Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][CH2:29][CH2:30]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][CH2:30][CH2:29][CH2:28][O:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCc1ccccc1
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CCCNCCCOc2ccc3ccccc3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 3-phenylpropylamine (0.44 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3-phenylpropyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 109° C., (yield 0.645 gm, 89.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][CH:8]=[CH:7]2)([O-])=O.[H][H]>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:9][CH:8]=[CH:7]2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Yield: 94.7 %

Procedure:
di-tert-butyl (6-nitroisoquinolin-1-yl)imidodicarbonate (75.00 g, 0.193 mol) in methanol/THF (500 ml/500 ml) was hydrogenated with a hydrogen balloon in the presence of Pd/C (5%, 5 g) for 2.0 h. Filtration of the Pd/C and concentration gave a solid, which was recrystallized from methanol to give 65.72 g (94.97%) of di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (m, 18 H) 4.18 (s, 2 H) 6.89 (d, J=2.20 Hz, 1 H) 6.99 (dd, J=9.01, 2.42 Hz, 1 H) 7.35 (d, J=6.59 Hz, 1 H) 7.75 (d, J=8.79 Hz, 1 H) 8.22 (d, J=5.71 Hz, 1 H). LC-MS: 741 (2M+Na)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)O1.Cl[C:21]1[N:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].O>[CH3:27][C:24]1[CH:23]=[N:22][C:21]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)=[N:26][CH:25]=1
Reactant: Cc1cnc(Cl)nc1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(-c2ccc3c(c2)CCC3=O)nc1
Temperature: 25 °C

Procedure:
To a 100 mL round-bottomed flask was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 1.50 g, 5.81 mmol), 2-chloro-5-methylpyrimidine (747 mg, 5.81 mmol), sodium carbonate (2.47 g, 23.3 mmol), 27 mL of dioxane, and 3 mL of water. The mixture was degassed with nitrogen for 15 minutes. Palladium tetrakis(triphenylphosphine) (356 mg, 0.31 mmol) was added and the mixture was degassed with nitrogen for an additional 15 minutes. The reaction was heated at reflux overnight. The reaction was cooled to room temperature and was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The final product was purified by silica chromatography on a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.) eluting with 20-35% ethyl acetate in heptanes to provide a white solid (SM-1d, 1.12 g, 86%). MS (ES+) 225.2 (M+H+). 1H NMR (CDCl3) δ 2.38 (s, 3H), 2.74-2.78 (m, 2H), 3.23 (t, 2H), 7.85 (d, 1H), 8.44 (d, 1H), 8.53 (s, 1H), 8.68 (s, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8](=[O:31])[CH2:9][NH:10][C:11](=[O:30])[CH2:12][NH:13][C:14](=[O:29])[C@@H:15]([NH:17][C:18](=[O:28])[CH2:19][NH:20][C:21]2[S:22][C:23]([CH:26]=[O:27])=[CH:24][N:25]=2)[CH3:16])[C@@H:3]1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1.[BH4-].[Na+]>CCO.O>[OH:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8](=[O:31])[CH2:9][NH:10][C:11](=[O:30])[CH2:12][NH:13][C:14](=[O:29])[C@@H:15]([NH:17][C:18](=[O:28])[CH2:19][NH:20][C:21]2[S:22][C:23]([CH2:26][OH:27])=[CH:24][N:25]=2)[CH3:16])[C@@H:3]1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1
Reactant: COc1ccc(C[C@@H]2[C@H](O)[C@@H](O)CN2C(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)CNc2ncc(C=O)s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C[C@@H]2[C@H](O)[C@@H](O)CN2C(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)CNc2ncc(CO)s2)cc1

Procedure:
Following the procedure as described ion Example 32, except using material from Example 44 (21.4 mg, 0.031 mmol), EtOH/H2O (4:1) (2.0 mL) and sodium borohydride (7.2 mg, 0.190 mmol), the title compound is isolated (quantitative yield) and is used crude, “as is”, in the macrocyclization step. LC/MS (Condition A): ret. T=1.90 min, (M+Na) 601.29.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl.[BH3-]C#N.[Na+]>CC(O)=O.CO>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1c(=O)[nH]c(N)c(N=Cc2ccccc2)c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cn1c(=O)[nH]c(N)c(NCc2ccccc2)c1=O
Reaction time: 0.5 h

