Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=O)C=CC(N=C=O)=CC=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:24])[CH3:23])#[CH:14].[CH2:25]([O:27][C:28](=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N+:34]([O-])=[O:35])[CH3:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22](=[O:24])[CH3:23])[O:35][N:34]=1)[CH3:26]
Reactant: CCOC(=O)CCCCC[N+](=O)[O-]
Reactant: C#Cc1ccccc1NC(C)=O
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCc1cc(-c2ccccc2NC(C)=O)on1
Yield: 116.6 %

Procedure:
Add 1,4-phenylenediisocyanate (5.15 g, 32.2 mmol) to a stirred solution of N-(2-ethynyl-phenyl)-acetamide (2.56 g, 16.1 mmol) and 6-nitro-hexanoic acid ethyl ester (4.56 g, 24.1 mmol) in toluene (200 mL, anhydrous) and stir under N2. Add triethylamine (4.5 mL, 32.2 mmol) and heat to reflux under N2 overnight. Filter mixture through a pad of Celite® and rinse with toluene. Concentrate to get 6.2 g yellow oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-60% EtOAc/hexanes to afford the title compound (4.02 g, 76%). Correct regioisomer is confirmed by NOESY. MS (IS) 331 (M+1)+.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[CH:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=[CH:18]4)[CH:11]=2)[CH2:6][NH:5][CH2:4]1)[CH3:2].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:27]([N:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[CH:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=[CH:18]4)[CH:11]=2)[CH2:6]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCC1CNCc2ccc(C=Cc3ccc4cc(C#N)ccc4c3)cc21
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1CN(Cc2ccccc2)Cc2ccc(C=Cc3ccc4cc(C#N)ccc4c3)cc21
Reaction time: 24 h

Procedure:
A solution of Example 49A (600 mg) in dichloromethane (25 mL) was treated sequentially with benzaldehyde (0.7 mL), sodium triacetoxyborohydride (1.3 g), and acetic acid (319 mg), stirred for 24 hours, diluted with dichloromethane, washed with 1M NaOH and brine, dried (MgSO4), filtered, and concentrated. The concentrate was crystallized from diethyl ether/hexanes to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:33][C:32](=O)[CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:33][C:32](=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a cooled (-70° C.) and stirred solution of trimethyl phosphonoacetate (1.5 g) in anhydrous tetrahydrofuran (40 ml) was added potassium bis(trimethylsilyl)amide (0.5M in toluene; 15.07 ml) at such a rate as to maintain the internal temperature below -62° C. (ca 8 min). After 15 minutes of stirring at -70° C., a solution of 3-(tert-butyloxycarbonylamino)cyclobutan-1-one (1.27 g) in anhydrous tetrahydrofuran (10 ml) was added over 9 minutes, under a nitrogen atmosphere. The mixture was then allowed to warm to room temperature and it was stirred for 1 hour before it was quenched with saturated aqueous ammonium chloride (40 ml). Products were extracted with ethyl acetate (2×50 ml) and the combined organic solutions were washed with brine (1×40 ml), dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, hexane-ethyl acetate, 75:25) gave 1.61 g (97%) the title compound as a white solid; mp 79°-82° C. δ (250 MHz, CDCl3) 5.70 (1H, m, --CH--), 4.81 (1H, br s, --NH--), 4.32-4.13 (1H, m, --CH--), 3.69 (3H, s, --OMe), 3.64-3.50 (1H, m, --CH2 --), 3.26-3.10 (1H, m, --CH2 --), 3.00-2.86 (1H, m, --CH2 --), 2.80-2.68 (1H, m, --CH2 --), 1.45 (9H, s, t--Bu); m/z (CI) 240 (M- -1). (Found: C, 60.28; H, 7.87; N, 5.76. C12H19NO4 ×0.03 C6H14 requires: C, 59.99; H, 8.02; N, 5.75%.)
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[N:5][C:6](Cl)=[CH:7][C:8]=1[CH3:9])#[N:2]>[Pd](Cl)Cl.[Pd]>[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2]
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Agent: Cl[Pd]Cl
Agent: [Pd]
Product: Cc1ccncc1C#N

