Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:28]([OH:30])=O)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[NH:54][C:55](=[O:62])[C:56](=[CH:60][CH:61]=2)[C:57]([OH:59])=[O:58])=[CH:49][CH:48]=1.C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:28]([NH:46][C:47]1[CH:48]=[CH:49][C:50]([C:53]2[NH:54][C:55](=[O:62])[C:56](=[CH:60][CH:61]=2)[C:57]([OH:59])=[O:58])=[CH:51][CH:52]=1)=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1)OCc1ccccc1
Reaction time: 0.67 h
Yield: 75.7 %

Procedure:
A solution of 29.0 g (70 mmol) of N,N'-bis(benzyloxycarbonyl)-L-lysine [Helv. Chem. Acta, 41, 1778 (1958)] in 200 ml of dichloromethane is stirred at -10° and 7.2 g (70 mmol) of N-methylmorpholine is added. The temperature is lowered to -14° and 9.55 g (70 mmol) of isobutyl chloroformate is added dropwise over a period of 10 min and stirring is continued at -14° to -11° for 40 min. A suspension of 8.0 g (35 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 10.5 g (35 mmol) of triethylamine and 200 ml of dichloromethane is stirred at 5° and 12.0 g (35 mmol) of chlorotrimethylsilane is added. After 1 hr at room temperature this solution is added over a period of 30 min at -12° to -14° to the mixed anhydride formed above. After 3 hrs at 0°, the solution is allowed to stir overnight at room temperature. The reaction mixture is filtered and the filtrate is stirred with 15 ml of isopropanol for 30 min. The resulting yellow precipitate is filtered, washed, and dried to give 16.6 g of 6-[4-(N,N'-bis(benzyloxycarbonyl)-L-lysylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp 199°-200°, [α]D23 +24.2° (cl, DMSO).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1.[Br:9][CH2:10][C:11]([NH:13][C:14]1[CH:18]=[CH:17][O:16][N:15]=1)=[O:12]>C(Cl)(Cl)Cl.C(#N)C>[Br-:9].[OH:8][C@@H:4]1[CH2:5][CH2:6][CH2:7][N+:2]([CH2:10][C:11](=[O:12])[NH:13][C:14]2[CH:18]=[CH:17][O:16][N:15]=2)([CH3:1])[CH2:3]1
Reactant: O=C(CBr)Nc1ccon1
Reactant: CN1CCC[C@@H](O)C1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H](O)C1
Product: [Br-]

