Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][CH2:4][C:5]([NH:7][C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:6].C(O)(C(F)(F)F)=O.O.[OH-].[Li+]>C1COCC1.O>[CH3:47][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([NH:7][C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:6]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-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]chrysen-9-yl)benzoate, TFA (87.9 mg, 0.116 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (19.49 mg, 0.464 mmol) in water (1.00 mL). The reaction was stirred at 75° C. After 8 h, the reaction was concentrated to dryness. The crude material was dissolved in THF (1 mL) and MeOH (1.5 mL), filtered and purified by reverse phase preparative HPLC using HPLC method 1 to give the title compound (59.5 mg, 0.078 mmol, 67.6% yield) as a white solid. LCMS: m/e 629.4 (M+H)+, 4.17 min (method 8). 1H NMR (500 MHz, METHANOL-d4) δ=7.95 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.2 Hz, 3H), 5.33 (dd, J=1.5, 6.1 Hz, 1H), 4.80 (d, J=1.5 Hz, 1H), 4.67 (s, 1H), 3.40 (t, J=6.6 Hz, 2H), 2.92 (s, 6H), 2.88-2.69 (m, 4H), 2.42 (dd, J=8.4, 12.4 Hz, 1H), 2.18 (dd, J=6.4, 17.1 Hz, 1H), 2.05-1.89 (m, 2H), 1.83 (d, J=11.3 Hz, 1H), 1.79-1.76 (m, 1H), 1.75 (s, 3H), 1.74-1.71 (m, 1H), 1.66-1.56 (m, 3H), 1.56-1.49 (m, 4H), 1.47-1.28 (m, 5H), 1.22-1.17 (m, 1H), 1.16 (s, 3H), 1.15-1.10 (m, 1H), 1.07 (s, 6H), 0.99 (s, 3H), 0.97 (s, 3H). 13C NMR (MeOD) δ ppm 14.5, 16.1, 16.8, 19.1, 20.6, 21.3, 22.1, 26.2, 28.2, 29.4, 29.7, 30.4, 34.5, 35.5, 37.1, 38.1, 38.2, 41.5, 42.5, 42.8, 43.2, 47.6, 49.3, 50.1, 50.5, 54.0, 55.1, 66.4, 110.4, 124.9, 129.5, 130.9, 147.4, 149.6, 150.8, 169.6, 171.0.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:39])[NH:24][C:25]4[CH:31]=[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])[CH:29]=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:30]1[CH:29]=[CH:28][C:26]2[N:27]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[CH2:22][C:23](=[O:39])[NH:24][C:25]=2[CH:31]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)c1

Procedure:
) The title compound was prepared from the above described 3′-[7-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (430 mg, 0.795 mmol) and TFA (5 mL) according to the general procedure I step 2. Obtained as a white solid (380 mg, 99%). MS (ISP) 486.0 [(M+H)+]; mp 230-232° C.
Reaction SMILES: [I:1]I.[CH2:3]([C:6]1[CH:11]=[C:10]([Sn](C)(C)C)[N:9]=[C:8]([C:16]#[N:17])[N:7]=1)[CH2:4][CH3:5]>C1COCC1.S([O-])([O-])(=O)=S.[Na+].[Na+]>[I:1][C:10]1[CH:11]=[C:6]([CH2:3][CH2:4][CH3:5])[N:7]=[C:8]([C:16]#[N:17])[N:9]=1
Reactant: II
Reactant: CCCc1cc([Sn](C)(C)C)nc(C#N)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc(I)nc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
Iodine (1.64 g, 6.5 mmol) was added at room temperature to a solution of 4-propyl-6-trimethylstannanyl-pyrimidine-2-carbonitrile (2.0 g, 6.5 mmol) in THF (100 mL). The mixture was stirred at room temperature for 2 hours, then diluted with a saturated solution of sodium thiosulfate and the THF was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent:Cyclohexane/Ethyl acetate 5/5) to afford 4-iodo-6-propyl-pyrimidine-2-carbonitrile (1.28 g, 72%) as a colorless oil.
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[CH2:8]([CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=[O:12])[CH3:9]>>[CH2:8]([CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([O-:13])=[O:12])[CH3:9].[V+5:6].[CH2:8]([CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([O-:13])=[O:12])[CH3:9].[CH2:8]([CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([O-:13])=[O:12])[CH3:9].[CH2:8]([CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([O-:13])=[O:12])[CH3:9].[CH2:8]([CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([O-:13])=[O:12])[CH3:9]
Reactant: CCCCC(CC)C(=O)O
Agent: [V+5]
Agent: [O-2]
Product: CCCCC(CC)C(=O)[O-]
Temperature: 95 °C