Procedure:
hydrogenating the 3-cyano-2,6-dichloro-4-methylpyridine produced in b) in the presence of an organic solvent, with an hydrogenation catalyst selected from the group consisting of palladium (II) chloride and 10% Pd/C, at 50 to 150 psi, at a temperature of from 20° C. to 100° C., for 6 to 24 hours, to produce 3-cyano-4-methylpyridine;
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:15]([NH:25][C@H:26]([C:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:29])[CH3:27])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl N-benzyl-glycinate (47.5 g, 0.268 mol) and N-carbobenzyloxy-L-alanine (60.0 g, 0.268 mol) in 600 ml of methylene chloride at 0° C. was added dropwise a solution of N,N'-dicyclohexylcarbodiimide (55.2 g, 0.268 mol) in 600 ml methylene chloride over a 1 hour period. After the addition was complete the solution was stirred for 10 min., warmed to room temperature and continued stirring overnight. The solution was filtered, washed with dilute aqueous HCl, H2O, saturated NaHCO3, brine, dried (MgSO4). Concentration of the solution in vacuo yielded the oily product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>C(#N)C.Cl>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:3][CH:4]=1)(=[O:9])(=[O:10])[NH2:11]
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCCCOc1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of 4-hydroxybenzenesulfonamide (1.73 g, 10.0 mmol) and tert-butyl (6-bromohexyl)carbamate (2.1 g, 7.5 mmol) in acetonitrile (50 mL) was added anhydrous K2CO3 (2.07 g, 15 mmol). The reaction mixtures were stirred at 75° C. for overnight. Solvent was evaporated under reduced pressure to give a residue. The residue was diluted with 1 N HCl (40 mL), extracted with DCM, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with DCM to 10% MeOH in DCM to afford tert-butyl (6-(4-sulfamoylphenoxy)hexyl)carbamate (1.192 g, 43%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:7][CH2:8][CH3:9])=O)C.[NH3:16]>>[C:4]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:7][CH2:8][CH3:9])(=[O:3])[NH2:16]
Reactant: N
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Product: CCC[C@H](N[C@@H](C)C(=O)O)C(N)=O
Yield: 95 %

Procedure:
10 g of (S)-N-[(S)-1-(ethoxycarbonyl)butyl]alanine are placed in 100 ml of 28% strength aqueous ammonia solution at 100° C. for 18 hours. After evaporation of the solvent, the residue is taken up with 50 ml of water. The solution is evaporated to dryness, then taken up with 100 ml of isopropanol and evaporated. The expected product is obtained after drying under vacuum.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1.CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:6][C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:11]
Reactant: COc1cccc(C=O)c1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NCc1cccc(OC)c1
Yield: 58.2 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-leucine methyl ester hydrochloride (2 gm, 11.0 mmol), THF (30 mL), MgSO4 (2.24 gm, 18.7 mmol), m-anisaldehyde (2.67 mL, 22.0 mmol), Et3N (1.53 mL, 11.0 mmol), sodium borohydride (833 mg, 22.0 mmol), and methanol (40 mL) to give 11d (1.7 gm, 58%) in FIG. 2. 1H NMR (500 MHz, CD3OD): δ 0.86 (3H, d, J=6.59 Hz), 0.92 (3H, d, J=6.59 Hz), 1.5 (2H, dt, J=2.68, 7.32 Hz), 1.71 (1H, heptet), 3.3 (1H, t, J=7.32 Hz), 3.59 (1H, d, J=13.18 Hz), 3.72 (3H, s), 3.76 (1H, d, J=12.93 Hz), 3.8 (3H, s), 6.82 (1H, dd, J=2.44, 8.29 Hz), 6.89 (1H, d, J=7.56 Hz), 6.93, (1H, t, J=1.95 Hz), 7.23 (1H, t, J=7.81). ESI-MS: 288.2 (M+23).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:26]([CH2:25][N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccc(-c2ccccc2)cc1

Procedure:
Ethyl 1-(1,1′-biphenyl-4-ylmethyl)-5-nitro-3-phenyl-1H-indole-2-carboxylate was prepared from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate and 4-bromomethylbiphenyl according to the procedure of Example 1 Step 1 as a yellowish solid: 1H NMR (DMSO-d6) δ 0.95 (t, J=7.0 Hz, 3 H), 4.13 (q, J=7.0 Hz, 2 H), 5.96 (s, 2 H), 7.30-7.32 (m, 14 H), 7.62 (d, J=2.3 Hz, 1 H), 8.25 (d, J=2.8 Hz, 1 H), 8.36 (s, 1 H); MS (ESI) m/z 477 (MH+); HRMS calcd. for C30H25N2O4: 477.1815; found (ESI+): 477.1806; Anal. calcd. for C30H24N2O4: C, 75.62; H, 5.08; N, 5.88. Found: C, 75.25; H, 5.18; N, 5.47.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH2:12][CH3:13])[C:3]=1[F:14].[Cu][C:16]#[N:17].C(OCC)(=O)C.[NH4+]>CN(C)C=O>[CH2:12]([O:11][C:4]1[C:3]([F:14])=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH3:10])[C:16]#[N:17])[CH3:13]
Reactant: N#C[Cu]
Reactant: CCOc1ccc(Br)c(F)c1OCC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(C#N)c(F)c1OCC
Temperature: 155 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of 1-bromo-3,4-diethoxy-2-fluorobenzene (12.0 g, 45.6 mmoL) in N,N-dimethylformamide (DMF) (60 mL), copper (I) cyanide (6.8 g, 68.3 mmoL) was added at room temperature and then stirred at 155° C. for 3 hours. After ice cooling the reaction solution, ethyl acetate and 28% aqueous ammonium were added thereto to separate the organic layer. This organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated. The residue was purified by silica gel column chromatography (n-hexane, ethyl acetate) to give 9.0 g of the captioned compound (yield: 94.3%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[CH:22]=[CH2:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: C=Cc1cc(-c2ccc(O)c(F)c2)nc2c(Cl)cc(O)cc12
Yield: 84 %

