Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH:5][C@:6]1([C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:10]([CH2:11][CH2:12][CH2:13][B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)[CH2:9][NH:8][CH2:7]1)(=[O:4])[CH3:3].CCN(CC)CC.[Cl:37][C:38]1[CH:47]=[C:46]2[C:41]([CH2:42][CH:43]([CH:55]=O)[N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:45]2)=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:2]([NH:5][C@:6]1([C:23](=[O:24])[NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:10]([CH2:11][CH2:12][CH2:13][B:14]2[O:18][C:17]([CH3:19])([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15]2)[CH2:9][N:8]([CH2:55][CH:43]2[CH2:42][C:41]3[C:46](=[CH:47][C:38]([Cl:37])=[CH:39][CH:40]=3)[CH2:45][N:44]2[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(CC2Cc3ccc(Cl)cc3CN2C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
A stirred mixture of (3R,4S)-3-acetamido-N-tert-butyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxamide hydrochloride (226 mg, 0.524 mmol) and Et3N (0.110 mL, 0.786 mmol) in methylene chloride (2.5 mL) was treated with a solution of tert-butyl 7-chloro-3-formyl-3,4-dihydroisoquinoline-2(1 H)-carboxylate (155 mg, 0.524 mmol) in methylene chloride (2.5 mL). After stirring for 20 min, sodium triacetoxyborohydride (233 mg, 1.10 mmol) was added and stirring was continued for 1 h. The resulting mixture was carefully quenched with saturated aqueous NaHCO3 (5 mL), diluted with saturated aqueous sodium chloride (15 mL) and extracted with methylene chloride (4×15 mL). The combined organic phase was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (40 g column, 2-4% MeOH in ethyl acetate) gave tert-butyl 3-({(3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidin-1-yl}methyl)-7-chloro-3,4-dihydroisoquinoline-2(1 H)-carboxylate (296 mg, 84%, mixture of diastereomers) as a clear gum. LC-MS gives ESI+ MS found for C35H56BClN4O6 m/z 675.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:12]1([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:26][CH2:25]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCN(CCCN2CCNCC2)CC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CCCN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dichlorophenylisocyanate (0.3 g; 1.5 mmol) in a mixture of DMF (0.5 ml) and dichloromethane (5 ml) was added to 1-(3-piperidinopropyl)-piperazine (0.21 g; 1 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([O-])([O-])=O.[K+].[K+].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[N+:13]([C:5]1[CH:4]=[CH:3][C:2]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:15])=[O:14]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 36 %

Procedure:
To a stirring suspension of ethyl 5-chloro-2-nitrobenzoate (15 g, 65.3 mmol) and K2CO3 (13.54 g, 98 mmol) in DMF (5 ml) was added phenol (6.76 g, 71.9 mmol). Reaction mixture was heated at 130° C. for 16 h. Reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated and distilled out to get crude product which was column purified using 10% EtOAC in hexane to get the titled compound in 36% yield.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][C:22]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][NH2:29])=[CH:23][C:15]=2[C:14]1=[O:30])([OH:10])=[O:9].[C:31](S(O)(=O)=O)([NH2:33])=[NH:32]>C(O)(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][C:22]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][NH:29][C:31]([NH2:33])=[NH:32])=[CH:23][C:15]=2[C:14]1=[O:30])([OH:10])=[O:9]
Reactant: NCCCC#Cc1ccc2c(c1)C(=O)N(CCC(=O)O)CCC2
Reactant: N=C(N)S(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: N=C(N)NCCCC#Cc1ccc2c(c1)C(=O)N(CCC(=O)O)CCC2
Reaction time: 2 h
Yield: 15.2 %

Procedure:
A solution of 2-(2-carboxyethyl)-8-(5-aminopentynyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one trifluoroacetate (20 mg, 0.063 mmol) in saturated aqueous KHCO3 (1 mL) was treated with formamidine sulfonic acid (80 mg, 1.0 mmol), and the resulting mixture stirred for 2 hours. The mixture was then treated with acetic acid, and the volatiles were removed. The residue was purified by HPLC (1/2' C-18 reverse-phase column) eluting with a gradient of 3:7 methanol (0.1% trifluoroacetate)/water (0.1% trifluoroaceate), time 0 to 10 min, to 7:3 methanol(0.1% trifluoroaceate)/water(0.1% trifluoroaceate), time 10 to 40 min, to yield 4.5 mg (15%) of 2-(2-carboxyethyl)-8-(5-guanidinopentynyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one trifluoroacetate as a light brown solid; 1H NMR(D2O) d7.40(s, 1H), 7.25(dd, J=3, 6 Hz, 1H), 7.15(d, J=6 Hz, 1H), 3.80(t, J=6 Hz, 2H), 3.30(m, 4H), 3.15(t, J=6 Hz, 2H), 2.00(t, J=6 Hz, 2H), 1.80(m, 2H); MS(FAB) m/z=357.1(MH+).
Reaction SMILES: C(C1NC=CN=1)(C1[NH:4]C=CN=1)=O.[N:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]([CH:27]([C:37]([NH2:39])=[O:38])[C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[CH3:26])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.N>N1C=CC=CC=1>[N:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]([CH:27]([C:37]([NH2:39])=[O:38])[C:28]2[CH:36]=[CH:35][C:31]([C:32]([NH2:4])=[O:34])=[CH:30][CH:29]=2)[CH3:26])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: c1ccncc1
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(N)=O)cc1
Reaction time: 8 h