Procedure:
A mixture of 21.5 grams (0.236 mole) of vanadium pentoxide, 128.1 grams (0.884 mole) of 2-ethylhexanoic acid (acid number 387) and 100 grams of mineral spirits was heated to 95° C. for 4.5 hours with no reaction occurring.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[CH:85](=O)[CH2:86][CH2:87][CH2:88][CH3:89].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.N1C=CC=CC=1.CC(=O)CC(=O)C>[NH2:1][CH2:2][C@H:3]1[O:7][CH:6]([O:8][C@@H:9]([C@@H:49]2[C@@H:53]([OH:54])[C@@H:52]([OH:55])[C@H:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[N:11]([CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C@H:5]([O:64][CH3:65])[C@H:4]1[OH:66]
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Reactant: CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[Si]=O
Agent: [Al+3]
Solvent: c1ccncc1
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: CCCCCN(CCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C1CCNC(=N)N1)C(O)C(C)C)C(C(=O)O)[C@@H](OC1O[C@H](CN)[C@H](O)[C@H]1OC)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared by the procedure of Example 8, using 56.8 mg (60 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid (λmax nm in water=259) in 3.0 ml of methanol, 300 μl of pyridine, 300 μl of 2,4-pentanedione, 15 mg montmorillonite K-10, 18 μl of pentanal and 180 μmol of sodium triacetoxyborohydride to give 21 mg of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:9][C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:22])[F:23])=[N:11]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)c2)C1
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: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
5-(3-Bromo-phenyl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20.0 mg, 0.04 mmol) prepared in Step 1 of Preparation 6, 3-(trifluoromethyl)phenylboronic acid (17.0 mg, 0.09 mmol), Pd(PPh3)4 (2.5 mg, cat.) and a 2N sodium carbonate solution (1.0 mL) were added to N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred at 80° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8) to give 18.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[CH3:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([N:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[CH:21]=1>CN(C)C(=O)C>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([CH3:34])=[C:12]([NH:11][C:7]([C:6]5[CH:5]=[C:4]([CH3:10])[O:3][C:2]=5[CH3:1])=[O:8])[CH:13]=4)=[CH:21][N:20]3[N:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)c(C)o1
Yield: 58.9 %

Procedure:
In the same manner as in Example 58 and using 2,5-dimethyl-3-furoyl chloride (84.0 μL, 0.630 mmol), N,N-dimethylacetamide (5 mL) and N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (185 mg, 0.572 mmol) as starting materials, the title compound (150 mg, 56%) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:21])([CH:18]([CH3:20])[CH3:19])[CH2:14][C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:22]([NH:29][C@@H:30]([CH3:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:22]([NH:29][C@@H:30]([CH3:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C@@:13]([OH:21])([CH:18]([CH3:19])[CH3:20])[CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(CCC(O)(CC(=O)O)C(C)C)cc1
Agent: C[C@H](NCc1ccccc1)c1ccccc1
Solvent: CCO
Product: CC(=O)Nc1ccc(CC[C@](O)(CC(=O)O)C(C)C)cc1
Temperature: 20 °C
Reaction time: 23 h
Yield: 43 %

