Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:57])[CH2:32][CH2:33][C@@H:34]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][C:45]=1[N+:54]([O-:56])=[O:55])[CH2:35][S:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:53][S:50]([C:47]4[CH:48]=[CH:49][C:44]([NH:43][C@@H:34]([CH2:35][S:36][C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH2:33][CH2:32][N:31]([CH3:30])[CH3:57])=[C:45]([N+:54]([O-:56])=[O:55])[CH:46]=4)(=[O:51])=[O:52])=[O:26])=[CH:28][CH:29]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCN(Cc4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1[N+](=O)[O-]

Procedure:
A mixture of EXAMPLE 2C (3.683 g), 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide (3.53 g), EDAC.HCl (3.32 g) and DMAP (2.12 g) in dichloromethane (500 mL) at 25° C. was stirred for 8 hours, washed with saturated NH4Cl (330 mL), and dried (MgSO4), filtered, and concentrated. The concentrate was flash chromatographed on silica gel with 1%, 2%, 5%, 10%, and 15% methanol/NH3-saturated dichloromethane. 1H NMR (DMSO-d6) δ 12.10 (br s, 1H), 11.18 (br s, 1H), 10.40 (br s, 1H), 8.54 (s, 1H), 8.29 (d, 1H), 8.10 (br s, 1H), 7.85 (d, 1H), 7.77 (d, 2H), 7.52 (d, 4H), 7.40-7.36 (m, 2H), 7.35-7.32 (m, 1H), 7.26-7.21 (m, 2H), 7.16-7.09 (m, 3H), 6.93 (d, 2H), 4.34 (br s, 2H), 4.35-4.23 (m, 1H), 3.88 (br s, 2H), 3.42-3.36 (m, 4H), 3.17-3.07 (m, 2H), 2.90-2.78 (m, 2H), 2.50 (s, 6H), 2.20-2.15 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]12(O)[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2.CS(O)(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[C:10]12([C:6]3[CH:7]=[C:2]([Br:1])[C:3]([CH3:9])=[CH:4][C:5]=3[OH:8])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2
Reactant: Cc1cc(O)ccc1Br
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Temperature: 54 °C
Yield: 84.3 %

Procedure:
A mixture of 4-bromo-3-methylphenol (4.68 g, 25 mmol), 1-adamantanol (3.81 g, 25 mmol), and MeSO3H (1.2 mL) in CH2Cl2 (18 mL) was stirred and heated at 54° C. (oil-bath) for 28.8 h. The resulting solution was diluted with CHCl3 (150 mL), washed with H2O, 5% NaHCO3, and brine and dried. The residue obtained on concentration was washed with hot hexane to give 6.77 g (85%) of 2-(1-adamantyl)-4-bromo-5-methylphenol as a white solid, mp 155-156° C. IR 3541, 2905, 2845, 1147 cm−1; 1H NMR δ (CDCl3) 1.77 (bs, 6H, AdCH2), 2.07 (bs, 9H, AdCH and AdCH2), 2.28 (s, 3H, CH3), 4.67 (s, 1H, OH), 6.54 (s, 1H, 6-ArH), 7.30 (s, 1H, 3-ArH).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@@H:17]([O:19][CH:20]=[CH2:21])[C@H:16]([O:22][CH2:23][O:24][CH3:25])[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:27]I.C([Zn]CC)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@@H:17]([O:19][CH:20]3[CH2:27][CH2:21]3)[C@H:16]([O:22][CH2:23][O:24][CH3:25])[CH2:15]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OCOC
Reactant: ICI
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COCO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OC1CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 229 mg of 2-benzyl-6-[(3R,4R)-3-methoxymethyloxy-4-vinyloxypyrrolidine-1-yl]pyridine, 217 μl of diiodomethane, 1.35 ml of hexane solution containing 1.0 mol of diethylzinc and 3 ml of toluene was stirred at 80° C. for 3 hours. Ammonium chloride was added to the reaction solution, and the mixture was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 15% ethyl acetate/hexane, to give 47.8 mg of the target compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10]Br.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21].O>CC(CC)=O>[C:20]([C:19]1([C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:10][C:4]2[C:3](=[CH:8][CH:7]=[C:6]([F:9])[CH:5]=2)[CH2:2]1)(=[O:21])[CH3:22]
Reactant: Fc1ccc(CBr)c(CBr)c1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)C1(C(=O)OCc2ccccc2)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.9 %

