Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:20]([N:22]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:23]1[C:24]([NH:26][C@H:27]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:37])[NH:33][N+:34]([O-:36])=[O:35])=[O:25])=[O:21])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].Cl.CCOC(C)=O.CN1CCOCC1.[N:73]1([C:88]([O:90][CH2:91][C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)=[O:89])[CH2:87][CH2:86][CH2:85][C@H:74]1[C:75]([O:77]N1C(=O)CCC1=O)=O>>[N:73]1([C:88]([O:90][CH2:91][C:92]2[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=2)=[O:89])[CH2:87][CH2:86][CH2:85][C@H:74]1[C:75]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:20]([N:22]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:23]1[C:24]([NH:26][C@H:27]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:37])[NH:33][N+:34]([O-:36])=[O:35])=[O:25])=[O:21])[CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:77]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 0.68 g of Boc-Asn-Ser(Bzl)-Pip-Arg(NO2)-OBzl, 3 ml of 4N HCl-AcOEt, 0.14 ml of NMM and 0.32 g of Z-Pro-OSu in the same manner as in Example 12-(2).
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: Cc1ccc(SSN(C)C(=O)F)cc1
Reactant: CC1OCSC1=NO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(SSN(C)C(=O)ON=C2SCOC2C)cc1

Procedure:
4-[[O-[N-Methyl-N-(4-methylphenylthiosulfenyl)carbamoyl]oximino]]-5-methyl-1,3-oxathiolane was prepared by the procedure described in Example I by reacting 4.0 g (0.03 m) of 5-methyl-4-oximino-1,3-oxathiolane, 6.95 g (0.03 m) of N-methyl-N-(4-methylphenylthiosulfenyl) carbamoyl fluoride and 3.07 g (0.03 m) of triethylamine in 50 ml of dioxane. The crude residual oil (7.3 g) was purified by dry column chromatography using silica gel.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O)([O-:15])=[O:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[N+:13]([O-:15])=[O:14]
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccccc1C=NNC(=S)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 2-nitrobenzaldehyde (85 mg, 0.56 mmol) similar to Example 3 and isolated as a yellow solid (20 mg, 11%). 1H NMR (CDCl3): 9.37 (s, 1H), 8.27 (s, 1H), 8.00 (d, J=8.1 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 6.24-6.14 (m, 2H), 4.30-4.26 (m, 1H), 3.07 (s, 1H), 2.97 (s, 1H), 1.94-1.86 (m, 1H), 1.67 (d, J=8.4 Hz, 1H), 1.52 (d, J=9.0 Hz, 1H), 1.46-1.40 (m, 1H).
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]1([CH:20]([OH:25])[CH2:21][CH2:22][CH2:23][OH:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:25][CH:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:21][CH2:22][CH2:23][O:24][C:12](=[O:13])[NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: OCCCC(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2ccccc12)OCCCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
1-Naphthyl isocyanate (4.3 ml, 30 mmol) in 50 ml of methylene chloride was added under nitrogen dropwise over 1 hour to a solution of 4-phenyl-4-hydroxybutanol (5.00 g, 30 mmol), prepared in step (a) of Example 6, and triethylamine (4.2 ml, 30 mmol) in 200 ml of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 18 hours. The solid present in the reaction was removed by filtration. The filtrate was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 10.08 g of a clear oil Purification of the oil by chromatography on 1 kg of silica gel (230-400 mesh) using 3%-20% ethyl acetate-methylene chloride as the eluent gave naphthalen-1-yl-carbamic acid 4-hydroxy-4-phenyl-butyl ester (7.73 g, 77%) as a white solid, mp 92-92° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.CCN=C=NCCCN(C)C.