Procedure:
(R)-1-Methyl-piperidin-3-ol (1.15 g, 10 mmol) and 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) (2.25 g, 11 mmol) are stirred together in chloroform/acetonitrile (20 ml of a 1:1 mixture) at room temperature for 1 hour. The solvent is removed in vacuo and the resulting oil is purified using C-18 reverse phase column chromatography (eluent-water:acetonitrile from 0% to 30% acetonitrile) to yield the titled compound.
Reaction SMILES: ON1C(=O)CCC1=O.N1C=CC=CC=1.[CH2:15]([O:22][CH2:23][C@@:24]1([N:49]2[CH:57]=[C:55]([CH3:56])[C:53](=[O:54])[NH:52][C:50]2=[O:51])[O:48][C@H:28]([CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:26]([OH:27])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:58]1[CH:63]=[CH:62][C:61]([O:64][C:65](Cl)=[S:66])=[CH:60][CH:59]=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][CH2:23][C@@:24]1([N:49]2[CH:57]=[C:55]([CH3:56])[C:53](=[O:54])[NH:52][C:50]2=[O:51])[O:48][C@H:28]([CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:26]([O:27][C:65]([O:64][C:61]2[CH:62]=[CH:63][CH:58]=[CH:59][CH:60]=2)=[S:66])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: O=C1CCC(=O)N1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=S)Oc3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
N-hydroxysuccinimide (3.9 g, 34 mmol) and pyridine (24.3 mL, 300 mmol) were added to a solution of the alcohol 3 (90.0 g, 150 mmol) in 1 L of toluene. The mixture was warmed up to 80° C. and stirred for 10 min. Phenyl chlorothionoformate (30 g, 174 mmol) was added to the solution and the resultant reaction mixture was stirred at 80° C. for 8 h. The hot toluene solution was decanted from solids. The solids were rinsed with AcOEt (2×30 mL) and the combined toluene solution and AcOEt washes were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes/AcOEt 9:1 then 3:1) to give 83.0 g (75.2%) of the title compound, 17, as a light yellow foam. Rf (hexanes/AcOEt 9:1) 0.24. 13C-NMR (CDCl3): 12.97 (5-CH3), 19.49 (2'-C), 27.16 (Me3C), 38.32 (Me3C), 64.87 (O--C-Ph), 70.75 (N--C--O), 72.28 (5'-C), 84.21 (4'-C), 84.90 (3'-C), 85.39 (1'-C), 110.82 (5-C), 121.95, 126.94, 127.72, 128.27, 128.40, 129.81 (Ar--C), 130.35 (6-C), 131.93, 132.79, 133.76, 135.38, 135.76, 138.30 (Ar--C), 151.05 (2-C), 153.42 (Ar--C), 163.40 (4-C), 194.36 (thioformate-C).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][S:13][S:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[C:1]([NH:10][CH2:11][CH2:12][S:13][S:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NCCSSCCN
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCSSCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
Separately, nicotinic acid (246 mg, 2.0 mmol) was taken up in CH3CN (10 mL) along with tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (503 mg, 2.0 mmol), EDCI (422 mg, 2.2 mmol). The resulting reaction mixture was stirred at room temperature for 4 h and then diluted with EtOAc. The organic layer was washed with dilute aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded tert-butyl 2-(2-(2-(nicotinamido)ethyl)disulfanyl)ethylcarbamate (400 mg, 56%).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[OH:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:22]([O:21][C:19]([C:18]1[CH:27]=[CH:28][C:15]([O:14][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])=[CH:16][CH:17]=1)=[O:20])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CCCCCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCOC(=O)c1ccc(Oc2ccc(C#N)c(C#N)c2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 4-nitrophthalonitrile (1.00 g, 7 mmol), pentyl 4-hydroxybenzoate (1.45 g, 7 mmol) and dried potassium carbonate (6.38 g, 46.2 mmol) in anhydrous DMF (50 mL) was stirred overnight at 85° C. under argon. After cooling to room temperature, the mixture was diluted with ethyl acetate (60 mL) and water (40 mL). The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (40 mL), brine (40 mL) and dried over anhydrous sodium sulfate. The solvents were removed in vacuo, and the crude product was purified by column chromatography on silica gel using a dichloromethane/acetonitrile mixture (20:1) as an eluent to give the product in 85% yield. [1H NMR (δ, ppm, CDCl3): 8.15 (d, 2H, J=8.7 Hz), 7.77 (d, 1H, J=8.7 Hz), 7.35 (d, 1H, J=2.3 Hz), 7.30 (d, 1H, J=8.7 Hz), 7.12 (d, 2H, J=8.7 Hz), 4.34 (2H, t, OCH2, J=6.7 Hz), 1.79 (m, 2H, CH2), 1.42 (m, 4H, CH2CH2), 0.94 (t, 3H, J=7 Hz, CH3).]
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[CH:19][C:20]([F:25])=[C:21]([CH:24]=1)[C:22]#[N:23]>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:17]3[CH:18]=[CH:19][C:20]([F:25])=[C:21]([CH:24]=3)[C:22]#[N:23])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OCC(=O)Nc2ccc(-c3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-2-fluorobenzonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.02 (s, 1H), 8.32 (dd, J=6.3, 2.4 Hz, 1H), 8.11 (m, 1H), 7.62 (m, 1H), 7.58 (m, 2H), 7.19 (d, J=8.8 Hz, 1H), 4.26 (s, 2H), 1.62 (s, 6H); MS (ES) m/z 311 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2:5].[OH2:6].[S:7](=[O:9])=[O:8].[CH3:10][C:11]([CH3:13])=[O:12]>>[OH2:2].[OH:12][C:11]([S:7]([O-:6])(=[O:9])=[O:8])([CH3:13])[CH3:10].[Ca+2:5].[OH:12][C:11]([S:7]([O-:2])(=[O:9])=[O:8])([CH3:13])[CH3:10]
Reactant: O=S=O
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Agent: [Ca+2]
Solvent: O
Product: CC(C)(O)S(=O)(=O)[O-]