Procedure:
To 5 g of 1,2-bis-(bromomethyl)-4-fluoro-benzene in 100 ml of methylethylketone were added 14.7 g of potassium carbonate followed by 4.1 g of benzyl acetoacetate. The mixture was stirred for 16 h at ambient temperature. 100 ml of water were added. The phases were separated and the aqueous phase was extracted once with 50 ml of methylethylketone. The combined organic phases were evaporated to give 6.2 g of crude product as an oil. The crude product was crystallized from cold heptane and from cold methanol. Melt.p. 55° C. 1HNMR: δ=2.16 ppm (s, 3H); 3.50 ppm (AB, 2H); 3.53 ppm (AB, 2H); 5.22 (s, 2H); 6.88 ppm (m, 2H); 7.12 ppm (dd, 1H) 7.30-7.42 ppm (m, 5H).
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[CH:30]([O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([CH3:32])[CH3:31].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[N:9]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH:30]([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(-c3ccc(OC(C)C)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reaction time: 48 h
Yield: 75.1 %

Procedure:
To a suspension (20 mL) of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.5 g), (4-isopropoxyphenyl)boronic acid (0.43 g), triethylamine (0.86 mL), pyridine (0.48 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.45 g) and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.5 g, 75%).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:32][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccc(C#N)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (400 mg, 1.94 mmol), 2-amino-5-cyano-indan-2-carboxylic acid ethyl ester (670 mg, 2.91 mmol), HATU (1.11 g, 2.91 mmol) in anhydrous DMF (15 mL) is added DIPEA (480 μL, 2.91 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-60% EtOAc in heptane) to give a pure product (114) as a white semisolid (682 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:29])[C@H:19]([N:26]([CH3:28])[CH3:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([S:44][C:45]2[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][C:46]=2[NH:54][C:55]2[C:56]3[CH:64]=[CH:63][C:62]([CH:65]([CH3:67])[CH3:66])=[N:61][C:57]=3[N:58]=[CH:59][N:60]=2)=[CH:40][CH:39]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[CH3:28][N:26]([CH3:27])[C@H:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:10]1[NH:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:49]([C:48]3[CH:52]=[CH:53][C:45]([S:44][C:41]4[CH:40]=[CH:39][C:38]([NH:37][C:35](=[O:36])[O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:43][CH:42]=4)=[C:46]([NH:54][C:55]4[C:56]5[CH:64]=[CH:63][C:62]([CH:65]([CH3:67])[CH3:66])=[N:61][C:57]=5[N:58]=[CH:59][N:60]=4)[CH:47]=3)=[O:50])=[CH:3][CH:4]=2)[N:9]=1)=[O:29]
Reactant: CN(C)[C@@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(N)cc2)c[nH]1)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](c6ccccc6)N(C)C)n5)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 55.4 %

Procedure:
A solution of the Product of Example 2C (0.081 g, 0.21 mmol) and the product from Example 1E (0.10 g, 0.188 mmol) was processed in the same manner as in Example 1K to give a solid (0.094 g, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].COC(OC)N(C)C>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:6]2[C:5]([CH:12]=[CH:10][O:9][C:7]2=[O:8])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: O=c1occc2c([N+](=O)[O-])cc(Br)cc12
Temperature: 25 °C
Yield: 33.6 %

Procedure:
A solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (29.0 g, 106 mmol) and N,N-dimethylformamide dimethyl acetal (42.0 mL, 317 mmol) in N,N-dimethylformamide (200 mL) was stirred at 110° C. overnight. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (300 mL) and water (300 mL). The organic phase was separated, washed with water (2×300 mL) and brine (1×3 00 mL), concentrated to dryness in the presence of silica gel, and purified by silica gel chromatography (eluting with a gradient of 0-80% ethyl acetate in heptane) to give 7-bromo-5-nitro-1H-isochromen-1-one (293a, 9.62 g, 32% yield) as a solid. 1H NMR (400 MHz, CDCl3-d) δ 8.76 (d, J=1.47 Hz, 1H), 8.60 (d, J=2.20 Hz, 1H), 7.46 (d, J=6.11 Hz, 1H), 7.34 (d, J=6.11 Hz, 1H). MS: 269 [M+1]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[NH:6][C:7]1[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[N+:20]([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:20][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])[C:7]=1[NH:6][C:5]1[CH:23]=[CH:24][CH:25]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1cccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)c1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: COc1cccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)c1

