Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH2:12][NH:13][C:14](=[O:16])[CH3:15].C(OCCCC)(=O)C>S(=O)(=O)(O)O>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[CH2:12][NH:13][C:14](=[O:16])[CH3:15]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NCO
Agent: O=S(=O)(O)O
Solvent: CCCCOC(C)=O
Product: CC(=O)NCc1cc([N+](=O)[O-])ccc1C
Yield: 38 %

Procedure:
A solution of p-nitrotoluene (6.85 g; 0.05 mol) in concentrated sulfuric acid (60 ml) is cooled in an ice bath and N-(hydroxymethyl)acetamide (4.45 g; 0.05 mol) is added. The reaction mixture is stirred until a solution is obtained and then continuously stirred for 16 hours at 55° C. The mixture is then poured onto ice and the resulting precipitate is isolated. This solid material is extracted with 85 ml of butyl acetate on a steambath. Concentration of the butyl acetate solution with subsequent cooling gives 3.9 g (i.e., 38% yield) of product. The butyl acetate insoluble material (2.5 g) is methylene bis(4-nitro-o-toluene).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[CH3:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[N:16][N:15]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:19]([C:17]1[S:18][C:14]([CH3:13])=[N:15][N:16]=1)(=[O:21])=[O:20])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: Cc1nnc(S(=O)(=O)Cl)s1
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(C)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-methyl-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H HMR (500 MHz; DMSO-d6) δ 4.07 (q, 2H), 3.27 (s, 2H), 3.09 (t, 2H), 2.82 (s, 3H), 2.62 (t, 2H), 1.18 (t, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH3:11])[CH:6]=[C:7]([CH:9]=O)[N:8]=2)[CH2:3][CH2:2]1.C1(C2N(C)C(C=O)=CN=2)CC1.N(C1C=C(C=CC=1C)C(NC1C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=1OC)=O)=[N+]=[N-].[C:53]([C:57]1[CH:58]=[C:59]([NH:89][S:90]([CH3:93])(=[O:92])=[O:91])[C:60]([O:87][CH3:88])=[C:61]([NH:63][C:64](=[O:86])[C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[C:67]([N:72]3[CH:76]=C(C4N(C)C(C5CC5)=NC=4)[N:74]=[N:73]3)[CH:66]=2)[CH:62]=1)([CH3:56])([CH3:55])[CH3:54]>>[C:53]([C:57]1[CH:58]=[C:59]([NH:89][S:90]([CH3:93])(=[O:91])=[O:92])[C:60]([O:87][CH3:88])=[C:61]([NH:63][C:64](=[O:86])[C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[C:67]([N:72]3[CH:76]=[C:9]([C:7]4[N:8]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]([CH3:11])[CH:6]=4)[N:74]=[N:73]3)[CH:66]=2)[CH:62]=1)([CH3:56])([CH3:54])[CH3:55]
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C5CC5)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cn1cc(C=O)nc1C1CC1
Agent: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cn1c(C=O)cnc1C1CC1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cn(C)c(C5CC5)n4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 47 was prepared from 2-cyclopropyl-1-methyl-1H-imidazole-4-carbaldehyde (as a 1:1 mixture with 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde) and 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide in the same manner as Example 39. Chromatography allowed separation of Example 47 from Example 46. ESI MS m/z 578 [C29H35N7O4S+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:32])[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[N:29]O)[NH2:28])=[CH:23][C:22]=3[Cl:31])=[O:19])[C:12]2=[O:33])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]([OH:37])=[O:36]>CCO.[Ni]>[C:35]([OH:37])(=[O:36])[CH3:34].[C:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18](=[O:19])[C@@H:17]([C@H:13]2[O:14][CH2:15][CH2:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)[C:12]2=[O:33])[OH:32])=[C:22]([Cl:31])[CH:23]=1)(=[NH:28])[NH2:29]