Procedure:
Pure calcium 2-hydroxy-2-propanesulfonate monohydrate was prepared by reacting 40 g of calcium carbonate with 114 g of water, 86 g of acetone and excess sulfur dioxide for 3 hours at 25° C. The reaction mixture was filtered, and the white solids washed with 50 ml of acetone, then with ether, then air dried for 30 minutes and chemically analyzed. Calculated for Ca[(CH3)2C(OH)SO3 ]2 ·H2O: Ca 11.9 percent, C 21.4 percent, H 4.8 percent, S 19.1 percent; observed: Ca 12.2 percent, C 21.0 percent, H 4.3 percent, S 18.8 percent.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)[OH:4].[H][H]>CO.[Pd]>[F:22][C:2]([F:1])([F:21])[CH:3]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[OH:4]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(C(O)C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: OC(C1CCNCC1)C(F)(F)F

Procedure:
A suspension of 3.11 g (9.80 mmol) of benzyl 4-(2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate and 300 mg Pd/C (10%) in 30 mL of MeOH was hydrogenated at RT and 3 bar hydrogen pressure for 4 hours. The catalyst was filtered off and the filtrate was evaporated down in vacuo. Yield: 1.82 g (quant. yield); C7H12F3NO (M=183.172); calc.: molpeak (M+H)+: 184; found: molpeak (M+H)+: 184; Rf value: 0.20 (silica gel, EtOAc/MeOH/conc. aqueous ammonia 5:5:0.5).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[Cl:34])=O>>[Cl:34][C:28]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Product: O=C(O)c1cc(-c2nc(-c3cc(Cl)ccc3Cl)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 44 %

Procedure:
4-[4-(2,5-Dichloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (130 mg, 44%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-(2,5-dichlorophenyl)ethanone (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J=1.5 Hz, 1H), 8.33 (s, 1H), 8.05-8.19 (m, 3H), 7.74 (t, J=7.6 Hz, 1H), 7.50-7.66 (m, 3H), 7.37 (d, J=7.8 Hz, 2H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[C:12]1C=CC=[CH:17][C:13]=1[C:14](Cl)=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:13]([CH3:17])([CH3:14])[CH3:12])=[O:5]
Reactant: O=C(O)c1ccccc1I
Reactant: O=C(Cl)c1ccccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1I
Reaction time: 0.33 h

Procedure:
2-Iodobenzoic acid (10.06 g, 40.56 mmol) was converted to 2-iodobenzoic chloride by reacting with oxalyl chloride (5.34 mL, 60.84 mmol) in methylene chloride (100 mL), initiated by a drop DMF. The solvent and excess oxalyl chloride were removed by rotary evaporation. To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) and then cooled to −78 C. A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added, followed by the solution of 2-iodobenzoic chloride in THF (50 mL). The resulting reaction mixture was stirred at −78 C for 20 min and then at rt for 2 hours. The reaction was quenched by water and worked up. The product was purified by flash chromatography to afford the title compound as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:26][CH2:25]C2[C:19](=CC=CC=2)[CH2:18]1.Cl.CC1N(C2N=CC=CN=2)N=CC=1/C=C/CN1CCC2C(=CC=CC=2)C1.Cl.[F:55][C:56]([F:70])([F:69])[C:57]1[CH:58]=[C:59]([N:63]2CCNCC2)[CH:60]=[CH:61][CH:62]=1>>[ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:18][CH2:19][N:63]([C:59]2[CH:60]=[CH:61][CH:62]=[C:57]([C:56]([F:55])([F:69])[F:70])[CH:58]=2)[CH2:25][CH2:26]1
Reactant: Cc1c(C(=O)CCN2CCc3ccccc3C2)cnn1-c1ncccn1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cc1c(/C=C/CN2CCc3ccccc3C2)cnn1-c1ncccn1
Agent: Cl
Product: Cc1c(/C=C/CN2CCN(c3cccc(C(F)(F)F)c3)CC2)cnn1-c1ncccn1

Procedure:
The procedures of Example 6 (1) and (2) were repeated but substituting the 1,2,3,4-tetrahydroisoquinoline hydrochloride employed in Example 6 (1) by 730 mg of 1-(3-trifluoromethylphenyl)piperazine hydrochloride. After the completion of the post treatment, 75 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13]C)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[C:7]2[CH3:12]>Br>[ClH:1].[Cl:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[C:7]2[CH3:12]
Reactant: COc1ccc2c(C)cncc2c1Cl
Agent: Br
Product: Cc1cncc2c(Cl)c(O)ccc12
Product: Cl

