Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1[C@@H]([C@H:12]2[O:21][C:19](=[O:20])[C:18]3[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=[CH:14][C:13]2=3)C2C(OC)=C3OCOC3=CC=2CC1.N1C=CC=CC=1.ICl.N>C(#N)C>[CH3:25][O:24][C:16]1[C:17]([O:22][CH3:23])=[C:18]2[C:13]([CH2:12][O:21][C:19]2=[O:20])=[CH:14][CH:15]=1
Reactant: COc1ccc2c(c1OC)C(=O)O[C@@H]2[C@H]1c2c(cc3c(c2OC)OCO3)CCN1C
Agent: ClI
Agent: N
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc2c(c1OC)C(=O)OC2
Reaction time: 6 h
Yield: 76 %

Procedure:
Iodination of noscapine was now carried out by addition of pyridine-iodine chloride (1.46 g, 6 mmol) to a solution of noscapine (1 g, 2.42 mmol) in acetonitrile (20 ml) and the resultant mixture was stirred at room temperature for 6 hours and then at 100° C. for 6 hours. After cooling, excess ammonia was added and filtered through celite pad to remove the black nitrogen triiodide. The filtrate was made acidic with 1 M HCl and filtered to collect the yellow solid, washed with water and air-dried to afford (S)-3-(R)-9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyisobenzofuran-1 (3H)-one (5). Yield: 76%, mp 172.3-172.6° C.; 1H NMR (CDCl3, 400 MHz): δ 7.15 (d, 1H, J=8.1 Hz), 7.01 (d, 1H, J=8.1 Hz), 6.11 (s, 2H), 5.36 (d, 1H, J=4.8 Hz), 4.25 (d, 1H, J=4.8 Hz), 3.85 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H), 2.78-2.72 (m, 2H), 2.55-2.50 (m, 2H), 2.32 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 168.2, 155.1, 151.5, 148.3, 146.5, 143.1, 140.3, 120.4, 119.5, 113.3, 101.5, 85.9, 82.2, 61.8, 56.6, 55.7, 54.5, 54.1, 51.2, 39.8, 30.1, 18.8; HRMS (ESI): m/z Calcd. for C22H23INO7 (M+1), 540.3209. Found, 540.3227 (M+1).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[K+]>C1COCC1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 92.3 %

Procedure:
4-Chlorobenzonitrile (140 mg, 1.02 mmol) reacted with p-methoxyphenylboronic acid (200 mg, 1.32 mmol) using 1/2 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (182 mg, 3.00 mmol) in THF solvent to give the title compound (197 mg, 94%) as white solid after recrystallization from hexane: 1H-NMR (400 MHz, CDCl3): δ 7.70 (d, 2H, J=8.41 Hz), 7.65 (d, 2H, J=8.40 Hz), 7.55 (d, 2H, J=8.80 Hz), 7.02 (d, 2H, J=8.79 Hz), 3.88 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 160.18, 145.17, 132.52, 131.45, 128.31, 127.06, 119.04, 114.52, 110.07, 55.35. GC/MS(EI): m/z (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]([CH3:58])[CH3:57])[C:7]([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:19][C:18]2[C:20]3[C:25]([CH:26]=[CH:27][C:17]=2[N:16]=1)=[CH:24][C:23]([C:28]1[CH:29]=[C:30]2[C:53](=[CH:54][CH:55]=1)[C:34]1[NH:35][C:36]([C@@H:38]4[CH2:42][C@H:41]([CH2:43][O:44][CH3:45])[CH2:40][N:39]4C(OC(C)(C)C)=O)=[N:37][C:33]=1[CH:32]=[CH:31]2)=[CH:22][CH:21]=3)=[O:8])=[O:4].Cl.[CH3:60][O:61][C@H:62]([CH3:72])[C@H:63]([NH:67][C:68]([O:70][CH3:71])=[O:69])[C:64]([OH:66])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:71][O:70][C:68]([NH:67][C@@H:63]([C@H:62]([O:61][CH3:60])[CH3:72])[C:64]([N:39]1[CH2:40][C@@H:41]([CH2:43][O:44][CH3:45])[CH2:42][C@H:38]1[C:36]1[NH:35][C:34]2[C:53]3[C:30]([CH:31]=[CH:32][C:33]=2[N:37]=1)=[CH:29][C:28]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[C:18]1[NH:19][C:15]([C@@H:10]4[CH2:11][C@H:12]([CH3:14])[CH2:13][N:9]4[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:56]([CH3:58])[CH3:57])=[N:16][C:17]=1[CH:27]=[CH:26]2)=[CH:55][CH:54]=3)=[O:66])=[O:69]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8C[C@H](C)CN8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8C[C@H](C)CN8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
(2S,4S)-tert-Butyl 2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (120 mg, 0.152 mmol) was dissolved in DCM (5 mL) and treated with HCl (4.0 mL in dioxane, 1 mL). After stirring for 1 h, the reaction mixture was concentrated under reduced pressure. The crude residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (35 mg, 0.18 mmol), HATU (69 mg, 0.18 mmol), DMF (1 mL) and DIPEA (0.26 mL, 1.5 mmol). After 20 min, the reaction was quenched with water. The product was purified by reverse-phase HPLC to afford methyl (S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (120 mg). MS (ESI) m/z 862 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]4[NH:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)[CH:20]=3)[CH:15]=2)[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1>[C:1]1([CH2:7][CH:8]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]4[NH:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)[CH:20]=3)[CH:15]=2)[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of methyl 3-phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoate (0.25 g, 0.56 mmol), prepared in the previous step, and 1N NaOH (1.1 mL, 1.1 mmol) in THF (25 mL) was stirred under nitrogen at ambient temperature overnight. By TLC analysis, starting material was still present. The mixture was heated to 60° C. for two hours, at which time no starting material remained. The mixture was cooled to ambient temperature, acidified with 1N HCl (2 mL) and the volatiles were removed under reduced pressure (without the application of heat). The residue was slurried with water, the solids filtered and washed with water. The solids were dissolved in methylene chloride, the solution dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound as an off-white solid (0.22 g, 90%), mp 176–178° C. Elemental Analysis for C29H23NO3 Calc'd: C, 80.35; H, 5.35; N, 3.23. Found: C, 79.19; H, 5.31; N, 2.97.
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:10]([CH2:9][N:8]([CH2:7][C:3]1[N:2]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][N:4]=1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:27])(=[O:28])[NH2:26])=[CH:21][CH:20]=1)([OH:12])=[O:11]
Reactant: Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(CCN(CC(=O)O)Cc2nccn2CC(=O)O)cc1