Procedure:
Add 6-amino-3-methyl-5-(phenylmethyleneamino )pyrimidine-2,4-dione (85 g=0.35 mol) to CH2Cl2 (1.6L) and MeOH (1.6L). Stir the suspension, add HOAc (21.9 ml=0.35 mol), then NaCNBH3 (21.9 g=0.35 mol). Stir 1.5 hr, and add HOAc (2 ml) and NaCNBH3 (2.0 g). After another 30 min, concentrate to ca. 1.6L on a rotovap (35° C. bath). Chill the crystalline mixture, filter, and wash with cold MeOH. Stir the product 15 min in 0.5L boiling MeOH, chill, filter, and dry to obtain the title compound, m.p. 206°-218° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Cl.[NH2:16][OH:17].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[OH:17]/[N:16]=[C:13](\[N:10]1[CH2:11][CH2:12][N:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:8][CH2:9]1)/[NH2:14]
Reactant: NO
Reactant: N#CN1CCN(C2CCOCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N/C(=N/O)N1CCN(C2CCOCC2)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
A mixture of 4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carbonitrile (632 mg, 3.24 mmol), Ethanol (10 mL), hydroxylamine hydrochloric acid (257 mg, 3.70 mmol) and Na2CO3 (785 mg, 7.40 mmol) was heated to 80° C. After 1.5 h, the solids were filtered off and the filtrate concentrated in vacuo. The residue was dissolved into a minimum amount of methanol and treated with 5 mL of 1 M of HCl/Ether and diluted by acetone. Resulting solids were collected and dried in vacuo to afford the title compound (566 mg, 1.879 mmol, 76% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=11.88 (br. s., 4H), 11.20 (br. s., 1H), 10.17 (br. s., 1H), 8.26 (br. s., 2H), 4.09-3.87 (m, 5H), 3.69-3.49 (m, 4H), 3.42 (br. s., 1H), 3.26 (t, J=11.5 Hz, 2H), 3.17-2.98 (m, 2H), 2.00 (d, J=11.1 Hz, 2H), 1.83-1.64 (m, 2H); LC/MS (m/z) ES+ (ELSD)=229.2 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:13]([I:14])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:15])[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:4]2[C:13]([I:14])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:15])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(I)c(C2CC2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C2CC2)c(I)cc1C(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate (compound 86.2, 15.0 g, 47.5 mmol) in methanol (150 mL). A solution of sodium hydroxide (5.70 g, 143 mmol) in water (75 mL) was added and the resulting solution was stirred for 4 h at 60° C., then cooled to room temperature. The volatiles were removed under reduced pressure and the remaining solution was adjusted to pH 3 with aqueous hydrogen chloride (12 M). The mixture was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with NH4Cl (aq.) (2×400 mL) and brine (400 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 13.0 g (91%) of the title compound as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].CO[CH:15](OC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CN(C)C=O>[CH2:11]1[O:12][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:10][C@@H:9]1[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6]
Reactant: COC(OC)c1ccccc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1O[C@H]([C@@H]2COC(c3ccccc3)O2)C(O)=C1O