Procedure:
8-Chloro-7-methoxy-4-methylisoquinoline (0.89 g.) in 48% hydrobromic acid is refluxed for 48 hours. The mixture is evaporated to dryness in vacuo, redissolved in water and neutralized with ammonium hydroxide. The mixture is cooled and the precipitate is filtered off and treated with hydrogen chloride in ethanol. Ether is added and the precipitate is filtered off to give 8-chloro-7-hydroxy-4-methylisoquinoline hydrochloride.
Reaction SMILES: [H-].[Na+].O.[N:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)=[O:5].[CH3:22]I>CN(C)C=O>[CH3:22][N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]([N:4]=[O:5])[C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]1=2
Reactant: O=NN1c2ccccc2NC(=O)c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2N(N=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (2.4 g, 50% oil dispersion) was added in small portions to a water cooled solution of 10,11-dihydro-5-nitrosodibenzo[b,e][1,4]diazepin11(5H)-one (13.5 g) in dimethylformamide (200 ml) such that the temperature did not exceed 20° C. After the addition was complete the mixture was stirred at room temperature for 30 minutes and then treated with methyl iodide (7.0 g) added in one lot. The resulting mixture, after being stirred at room temperature for 2 hours, was poured into an excess of ice and water, and extracted with methylene chloride. The methylene chloride extract was washed with water, dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue, which contained some dimethylformamide, was repeatedly triturated with water until it turned to a crystalline solid. It was filtered off, washed with water and air-dried to yield the title compound, m.p. 95°-98°.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14](O)=[O:15])=[CH:8][C:6]=2[N:7]=1.[CH2:26]([NH2:28])[CH3:27].CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=5)[C:14]([NH:28][CH2:26][CH3:27])=[O:15])=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CCN
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: CCNC(=O)c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (55 mg) was reacted with ethylamine via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-ethylbenamide. Crude 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-ethylbenamide (59 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 14.5 mg of 329. MS (Q1) 485.1 (M)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-])=O)=[CH:8][C:7]=1[N+:17]([O-])=O>ClCCl.CO.[Pd]>[CH3:1][O:2][C:3]([C:4]1[NH:17][C:7]2[C:6]([CH:5]=1)=[CH:11][C:10]([O:12][CH3:13])=[C:9]([NH2:14])[CH:8]=2)=[O:21]
Reactant: COC(=O)C(=O)Cc1cc(OC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc2cc(OC)c(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(5-methoxy-2,4-dinitro-phenyl)-2-oxo-propionic acid methyl ester (about 100.0 g, 0.32 mol) in a mixture of dichloromethane and methanol (about 1.5 L), 10% Pd/C (about 30 g, 50% wet) is added at about 25° C. The reaction mixture is stirred under hydrogen atmosphere at a temperature of about 25° C. over a period of about 4 hours. The resulting reaction mixture is filtered through celite pad and concentrated under reduced pressure to yield the product [6-amino-5-methoxy-1H-indole-2-carboxylic acid methyl ester] as yellow color solid (about 59 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1.O>C(Cl)Cl>[C:14]([O:18][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
A solution of 4-chloro-3-nitrobenzoylchloride (8.80 g, 40 mmol) in CH2Cl2 (20 mL) was added to a solution of tert-butyl alcohol (7.6 mL, 80 mmole) and pyridine (6.6 mL, 80 mmole) at 25° C. The mixture was stirred at 25° C. for 12 h then H2O (30 mL) was added. The aqueous solution was extracted with ethyl ether (3×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give a yellowish solid residue. Purification of the residue by flash column chromatography (gradient elution 0 to 15% EtOAc/hexanes) provided the title compound (8.11 g, 79%): TLC (Rf =0.50; 15% EtOAc/hexanes); 1H NMR (CDCl3) δ 8.41 (s, 1H), 8.13 (d, 1H, J=8.0), 7.63 (d, 1H, J=8.3), 1.63 (s, 9H); 13C NMR (CDCl3)δ 162.4, 147.6, 133.2, 131.6, 130.5, 126.0, 124.4, 82.6, 27.8; Anal. (C11H12N1O4Cl) C, H, N.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH:12](OCC)[O:13]CC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>O1CCCC1>[C:1]([O:9][CH2:10][CH2:11][CH:12]=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CCOC(=O)c1ccccc1)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=CCCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
To a stirred solution of 5.0 grams (0.020 mole) of 3-ethoxy-4-oxahexyl benzoate in 100 ml of tetrahydrofuran was added 100 ml of aqueous 5% hydrochloric acid. The reaction mixture was stirred at ambient temperature for three hours, and then it was poured into 100 ml of water. The mixture was extracted with two 100 ml portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 1.9 grams of 3-oxopropyl benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][O:4][C@H:5]([C@@H:8]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C@@H:9]([OH:11])[CH3:10])[CH2:6][OH:7].[N@:18]1([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:20][CH:19]1[C:21]([O:23][CH3:24])=[O:22].B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH2:28]([O:27][C:25]([NH:18][C@@H:19]([CH2:20][O:7][CH2:6][C@H:5]([O:4][CH2:3][C:2]([CH3:1])=[CH2:17])[C@@H:8]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C@@H:9]([OH:11])[CH3:10])[C:21]([O:23][CH3:24])=[O:22])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1.[CH2:28]([O:27][C:25]([NH:18][C@@H:19]([CH2:20][O:11][C@H:9]([C@H:8]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C@@H:5]([O:4][CH2:3][C:2]([CH3:1])=[CH2:17])[CH2:6][OH:7])[CH3:10])[C:21]([O:23][CH3:24])=[O:22])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Reactant: C=C(C)CO[C@@H]([C@H](C)O)[C@H](CO)OCC(=C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C=C(C)CO[C@@H]([C@H](C)O)[C@H](COC[C@H](NC(=O)OCc1ccccc1)C(=O)OC)OCC(=C)C
Product: C=C(C)CO[C@@H]([C@H](C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OC)[C@H](CO)OCC(=C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %
Yield: 17 %