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:34]1[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[CH2:32][CH2:33]1)=[O:13])=[CH:5]2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(c1cc2cc(F)ccc2[nH]1)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Fluoro-1H-indole-2-carboxylic acid (4.0 g) and EDCI (4.29 g) were combined in dichloromethane (90 mL) and treated with 1-(2-pyridinyl)piperazine (3.64 g). After stirring at 25° C. for 24 hours, the mixture was washed with 150 mL of water and filtered. The filter cake was washed in succession with 300 mL of water, 250 mL of dichloromethane and 20 mL of ethyl acetate to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 3.61 (m, 4H), 3.85 (m, 4H), 6.67 (dd, 1H, J=7.5,4.8 Hz), 6.85 (m, 2H), 7.06 (m, 1H), 7.40 (m, 2H), 7.65 (m, 1H), 8.04 (dd, 1H, J=4.5,1.8 Hz), 11.72 (bs, 1H). MS (DCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: [C:1]([C:3](=[C:9]([CH3:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][Mg]Cl.COC1C=C(C=CC=1)CCl.[NH4+].[Cl-]>C1COCC1.CCOCC>[C:1]([CH:3]([C:9]([CH3:10])([CH3:11])[CH2:17][C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: COc1cccc(C[Mg]Cl)c1
Reactant: CCOC(=O)C(C#N)=C(C)C
Agent: COc1cccc(CCl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C(C)(C)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of ethyl 2-cyano-3-methylcrotonate (10.8 g, 0.07 mol) in THF (100 mL) was added dropwise to a stirred ethereal solution of 3-methoxybenzylmagnesium chloride (prepared by adding a solution of 3-methoxybenzyl chloride (9.3 mL, 0.064 mol) in ether (48 mL) to a slurry of Mg (1.7 g, 0.07 mol) in ether (20 mL)). After addition the mixture was stirred at room temperature for a further 2 h then NH4Cl (sat., 50 mL) was added. The solution was partitioned between EtOAc (200 mL) and water (200 mL) and the organic layer separated and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel, eluting with petrol:EtOAc (5:1). The title compound (9.0 g, 51%) was isolated as a colourless oil. 1H NMR (360 MHz, CDCl3) δ 1.10 (3H, s), 1.20 (3H, s), 1.33 (3H, t, J=7.1 Hz), 2.74 (1H, d, J=13.5 Hz), 2.78 (1H, d, J=13.5 Hz), 3.33 (1H, s), 3.81 (3H, s), 4.26 (2H, q, J=7.1 Hz), 6.72-6.82 (3H, m), 7.22 (1H, t, J=7.8 Hz). MS (ES+) 276 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:22][NH:23][O:24][CH3:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])[CH2:9][C:10]([N:23]([O:24][CH3:25])[CH3:22])=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)O)c1ccc(Br)cc1
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccc(Cl)cc1C

Procedure:
In analogy to example 74, step 4, from 3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-propanoic acid and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as a colorless oil, MS (ESI+): m/z=398.03 [M+H]+.
Reaction SMILES: [K].[S:2]([NH2:6])([NH2:5])(=[O:4])=[O:3].[C:7](OCC)(=[O:13])[C:8](OCC)=[O:9]>C(O)(C)C.CO>[OH:9][C:8]1[C:7]([OH:13])=[N:6][S:2](=[O:4])(=[O:3])[N:5]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NS(N)(=O)=O
Agent: [K]
Solvent: CC(C)O
Solvent: CO
Product: O=S1(=O)N=C(O)C(O)=N1
Yield: 145 %

Procedure:
The compound was prepared according to Carmack et al. (J. Org. Chem. 1975, 40, 2743) as follows. Potassium metal (10.0 g, 0.26 mol) was dissolved in cool isopropanol (50 mL) which was then diluted with methanol (50 mL). A methanolic solution (100 mL) of sulfamide (12.32 g, 0.13 mol) was added dropwise with vigorous stirring, followed by dropwise diethyl oxalate (17.4 mL, 0.13 mol). The resulting mixture was heated at reflux for 18 hours. The mixture was cooled, filtered, and the solid was washed with methanol and dried to give 28.3 g of 3,4-dihydroxy-[1,2,5]thiadiazole-1,1-dioxide as the di-potassium salt. This was stirred with PCl5 (90.0 g, 0.43 mol) at 150° C. for 10 minutes. When enough POCl3 was generated to maintain stirring, the mixture was cooled to 60° C. and stirred for 18 hours. The reaction was cooled, diluted with diethyl ether, filtered, and washed with additional diethyl ether. The ether filtrate was added dropwise to ethanol (500 mL) at 0° C. The resulting solution was heated to reflux for 1.5 hours, cooled, and concentrated to 1/4 volume. The diethoxy derivative was collected as a white solid (4.80 g). The mother liquor afforded an additional 1.80 g. (Total yield: 26%): mp 171°-172° C. (Th. 178°-179° C.); 1H NMR (CDCl3): δ 4.59 (q, 4H), 1.50 (t, 6H).