Procedure:
This compound was prepared from 45a based on method J using 1.1 equiv. of tributyl(vinyl)tin at 90° C. Red solid; Yield: 84%; mp 225° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 5.74 (dd, J=11.1, 1.0 Hz, 1H), 6.30 (dd, J=17.3, 1.1 Hz, 1H), 7.10 (dd, J=8.8, 8.8 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H), 7.38 (dd, J=17.3, 11.1 Hz, 1H), 7.53 (d, J=2.5 Hz, 1H), 8.04 (dd, J=8.4, 1.7 Hz, 1H), 8.16 (dd, J=13.1, 2.1 Hz, 1H), 8.16 (s, 1H), 10.27 (s, 1H), 10.35 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.51 (dd, J=13.2, 9.3 Hz); MS (ESI) m/z 314/316 ([M−H]−), 316/318 ([M+H]+); Anal. Calcd for C17H11ClFNO2: C: 64.67, H: 3.51, N: 4.44. Found: C: 63.57, H: 3.61, N: 4.04.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][NH:17][C:18]([CH3:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>[Pd].CO>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][NH:17][C:18]([CH3:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CN
Yield: 26.4 %

Procedure:
Z-Gly-Phe-NHNH-COCH3 (5 g) is hydrogenated over a Pd-black as a catalyst in MeOH (100 ml). The catalyst is filtered and the filtrate is evaporated to give 3.5 g of H-Gly-Phe-NHNH-COCH3 as crystals, H-Gly-Phe-NHNH-COCH3 (0.89 g) and Z-(D)-Nva-ONB, which is prepared from Z-(D)-Nva-OH (0.80 g) and HONB (0.63 g) by the DCC method, are dissolved in DMF (10 ml). The mixture is stirred for 10 hr. at room temperature and evaporated. The residue is treated with diethylether to give a powder which is crystallized from acetonitrile; yield 1.3 g. m.p. 235°-237° C., [α]D23 +3.4° (c=0.45, DMF), Rf1 =0.44.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=4)=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:32]([CH2:35][CH3:36])=[C:33]=[O:34]>C1COCC1.O>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:19]([CH:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:33]([NH:32][CH2:35][CH3:36])=[O:34])[CH:7]=4)=[CH:10][CH:11]=3)[CH2:16]2)=[O:20])[CH:27]=[CH:26][CH:25]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N)c4)cc3C2)c1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-[(2-aminopyridin-4-yl)oxy]-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (0.183 g, 0.044 mmol) in THF (4.5 mL) under an atmosphere of nitrogen at 0° C. was added isocyanatoethane (0.035 mL, 0.44 mmol) in THF (0.2 mL) dropwise. The reaction mixture was allowed to warm to rt. After 3 h, additional isocyanatoethane (0.104 mL, 1.32 mmol) was added, and after 4 h isocyanatoethane (0.104 mL, 1.32 mmol) was added again. The reaction mixture was heated at 50° C. for 4 h and then diluted with water. The mixture was extracted with EtOAc. The organic solutions were combined, washed with water and brine, and dried over Na2SO4. The solution was filtered and concentrated. The residue was purified by column chromatography and then the product dissolved in DCM/MeOH. 2M HCl in Et2O was added and the mixture was concentrated to give N-(3-tert-butylphenyl)-7-[(2-{[(ethylamino)carbonyl]amino}-pyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-370 as its HCl salt (143 mg, 62%). 1H NMR (300 MHz, d6-DMSO; HCl salt) δ: 10.02 (s, 1H), 8.16 (d, 1H), 7.65 (dd, 1H), 7.49 (d, 2H), 7.17-7.28 (m, 2H), 6.95-7.09 (m, 2H), 6.87 (d, 1H), 6.70 (s, 1H), 3.10-3.20 (, 2H), 2.72-2.97 (m, 5H), 2.09 (d, 1H), 1.71-1.81 (m, 1H), 1.26 (s, 9H), and 1.06 (dd, 3H). LCMS: (FA) ES+ 487.4, ES− 485.3.
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](N(CC)CC)(O)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C1C=CC=CC=1.CCCCCC[O:36][C:37]([C:39]1[C:44]([C:45](C2C=CC(N(CC)CC)=CC=2O)=O)=[CH:43][CH:42]=[CH:41][CH:40]=1)=O>>[CH3:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:37][O:36][C:12]1[CH:13]=[CH:14][C:15]([C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:23])=[C:10]([OH:9])[CH:11]=1
Reactant: CCN(CC)C(O)(CCCCCOC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: CCCCCCOC(=O)c1ccccc1C(=O)c1ccc(N(CC)CC)cc1O
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1