Procedure:
Ethanol (125 g) was added to (+/−)-3-[2-(4-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (11a, 25 g, 85 mmol) and the resulting solution stirred at 20° C. (S)-N-Benzyl-α-methylbenzylamine (21, 22.5 g, 106 mmol) was added to the solution and the resulting mixture allowed to stir at 20° C. for 23 hours. The mixture was filtered and the product washed with ethanol (10 mL) and vacuum dried at ambient temperature to give (S)-3-[2-(4-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (S)-N-benzyl-α-methylbenzylamine salt (22a): 18.6 g (36.8 mmol, 43% yield or 86% of theory); Chiral assay (HPLC): 99.2 area % (S) isomer 23a; mp: 152-154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35].N1C=CC=CC=1.[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51](Cl)(=[O:53])=[O:52])([O-:44])=[O:43]>ClCCl>[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51]([NH:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35])(=[O:53])=[O:52])([O-:44])=[O:43]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.8 %

Procedure:
To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (327 mg) and pyridine (80.3 mg) in dichloromethane (6 ml) was added dropwise 2-nitrobenzenesulfonyl chloride (150 mg) at ambient temperature and the mixture was stirred at ambient temperature for 5 hours. The resulting mixture was diluted with dichloromethane (10 ml) and the organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent; 2-4% methanol in chloroform) to give 4-(2-nitrobenzenesulfonyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (460 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[C:11]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12]1.C(N(CC)CC)C>CCCCCCC.CC(OC)(C)C.O.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:13]1[CH2:14][CH2:15][C:11](=[O:16])[CH2:12]1
Reactant: O=C1C=CCC1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCCCCCC
Solvent: COC(C)(C)C
Solvent: O
Product: O=C1CC[C@H](c2ccccc2F)C1
Reaction time: 2 h
Yield: 60.5 %

Procedure:
According to the method described in J. Org. Chem., 2009, 74, 929, bis(norbornadiene)rhodium tetrafluoroborate (0.22 g, 0.59 mmol) and (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.39 g, 0.62 mmol) were added to a mixture of 2-fluorophenylboronic acid (5.37 g, 38.4 mmol) in nitrogen sparged dioxane (30 mL) under nitrogen atmosphere. After 2 hours of agitation at ambient temperature, water was added (4.6 mL) followed by 2-cyclopenten-1-one (3.06 mL, 36.5 mmol) and triethylamine (5.09 g, 36.5 mmol). The agitation was continued for 24 h at 30° C. then the mixture was diluted with heptane (30 mL), MTBE (10 mL), and water (30 mL). The organic layer was separated and washed with water (50 mL). The aqueous layers were combined and extracted with MTBE/heptane (1:2, 50 mL). Combined organic extracts were dried (Na2SO4) and concentrated. Purification by chromatography (SiO2, hexane/20% ethyl acetate) afforded the title compound (3.94 g, 22.1 mmol, 61%). 1H NMR (300 MHZ, DMSO-d6) δ 7.46-7.27 (M, 1H), 7.25-7.05 (M, 3H), 3.56-3.26 (M, 1H), 2.22-1.41 (M, 6H). MS (ESI) m/z 177 (M−H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].C(O)C.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>C(Cl)(Cl)Cl>[CH2:16]([NH:23][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(O)CNCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
In a 250 mL round-bottomed flask, 2-bromo-1-(3-methoxyphenyl)ethanone (3 g, 13.1 mmol) was combined in CHCl3 (55.0 ml) and ethanol (11.0 ml) to give a colorless solution. The solution was cooled to 0° C. Benzylamine (5.61 g, 5.72 ml, 52.4 mmol) was added. After stirring for 0.5 h at 0° C. and then 2 h at room temperature, LCMS indicated that the reaction was mostly complete. (M+H)+=256 m/e. The reaction was cooled again to 0° C. and NaBH4 (743 mg, 19.6 mmol) was added. The reaction was allowed to warm to room temperature and was stirred at this temperature for 2.5 h until reaction was complete. The reaction mixture was quenched with 1M HCl (25 mL) at 0° C. followed by stirring at room temperature for 1 h. The reaction mixture was poured into 150 mL 1 M NaOH and extracted with ethyl acetate (3×150 mL). Combined organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 100% ethyl acetate) to yield 2-Benzylamino-1-(3-methoxy-phenyl)-ethanol (1.95 g, 58%). (M+H)|=258 m/e.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[N:29]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:37]([C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]([CH3:27])[N:29]=3)=[O:38])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC(=O)c2nn(C)c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (0.53 g) was dissolved in dimethylformamide (20 ml). 1-Methylindazole-3-carboxylic acid (0.27 g) and 1-hydroxybenzotriazole (0.25 g) were added, and the mixture was stirred at 0° C. for 15 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.35 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.20 g of N-(5-(4-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)piperidin-1-yl)pentyl)-1-methyl-1 H-indazole-3-carboxamide.
Reaction SMILES: CS([C:5]1[S:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)(=O)=O.[NH3:25].CC(O)C>>[NH2:25][C:5]1[S:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2
Reactant: CCOC(=O)c1cccc(-c2ccc3nc(S(C)(=O)=O)sc3n2)c1
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cccc(-c2ccc3nc(N)sc3n2)c1
Temperature: 90 °C
Reaction time: 30 h
Yield: 91 %

