2,3,5,6-tetrafluoropyridine and 10 ml of methylamine (10% aqueous solution), and the mixture was stirred at 50° C. for 2 hours. To the solution was added 50 ml of chloroform, and the mixture was washed four times with 250 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a pale brown crude oil.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:15])([O-:11])=[O:10]
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: Cc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])cc1
Yield: 65 %

Procedure:
Using the procedure described in Example 93, Part A, 4-methylaniline (9.3 mmol) and 2-nitrobenzoyl chloride (10.3 mmol) yielded 1.55 g (65%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[I:29][CH2:30][CH2:31][CH2:32]O>CO.C(Cl)Cl>[I:29][CH2:30][CH2:31][CH2:32][O:27][C:26](=[O:28])[C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: OCCCI
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCCCI

Procedure:
Following General Procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared by coupling IV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine (Aldrich) using General Procedure B) and 3-iodo-1-propanol (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.45 in 5% MeOH/methylene chloride) and the product was purified by preparative tlc using 5% MeOH/methylene chloride.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:17][CH2:18][C:19]([OH:21])=O.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41]>ClCCl>[CH3:25][C:23]1[CH:22]=[C:16]([CH:15]=[C:14]([CH3:13])[CH:24]=1)[O:17][CH2:18][C:19]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[O:21]
Reactant: Cc1cc(C)cc(OCC(=O)O)c1
Reactant: COC(=O)CCCCCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCCNC(=O)COc1cc(C)cc(C)c1
Yield: 62.3 %

Procedure:
In a 5L 3-necked flask equipped with a mechanical stirrer and a dropping funnel was placed 1,1′-carbonyldiimidazole (94.4 g, 0.583 mol) in dichloromethane (1 L). A solution of 3,5-dimethylphenoxyacetic acid (Intermediate A77, 95.4 g, 0.53 mol) in dichloromethane (1250 mL) was added over a period of 60 min under argon. Triethylamine (107.1 g, 1.06 mol) was added followed by addition of a suspension of methyl 6-aminohexanoate hydrochloride (101.1 g, 0.555 mol) in dichloromethane (250 mL) in five portions. After 1 hr the reaction mixture was washed with 3 M HCl (1×1L), 2 M ammonium hydroxide (1×1L), and water (1×1L). The organic phase was then filtered through 1PS filter paper and concentrated under reduced pressure to give an oil. Distillation of the oil gave 101.5 g (62%) of the title compound, amide boiling at 197-202° C. (1 mm). The oil solidified on standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:20][O:14][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[N:11]=1
Reactant: CI
Reactant: O=c1nc(-c2ccccc2F)c2ccsc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2F)c2ccsc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 9.49 g of 4-(o-fluorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 200 ml of dimethylformamide is added 1.76 g of 63% sodium hydride. The mixture is stirred at 60°C for 1 hour. The mixture is cooled to room temperature and 10.93 g of methyl iodide in 33 ml of dimethylformamide is added dropwise thereto. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-(o-fluorophenyl)-thieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 175° - 176.5°C (after recrystallization from ethanol). From the second fraction, 1-methyl-4-(o-fluorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 222° - 223°C (after recrystallization from ethanol). From the third fraction, 3-methyl-4-(o-fluorophenyl)-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 191° - 192.5°C (after recrystallization from ethanol).
Reaction SMILES: [C:1]([CH:8]([NH2:15])[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>[Rh]>[C:1]([CH:8]([NH2:15])[CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C(N)c1ccncc1
Agent: [Rh]
Product: CC(C)(C)OC(=O)C(N)C1CCNCC1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A solution of 4-(Boc-aminomethyl)pyridine (20 g, 96 mmol) was treated with 5 g of 5% rhodium on carbon and was stirred under 4.1 bar (60 psig) of H2 overnight. Filtration through diatomaceous earth and evaporation of the solvent afforded 20 g (99%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[H][H]>C1(C)C=CC=CC=1>[CH3:12][C:7]1[C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc2c1CCCC2C
Reactant: [H][H]
Solvent: Cc1ccccc1
Product: Cc1cccc2c(C)cccc12

Procedure:
Using a 10% toluene solution of 1,5-dimethyltetralin obtained by the above method (A), dehydrogenation was conducted at 400° C. in a hydrogen atmosphere in the presence of a 0.3% Pt/Al2O3 catalyst for dehydrogenation to obtain 1,5-dimethylnaphthalene. Conversion of 1,5-dimethyltetralin was 100%, and selectivity to 1,5-dimethylnaphthalene was 97%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Reactant: COc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cccc(C#N)c2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 22 (57 mg, 0.13 mmol) is treated with acid chloride 6 (38 mg, 0.15 mmol) using Method D to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:23])(=[O:22])[N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:24]([O:26][CH3:27])=[O:25])=[CH:7][C:6]=2[CH:28]=1.B([O-])([O-])O[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:41]([O:40][CH2:39][CH2:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([C:12]4[CH:13]=[CH:14][C:15]([S:18](=[O:23])(=[O:22])[N:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=4)[CH2:10][CH2:9][C:8]([C:24]([O:26][CH3:27])=[O:25])=[CH:7][C:6]=3[CH:28]=2)=[CH:36][CH:35]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccc(S(=O)(=O)N(C)C)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A mixture of methyl 7-bromo-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35 g), 4-(2-butoxyethoxy)phenyl borate (0.19 g), 1M potassium carbonate solution (2 ml), ethanol (2 ml) and toluene (50 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35 g) as colorless crystals.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[OH:34]N1C(=O)C2=CC=CC=C2C1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(C(C)=O)C>[C:1]([O:4][CH:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:7](=[CH:8][C:9](=[O:34])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCC(C)=O
Product: CC(=O)OC1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-acetoxy-20-tert-butyldimethylsilyloxy-pregn-5-ene (337 gm, 0.71 mol, product of Step 2) in methyl ethyl ketone (4 L) was added N-hydroxyphthalimide (115.8 gm, 0.71 mol) and dibenzoyl peroxide (1.1 gm, 4.4 mmol). Air was bubbled through the reaction as the reaction was refluxed for 7.5 hr. Additional N-hydroxyphthalimide (9 gm) and dibenzoyl peroxide (0.1 gm) were added and reflux continued for 5 hr. The solvent was removed by rotoevaporation and methylene chloride (0.7 L) was added and warmned to 40° C. Upon cooling to room temperature, the suspension was filtered and the filtrate washed with methylene chloride (0.2 L). The filtrate was rotoevaporated and treated with pyridine (1.35 L) and acetic anhydride (135 mL). After stirring overnight, the solvent was removed by rotoevaporation and the dark orange oil dissolved in methanol (0.6 L). The mixture was heated to 50° C. and then cooled to room temperature. The solution was allowed to stand for 3 days and then cooled in an ice bath. The precipitate was filtered, washed with methanol, and dried to yield the title compound. The filtrate was rotoevaporated to a dry gum to yield the crude product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(CC(N)=O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)(C)C)c(=O)c2ccc(CC(N)=O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Tert-butyl[6-(2-amino-2-oxoethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (95 mg, 0.2 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the residue was crystallized from methanol-diisopropyl ether to give 2-[3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]acetamide hydrochloride (75 mg, 91.5%) as crystals.