Procedure:
Diethylaminohydroxybenzoylhexyl benzoate sold under the trade name “Uvinul A Plus” by BASF,
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([C:16]1[S:17][C:18]2[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][C:19]=2[N:20]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[S:17][C:18]2[CH2:24][CH2:23][CH:22]([CH2:25][O:26][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:21][C:19]=2[N:20]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nc2c(s1)CCC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCc1nc2c(s1)CCC(COS(=O)(=O)c1ccc(C)cc1)C2

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. It is obtained as an undistillable oil which is used crude for the subsequent reactions.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][N:2]=1.[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[NH:10][C:7]([C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:9])(=[O:14])[NH2:15]
Reactant: O=C(O)c1ccnnc1
Reactant: NC(=O)c1ccccc1N
Agent: CN(C)C(On1nnc2ccccc21)=[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: NC(=O)c1ccccc1NC(=O)c1ccnnc1
Yield: 40 %

Procedure:
A mixture of pyridazine-4-carboxylic acid (500 mg, 4.0 mmol, 1.0 eq.), 2-aminobenzamide (603 mg, 4.4 mmol, 1.1 eq.) and HBTU (3.0 g, 8.0 mmol, 2.0 eq.) was suspended in 15 mL of DMF. DIPEA (2.0 mL, 1.56 g, 12.0 mmol, 3.0 eq.) was added dropwise at room temperature and was stirred over night. After quenching with water, the resulting precipitate was collected and washed with a small amount of DCM. A white solid (388 mg) was obtained, LCMS m/z=243.1 (M+1) (Method B) (retention time=0.99 min) was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([NH:23]C(=O)OCC=C)[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([CH:20]=[CH:21][CH:22]=2)[NH2:23])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)oc2-c2ccnc(Cl)n2)c1F
Agent: CCCC[SnH](CCCC)CCCC
Product: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 13 using 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}carbamate (1.2 g, 2.78 mmol) and tri-n-butyltin hydride (1.21 g, 4.17 mmol), the title compound was obtained as a yellow solid (530 mg, 55%). MS (ESI): 347 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)[C:4]=2[CH:3]=[CH:2]1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16]1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][N:27]3[CH2:28][CH2:29][N:24]([C:23]4[C:18]5[N:17]=[CH:16][NH:15][C:19]=5[CH:20]=[CH:21][CH:22]=4)[CH2:25][CH2:26]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1cc(N2CCNCC2)c2nc[nH]c2c1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Product: OC(COc1cccc2[nH]ccc12)CN1CCN(c2cccc3[nH]cnc23)CC1

Procedure:
The title compound is prepared from the reaction of 1-(indole-4-oxy)-2,3-epoxypropane (2.0 mmole) and 1-(1H-benzimidazole-4-yl)piperazine (2 mmole) according to the above procedures.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(O)cc1F
Temperature: 50 °C

Procedure:
To a mixture of 10.0 g (0.0640 mole) of 3-fluoro-4-nitrophenol in 100 mL of acetic acid and 10 mL of water heated to 50° C. was added 10.0 g (0.179 mole) of iron powder in small portions during a 35 minute period. The stirred reaction mixture was heated at 50° C. for an additional three hours, after which it was cooled and filtered. The filtrate was used in Step B without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:11]F.C(=O)([O-])[O-].[Ca+2]>O>[F:11][C:5]1[N:4]=[C:3]([C:8]([NH2:10])=[O:9])[C:2]([OH:1])=[N:7][CH:6]=1
Reactant: NC(=O)c1nccnc1O
Reactant: FF
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: NC(=O)c1nc(F)cnc1O

Procedure:
In 200 mL of water was suspended 1.0 g of 3-hydroxy-2-pyrazinecarboxamide. At room temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced at a rate of 45 mL per minute for a period of 25 minutes. Then, nitrogen gas was introduced for 45 minutes, and the liquid reaction mixture was neutralized with calcium carbonate, the deposited precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the solid product thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=5:1] to obtain 0.008 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a white-colored solid product.