Reaction SMILES: O.NN.[CH3:4][C:5]1([CH3:19])[CH2:11][CH2:10][CH2:9][NH:8][C:7]2[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:6]1=2>[Pd].C(O)C>[CH3:4][C:5]1([CH3:19])[CH2:11][CH2:10][CH2:9][NH:8][C:7]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:6]1=2
Reactant: CC1(C)CCCNc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1(C)CCCNc2ccc(N)cc21
Yield: 90.5 %

Procedure:
Added 6 mL of ethanol, 10% Palladium on activated carbon (50% wet with water for safety) (60 mg), and hydrazine monohydrate (89 ul) to 5,5-Dimethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (101 mg, 0.459 mmol). Heated reaction to 60° C. for 22 hours. Filtered reaction through Celite, and concentrated under reduced pressure. Purified with normal phase silica gel chromatography eluting with 5% methylene chloride in methanol to obtain a brown oil, 5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (79 mg, 91%). LCMS: m/z=190.99 (M+H+), 1H NMR (400 MHz, CDCl3) δ 6.73 (d, 1H, J=2.0 Hz), 6.55 (d, 1H, J=8.1 Hz), 6.43 (dd, 1H, J=8.1, 1.5 Hz), 3.40 (br s, 3H), 2.97 (m, 2H), 1.86 (m, 2H), 1.59 (m, 2H), 1.38 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (281 mg, 1.1 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (170 mg, 1.1 mmol) and DIPEA (1 mL, 5.5 mmol) in IPA (2 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-20% DCM in EtOAc) to afford 275 as a white solid (295 mg, 72%). LCMS (Method K): RT 3.37 min [M+H]+ 375.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.60 (1H, ddd, J=4.88, 1.91, 0.81 Hz), 8.06 (1H, td, J=7.75, 1.94 Hz), 7.86 (1H, s), 7.78-7.68 (3H, m), 7.50 (1H, ddd, J=7.52, 4.87, 0.98 Hz), 7.21-7.11 (4H, m), 5.87-5.78 (1H, m), 1.53 (3H, d, J=6.83 Hz)
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:31])=[O:30])[C:9]1[CH:28]=[CH:27][C:12]2[N:13]([CH3:26])[C:14]([CH2:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[NH:22])=[CH:19][CH:18]=3)=[N:15][C:11]=2[CH:10]=1)=[O:6])[CH3:3].Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>CC(C)=O.O>[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:30])=[O:31])[C:9]1[CH:28]=[CH:27][C:12]2[N:13]([CH3:26])[C:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:23])=[N:22][C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[O:44])=[CH:24][CH:25]=3)=[N:15][C:11]=2[CH:10]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OCc3ccccc3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-ethyloxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and benzyl chloroformate in acetone/water.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[O:11]([C:13]1[CH:14]=[C:15]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:16][C:17]1[S:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]=1[S:26](Cl)(=[O:28])=[O:27])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:13]([O:11][CH3:12])[CH:14]=1)(=[O:27])=[O:28]
Reactant: Cc1noc(N)c1Br
Reactant: COc1cc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc(OC)c1OC

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-trimethoxybenzyl)benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-amino-isoxazole (0.55 mmoles, 97 mg), NaH (1.4 mmoles, 55 mg), and 2-(3,4,5-trimethoxylbenzyl)-benzo[b]thiophene-3-sulfonyl chloride (0.66 mmoles, 0.27 g) in THF (2 ml) yielded, after flash chromatography using 50% ethyl acetate/haxanes and recrystallization from chloroform and hexanes, 94 mg of a tan solid, m.p. 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C1(C)C=CC=CC=1.[CH2:31]([N:38]=[C:39]=[S:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C>[CH2:31]([NH:38][C:39]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[S:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: S=C=NCc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NCc4ccccc4)cc3Cl)c2cc1OC
Temperature: 80 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (2 ml) and ethanol (2 ml) to prepare a solution. Benzyl isothiocyanate (48 μl) was then added to the solution, and the mixture was stirred at 80° C. for 6 hr. The reaction solution was concentrated, and ether and hexane were added to the residue. The resultant crystal was collected by filtration to give the title compound (46 mg, yield 65%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:24][N:25](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:24]#[N:25])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1oc2cccc(C#N)c2c1C
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (721 mg, 2.0 mmol, 1 eq) in 10 mL of DMF under nitrogen was added 322 mg of Zn(CN)2 (2.74 mmol, 1.37 eq), and 123 mg of Pd(PPh3)4 (0.1 mmol, 0.05 eq). The reaction mixture was heated to 85° C. The reaction was complete in 2.5 h by TLC. After work up and column chromatography eluting with 5% ethyl acetate/hexane, 4-cyano-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 80% yield (367 mg). 1H NMR (400 MHz, CD3OD) δ ppm 1.6 (t, J=7.1 Hz, 3 H) 3.0 (s, 3 H) 4.6 (q, J=7.2 Hz, 2 H) 7.8 (dd, J=8.3, 7.6 Hz, 1 H) 7.9(m, 1 H) 8.1 (dd, J=8.3, 1.0 Hz, 1 H).
