Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3]([NH2:5])=[O:4].[Br:7][C:8]1[CH:14]=[CH:13][C:11](N)=[CH:10][CH:9]=1.ClC1C=CC(Cl)=CC=1Cl.CNC>>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:5][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CN(C)C(N)=O
Agent: CNC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CN(C)C(=O)Nc1ccc(Br)cc1
Temperature: 205 °C
Reaction time: 5.5 h

Procedure:
3.35 g (0.038 mol) of N,N-dimethylurea and 4.3 g (0.025 mol) of 4-bromoaniline were added with stirring into 28 ml of 1,2,4-trichlorobenzene, after which the mixture was slowly heated to 205° C. Dimethylamine was introduced from 50° C. After 5.5 hours, 11.6 g (0.25 mol) of dimethylamine had been introduced, and the reaction was complete. The reaction mixture was cooled to room temperature whereupon a precipitate deposited, which was filtered off, washed with 1,2,4-trichlorobenzene, dried at 100° C. in vacuo and then boiled in 100 ml of water. The aqueous mixture was cooled, and the precipitate was filtered off with suction and dried. 4.73 g of N-(4-bromophenyl)-N',N'-dimethylurea, i.e. 78% of theory, having a melting point of 168° to 170° C. were obtained in this way.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-:18].[C:19]([O:23][C:24]([N:26]([CH3:52])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]2[CH:51]=[CH:50][C:38]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44]OS(C)(=O)=O)=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].ClCCl>C1COCC1>[C:19]([O:23][C:24](=[O:25])[N:26]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]2[CH:51]=[CH:50][C:38]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][F:18])=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)[CH3:52])([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCOS(C)(=O)=O)cc2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCF)cc2)cc1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
Anhydrous TBAF (Cox D P, et al., J Org Chem. 1984; 49:3216-19) (38.5 mg 0.15 mmol) was added to a solution of compound 10a (14.5 mg, 0.03 mmol) in anhydrous THF (3 ml). The mixture was refluxed for 4 hours. After cooled to room temperature, standard workup with dichloromethane was applied and the residue was purified by silica gel preparative TLC (2% methanol in dichloromethane) to afford compound 11a (7 mg, 57%): 1H NMR δ 7.43 (d, 4H, J=8.6 Hz), 7.20 (d, 2H, J=8.4 Hz), 6.97 (q, 2H), 6.91 (d, 2H, J=8.6 Hz), 4.60 (d, t, 2H, J1=47 Hz, J2=4.0 Hz), 4.17 (t, 2H), 3.90 (t, 3H), 3.75 (t, 1H), 3.27 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]=1[NH:6][C:7](=[O:10])[CH2:8][Cl:9])([O-:3])=[O:2].[CH3:18][O:19][CH2:20]Cl.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:9][CH2:8][C:7]([N:6]([CH2:18][O:19][CH3:20])[C:5]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2])=[O:10]
Reactant: O=C(CCl)Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCN(C(=O)CCl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 0.83 h
Yield: 80 %

Procedure:
To a 500 ml. stirred flask was added 3.0 g. (0.012 moles) of 2',6'-dinitro-2-chloroacetanilide, 2.5 ml. of chloromethyl methyl ether, 1.0 g. of phase transfer catalyst and 150 ml. of methylene chloride. Thereafter, 75 ml. saturated sodium carbonate solution was added in one portion and stirring continued for 50 minutes. At the end of this period, water was added to aid separation and the aqueous/organic mixture was allowed to stand overnight. The product, 2-chloro-2',6'-dinitro-N-(methoxymethyl)acetanilide, 2.9 g. m.p. 105.5°-108° C. was obtained in 80% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[C:24]([N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])(=[O:26])[CH3:25]>>[C:24]([N:27]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[N:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:28]1=[O:32])(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)nc2)C1=O
Yield: 52 %

Procedure:
Using (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (550 mg) described in Preparation Example 134 and 1-acetyl-2-imidazolidinone (188 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (322 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=O)[CH:25]=2)[CH:20]=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:27]([C:24]5[CH:25]=[C:26]6[C:21]([CH:20]=[CH:19][NH:18]6)=[CH:22][CH:23]=5)=[O:29])=[CH:13][CH:12]=3)[N:6]=[CH:5]4)=[O:29])[CH:25]=2)[CH:20]=[CH:19]1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: O=C(Nc1ccc(-n2ncc3cc(NC(=O)c4ccc5cc[nH]c5c4)ccc32)cc1)c1ccc2cc[nH]c2c1

