Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:30])[CH:13]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])=[CH:7][CH2:6]1)[CH3:3].N1CC[CH2:34][CH2:33][CH2:32]1.CC(O)=O>>[N:2]1([N:4]=[C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:30])[CH:13]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[NH:14][C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[O:16])=[CH:9][CH2:10]2)[CH2:1][CH2:34][CH2:33][CH2:32][CH2:3]1
Reactant: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2cccs2)=CC1
Reactant: C1CCNCC1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=CCC(=NN2CCCCC2)C=C1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.24 mmol) from Example 19, a pre-mixed piperidine (0.12 mL, 1.21 mmol) and HOAc (0.11 mL, 1.92 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (21 mg). MS 496.1 and 498.1 (M+H, Cl pattern).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([C@:13]12[CH2:21][CH2:20][C@@H:19]3[C:22]4[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[CH:26][C:27]=4[CH2:28][CH2:29][C@H:18]3[C@@H:17]1[CH2:16][CH2:15][C:14]2=[O:32])[CH3:12].[CH3:33][CH2:34][O:35]CC>S(=O)(=O)(O)O>[CH2:11]([C@:13]12[CH2:21][CH2:20][C@@H:19]3[C:22]4[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[CH:26][C:27]=4[CH2:28][CH2:29][C@H:18]3[C@@H:17]1[CH2:16][CH2:15][C@@H:14]2[O:32][CH2:33][CH2:34][OH:35])[CH3:12]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCO
Reaction time: 0.33 h

Procedure:
Prepare a solution of ether (100 ml), aluminum chloride (13.3 g) and lithium aluminum hydride (15 ml. of a 1 M solution). Stir for 20 minutes. Add to a cool solution of dl-13-ethyl-3-methoxygona-1,3,5(10)-trien-17-one, cyclic ethylene ketal (17.1 g) in ether (1,000 ml). Stir the reaction mixture and cool in an ice-water bath for 4 hours. Dilute with 2 N sulfuric acid until a clear solution results. Separate the ether layer, wash with saturated sodium bicarbonate solution, and evaporate. Treat the residue with ethanol (200 ml), concentrated hydrochloric acid (5 ml) and water (10 ml) on a steam bath for 30 minutes. Evaporate, then recrystallize from ethanol to obtain dl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene (8.1 g), m.p. 131°-132°; ultraviolet absorption peak at 278 mμ (ε2,130), infrared maximum at 2.93 μ.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[CH2:43]([O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@H:29]([NH:28][C:2]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=3)[NH:4][C:3]2=[O:12])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:37][CH:38]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 4.58 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 86-3 (5.02 mmol, crude form) as starting materials, 1.09 g (Isomer A, yellow solid) and 1.67 g (Isomer B, colorless amorphous) of the respective diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][C:4]1[N:5]=[C:6]([CH2:11][C:12]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)([OH:17])[C:13]([F:16])([F:15])[F:14])[NH:7][C:8]=1[CH:9]=[CH2:10]>CO.[Pd]>[CH3:31][C:2]([CH3:1])([CH3:32])[CH2:3][C:4]1[N:5]=[C:6]([CH2:11][C:12]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)([OH:17])[C:13]([F:16])([F:15])[F:14])[NH:7][C:8]=1[CH2:9][CH3:10]
Reactant: C=Cc1[nH]c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)(F)F)nc1CC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCc1[nH]c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)(F)F)nc1CC(C)(C)C
Reaction time: 1 h

Procedure:
Pd (10 wt % on activated carbon) (ca. 1 mg, cat.) was added to a degassed solution of 3-[4-(2,2-dimethylpropyl)-5-vinyl-1H-imidazol-2-yl]-1,1,1-trifluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]propan-2-ol (3 mg, 0.007 mmol) in methanol (1 mL). After stirring under an atmosphere of hydrogen for 1 h, the reaction mixture was filtered through celite rinsing with methanol. The filtrate was concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CD3OD) δ 8.53 (d, J=3.0 Hz, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.90 (dd, J=4.3, 8.8 Hz, 1H), 7.72-7.60 (m, 4H), 3.63 (bs, 2H), 2.52 (1, J=7.6 Hz, 2H), 2.38 (AB, J=14.9 Hz, 2H), 1.10 (t, J=7.6 Hz, 3H), 0.76 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:10])[N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: Nc1cc(Cl)cc(Cl)n1
Reactant: CB1OB(C)OB(C)O1
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: C1COCCO1
Product: Cc1cc(Cl)cc(N)n1
Temperature: 120 °C
Yield: 23 %