Reactant: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C(N)=NO)cc3Cl)C2=O)cc1
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C(=N)N)cc3Cl)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound 66-2 (19 mg) in EtOH (3 mL), were added cat. Raney-Ni and AcOH (0.1 mL). The mixture was stirred under hydrogen atmosphere for 3 hours at room temperature. The mixture was filtered with Celite® pad to remove catalyst. The filtrate was concentrated with toluene in vacuo. The residue was dried by vacuum pump to obtain EXAMPLE 66 (15 mg) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15](O)=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:24]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:24])=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)cc(O)c2c(=O)n(Cc3ccccc3)cnc21
Product: Cn1c(=O)cc(Cl)c2c(=O)n(Cc3ccccc3)cnc21
Yield: 94 %

Procedure:
3-Benzyl-5-hydroxy-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (1.1 g, 3.88 mmol) was dissolved in excess POCl3 (5 mL) and subjected to microwave irradiation at 70° C. for 30 minutes. The POCl3 was removed in vacuo and the residue dissolved in DCM then quickly washed with saturated sodium bicarbonate solution until neutral pH was observed. The organic layer was dried over MgSO4 and evaporated to dryness to give 1.5 g of the title compound as a reddish brown solid (94%). [M+H] calc'd for C15H12ClN3O, 302. found, 302.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]3[N:11]=[C:12]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[O:29]1C2C=C(C3N=C(C4C=CC(C#N)=CC=4)N(O)C=3C3C=CC=CN=3)C=CC=2CC1>>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]3[N:11]=[C:12]([C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:29])=[CH:27][CH:28]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2nc(-c3ccc4c(c3)OCC4)c(-c3ccccn3)[nH]2)cc1
Reactant: N#Cc1ccc(-c2nc(-c3ccc4c(c3)OCC4)c(-c3ccccn3)n2O)cc1
Product: NC(=O)c1ccc(-c2nc(-c3ccc4c(c3)OCC4)c(-c3ccccn3)[nH]2)cc1

Procedure:
Prepared according to the method of Example 14 from 4-[4-(2,3-dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrile which was prepared from 4-[4-(2,3-dihydro-benzofuran-6-yl)-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrile according to the method of Example 2. 1H NMR (250 MHz, CDCl3) δ: 3.27 (2H, brt, J=8.5 Hz), 4.63 (2H, brt, J=8.5 Hz), 5.50-5.90 (1H, brs), 6.05-6.35 (1H, brs), 7.08-7.20 (3H, m), 7.18-7.30 (3H, m) 7.56 (2H, brs), 8.86 (2H, d, J=8.3 Hz), 8.04 (2H, d, J=8.3 Hz), 8.54 (1H, brd, J=4.5 Hz); m/z (ESMS): 383.5 (MH+).
Reaction SMILES: [CH2:1]([N:3]([C:11]1[S:12][C@H:13]2[O:19][C@@H:18]3[CH2:20][O:21][CH:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:23][C@H:17]3[C@H:16]([OH:30])[C@H:14]2[N:15]=1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C.CCOC(C)=O>C(Cl)Cl>[CH3:31][S:32]([O:30][C@@H:16]1[C@H:14]2[N:15]=[C:11]([N:3]([C:4]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:10])[CH2:1][CH3:2])[S:12][C@H:13]2[O:19][C@@H:18]2[CH2:20][O:21][CH:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:23][C@@H:17]12)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@@H]3OC(c4ccccc4)OC[C@H]3O[C@@H]2S1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OS(C)(=O)=O)[C@@H]3OC(c4ccccc4)OC[C@H]3O[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl ethyl[(3aR,4aR,8aS,9R,9aR)-9-hydroxy-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-2-yl]carbamate (199.00 mg; 0.46 mmol; 1.00 eq.) in DCM (2.00 ml) was added methanesulfonyl chloride (0.05 ml; 0.68 mmol; 1.50 eq.) and N,N-diethylethanamine (0.09 ml; 0.68 mmol; 1.50 eq.). The reaction was stirred at room temperature for 2 h. The desired product was isolated by flash chromatography (KPNH, 20 to 75% EtOAc/Hex) to afford (3aR,4aR,8aR,9R,9aR)-2-[(tert-butoxycarbonyl)(ethyl)amino]-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-9-yl methanesulfonate (90 mg, 38%) as a white solid (once lyophilized).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[CH3:26]C(O)=O>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]([OH:22])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CC(O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1.75 h