Procedure:
An amount of 2.3 gm (0.0142 mol) of carbonyl diimidazole was mixed with 4.76 gm (0.013 mol) of 4-[(1-(2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 60 ml of absolute pyridine, and the mixture was subsequently heated for 45 minutes to 50° C. After cooling in a carbon dioxide/methanol bath, 7 ml of liquid ammonia were added, and the mixture was heated for 20 hours to 80° C. in an autoclave. Subsequently the reaction mixture was cooled and evaporated in vacuo. The residue was dissolved in 50 ml of hot methanol, 200 ml of water were added, and the mixture was allowed to stand overnight. The crystalline precipitate was recovered by suction filtration and recrystallized from methanol by addition of activated charcoal.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[CH:19]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[CH:32]=O>>[CH:19]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:32][N:1]1[CH:2]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])[CH2:3][CH2:4][C:5]1=[O:7]
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: δ 401.83 g/mol.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[S:22](Cl)(=[O:24])=[O:23]>O>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[S:22]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH:10]=1)(=[O:24])=[O:23]
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2ccc(OS(=O)(=O)c3c(F)cccc3F)cc2s1
Temperature: 20 °C
Reaction time: 120 h
Yield: 102 %

Procedure:
To a solution of 1 g of 2-amino-1,3-benzothiazol-6-ol in 66 cm3 of aqueous 0.1N sodium hydroxide solution are added 1.279 g of 2,6-difluorobenzenesulfonyl chloride. The solution is stirred for 5 days at a temperature in the region of 20° C. After addition of 10 cm3 of water, the precipitate is filtered off by suction and then washed with twice 3 cm3 of ice-cold water and dried under reduced pressure over phosphorus pentoxide. 2.1 g of 2-amino-1,3-benzothiazol-6-yl 2,6-difluorobenzenesulfonate are obtained in the form of a pink powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][CH2:9][C:10]([C:13]2[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=2)([CH3:12])[CH3:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:43])[CH3:42]>C1COCC1>[C:41]([N:8]([CH2:7][C:6]1[CH:33]=[CH:34][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:9][C:10]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:21])([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH3:31])[O:15][N:14]=1)([CH3:12])[CH3:11])(=[O:43])[CH3:42]
Reactant: COc1ccc(CNCC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)on2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(CN(CC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)on2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75 %

Procedure:
To a solution of N-{3-[2-(4-methoxy-benzylamino)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (143 mg, 0.29 mmol) in THF (1.5 mL) are added pyridine (0.035 mL, 0.44 mmol) and acetyl chloride (0.031 mL, 0.44 mmol). The reaction mixture is stirred at room temperature for 3.5 h. After this time, more pyridine (0.018 mL, 0.22 mmol) and acetyl chloride (0.016 mL, 0.22 mmol) are added to the reaction mixture and the stirring is continued for 1 h. After this time, the reaction mixture is quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate twice. The organic extracts are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/DCM provides the title compound. Yield: 75%; LC-MS retention time: 1.62 mins. ESI+ion mode. Zorbax SB-C18 column (3.5 μm, 4.6×30 mm). Gradient: 5% B to 80% B (0 min to 1.7 mins), 80% B to 95% B (1.7 mins to 2 mins), 95% B to 95% B (2 mins to 2.1 mins). Flow rate: 2.5 mL/min. A=(Water+0.1% Formic Acid), B=(Acetonitrile+0.1% Formic Acid). Diode Array Detector; m/z 536 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18]([CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)(=[O:20])=[O:19])[CH2:14]1.[ClH:31]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:31].[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18]([CH2:21][CH2:22][NH2:23])(=[O:20])=[O:19])[CH2:14]1
Reactant: COc1ccc2nccc(N3CCC(S(=O)(=O)CCNC(=O)OC(C)(C)C)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc2nccc(N3CCC(S(=O)(=O)CCN)C3)c2n1
Reaction time: 2 h

