Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:42]=[CH:41][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)=[CH:20][C:19]=3[N:32](C)[C:33](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1>Cl.O1CCOCC1>[CH3:33][N:32]1[C:19]2[CH:20]=[C:21]([S:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:42][CH:41]=1
Reactant: Cc1ccc(Sc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(Sc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Yield: 90.5 %

Procedure:
In a similar manner to that described in Example (2-2a), a reaction was carried out using t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-methylthiophenoxy)phenyl}-N-methylcarbamate (2.95 g) and 4N hydrogen chloride/dioxane (60 ml) and the reaction mixture was purified to give the title compound (2.15 g)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH3:14])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.O1CCOCC1>C1(C)C=CC=CC=1.O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH3:14])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)Cc1nc(Cl)ccc1C
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1nc(-c2ccc(OC)cc2)ccc1C

Procedure:
Following the same procedure described for Example 472 (Step 1) and starting from ethyl (6-chloro-3-methyl-2-pyridinyl)acetate (Example 478, 0.20 g, 0.94 mmol), Na2CO3 (0.24 g, 2.24 mmol), 4-methoxyphenyl boronic acid (0.57 g, 3.74 mmol), and PdCl2(dppf)CH2Cl2 (0.15 g, 0.19 mmol) in a mixture of toluene (1.50 mL), 1,4-dioxane (0.50 mL) and water (0.60 mL), the title compound was obtained (0.25 g, 94%). 1H NMR (400 MHz, CD2Cl2) δ 7.95 (d, 2H), 7.53 (s, 2H), 6.98 (d, 2H), 4.20 (q, 2H), 3.92 (s, 2H), 3.86 (s, 3H), 2.33 (s, 3H), 1.29 (t, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][N:4]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:16][O:15][N:14]([CH3:13])[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)=[O:11]
Reactant: CNOC
Reactant: CSc1nccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccnc(SC)n1
Reaction time: 20 h

Procedure:
A mixture of 2-(methylthio)pyrimidine-4-carboxylic acid (1-1, prepared according to Kim, C.-H., et al J. Med. Chem. 1986, 29, 1374–1380 and McOmie, W. J. Chem. Soc. 1953, 3129, 2.00 g, 11.8 mmol, 1 equiv), N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.3 mmol, 3.00 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.38 g, 17.6 mmol, 1.50 equiv), 1-hydroxy-7-azabenzotriazole (2.40 g, 17.6 mmol, 1.50 equiv), and triethylamine (6.55 mL, 47.0 mmol, 4.00 equiv) in DMF (40 mL) was stirred for 20 hours. The reaction mixture was partitioned between a 1:1 mixture of brine and saturated aqueous sodium carbonate solution (100 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexane initially, grading to 40% hexane in ethyl acetate) to give N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (1-2) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H, J=4.9 Hz), 7.13 (br s, 1H), 3.74 (br s, 3H), 3.36 (br s, 3H), 2.59 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([CH2:39][C:40](O)=[O:41])[CH:36]=[CH:37][CH:38]=1.CCN(C(C)C)C(C)C>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:43])([F:31])[F:44])[CH:34]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncnc21

Procedure:
Prepared according to the method described for Example 1 using (5-aminopyridin-3-yl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Preparation 38), and 3-trifluoromethylphenylacetic acid with DIPEA.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.B([C:47]1[CH:55]=[CH:54][C:50]([C:51]([OH:53])=[O:52])=[C:49]([F:56])[CH:48]=1)(O)O.B(O)O>>[C:51]([C:50]1[CH:54]=[CH:55][C:47]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:48][C:49]=1[F:56])([OH:53])=[O:52]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 4-borono-2-fluorobenzoic acid as the reactant boronic acid. The product was isolated as a white solid (6.46 mg, 19%). LCMS: m/e 575.54 (M−H)−, 3.88 min (method 2). 1H NMR (599 MHz, DMSO-D6_CDCl3) δ ppm 0.95 (s, 6H), 0.98 (s, 3H), 1.00 (s, 3H), 1.02 (s, 3H), 1.04-1.76 (m, 17H), 1.71 (s, 3H), 1.88 (d, J=7.03 Hz, 2H), 2.13 (dd, J=17.58, 6.44 Hz, 1H), 2.20 (d, J=12.30 Hz, 1H), 2.29-2.39 (m, 1H), 2.98-3.07 (m, 1H), 4.61 (s, 1H), 4.74 (s, 1H), 5.33 (d, J=5.27 Hz, 1H), 6.96 (d, J=11.13 Hz, 1H), 7.02 (d, J=8.20 Hz, 1H), 7.79 (t, J=7.62 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([O:57][C:58](=[O:64])[NH:59][CH2:60][CH2:61][CH2:62]O)([CH3:56])([CH3:55])[CH3:54].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:53]([O:57][C:58]([NH:59][CH2:60][CH2:61][CH2:62][O:23][C:22]([C:21]1[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]2[C:19]([C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=2)=[O:24])=[O:64])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCCCNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Yield: 56 %