Procedure:
To a solution of intermediate 5B (˜0.05 M in THF) at −78° C. was added dropwise MeMgBr (3.0M in Et2O, 3 eq). The reaction was stirred at −78° C. for 1.5-2 h (quench small aliquot in 10% MeOH/DCM, spot TLC-silica gel, 30% EtOAc/Hex-stain with 5% HCl/MeOH, heat and then ninhydrin, heat). Quench reaction by addition of HOAc (3 eq) at −78° C. Warm to RT, dilute with EtOAc and wash with a 1:1 mixture of sat. aq. NaHCO3 and sat aq. NaCl. Back extract aqueous layer. Combine organic extracts, dry over MgSO4, filter and concentrate. Purification by flash chromatography (silica gel, step gradient 0-10-20% EtOAc in hexane) provided the title compound.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]([F:22])([F:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][NH2:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ON1[C:47](=[O:48])[C:46]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:45]2[C:44]1=[O:53]>>[F:13][C:14]([F:22])([F:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][N:20]1[C:47](=[O:48])[C:46]2[C:45](=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:44]1=[O:53]
Reactant: NOCCNCC(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1c2ccccc2C(=O)N1OCCNCC(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
Diethylazodicarboxylate (3.60 mL, 22.9 mmol) was added dropwise over 30 min to a solution comprised of O-[2-(2,2,2-trifluoro-ethylamino)-ethyl]-hydroxylamine (3.19 g, 22.3 mmol, prepared as in J. Am. Chem. Soc. 1979, 101, 4300), triphenylphosphine (6.05 g, 23.1 mmol), and N-hydroxyphthalimide (3.65 g, 22.4 mmol). The resultant reaction mixture was stirred at ambient temperature. After 20 h, the reaction mixture was concentrated and the residue was dissolved in 60 mL of warm chloroform. Upon cooling, crystallization of diethyl 1,2-hydrazaine dicarboxylate ensued. The precipitate was filtered and the filtrate was concentrated and further diluted with ether. A single crystal of triphenylphosphine oxide was added, initiating copious precipitation. The resultant precipitate was removed by filtration and the filtrate was concentrated in vacuo and chromatographed on silica gel. Elution with hexanes-ethyl acetate (2:1) afforded 2-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-isoindole-1,3-dione (4.05 g, 63% yield) as a colorless oil: 1H NMR (400 Mz, CDCl3) δ 7.84-7.73 (m, 4H), 4.30 (t, J=4.8 Hz, 2H), 3.26 (q, J=9.5 Hz, 2H), 3.00 (t, J=4.9 Hz, 2H), 2.33 (br s, 1H); MS (APCI+)=289.0.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[C:7]1[CH3:17])=[N+]=[N-]>CO.[C].[Pd]>[CH3:17][C:7]1[N:6]([CH2:5][CH2:4][NH2:1])[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=1
Reactant: Cc1cc(-c2ccccc2)cn1CCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2ccccc2)cn1CCN
Yield: 82.7 %

Procedure:
10% Palladium-carbon (100 mg) was added to a solution of 1-(2-azidoethyl)-2-methyl-4-phenyl-pyrrole (640 mg, 2.96 mmol) in methanol (20 mL) at room temperature and hydrogenated at atmospheric pressure for 27 h. The catalyst was filtered and washed with methanol (20 mL). The combined filtrate and washings were concentrated in vacuo to afford 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethanamine (490 mg, 83%) as a brown syrup.