Procedure:
Ethyl 3-(2-(methylsulfonyl)thiazolo[5,4-b]pyridin-5-yl)benzoate (3.6 g, 9.91 mmol) was added to a 2N ammonia solution in IPA (24.8 mL, 49.57 mmol). The reaction mixture was heated at 90° C. and stirred for 30 h. The solvent was removed with in vacuo to give 2.7 g (91%, crude yield) ethyl 3-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzoate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[C:5]=1[C:12]([O:14][CH3:15])=[O:13].[H][H].[ClH:19]>CO.[Pd]>[ClH:19].[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH2:11])[C:5]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: [H][H]
Reactant: COC(=O)c1cccc(C#N)c1C(=O)OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc(CN)c1C(=O)OC
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of methyl-3-cyano-2-(methoxycarbonyl)benzoate (12.3 g, 57 mmol) in methanol (250 ml) and 4N HCl (40 ml) was added 10% Pd/C (1.2 g). The mixture was hydrogenated under 50 psi of hydrogen in a Parr Type Shaker for 17 hours. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was further evaporated with ethanol (2×25 ml) and toluene (25 ml) and dried under vacuum. The resulting solid was slurried in ether (50 ml) for 1 hour. The slurry was then filtered and dried to give 13.46 g (90%) of the product as a white solid: 1H NMR (DMSO-d6) δ 8.79 (b, 2H), 7.94 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 4.03 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H); 13C NMR (DMSO-d6) δ 167.58, 166.12, 133.41, 133.18, 132.28, 130.62, 129.49, 52.99, 52.92, 39.25.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[CH3:2].[CH2:15]([O:17][C@H:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([OH:28])=O)=[CH:22][CH:21]=1)[CH3:16].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:15]([O:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=2)=[O:28])=[CH:29][CH:30]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:16]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCNCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(C(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of N-ethyl-N-[4-(trifluoromethyl)benzyl]amine (0.213 g, 1.05 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.296 g, 1.00 mmol) in methylene chloride (10 mL) were added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.337 g, 1.05 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (90 mL) and the organic phase was washed with 5% HCl (2×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.339 g (70%) of a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[F:21][C:22]1[CH:23]=[C:24]([C@H:28]([NH2:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([C@H:28]([NH:30][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:29])[CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: C[C@@H](N)c1cccc(F)c1
Agent: Cl
Product: COc1ccc(C(N[C@H](C)c2cccc(F)c2)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
Following a similar procedure to that described in Example (1a), 11.16 g of 4-methoxyphenyl 3-nitrophenyl ketone and 7.62 g of (R)-1-(3-fluorophenyl)ethylamine hydrochloride were reacted, to obtain 15.11 of the title compound as a pale yellow oil.