Procedure:
By substituting 4-(m-methoxyanilino)-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 232°-234° C after recrystallization from aqueous methanol.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[CH3:8].[CH3:14][C:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[C:16](Cl)=[O:17]>O.CCOCC>[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH:12][C:16](=[O:17])[C:15]([CH3:14])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH3:8]
Reactant: CC(C)C(C)(C(=O)Cl)C(C)C
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CNC(=O)C(C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium bicarbonate (1.7g, 0.02 mole) and glycine ethyl ester hydrochloride (1.4g, 0.01 mole) were dissolved in water (10 ml) and a solution of 2,3-dimethyl-2-isopropylbutanoyl chloride (1.6g, 0.009 mole) in ether (10 ml) was added. The mixture was stirred vigorously at room temperature for 2 hours. After 16 hours at room temperature the ether layer was separated and dried (MgSO4). Removal of the solvent left a white solid which was recrystallised from ether/petroleum ether to give N-(2,3-dimethyl-2-isopropylbutanoyl)glycine ethyl ester, mp. 74.5°-75.5°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C[Si]([C:23]#[CH:24])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:23]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)#[CH:24]
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#Cc1cc(Oc2ccc([N+](=O)[O-])nc2C)ccn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 10.6 %

Procedure:
To a degassed solution of Example A4 (5.0 g, 18.8 mmol) in DMF (30 mL) was added TEA (7.87 mL, 56.5 mmol), Pd(PPh3)2Cl2 (0.661 g, 0.941 mmol), copper(I) iodide (0.179 g, 0.941 mmol), and trimethylsilylacetylene (7.9 mL, 56 mmol) and the mixture was stirred at 50° C. for 16 h. The mixture was diluted with EtOAc (60 mL) and filtered through diatomaceous earth, washing the pad with EtOAc (5×10 mL). The combined filtrates were concentrated to a volume of ˜20 mL, treated with a solution of TBAF (1M in THF, 38 mL, 38 mmol), and stirred at RT for 3 h. The mixture was partitioned between EtOAc (200 mL) and water (200 mL) and stirred for a few minutes. The resultant emulsion was filtered through diatomaceous earth, washing with water (2×20 mL) and EtOAc (3×20 mL). The filtrate layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (EtOAc/Hex) to afford 3-((2-ethynylpyridin-4-yl)oxy)-2-methyl-6-nitropyridine (0.51 g, 10.6%) as a light brown solid. MS (ESI) m/z: 256.1 (M+H+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][C@@H:26]4[CH3:35])=[CH:21][N:20]=3)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=2)=[CH:10][C:9]([F:38])=[CH:8][C:7]=1[N:39]1[CH2:53][CH2:52][N:42]2[C:43]3[CH2:44][C:45]([F:51])([F:50])[CH2:46][CH2:47][C:48]=3[CH:49]=[C:41]2[C:40]1=[O:54])(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[F:51][C:45]1([F:50])[CH2:44][C:43]2[N:42]3[CH2:52][CH2:53][N:39]([C:7]4[CH:8]=[C:9]([F:38])[CH:10]=[C:11]([C:12]5[CH:17]=[C:16]([NH:18][C:19]6[CH:24]=[CH:23][C:22]([N:25]7[CH2:30][CH2:29][N:28]([CH:31]8[CH2:32][O:33][CH2:34]8)[CH2:27][C@@H:26]7[CH3:35])=[CH:21][N:20]=6)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=5)[C:6]=4[CH2:5][OH:4])[C:40](=[O:54])[C:41]3=[CH:49][C:48]=2[CH2:47][CH2:46]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(F)(F)CC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(F)(F)CC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
A mixture of 113q (37 mg, 0.05 mmol) and lithium hydroxide (12 mg, 0.5 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure. Water (10 mL) was added to the residue and the resulting mixture was extracted with ethyl acetate (2×10 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 113 (20 mg, 57%) as a white solid. MS: [M+H]+ 704.3. 1H NMR (500 MHz, CDCl3) δ 8.57-8.54 (m, 1H), 7.95 (d, J=3.0 Hz, 1H), 7.82 (d, J=3.5 Hz, 1H), 7.45-7.41 (m, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.19-7.16 (m, 1H), 6.99-6.95 (m, 1H), 6.88 (d, J=6.5 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 5.97 (d, J=11.5 Hz, 1H), 4.71-4.64 (m, 4H), 4.54 (d, J=12.0 Hz, 1H), 4.35-4.18 (m, 5H), 3.99-3.95 (m, 1H), 3.71 (s, 3H), 3.53 (t, J=6.0 Hz, 1H), 3.47-3.45 (m, 1H), 3.17 (t, J=12.0 Hz, 1H), 3.08 (t, J=5.0 Hz, 2H), 2.90 (t, J=8.5 Hz, 1H), 2.79 (t, J=6.0 Hz, 1H), 2.66-2.63 (m, 1H), 2.56 (d, J=11.0 Hz, 1H), 2.49-2.47 (m, 2H), 2.30-2.20 (m, 2H), 0.99 (d, J=6.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C([Li])CCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:25])=[C:20]([CH:24]=1)C(Cl)=O>C1COCC1.N1C=CC=CC=1C1C=CC=CN=1>[Br:15][C:16]1[CH:24]=[CH:20][C:19]([F:25])=[C:18]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH:17]=1
Reactant: O=C(Cl)c1cc(Br)ccc1F
Reactant: CCOC(=O)CC(=O)O
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Br)ccc1F
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
3-Ethoxy-3-oxopropanoic acid (B) (2.16 mL, 18.3 mmol, 2.00 eq) was dissolved in THF (91 mL) in an oven dried round-bottom flask and 2,2′-bipyridyl (8.00 mg, 0.0512 mmol, 0.0056 eq) was added as an indicator. The reaction was cooled to −30° C. and n-butyllithium (1.6 M in hexanes) (29.0 mL, 45.6 mmol, 4.00 eq) was added dropwise over 20 minutes. Upon final addition the reaction turned red at which point it was allowed to warm to −5° C. The reaction was allowed to stir at −5° C. for 15 minutes, during which time the red color began to dissipate. Enough n-butyllithium was added to cause the red color to persist. The reaction was then cooled to −78° C. and 5-bromo-2-fluoro-benzoyl chloride (A) (2.17 g, 9.14 mmol, 1.00 eq) was added dropwise as a solution in THF (6.9 mL). The reaction was allowed to stir at −78° C. for 30 minutes and then allowed to warm to −30° C. and stirred for an additional 30 minutes. The reaction was poured onto ice-cold 1N HCl (92 mL) and the mixture was extracted with ethyl acetate (lx) and DCM (2×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using 0-10% hexanes/ethyl acetate afforded 1.78 g (67%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J=6.5, 2.6 Hz, 1H), 7.91-7.86 (m, 1H), 7.40-7.34 (m, 1H), 4.13-4.07 (m, 4H), 1.15 (t, J=7.1 Hz, 3H); ES-MS [M+1]+: 289.0.
Reaction SMILES: CI.C(=O)([O-])[O-].[K+].[K+].O1CCOC[CH2:10]1.[F:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[NH:18][N:17]=1>C(OCC)(=O)C>[F:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[N:18]([CH3:10])[N:17]=1
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(F)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1nc(F)c2cc([N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Methyl iodide (41 μl) and potassium carbonate (114 mg) were added to a 1,4-dioxane (2.5 ml) solution containing 3-fluoro-5-nitro-1H-indazole (100 mg), followed by stirring at 100° C. for 2 hours. Ethyl acetate was added to the reaction solution. An insoluble precipitate was removed by filtration, the solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1). 3-Fluoro-1-methyl-5-nitro-1H-indazole was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[N+:16]([O-])=O.C(O)(=O)C>C(O)C.[Pd]>[NH2:16][C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[C:2]=1[NH2:1]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c2c1OCCO2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cc(N)c(N)c2c1OCCO2
Yield: 89.2 %