Reaction SMILES: [F:1][C:2]1[C:3]([C:23]([O:25]C)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][N:16]=2)=[N:11][CH:10]=1.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[C:3]([C:23]([OH:25])=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: COC(=O)c1nccc(Sc2cnc(Nc3ccc(CO)cn3)s2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nccc(Sc2cnc(Nc3ccc(CO)cn3)s2)c1F
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Methyl 3-fluoro-4-(2-(5-(hydroxymethyl)pyridin-2-ylamino)thiazol-5-ylthio)picolinate (0.750 g, 1.91 mmol) was dissolved in THF (20 mL) and treated with NaOH (5N, 2.5 mL, 12.5 mmol) at 23° C. The reaction was stirred for 2 hours, then water was added. The reaction was acidified with conc. HCl to pH ˜2. The solvent was evaporated and the residue was diluted with water. This was extracted with ethyl acetate/THF (3×) and the combined organic layers were then dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (0.630 g, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 4.46 (2H, s), 5.22 (1H, s), 7.04-7.12 (2H, m), 7.74 (1H, dd, J=8.34, 2.27 Hz), 7.84 (1H, br s) 8.24 (1H, d, J=1.52 Hz), 8.31 (1H, d, J=5.05 Hz), 11.89 (1H, s), 13.75 (1H, s). LC/MS (M+H)+: 379. HPLC ret. time (Condition N): 2.463 min.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7][NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[Br:1][C:2]1[O:6][C:5]([CH2:7][N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[S:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])(=[O:31])=[O:30])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)CNCc1ccc(Br)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(Br)o1)S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 136 %

Procedure:
To a stirred solution of the crude (5-bromo-furan-2-ylmethyl)-isobutyl-amine from step 1 (686 mg) in dichloromethane (8 mL) were added N,N-diisopropyl ethyl amine (686 mg) and 2-chlorobenzenesulfonylchloride (458 mg). The mixture was stirred for 18 h at r.t. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 4:2) to give N-(5-bromo-furan-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide (1.2 g) as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[As:12](O)(=[O:14])[OH:13])=[O:4].[Na+].[I-]>Br.CO>[Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[As:12]([OH:14])[OH:13])=[O:4]
Reactant: O=C(CBr)Nc1ccccc1[As](=O)(O)O
Agent: Br
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: O=C(CBr)Nc1ccccc1[As](O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
2-(2-Bromoacetylamino)benzenearsonic acid (6 g, 17.8 mmol) was dissolved in HBr/MeOH (1:1). NaI (80 mg) was added and the reaction was purged with N2 and cooled to 0° C. SO2 was bubbled through at ca. 4 bubbles/second and after 15 min a white precipitate started to form. SO2 was bubbled through for a further 2.5 h as the reaction was warmed to room temperature. The reaction was purged with N2 for 10 min, and the solid was collected by filtration washing with H2O (×3), ether (×2) to give 1.35 g of 2-(2-bromoacetylamino)benzenearsonous acid. A further 0.25 g was obtained from the initial filtrate. Total yield (1.60 g, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31](O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH:31]3[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][CH2:30]3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)CC1
Reaction time: 24 h
Yield: 62 %

Procedure:
A suspension of 4-(4-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (3.11 g), 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.51 g), and polymer supported triphenylphosphine (6.25 g; loading: 3 mmol/g) in DCM (100 mL) was treated with di-tert-butylazodicarboxylate (3.78 g). After 24 h, the resulting mixture was filtered, and the filtrate was evaporated. Chromatography of the residue (15-30% ethyl acetate/hexanes) gave the title compound as a white solid (3.20 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@@H:18]([O:19]C(=O)C)[C@H:13]3[O:14]C(=O)C)[C:6]=2[N:7]=1.N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@@H:18]([OH:19])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a solution of 79 (0.68 g, 2.28 mmol) in DMF (10 mL) was added imidazole (0.54 g, 7.93 mmol) and tert-butyldimethylsilyl chloride (0.68 g, 4.56 mmol) sequentially. The reaction mixture was stirred at room temperature for 2 h, at which point it was concentrated and purified by flash column chromatography (silica, MeOH/CHCl3; gradient=5-20%) to afford 0.49 g (52%) 87 as a white solid: 1H (400 MHz, d6-DMSO) δ 8.33 (s, 1H), 6.87 (s, 2H), 5.90 (d, J=4.0 Hz, 1H), 5.33 (d, J=5.6 Hz, 1H), 5.00 (d, J=5.2 Hz, 1H), 4.79 (q, J=5.2 Hz, 1H), 4.16 (q, J=5.2 Hz, 1H), 3.77 (m, 2H), 3.64 (dd, J=12.0, 7.2 Hz, 1H), 0.84 (s, 9H), 0.00 (s, 6H); MS (+)-ES [M+H]+ m/z 415.4.