Procedure:
1,1-dimethylethyl [2-({1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}sulfonyl)ethyl]carbamate (150 mg, 0.34 mmol) was dissolved in a minimum amount of chloroform and treated with 4N HCl in dioxane (2 mL). After stirring 2 h, the reaction mixture was concentrated to dryness and azeotroped with toluene to afford HCl salt of the title compound as a yellow solid which was used without further purification (100 mg, 88%): LC/MS m/z 337 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH2:31][CH2:32][CH:33]1[CH2:35][CH2:34]1>>[CH:33]1([CH2:32][NH:31][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=4[Cl:28])[C:15]=3[O:14]2)[CH2:35][CH2:34]1
Reactant: NCC1CC1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Product: Fc1cc2c(c(-c3c(Cl)cccc3Cl)c1)OC(CNCC1CC1)C2

Procedure:
The title compound was prepared (0.066 g, 54%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.30 mmol) and (aminomethyl)cyclopropane (0.21 g, 3.0 mmol). mp 130-133° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.C1N=[CH:16][N:15](C(N2C=NC=C2)=O)[CH:14]=1.CNC>C1COCC1>[CH3:14][N:15]([CH3:16])[C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 1-methyl-4-nitropyrazole-3-carboxylic acid (2.0 g) in THF (30 ml) was charged carbonyl-1,1′-diimidazole (1.9 g) over 1 hour at room temperature. The reaction was stirred overnight before cooling to 0° C. A solution of dimethylamine in THF (12 ml of a 2M solution) was added and the reaction stirred for 1 hour. The THF layer was separated and concentrated in vacuo. The crude product was purified by column chromatography on silica (30 g), eluting with 100% EtOAc (300 ml) to give N,N,1-trimethyl-4-nitropyrazole-3-carboxamide, 1235 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]=1[NH:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[O:4].OS(O)(=O)=O.[CH2:22](O)[CH2:23][CH3:24]>>[CH3:1][O:2][C:3]([C:5]1[C:9]([O:10][CH2:22][CH2:23][CH3:24])=[CH:8][S:7][C:6]=1[NH:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[O:4]
Reactant: COC(=O)C1=C(NC(=O)N(C)C)SCC1=O
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOc1csc(NC(=O)N(C)C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
A solution of 2-(3,3-Dimethyl-ureido)-4-oxo-4,5-dihydro-thiophene-3-carboxylic acid methyl ester (50 mg, 0.205 mmol) in n-propanol (5 mL) was treated with H2SO4 (5 microliters) and stirred at ambient temperature for 12 hours. Little reaction was observed so the temperature was increased to 100° C. Little reaction was observed after 2 hours so four angstrom seives were added and the reaction continued at 100° C. for two additional hours at which point sufficient product was observed. The mixture was then concentrated and the residue purified via radial chromatography on a 4 mm plate using hexanes/ethyl acetate (1/1) to afford the title compound as a white solid (31 mg, 0.108 mmol, 53%) 1H NMR (CDCL3, 400 MHz) 1.03 (t, 3H, J=7.3 Hz), 1.78-1.84 (m, 2H), 3.06 (s, 6H), 3.84-3.89 (m, 5H), 5.51 (s, 1H), 11.08 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=O)[C:2]1=2.[C:15]1([CH3:23])[CH:20]=[CH:19][CH:18]=[C:17]([Mg]Br)[CH:16]=1.Cl.[Sn](Cl)Cl>O1CCCC1>[C:15]1([CH3:23])[CH:20]=[CH:19][CH:18]=[C:17]([C:6]2[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]([C:12]3[CH:2]=[C:3]([CH3:4])[CH:6]=[CH:7][CH:11]=3)=[C:2]3[S:1][CH:5]=[CH:4][C:3]=23)[CH:16]=1
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Reactant: Cc1cccc([Mg]Br)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: Cc1cccc(-c2c3ccsc3c(-c3cccc(C)c3)c3ccsc23)c1
Temperature: 25 °C