Procedure:
To a 10% aqueous solution of dioxane (0.1 M) was added 4,6-dichloropyridin-2-amine (1.0 equiv.), trimethylboroxine (1.5 equiv.), Pd(PPh3)4 (0.10 equiv.) and K2CO3 (3.0 equiv.). The solution was heated in an oil bath to 120° C. for 18 hrs, cooled to room temperature (not all of starting material was consumed), extracted with EtOAc, dried with Na2SO4, and concentrated. The crude material was purified via SiO2 column chromatography eluting with 5% MeOH/DCM to yield 4-chloro-6-methylpyridin-2-amine as an off-white solid in 23% yield. LCMS (m/z): 143 (MH+); LC Rt=1.11 min.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([CH2:22][CH2:23][CH3:24])[C:20]=1[OH:21])[N:17]=[C:16]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[C:14]2Cl)(=[O:10])[CH3:9]>CO>[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([CH2:22][CH2:23][CH3:24])[C:20]=1[OH:21])[N:17]=[C:16]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[C:14]2[S:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:10])[CH3:9]
Reactant: Sc1ccccc1
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc2c(Sc3ccccc3)cc(C(=O)OC)nc12
Reaction time: 6 h

Procedure:
Phenylthiol (1.87 g) was added to a stirred boiling solution of methyl 6-acetyl-4-chloro-7-hydroxy-8-propyl-quinoline-2-carboxylate (4.97 g) in dry methanol (600 ml) and the solution was boiled for 6 hours. The resulting suspension was cooled and the sub-title compound (2.2 g) filtered off and recrystallised from methanol as yellow needles m.p. 171°-2° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]3[NH:17][N:18]=[N:19][C:15]=3[CH:14]=2)=[O:12])=[CH:6][CH:5]=1.CO.[OH-].[Na+].Cl>C1COCC1.O>[NH:17]1[C:16]2[CH:20]=[CH:21][C:13]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][CH:6]=3)=[O:12])=[CH:14][C:15]=2[N:19]=[N:18]1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3[nH]nnc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(NC(=O)c2ccc3[nH]nnc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
4-[(1H-Benzotriazole-5-carbonyl)amino]benzoic acid methyl ester (5.2 g, 17.6 mmol) was dissolved in THF (60 mL) and methanol (10 mL) was added followed by 1N sodium hydroxide (35 mL). The mixture was stirred at room temperature for 16 hours and then 1N hydrochloric acid (45 mL) was added. The mixture was added water (200 mL) and extracted with ethyl acetate (2×500 mL). The combined organic phases were evaporated in vacuo to afford 0.44 g of 4-[(1H-benzotriazole-5-carbonyl)amino]benzoic acid. By filtration of the aqueous phase a further crop of 4-[(1H-benzotriazole-5-carbonyl)amino]benzoic acid was isolated (0.52 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.[Li+].CC([N-]C(C)C)C.[I:39]I>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[I:39])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1OC
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(cc(I)n2S(=O)(=O)c2ccccc2)c1OC
Reaction time: 0.75 h
Yield: 98.9 %

Procedure:
To 541 mg (1.71 mmol) of the protected indole from step 1 in 20 mL dry THF at −20° C. was added 269 μL (1.8 mmol, 1.05 eq) TMEDA, then LDA (1.1 mL, 2.22 mmol, 1.3 eq) dropwise. The reaction was stirred for 45 minutes and iodine (879 mg, 3.42 mmol, 2 eq) in 4 mL THF was added slowly, and stirred an additional 45 minutes at −20° C. The reaction was then quenched with H2O, concentrated and partitioned with EtOAc and 2N Na2CO3 solution. The EtOAc layer was washed with H2O, aqueous NaCl, dried (MgSO4), and concentrated under vacuum to yield 750 mg of 1-benzenesulfonyl-2-iodo-4,5-dimethoxy-1H-indole.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:9][C:4]1[CH:3]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[CH:7]=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)sc1C=O
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: COCCOC
Product: Cc1cc(-c2ccccc2)sc1C=O
Yield: 91.2 %