Procedure:
To a mixture of 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg), triphenylphosphine (140 mg), (3-hydroxypropyl)carbamic acid tert-butyl ester (92 mg) and THF (4.0 ml), 0° C. with stirring, diethyl azodicarboxylate (90 μl) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by medium pressure preparative LC (hexane/ethyl acetate=5/1-3/2) to give the title compound (150 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:34]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)CO[C@H]1CC[C@H](CCNS(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CO[C@H]1CC[C@H](CCN(C(=O)c2ccccc2)S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C

Procedure:
To an ice-cold mixture of 4.0 g. (10 mMol) ethyl trans-4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-cyclohexyloxyacetate, 50 ml. methylene chloride and 1.5 g. (15 mMol) triethylamine is added dropwise a mixture of 1.4 g. (10 mMol) benzoyl chloride and 30 ml. methylene chloride. The reaction mixture is maintained for 4 hours at reflux temperature, cooled, filtered and the filtrate washed with dilute hydrochloric acid and water. It is then dried with anhydrous sodium sulphate and evaporated After purification over silica gel/ cyclohexane/diethyl ether (2:1 v/v), there is obtained a yield of 1.7 g (67% of theory); m.p. 81°-82° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:15]=2)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:31]([CH2:39][C:40](=O)[CH3:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[C:23]([CH2:22][NH:21][CH2:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][C@H:2]([NH:1][C:40]([CH3:41])=[CH:39][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)NC(C)=CC(=O)c1ccccc1
Yield: 70 %

Procedure:
To 0.65 g (1.62 mmol) of methyl (S)-2-amino-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}propionate, 0.32 g (1.94 mmol) of benzoylacetone, 3 g of molecular sieve 4A are added to 15 ml of methanol. The reaction mixture is refluxed for 14 h and then filtered through Celite. After evaporation of the solvents, the residue is purified by chromatography on a column of silica and eluted with a 7/3 heptane/ethyl acetate mixture. 0.62 g of desired product is isolated with 70% yield.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:23])[C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1.CCN(CC)CC>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:23][CH2:12][C:13]2[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3[nH]cnc23)cc1OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
2,6-Dichloro-9H-purine (1.7 g, 9 mmol), veratrylamine (1.5 g, 9 mmol) and Et3N (2.51 mL, 18 mmol) were dissolved in BunOH (10 ML). The solution was stirred for 2 h at 90° C. After cooling, PriOH (90 mL) was added slowly with stirring. After 1 h the precipitate was filtered, washed successively with small quantities of PriOH and Pri2O, and dried in vacuo to afford the title compound as a white powder (2.69 g, 93.4%). TLC (9:1 CH2Cl3/MeOH/AcOH): RF=0.33.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=3[CH3:26])=[C:16]([F:27])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])#[CH:29]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:29]#[C:28][Si:30]([CH3:33])([CH3:32])[CH3:31])=[CH:21][C:20]=3[CH3:26])=[C:16]([F:27])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11ccc (0.025 g, 0.052 mmol) is dissolved in 1:1 acetonitrile/triethylamine (0.50 mL). Ethynyl-trimethylsilane (0.013 mL, 0.092 mmol), Pd(PPh3)2Cl2 (0.004 g, 0.006 mmol), and CuI (0.002 g, 0.011 mmol) are added consecutively and the reaction mixture is stirred at 60° C. for 1 hour under N2. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by FCC (eluting with 20:1 methylene chloride:methanol) to yield 0.020 g (87%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[C:21]4=[CH:22][CH:23]=[CH:24][N:20]4[CH2:19][C:18]4[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=4[O:16]3)[CH2:11][CH2:10]2)=O)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:9]2[CH2:10][CH2:11][CH:12]([CH:15]3[C:21]4=[CH:22][CH:23]=[CH:24][N:20]4[CH2:19][C:18]4[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=4[O:16]3)[CH2:13][CH2:14]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)N2CCC(C3Oc4ccccc4Cn4cccc43)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(CN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution of 11-[1-(4-methoxybenzoyl)piperidin-4-yl]-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (13.0 g in 100 ml THF) was added 45 ml of a 1 molar lithium aluminum hydride solution in ethyl ether. This was stirred at room temperature for 2 hours.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)#[N:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(C#N)cc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (103 mg), p-cyanophenol (127 mg), triphenylphosphine (126 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (90 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hr and then concentrated in vacuo. The residue was purified by alumina column chromatography (ethyl acetate:hexane=1:4) and then with recrystallization from ethyl acetate-hexane to obtain the entitled compound (118 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH2:12][NH:11][C:10]1=[O:20])=O)(C)(C)C.[ClH:21]>C(OCC)C>[ClH:21].[NH2:8][C@H:9]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH2:12][NH:11][C:10]1=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2CNC1=O
Agent: Cl
Solvent: CCOCC
Product: N[C@H]1Cc2ccccc2CNC1=O
Reaction time: 16 h