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@H:18]([NH2:20])[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH:1]([C@H:14]1[CH2:19][C@H:18]([NH:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc(CN[C@@H]2CCO[C@@H](C(c3ccccc3)c3ccccc3)C2)cc1
Yield: 53.3 %

Procedure:
trans-4-Amino-2-diphenylmethylpyran 6b (0.24 g, 0.90 mmol) was reacted with 4-fluorobenzaldehyde (0.11 g, 0.90 mmol) in presence of acetic acid (0.05 g, 0.9 mmol), and then reduced with NaCNBH3 (0.07 g, 1.08 mmol) to yield compound 7b (0.18 g, 54%) (Procedure D).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Br:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[Br:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccccc1Br
Product: Brc1ccccc1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-bromobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): m/e 380.2, 382.2 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.44 (br s, 1H); 8.02 (br s, 1H); 7.85 (m, 1H); 7.64 (d, J=5.6 Hz, 1H); 7.48 (d, J=7.3 Hz, 1H); 7.18 (m, 1H); 6.86 (d, J=5.5 Hz, 1H); 6.18 (br s, 1H); 4.83 (d, J=6.4 Hz, 2H).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:13]=[N-:14]>>[ClH:1].[C:18]1([CH:17]=[CH:16][CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCC=Cc1ccccc1
Agent: Cl
Product: Nc1nc(CCc2cn(CC=Cc3ccccc3)nn2)c[nH]1
Yield: 39 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.066 g, 0.383 mmol) was reacted with (3-azido-propenyl)-benzene, which was synthesized using previously reported methods (Rad et al., Tetrahedron Letters 2007, 48, 3445-3449), (0.079 g, 0.460 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(3-Phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.049 g, 39%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 8.19 (s, 1H), δ 7.44 (d, 2H), δ 7.29 (m, 3H), δ 6.73 (d, 1H), δ 6.53 (s, 1H), δ 6.42 (m, 2H), δ 5.24 (d, 2H), δ 3.07 (t, 2H), δ 2.88 (t, 2H) ppm; 13C 148.6, 145.3, 139.4, 139.2, 129.8, 129.7, 129.6, 128.5, 128.4, 127.6, 54.6, 47.3, 45.9, 26.3, 22.6 ppm; HRMS (ESI) calcd for C16H19N6 (M+) 295.1665. Found 295.1670.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6](B1OC(C)(C)C(C)(C)O1)[CH:5]=2.Cl[C:21]1[C:30]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[CH3:36])=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=2)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:21]1[C:30]([N:31]3[CH2:35][CH2:34][CH2:33][C@@H:32]3[CH3:36])=[N:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=3)[N:22]=1)=[CH:6][CH:5]=2
Reactant: Cc1cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N3CCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of 2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (378 mg, 1.47 mmol) in ethylene glycol dimethyl ether (5.5 mL) and water (3 drops) was added methyl 2-chloro-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (150 mg, 0.49 mmol), sodium carbonate (156 mg, 1.47 mmol) and Pd(PPh3)4 (29 mg, 0.03 mmol) with stirring for 2 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(2-methyl-1H-indol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate as light yellow solid (140 mg, 71%).