Procedure:
L-Ascorbic acid (20 g), α,α-dimethoxytoluene (20 g) and a catalytic quantity (160 mg) of p-toluenesulfonic acid were dissolved in 60 ml of dimethylformamide. The solution was heated at 55°-60° C. for 4 hours. The reactor used for carrying out the reaction was equipped with a reflux-condenser connected to an aspirator, and the methanol formed during the reaction process produces was evaporated out of the reaction mixture. When the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The resulting syrupy residue was washed with petroleum ether and water, each three times. Then, water and hexane were added to the washed syrup and the mixture was stirred to obtain a crystalline product of 5,6-O-benzylidene-L-ascorbic acid which was then filtrated off and dried to give 21.5 g of white colored crystals of 5,6-O-benzylidene-L-ascorbic acid (72% yield). The product thus obtained was nearly pure substance but was further purified by recrystallization from methanol or benzene. The final pure crystal showed mp. of 166°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 85 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 500 mg; 1.46 mmol) in DMF (30 mL) was added tert-butyl 2-bromoethylcarbamate (658 mg; 2.94 mmol) and Cs2CO3 (1.43 g; 4.39 mmol) and catalytic amount of tetrabutylammonium iodide (107 mg; 0.29 mmol) under nitrogen. The reaction mixture was stirred at 85° C. for 24 hours. Most of DMF was removed and the residue was diluted with EtOAc (100 mL), washed with water (50 ml×3), brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by reversed phase flash chromatography to afford 500 mg (70%) of the title compound as a yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CO.[Pt](=O)=O>[NH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)COc1ccc2ncccc2c1
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)COc1ccc2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 2-(quinolin-6-yloxy)acetate (0.3 g, 1.297 mmol) in MeOH (70 mL) was added Platinum(IV) oxide (0.08 g, 0.352 mmol) under N2 atmosphere. The reaction was stirred under 3 kg H2 pressure at RT for 18 hrs. The reaction was filtered through Celite, washed with methanol, and the filtrate was concentrated to afford ethyl 2-((1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate as a yellow gum (0.25 g 85%). 1H NMR: 400 MHz, DMSO-d6: δ 1.20 (t, J=7.20 Hz, 3H), 1.76 (t, J=6.40 Hz, 2H), 2.62 (t, J=6.00 Hz, 2H), 3.11 (dd, J=2.00, 7.20 Hz, 2H), 4.13 (q, J=7.20 Hz, 2H), 4.56 (s, 2H), 5.26 (s, 1H), 6.35 (d, J=8.40 Hz, 1H), 6.47-6.51 (m, 2H), 6.58-6.61 (m, 1H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:25])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=O)C>CCCCCC.CC(C)=O>[CH3:16][C@@:15]12[C:14](=[O:24])[CH2:13][CH2:12][C@H:11]1[C@@H:10]1[C:9]([CH:8]=[C:7]3[CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21][C@:20]3([CH3:23])[C@H:19]1[CH2:18][CH2:17]2)=[O:25]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C[C@]12CC[C@H](O)CC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
The last remains of the product (3) from the mother liquor were obtained by column chromatography of the mother liquor (adsorbed on silica gel) on a small column of silica gel (80-200 mesh) utilizing hexane-acetone (85:15) as eluent. An additional 0.15 gm of 7-oxo-DHEA-Ac (3) was obtained. Total yield 1.75 gm, 56.5% (based on 90% conversion), melting point 185-186° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CO.O.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>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)[CH:3]=2)=[CH:39][CH:38]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cccc(Br)c4)ccc3c1)n2C1CCCCC1
Reactant: OB(O)c1ccc(Cl)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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cccc(-c5ccc(Cl)cc5)c4)ccc3c1)n2C1CCCCC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 42.2 %

Procedure:
In dried vial with a Teflon lined screw cap, a solution of Compound 482 (156 mg, 0.31 mmol), 4-chlorophenylboronic acid (73 mg, 0.465 mmol), and Palladium Tetrakis (37 mg, 0.031 mmol) in toluene (9 mL), methanol (2 mL), and saturated sodium bicarbonate in water (900 μL) was degassed, flushed with argon, and sealed. The reaction was stirred for 16 h at 90° C. The completed reaction was then evaporated to dryness, purified via HPLC, and converted to the HCl salt using the standard procedure (as described in Compound 516) to produce the title compound (73 mg, 42% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13]CC)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[ClH:16]>>[ClH:16].[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(N)sc2c1
Agent: Cl
Product: Nc1nc2ccc(C(=O)O)cc2s1

Procedure:
500 mg of ethyl 2-aminobenzothiazole-6-carboxylate (Maybridge Co., UK) was stirred in 20 ml of 4 M hydrochloric acid at 80° C. for 5 hours. The solvent was evaporated, and the residue was washed with a solvent mixture of ethyl acetate/hexane to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:6][CH:7]=1
Reactant: COc1cccc(-c2ncc(Br)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ncc(Br)cc2N)c1
Temperature: 70 °C
Reaction time: 23 h