Procedure:
Compound 523 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 1H-indole-6-carboxylic acid. [M+H]+ calcd for C31H22N6O2: 511.18; found: 511.02.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([N:31]([CH2:33][C:34]2[O:38][C:37]([C:39](OC)=[O:40])=[N:36][N:35]=2)[CH3:32])(=[O:30])=[O:29])=[C:23]([CH3:43])[CH:22]=1.CO>C1COCC1>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([N:31]([CH3:32])[CH2:33][C:34]2[O:38][C:37]([C:39]([N:12]3[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH2:14][CH2:13]3)=[O:40])=[N:36][N:35]=2)(=[O:30])=[O:29])=[C:23]([CH3:43])[CH:22]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: C1CCN(CCCN2CCNCC2)C1
Agent: C[Al](C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CCCN4CCCC4)CC3)o2)c(C)c1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
1-(3-Pyrrolidin-1-ylpropyl)piperazine (128 mg, 1.65 mmol) was dissolved in THF (5 mL) and the resulting solution was cooled to −40° C. prior to the addition of trimethylaluminium (2 M in toluene, 0.59 mL). The reaction was stirred for 15 min at −40° C. and a solution of methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (200 mg, 0.54 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at ambient temperature for 18 h and MeOH (5 mL) was added. The solvents were removed in vacuo and the resulting residue was purified by FCC, eluting with 0-2% MeOH in DCM to afford the title compound as a pale yellow semi solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[C:18]([CH3:21])[N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Br)[N:24]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[S:20][CH:19]=[C:18]([CH3:21])[N:7]3[C:8](=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH3:3])[N:24]=1
Reactant: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc([C@H](C)Nc3nc(N)nc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 18.7 %

Procedure:
A solution of 7-[(1S)-1-aminoethyl]-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.33 mmol) and 2-amino-6-bromopurine (0.11 g, 0.49 mmol) in 1-butanol (0.66 mL) was treated with N,N-diisopropylethylamine (86 μL, 0.49 mmol), degassed with nitrogen for 5 min and heated at 100° C. for 18 hours. The reaction was not complete and was, therefore, heated at 115° C. for an additional 5 hours. The reaction mixture was diluted with methanol (10 mL), stirred, and filtered. The filtrate was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (27 mg, 19%) as a white solid. LCMS for C20H18FN8OS (M+H)+: m/z=437.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([C:3]3[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)=[CH:10][CH:9]=[C:8]4[C:4]=3/[C:5](=[CH:12]/[C:13]3[NH:14][CH:15]=[CH:16][C:17]=3[O:18][CH3:19])/[C:6](=[O:11])[NH:7]4)=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc4[nH]ccc4c3)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(-c3ccc4[nH]ccc4c3)c21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (Z)-5-amino-1,3-dihydro-4-(5-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (24 mg, 0.065 mmol) (from Step B above) in 2 mL tetrahydrofuran was added 2-thiopheneacetyl chloride (24 mg, 0.15 mmol) (Aldrich) and a saturated aqueous solution of sodium bicarbonate (0.15 mL). The reaction was stirred at room temperature for 14 hours at which time the reaction was diluted with water (10 mL), and the THF was evaporated in vacuo. The product was then extracted with EtOAc, and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The resulting powder was recrystallized from EtOAc/Hex to give product as yellow crystals. (Yield 23 mg, 72%).
Reaction SMILES: N[C:2]1C(=O)C2[C:9]([C:10](=[O:13])[C:11]=1N)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:15]1([C:21](=O)[C:22](=[O:24])[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C.O>[CH3:2][C:11]1[C:10](=[O:13])[C:9]2[C:23]([C:22](=[O:24])[C:21]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: NC1=C(N)C(=O)c2ccccc2C1=O
Reactant: CC(=O)C(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)c2ccccc2C1=O
Reaction time: 0.08 h
Yield: 94.5 %