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Br:17])[C:15]=1[F:16])[C:10]([NH2:12])=O>C(#N)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Br:17])[C:15]=1[F:16])[C:10]#[N:12]
Reactant: NC(=O)c1cc(Br)c(F)c(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1cc(Br)c(F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.5 %

Procedure:
(I14B): Phosphoryl trichloride (8.0 ml, 86 mmol) was added to a suspension of 3,5-dibromo-4-fluorobenzamide (11.27 g, crude, ˜22.7 mmol) in acetonitrile (400 ml) at room temperature. The reaction mixture was heated to reflux for 30 minutes. Additional Phosphoryl trichloride (8.0 ml, 86 mmol) was added and the mixture heated to reflux for an additional hour, then stirred at room temperature overnight. A precipitate had formed and was removed by filtration. (The product is well soluble in acetonitrile) The reaction mixture was evaporated to dryness, then partitioned between EtOAc and aq. NaHCO3 solution. The organic layer was washed one more time with aq. NaHCO3 solution, once with brine, then dried over MgSO4, filtered and evaporated to dryness. Purification by column chromatography on silica (gradient 100% hexanes to 25% DCM in hexanes). 3,5-dibromo-4-fluorobenzonitrile (7.5 g) was obtained. The material is (by 1H NMR and 19F NMR) a 76:17:7 mixture of 3,5-dibromo-4-fluorobenzonitrile (desired product), 2,3,5-tribromo-4-fluorobenzonitrile (over-bromination) and 2,5-dibromo-4-fluorobenzonitrile (wrong regio-isomere). The material was used without further purification in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]([CH3:33])[CH:16]2[CH2:20][CH2:19][C:18]3([CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:15]([CH3:33])[CH:16]2[CH2:20][CH2:19][C:18]3([CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCCNC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of tert-butyl 2-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(methyl)amino)-7-azaspiro[4.5]decane-7-carboxylate (270 mg, 0.567 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH3 in MeOH (7 M)/MeOH/DCM (v/v/v)=1/20/60) to give the title compound as a beige solid (0.20 g, 93.8%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[CH2:7][NH:6]1.[O:17]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NC(C)(C)CC)C>CN(C=O)C.O.C(OCC)C>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:31](=[O:32])[CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:25][CH:26]=3)[CH:12]=2)[CH:7]=[N:6]1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: COC(CN1NCc2ccc(N)cc21)OC
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(Cn1ncc2ccc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cc21)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(2,2-dimethoxyethyl)-2H-indazol-6-ylamine (1.89 g, 8.60 mmol), 4-phenoxyphenylacetic acid (2.06 g, 9.03 mmol), N-methyl morpholine (2.26 mL, 20.6 mmol), HOBt (1.45 g, 10.75 mmol), and ethyldimethylpropylcarbodiimide hydrochloride (2.06 g, 10.75 mmol) in DMF (40 mL) was stirred at room temperature for 3 hours, diluted with H2O (40 mL) and diethyl ether (30 mL). The layers were separated, and the aqueous was extracted with additional diethyl ether (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide a yellow oil which was purified by MPLC (SiO2, 1:1 hexane:ethyl acetate to 1:3 hexane:ethyl acetate) to provide N-[1-(2,2-dimethoxyethyl)-1H-indazol-6-yl]-2-(4-phenoxyphenyl)acetamide as a yellow solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.26 (m, 6 H), 3.68 (s, 2 H), 4.37 (d, J=5.42 Hz, 2 H), 4.73 (t, J=5.42 Hz, 1 H), 6.98 (m, 4 H), 7.15 (m, 2 H), 7.38 (m, 4 H), 7.66 (m, 1 H), 7.97 (m, 1 H), 8.11 (s, 1 H), and 10.35 (s, 1 H); MS (ESI) 431 (M−H)−.