Procedure:
To a stirred mixture of 5-bromo-2-(3-methoxyphenyl)-3-nitropyridine (0.19 g, 0.61 mmol) in EtOAc (10 mL) was added tin(II) chloride dihydrate (0.70 g, 3.10 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 70° C. After 23 h, the reaction was cooled to rt and diluted with ethyl acetate, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The beige solid was identified as mostly 5-bromo-2-(3-methoxyphenyl)pyridin-3-amine. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (1H, quin, J=1.6 Hz), 7.30 (1H, m), 7.12 (2H, m), 6.87 (1H, m), 3.96 (2H, br. s.), 3.72 (3H, t, J=1.4 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[CH:22][C:21]3[C:17](=[C:18]([CH3:27])[N:19]([CH:24]4[CH2:26][CH2:25]4)[N:20]=3)[CH:16]=2)[C:11](=[O:28])[CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[CH:24]1([N:19]2[C:18]([CH3:27])=[C:17]3[C:21]([CH:22]=[CH:23][C:15]([N:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]4=[O:28])=[CH:16]3)=[N:20]2)[CH2:25][CH2:26]1
Reactant: Cc1c2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc2nn1C1CC1
Agent: [Pd]
Solvent: CO
Product: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of 4-(benzyloxy)-1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)pyridin-2(1H)-one (256 mg) in methanol (5 ml) was added 10% palladium carbon (100 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere at the same temperature for 1 hr. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (182 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[C:8]([Cl:23])=[C:7]([CH3:24])[C:6]=1[C:25](=[O:27])[CH3:26].Cl.[F:29][C:30]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31]1>>[Cl:23][C:8]1[C:7]([CH3:24])=[C:6]([C:25](=[O:27])[CH3:26])[C:5]([O:4][CH2:3][CH2:2][N:32]2[CH2:33][CH2:34][C:30]([F:35])([F:29])[CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[O:21][CH3:22]
Reactant: FC1(F)CCNC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCC(F)(F)C2)c1OCCCc1ccccc1
Yield: 16 %

Procedure:
Example 34b (58 mg, 0.13 mmol) and 3,3-difluoropyrrolidine hydrochloride (2.5 eq.) were reacted as described under General Procedure J and the crude product was purified by flash chromatography (silica gel, hexane/Et2O 70:30) to afford the title compound as a pale yellow oil (10 mg, 16%). 1H NMR (300 MHz, CDCl3) δ 7.33-7.18 (m, 5H), 4.08 (t, J=6.2 Hz, 4H), 3.88 (s, 3H), 2.96 (t, J=13.4 Hz, 2H), 2.85-2.73 (m, 6H), 2.51 (s, 3H), 2.31-2.13 (m, 2H), 2.20-2.04 (m, 2H). MS (ES+) m/z 482.1 (M+H+).
Reaction SMILES: Cl.Cl[CH:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[C:15]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[CH:14]2.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>C(#N)C>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:5]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[C:15]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[CH:14]2
Reactant: C1CCNC1
Reactant: Cc1cccc(C(Cl)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: Cl
Solvent: CC#N
Product: Cc1cccc(C(c2ccccc2)N2CCCC2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 100 °C

Procedure:
A Smith synthesizer vial containing 6-(2-(chloro(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine hydrochloride (0.050 g, 0.104 mmol) and ACN (0.42 mL) was treated with pyrrolidine (0.052 mL, 0.624 mmol). The reaction mixture was warmed to 100° C. for 1 h and then allowed to cool to RT. The mixture was purified by HPLC (1-70% ACN/H2O, TFA modifier). A single clean fraction was treated with NH4OH and concentrated to ¼ volume. The resulting precipitate was collected and dried under a stream of N2 to afford 6-(2-methyl-6-(phenyl(pyrrolidin-1-yl)methyl)phenyl)-3-morpholinoquinolin-2-amine. MS (ESI, pos. ion) m/z: 479 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[N:9][CH:10]=[C:11]([CH:32]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26].O1CCOCC1>Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[N:9][CH:10]=[C:11]([CH:32]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[O:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 307.4 %

Procedure:
A solution of tert-butyl {[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetate (0.76 g, 1.7 mmol) in 4 M HCl in 1,4 dioxane (30 mL, 120 mmol) was heated at 70° C. for 1 h. The reaction mixture was concentrated to a solid that was suspended in diethyl ether, filtered, and washed with diethyl ether to give the desired product (0.82 g, 104%) as a white solid. LCMS for C19H17ClN5O3 (M+H)+: m/z=398.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:17])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:17][N:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8]1
Reactant: CCOC(=O)c1cc(-c2ccccc2)nn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.32 g, 1.39 mmol) was dissolved in 4.5 mL of tetrahydrofuran, 1.5 mL of methanol and 1.5 mL of water, and treated with lithium hydroxide hydrate (0.12 g, 2.78 mmol). After stirring at room temperature overnight, the mixture was acidified (pH =1) with hydrochloric acid, and extracted with ethyl acetate (3×10 mL) and the combined organic phases washed with 10 mL of brine. The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford a quantitative yield of the title compound.