Procedure:
In a 200 ml of Erlenmeyer flask were placed 5.0 g (26.5 mmols) of 2,3-diaminonaphthoquinone and 75 ml of acetic acid/water (1/1), a solution composed of 5.9 g (39.8 mmols) of 1-phenyl-1,2-propanedione and 25 ml of acetic acid/water (1/1) was added dropwise to the mixture under ice-cooling over a period of about 10 minutes, and after stirring the mixture for 5 minutes, yellow precipitates thus formed were collected by filtration and washed with water. The precipitates were dissolved in methylene chloride, and after purifying the product with silica gel short column (eluted by methylene chloride), the product was recrystallized from methylene chloridemethanol to provide 6.22 g (78%) of 2-methyl-3-phenylnaphthoquinone (Compound Id-11) as a yellow powder. Melting point 235°-236° C. The infrared spectrum of the compound obtained is shown in FIG. 7.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[CH3:17][CH:18]1[CH2:22][CH2:21][C:20](=O)[C:19]1=[O:24].C(O)(=O)C>C(O)C>[CH3:17][CH:18]1[C:19](=[O:24])[C:20]([N:14]2[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)=[CH:21][CH2:22]1
Reactant: CC1CCC(=O)C1=O
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(C#CC=C2CCN(C3=CCC(C)C3=O)CC2)n1

Procedure:
A mixture of the Compound of Example 3 (500 mg, 2.36 mmol), 3-methyl-1,2-cyclopentanedione (350 mg, 3.11 mmol), acetic acid (0.18 mL, 3.11 mmol) in ethanol (10 mL) was refluxed for 8 h. The reaction mixture was evaporated, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 85:15, affording the title product as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]2)=[N:21][CH:22]=1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]3)=[N:21][CH:22]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)C1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 45.6 %

Procedure:
Following General procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (284 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)pyrrolidin-3-ylcarbamate (439 mg, 1.5 mmol) to afford the desired product (240 mg, 46%) as a yellow solid: ESI MS ink 526 [C25H28BrN5O3+H]+.
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[CH3:18][NH:19][CH3:20]>C(Cl)Cl>[CH3:18][N:19]([CH3:20])[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3]
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Reactant: CNC
Solvent: ClCCl
Product: C[C@@H](CS(=O)(=O)N(C)C)C(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
A 100 mL round bottomed flask equipped with magnetic stir bar was charged with 1.7 g benzyl 3-chlorosulfonyl-2(R)-methylpropionate from Example 3 in 25 mL CH2Cl2. The solution was cooled to −78° C. and 15 mL of anhydrous dimethylamine was slowly added. After 30 minutes the reaction was concentrated in vacuo and the residue was partioned between EA/H2O. The organic phase was dried, concentrated in vacuo to yield 1.4 g of benzyl 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionate as a clear amber oil which was used directly in the next step. Part B: 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionic acid A 100 mL Fisher/Porter vessel was charged with 1.4 g of benzyl 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionate in 30 mL acetic acid with a catalytic amount of 10% Pd—C. The reaction was hydrogenated at 50 psi for 24 hours, filtered through Celite and concentrated in vacuo. The residue was azeotroped with toluene then concentrated in vacuo to afford 900 mg of 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionic acid which was used without further purification.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8].[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][N:23]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(c1ccccc1)CC2(C)C
Reaction time: 0.08 h

Procedure:
A mixture of Cu(OAc)2 (8.21 mg, 0.045 mmol) and pyridine (3.66 μl, 0.045 mmol) in CH2Cl2 (0.5 mL) was stirred for 5 min. Added to this were methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (10 mg, 0.023 mmol), phenylboronic acid (5.51 mg, 0.045 mmol) and 17 mg molecular sieves. The resulting mixture was stirred at room temperature open to air for 17 h. The mixture was adsorbed directly onto silica gel and purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane). 1H NMR (500 MHz, CDCl3) δ ppm 7.38 (ddd, J=8.4, 5.8, 2.3 Hz, 1H), 7.27-7.16 (m, 5H), 6.87-6.73 (m, 3H), 4.86 (s, 1H), 3.94 (d, J=15.6 Hz, 1H), 3.73 (s, 3H), 3.69 (d, J=15.6 Hz, 1H), 3.55 (dt, J=13.0, 6.4 Hz, 1H), 3.44-3.34 (m, 1H), 3.28 (d, J=12.5Hz, 1H), 1.49 (d, J=3.7 Hz, 6H), 1.33 (d, J=6.1 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H), 1.01 (s, 9H). 19F NMR (500 MHz, CDCl3) δ ppm −113.64. LCMS (M+H) calcd for C32H40FN2O3: 519.30. found: 519.45.
Reaction SMILES: O[C:2]1[C:7]([I:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:2]1[C:7]([I:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(I)c1
Temperature: 140 °C
Yield: 83.3 %