Procedure:
A clean and dry 2000 ml round bottom flask equipped with reflux condenser, magnetic stir bar, and thermometer with adapter was prepared, purged, and then charged with 4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophen-4,8-dione (7.34 g, 0.0333 mol). Anhydrous tetrahydrofuran (900.0 ml) was then added to this flask by cannula and stirring was initiated. Heat was applied to the reaction vessel to dissolve this material. The reaction vessel was placed into a water bath and m-tolylmagnesium bromide solution (100 ml, 0.1000 mol) was added via cannula. Following addition, the vessel was removed from the water bath and heated to reflux for 1 hour. The reaction was then removed from heat and allowed to cool to room temperature. m-tolylmagnesium bromide solution (100 ml, 0.1000 mol) was added via cannula and the reaction was again heated to reflux for 1 hour. The progress of the reaction was monitored by GC-MS and no starting material was present. The reaction was subsequently removed from heat and cool to room temperature overnight. A hydrochloric acid (160.0 ml, 10%)/tin (II) chloride (30.05 g, 0.1333 mol) solution was then prepared and added to the reaction via syringe. The reaction vessel was again heated to reflux for 1 hour, then removed from heat and allowed to cool to room temperature. Solvent was removed by rotary evaporation. Ethyl acetate (500.0 ml) was and the crude mixture was nearly dissolved. The volume was washed once with DI H2O (500 mL), and the organic layer containing solids was collected. Solids were removed by vacuum filtration, collected, and washed in hot methanol. The filtrate was dried over anhydrous magnesium sulfate, filtered, and removed of solvent by rotary evaporation. To the remaining crude material acetone (25.0 ml) and methanol (500.0 ml) were added and heated to reflux in trituration for 1 hour. The resulting solids in solution were vacuum-filtered and collected. All solids collected during purification were proved to be pure by NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][CH2:7][C:8](=[O:10])N)[CH3:2].N(OC(C)(C)C)=[O:24]>C(#N)C>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][CH2:7][C:8]([OH:24])=[O:10])[CH3:2]
Reactant: CCOC(=O)C(CCC(N)=O)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)C(CCC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A suspension of the amide (2) (38 g, 0.1233 mol) in anhydrous acetonitrile (400 ml) was stirred at reflux under nitrogen and t-butyl nitrite (35 ml, 3.17 equiv.) was added quickly. The reflux was continued for 2 hrs. After cooling, the solvent was removed in a rotary evaporator. The residue was taken in water (250 ml) and ethyl acetate (500 ml) and the biphasic mixture was stirred well while solid sodium bicarbonate was slowly added to pH=7.5. Phases were separated and the organic phase was washed with 10% sodium bicarbonate (200 ml). The combined aqueous extracts were washed with ethyl acetate (300 ml), made acidic with 6N hydrochloric acid and extracted with ethyl acetate (2×300 ml). The combined extracts were washed with water (150 ml), dried over sodium sulfate, stripped and the residue was dried in a vacuum oven (50° C.) to produce (3) (24.6 g, 64.7%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[CH:19]=O)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[N:24]1([CH2:19][C:18]2[CH:17]=[C:16]([N:8]3[C:9]4[CH:14]=[CH:13][N:12]=[CH:11][C:10]=4[N:15]=[C:7]3[C:3]3[C:2]([NH2:1])=[N:6][O:5][N:4]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: Nc1nonc1-c1nc2cnccc2n1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: Nc1nonc1-c1nc2cnccc2n1-c1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
The product of Step 1 was stirred in 1,2-dichloroethane, and treated with pyrrolidine (27 uL, 0.326 mmol) and stirred for 15 minutes at room temperature. The reaction was then treated with sodium triacetoxyborohydride (34 mg, 0.164 mmol) and stirred at room temperature for 16 hours. The reaction was diluted with methanol and applied to a Mega Bond Elute SCX ion exchange column, eluting sequentially with water, methanol and finally 0.880 ammonia:methanol (1:9). The residue was purified using silica gel chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the compound (20 mg, 34%); MS (ES+), m/e 362 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[S:24][C:25]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:26]=2[N:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[S:24][C:25]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: COc1ccc2nc(Oc3ccc(OC[C@H]4CCCN4C(=O)OC(C)(C)C)cc3)sc2c1
Yield: 77 %

Procedure:
Followed the same procedure as that of step 1 in Example 99 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester ((147 mg, 0.5 mmol) and 2-chloro-6-methoxy-benzothiazole (100 mg, 0.5 mmol) to afford the title product (185 mg, 77% yield); 1H NMR (400 MHz, CDCl3); δ 1.46 (s, 9H), 1.80-2.10 (m, 4H), 3.28-3.46 (m, 2H), 3.70-3.98 (m, 1H), 3.84 (s, 3H), 4.01-4.20 (m, 2H), 6.72-6.82 (m, 4H), 6.92-6.99 (m, 2H), 7.62 (d, J=8.8 Hz, 1H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CCO.[Pd]>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCN2CCOCC2)cc1N
Reaction time: 18 h

Procedure:
To a solution 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamine (1.0 equivalent) in EtOH was added Pd/C (0.1 equivalents). The reaction vessel was repeatedly purged with hydrogen, then stirred under a hydrogen atmosphere (1 atm) for 18 hours. The product was filtered through a Celite plug, and the plug washed with EtOH. The diamine was used without purification. LC/MS m/z 238.3 (MH+), Rt 0.295 minutes.