Procedure:
A stirred suspension of methyl 8-amino-7-nitro-1,4-benzodioxan-5-carboxylate (300 mg, 0.0012 mole) in ethanol (30 ml) together with glacial acetic acid (5 ml) was hydrogenareal over 10% Pd-C (100 mg) at atmospheric pressure and temperature for 5 h. The catalyst was filtered off and the filtrate concentrated in vacuo. The residue was basified with concentrated potassium carbonate solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford methyl 7,8-diamino-1,4-benzodioxan-5-carboxylate as a beige solid (240 mg, 92%). 1H NMR (CDCl3) δ:6.91(s,1 H), 4.21(s,4 H), 3.96(br s.2 H), 3.74(s,3 H), 3.0(br s,2 H).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([OH:21])[CH:15]=2)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(C)=O.C(OCC)(=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH:30]([O:21][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[C:12]([CH2:11][NH2:10])[NH:13]2)=[CH:18][CH:17]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:35]
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Reactant: O=C(NCc1cc2ccc(O)cc2[nH]1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Oc1ccc2cc(CN)[nH]c2c1)C(=O)OCC
Reaction time: 8 h

Procedure:
(6-Hydroxy-1H-indol-2-ylmethyl)-carbamic acid benzyl ester was dissolved in 10 ml acetone, Cs2CO3 and diethyl chloromalonate were added. The reaction is stirred overnight. HPLC and TLC indicated the reaction is done. The mixture was diluted with ethyl acetate and filtered through silica gel plug. The filtrate is concentrated and redissolved in ethanol, hydrogenated for 3 hours at 40 psi of hydrogen. The mixture is filtered, washed with ethyl acetate. The filtrate is concentrated to give 2-(2-Aminomethyl-1H-indol-6-yloxy)-malonic acid diethyl ester.