Procedure:
To a solution of 5-bromo-3-methyl-thiophene-2-carbaldehyde (1.00 g, 4.88 mmol) in ethylene glycol dimethyl ether (9 ml) was added phenylboronic acid (0.773 g, 6.34 mmol), 2M Na2CO3 solution (6.3 ml) and Pd(PPh3)4 [0.282 g, 0.24 mmol). The mixture was heated for 18 hours, cooled and the solvent removed at reduced pressure to leave a brown residue which was partitioned between water (15 ml) and dichloromethane (20 ml). The organic was separated, washed with water (2×5 ml), brine (10 ml), dried (MgSO4) and the solvent removed at reduced pressure to give a brown oil. Purification by flash column chromatography (6:1 petrol 40-60° C./ethyl acetate) gave the sub-title compound as a yellow oil (0.90 g, 91% yield): 1H NMR (400 MHz, CDCl3) δH 2.75 (3H, s), 7.25 (1H, s) 7.35-7.75 (5H, s), 10.05 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].I[C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cn1ccnc1I
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Product: Cc1cc(-c2nccn2C)cc(C)c1Cl

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-iodo-1-methyl-imidazole following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.80 min; Mass spectrum (ESI+): m/z=221/223 (Cl) [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1([CH3:37])[CH2:36][O:35][CH2:34]1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3([CH3:37])[CH2:36][O:35][CH2:34]3)=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CC1(CBr)COC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(C)COC2)c1OCC1CC1
Temperature: 70 °C
Yield: 19.9 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.740 mmol) and 3-bromomethyl-3-methyl-oxetane (122 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 20%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[N:5]([C:17]1[CH:22]=[C:21]([Br:23])[N:20]=[C:19](Br)[C:18]=1[N+:25]([O-:27])=[O:26])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[NH3:29]>>[CH2:1]([O:3][C:4](=[O:28])[N:5]([C:17]1[CH:22]=[C:21]([Br:23])[N:20]=[C:19]([NH2:29])[C:18]=1[N+:25]([O-:27])=[O:26])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Product: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 69 using (2,6-dibromo-3-nitro-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (2.75 g), aqueous ammonia (11 ml), and 2-methyl-THF (11 ml). This gave the product (1.92 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([CH2:20][NH2:21])=[CH:18][CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:22].CCN(C(C)C)C(C)C.Cl[C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([CH2:20][NH:21][C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:18][CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cc(-c2ncccc2-c2ccc(CN)nc2)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCc1ccc(-c2cccnc2-c2ccc(F)c(C)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of (2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine (2.0 g) in CH2Cl2 (30 mL) under nitrogen atmosphere, i-Pr2NEt (2.6 mL) was added and stirred for 10 min at room temperature. Ethyl 2-chloro-2-oxoacetate (1.1 mL) as neat was added dropwise for 10 min. After 1 h, the reaction mixture was concentrated, partitioned between CH2Cl2 (75 mL)/aq. NaCl (20 mL) and the organic layer was separated. Usual workup and purification by chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 50-100% EtOAc/hexanes as an elutant) provided 1.4 g of ethyl 2-(((2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)amino)-2-oxoacetate as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.41 (t, J=6.2 Hz, 1H), 8.67 (dd, J=4.7, 1.7 Hz, 1H), 8.30 (dd, J=2.4, 0.9 Hz, 1H), 7.87 (dd, J=7.8, 1.7 Hz, 1H), 7.56 (dd, J=8.1, 2.3 Hz, 1H), 7.49 (dd, J=7.8, 4.8 Hz, 1H), 7.29-7.22 (m, 2H), 6.98 (dd, J=7.7, 1.1 Hz, 2H), 4.42 (d, J=6.1 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 2.21-2.09 (m, 3H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.O1CCCC1.CO.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC)c3[nH]2)S1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.9 %