Procedure:
To a solution of (2S,3S,4S)-2,3-bis(2-methylallyloxy)pentane-1,4-diol (920 milligrams (mg), 3.77 mmol) and (S)-1-benzyl 2-methyl aziridine-1,2-dicarboxylate (0.739 mL, 3.74 mmol) in anhydrous chloroform (CHCl3; 5 mL) was added BF3-Et2O (26 microliters (μL) 0.55 mmol) at 0° C. and the solution was stirred at 0° C. for 3 h. The crude reaction mixture was concentrated and purified by flash chromatography (SiO2) to furnish (S)-methyl 2-(benzyloxycarbonylamino)-3-((2S,3S,4S)-4-hydroxy-2,3-bis(2-methylallyloxy)-pentyloxy)-propanoate as a colorless oil (620 mg, 35%) and (S)-methyl 2-(benzyloxycarbonylamino)-3-((2S,3S,4S)-5-hydroxy-3,4-bis(2-methylallyloxy)pentan-2-yloxy)propanoate as a colorless oil (300 mg, 17%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19](O)([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].FC(F)(F)C(O)=O.N>ClCCl.O>[N:23]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:7]2[NH:8][C:9](=[O:12])[C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)=[CH:14][CH:15]=1)([CH3:21])[CH3:20])=[N+:24]=[N-:25]
Reactant: CC(C)(O)c1ccc(-c2cc3ccc(F)cc3c(=O)[nH]2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N=[N+]=[N-])c1ccc(-c2cc3ccc(F)cc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 7-fluoro-3-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-isoquinolin-1-one (149 mg, 0.50 mmol) and sodium azide (71.5 mg, 1.10 mmol) in dichloromethane (1 ml) is added a solution of trifluoroacetic acid (316 μl, 4.1 mmol) in dichloromethane (0.5 ml) dropwise under external cooling with ice. The reaction mixture is stirred for 2 hours at room temperature. Water and 25% aqueous ammonia (0.5 ml) are added. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated to afford 3-[4-(1-azido-1-methyl-ethyl)-phenyl]-7-fluoro-2H-isoquinolin-1-one as white powder; HPLC/MS 2.07 min (A), [M+H] 323.