Procedure:
2-Hydroxy-3-iodo-5-nitropyridine (2.55 g, 9.5 mmol), phosphorous pentachloride (2.60 g, 12 mmol) and phosphorous oxychloride (2 mL) were combined in a flask under nitrogen and heated to 140° C. for 45 mins. The cooled reaction mixture was poured over ice to give a solid which was partitioned between CH2Cl2 and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and the solvent was removed in vacuo to give compound 765B (2.25 g, 83%) as a yellow solid. HPLC: 98.5% at 2.75 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:15]([CH3:29])[C:16]([C:18]1[CH:19]=[C:20]([CH:25]=[C:26](I)[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH2:12][CH2:13][CH3:14]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([N:15]([CH3:29])[C:16]([C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: c1cocn1
Reactant: CCCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (167 mg, 2.4 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.7 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 7.3 mL, 7.3 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-{[butyl(methyl)amino]carbonyl}-5-iodobenzoate (864 mg, 2.3 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0)tetrakis(triphenylphosphine) (112 mg, 0.10 mmol). The reaction mixture is heated at reflux for 1.5 h. The reaction mixture is cooled, diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound. ESI MS m/z 317.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:8][C:7]([O:16]CC1C=CC3C(=CC=CC=3)N=1)=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CS(C)=O.O>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][O:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]([CH3:1])=[C:10]2[CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH3:45]
Reactant: Cc1c(CC(=O)NN)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1
Reaction time: 4 h
Yield: 68.5 %

Procedure:
A solution of 310 mg (1 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide (Example 62) in 25 mL of DMSO was treated with 45 mg (1.1 mmol) of 60% NaH/mineral oil and after 0.25 hours, 0.16 mL (1.1 mmol) of ethyl 4-bromobutyrate was added. The mixture was stirred for 4 hours, diluted with water and extracted with EtOAc. The EtOAc solution was washed with NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with CH2Cl2 →4% MeOH/CH2C2, to give 290 mg (68% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid ethyl ester. This ester (0.685 mmol) and 2 mL of 2N NaOH in 25 mL of EtOH and 5 mL of THF was stirred for 22.5 hours. The mixture was diluted with water, made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (Na2SO4), and concentrated at reduced pressure. The residue was dissolved in EtOH and precipitated with ether to give 50 mg (47% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid, mp, 160° C. (decomposition).
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[C:13]([O:16][CH2:17][C:18]#[N:19])[C:12]=2[CH:20]=1)([O-])=O>[Fe].C(OCC)(=O)C>[NH2:5][C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[C:13]([O:16][CH2:17][C:18]#[N:19])[C:12]=2[CH:20]=1
Reactant: N#CCOc1nsc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#CCOc1nsc2ccc(N)cc12
Temperature: 50 °C

Procedure:
A mixture of iron powder (13.0 g, 0.233 mol) in a 5% acetic acid solution (65.0 mL) is heated to 50° C., treated portionwise with a mixture of [(5-nitro-1,2-benzisothiazol-3-yl)oxy]acetonitrile (11.0 g, 0.047 mol), acetic acid (100 mL) and ethyl acetate (65.0 mL), refluxed for two hours, cooled to 40° C., and filtered to remove solids. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and the organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as an oil which is identified by NMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@@H:17]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:18](OC)=[O:19])=[O:15])[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:9]=[CH:8]2.[BH4-].[Na+]>C1COCC1.CCO>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@@H:17]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][OH:19])=[O:15])[N:10]([CH2:27][CH:28]([CH3:29])[CH3:30])[N:9]=[CH:8]2
Reactant: COC(=O)[C@H](CCN(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H](CO)CCN(C)C)cc21
Temperature: 60 °C
Yield: 96.3 %

Procedure:
A mixture of (S)-methyl 2-(5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxamido)-4-(dimethylamino)butanoate (30d; Example 120, Steps A-E) (0.370 g, 0.76 mmol) and NaBH4 (0.114 g, 3.04 mmol) in THF/EtOH (20 mL, 3:2) was heated to 60° C. for 7 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane. The slurry was chromatographed on Biotage eluting with 10% MeOH in dichloromethane with 1% triethylamine. The product was obtained as 0.337 g of viscous oil (97% yield). MS (ESI+) m/z 461 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 8.34 (d, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.13 (m, 1H), 7.02 (s, 1H), 7.00 (m, 1H), 6.90 (m, 1H), 4.33 (m, 1H), 4.22 (d, 2H), 3.64 (m, 2H) 2.37 (m, 1H), 2.17 (s, 6H), 2.10 (m, 1H), 1.82 (m, 1H), 1.07 (m, 2H), 0.93 (d, 6H).