Procedure:
To a mixture of ethyl (2-{7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.42 g), tetrahydrofuran (8 mL) and methanol (8 mL) was added a solution of potassium hydroxide (85%, 0.25 g) in water (5 mL). The mixture was stirred at room temperature for 15 h and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light amorphous solid, which was crystallized from ethyl acetate-hexane to give the title compound (340 mg, 86%) as pale yellow crystals. MS 461 (MH+). mp 144-145° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](OC)=[O:10])[N:4]=1.O.[NH2:16][NH2:17]>CCO>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:16][NH2:17])=[O:10])[N:4]=1
Reactant: NN
Reactant: COC(=O)c1nccc(C(F)(F)F)n1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nccc(C(F)(F)F)n1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of methyl 4-(trifluoromethyl)pyrimidine-2-carboxylate (500 mg, 2.4 mmol) in EtOH (12 mL) was added hydrazine monohydrate (0.24 mL, 4.9 mmol). After 1 h, the reaction was concentrated to afford the desired product as a white solid (426 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J=5.0 Hz, 1H), 9.05 (s, 1H), 7.83 (d, J=5.0 Hz, 1H), 4.25 (br s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15]C(=O)C2C=CC(OC)=CC=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([OH:15])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A solution of Intermediate 118 (32.92 g) in methanol (400 ml) was added with 3 N aqueous sodium hydroxide (163 ml) at room temperature and stirred at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, then added with ethyl acetate (400 ml) and washed 4 times with 0.5 N aqueous sodium hydroxide (50 ml each) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (7.94 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[N:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[CH:23][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:26]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([NH:36][CH2:35][CH2:34][C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)[CH3:21])=[CH:18][CH:19]=1)=[CH:7]3
Reactant: NCCc1ccncc1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)NCCc4ccncc4)cc3)cc12

Procedure:
8-Methyl-2-(4-(1-(2-(pyridin-4-yl)ethylamino)ethyl)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and 2-(pyridin-4-yl)ethanamine (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ 8.94 (m, 2H), 8.92 (d, 2H), 8.73 (s, 1H), 8.43 (d, 1H), 7.60 (m, 2H), 7.40 (m, 2H), 7.16-7.26 (m, 3H), 4.55 (m, 1H), 3.55 (m, 4H), 2.56 (m, 4H), 2.12 (s, 3H), 1.73 (d, 3H) LRMS [M+H]=462.2
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][S:18][CH2:19][CH2:20][NH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([N:28]=[C:29](OC)[CH2:30][CH3:31])#[N:27]>C(#N)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][S:18][CH2:19][CH2:20][NH:21][C:29](=[N:28][C:26]#[N:27])[CH2:30][CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(=NC#N)OC
Reactant: NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CC#N
Product: CCC(=NC#N)NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 36.3 %

Procedure:
There were dissolved 4.0 g (0.0164 mol) of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-aminoethylthio)acetamide and 1.84 g (0.0164 mol) of methyl N-cyanopropioimidate in 40 ml of acetonitrile, and after reflux with heating for 3 hours, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethanol=10:1) to give 2.65 g of the titled compound as oily matter.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(OCC)(=O)C>[CH2:33]([O:20][C:19](=[O:21])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A solution of 30 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 400 ml of ethyl acetate was treated with 9.63 g of triethylamine and 16.31 g of benzyl bromide and then heated at reflux for 4 hours. On cooling the mixture to room temperature filtration and evaporation of the filtrate gave a residue which was purified by column chromatography on silica gel, using ethyl acetate/hexane (1:9) for the elution, to give 15.8 g of (E)-benzyl-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerate in the form of a clear oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:24])[CH2:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:23])[NH:18]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:25][CH:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:11](=[O:24])[CH2:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:23])[N:18]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc2c(OCC(=O)OCc3ccccc3)cccc2[nH]1
Reactant: CCCCCCCCCCCC(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(OCC(=O)OCc3ccccc3)cccc2n1CCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.093 g, 6.45 mmole) in DMF (10 mL), (2-methyl-1H-indol-4-yloxy)-acetic acid benzyl ester (2) (0.845 g, 2.3 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture, dibromododecane (0.765 g, 2.3 mmole) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was separated, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (10:1, hexane: EtOAc) to afford intermediate 3. Yield: 0.708 g, 45%.