Procedure:
(S)-4-(t-butyloxycarbonylamino)-2,3,4,5-tetrahydro-2-benzazepin-3(1H)-one (276 mg) was dissolved in 2 M hydrogen chloride in diethyl ether solution (25 mL) at room temperature. A precipitate slowly formed. After 16 h stirring the solvent was evaporated under vacuum. The residue was twice taken up in toluene (10 mL) and evaporated to provide (S)-4-amino-2,3,4,5-tetrahydro-2-benzazepin-3(1H)-one hydrochloride, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]2[C:12]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23][N:22]=3)=[N:13][CH:14]=[C:15]([C:18]#N)[C:16]=2[N:17]=1.C(O)=[O:29]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]2[C:12]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23][N:22]=3)=[N:13][CH:14]=[C:15]([CH:18]=[O:29])[C:16]=2[N:17]=1
Reactant: Cc1cc(Nc2ncc(C#N)c3nc(-c4c(F)cccc4Cl)sc23)ncn1
Reactant: O=CO
Solvent: O
Product: Cc1cc(Nc2ncc(C=O)c3nc(-c4c(F)cccc4Cl)sc23)ncn1
Temperature: 100 °C

Procedure:
To a solution of 2-(2-chloro-6-fluoro-phenyl)-4-[(6-methylpyrimidin-4-yl)amino]thiazolo[5,4-c]pyridine-7-carbonitrile (0.0500 mmol, 61.8 mg) in formic acid (2.25 mL) and water (0.75 mL) was added Al—Ni Alloy (130 mg). The mixture was heated at 100° C. for 4 hours. The mixture was then cooled to room temperature and filtered through celite, washed with 95% EtOH, concentrated via rotavap to give a yellow solid which was used in the next step without purification. LCMS (ESI) m/z 400.1 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[CH2:22]([Mg]Br)[CH3:23].C(OCC)C.O>O1CCCC1>[CH2:22]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12)[CH3:23]
Reactant: CC[Mg]Br
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To an ice-cold solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (2.95 g, 10.0 mmol) in tetrahydrofuran (100 mL), a solution of 3M ethylmagnesium bromide in diethyl ether (4.00 mL, 12.0 mmol) was added dropwise under an argon atmosphere, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was poured into iced water, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound (0.33 g, 11% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C@@H:10]2[NH:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C@@H:10]2[N:15]([CH3:33])[CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(Cl)c2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
Combine 10-((S)-3-[2-(3-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (608.3 mg, 1.53 mmol), formaldehyde (124.3 μL, 1.53 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (442.5 mg, 2.09 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 502.3 mg (80%) of the title compound as a brown foam: mp 69°, dec; mass spectrum (ion spray): m/z=451.2 (M+1).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=1)([CH3:15])([CH3:14])[CH3:13].[OH:37][C:38]1[CH:42]=[C:41]([CH2:43][CH2:44][C:45](O)=[O:46])[O:40][N:39]=1.COC(C1CCC(C(N2CCN(C3C=CC(C(=O)NC4C=CC=C(C(C)(C)C)C=4)=CN=3)CC2)=O)CC1)=O>>[C:12]([C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:45](=[O:46])[CH2:44][CH2:43][C:41]4[O:40][N:39]=[C:38]([OH:37])[CH:42]=4)[CH2:32][CH2:31]3)=[N:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Reactant: O=C(O)CCc1cc(O)no1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)CCc4cc(O)no4)CC3)nc2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-6-{4-[3-(3-hydroxy-isoxazol-5-yl)-propionyl]-piperazin-1-yl}-nicotinamide was synthesized from the EDCI coupling of N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and 3-(3-hydroxy-isoxazol-5-yl)-propionic acid in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester, above. LCMS calcd for C26H31N5O4 (m/e) 477, obsd 478 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:40][N:41]1[CH:45]=[C:44]([C:46](O)=O)[C:43]([C:49]([F:52])([F:51])[F:50])=[N:42]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:46]([C:44]2[C:43]([C:49]([F:52])([F:50])[F:51])=[N:42][N:41]([CH3:40])[CH:45]=2)[O:16][N:15]=1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cn(C)nc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.0194 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1 H), 7.88 (d, J=1.0 Hz, 1 H), 7.53 (d, J=8.5 Hz, 1 H), 7.45 (d, J=8.4 Hz, 1 H), 5.40 (s, 2 H), 4.01 (s, 3 H), 2.96 (t, 2 H), 1.82-1.67 (m, 2 H), 1.03 (t, 3 H); MS (ES) m/z 449 (M+1).