Procedure:
To a solution tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetate (40 mg, 0.079 mmol) in DCM (2.0 mL) and TFA (2.0 mL) was stirred at room temperature for 3 hrs. Solvent was removed under reduced pressure to give 2-(2-(((carboxymethyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetic acid. A solution of 2-(2-(((carboxymethyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetic acid and [NEt4]2[ReBr3(CO)3] (70 mg, 0.09 mmol) in MeOH (2.0 mL) and H2O (2.0 mL) was adjusted pH=9 using 2 N NaOH. The mixture was stirred at 95° C. for overnight at a pressure tube. The reaction mixture was purified by HPLC to give [Re(CO)3][2-(2-(((carboxymethyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetic acid] (20 mg, 38%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.76 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.36 (d, J=1.6 Hz, 1H), 7.26 (s, 2H), 7.16 (d, J=1.6 Hz, 1H), 5.05 (d, J=16.4 Hz, 1H), 4.98 (d, J=16.4 Hz, 1H), 4.73 (d, J=16.0 Hz, 1H), 4.43 (d, J=16.0 Hz, 1H), 4.00 (d, J=16.8 Hz, 1H), 3.60-3.51 (m, 3H), 3.10-3.05 (m, 2H); MS (ESI), 667.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO.O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:28])=[O:29])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[C:14]([C:22]([F:23])([F:24])[F:25])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccccc2)ccc1NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cc(NS(=O)(=O)c2ccccc2)ccc1NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
N-{3-nitro-4-(3,5-bis-trifluoromethyl-benzylamino)-phenyl}-benzenesulphonamide (8.6 g, 16.6 mmol) in 200 mL methanol are refluxed and within 0.5 h combined with a solution of Na2S2O4 (14.2 g, mmol) in 50 mL water. The mixture is refluxed until totally decolorised (this takes about 1 h). After cooling the mixture is diluted with water. About 100 mL of the methanol/water mixture are distilled off, the resulting solution is cooled, the crystals precipitated are filtered off and washed with water. The crystals are dissolved in ethyl acetate, dried and evaporated down until not quite dry. After cooling the crystals precipitated are filtered off and washed with diethylether.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:3]=[CH:2][CH:7]=[C:6]([C:27]4[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=4)[CH:5]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cnn(C)c3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (116 mg, 0.557 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.02 (s, 1H), 7.84 (s, 1H), 7.64 (d, 1H), 7.58 (m, 2H), 7.52 (s, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 7.02 (d, 1H), 4.4 (m, 2H), 3.96 (s, 3H), 3.8 (m, 1H), 3.58 (m, 1H), 3.0-3.2 (m, 5H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][CH:17]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:18](O)=[O:19])(=[O:15])=[O:14].C(N(CC)CC)C.[CH2:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:44].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH3:35][N:2]([CH3:1])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][CH:17]([C:18]([N:48]1[CH2:49][CH2:50][CH:45]([CH2:43][CH3:44])[CH2:46][CH2:47]1)=[O:19])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)NC(CCCNC(=O)OCc3ccccc3)C(=O)O)cccc12
Reactant: CCC1CCNCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC1CCN(C(=O)C(CCCNC(=O)OCc2ccccc2)NS(=O)(=O)c2cccc3c(N(C)C)cccc23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a cold (0° C.), nitrogen-blanketed mixture of 2d (48.90 g, 0.098 mol), triethylamine (25.0 mL, 0.18 mol) and 4-ethylpiperidine (20.0 g, 0.18 mol) in anhydrous dimethylformamide (160 mL) was added dropwise diphenylphosphoryl azide (21.1 mL, 0.098 mol). The mixture was stirred at about 0° C. for about 1 hour and at ambient temperature for about 2 hours before it was partitioned between ether (150 mL) and water (80 mL). The ethereal layer was separated and the aqueous layer was extracted four additional times with ether (80 mL). The combined ethereal extracts were then washed with saturated sodium bicarbonate solution and brine prior to drying (Na2SO4) and solvent concentration. Two identical reactions were performed in tandem. Purification of the combined residues by HPLC on silica gel (elution with 50% ethyl acetate in hexane) furnished 53.09 g (45%) of 3d as a yellow foam, m.p. 56°-62° C. (dec.); 1H NMR (CDCl3) δ 8.47 (d, 1H), 8.30 (t, 1H), 8.16 (d, 1H), 7.58 (m, 1H), 7.56-7.36 (m, 6H), 7.15 (d, 1H), 6.17-5.96 (dd, 1H), 5.10 (s, 2H), 4.75-4.62 (bm, 1H), 4.10-3.91 (bm, 2H), 3.42-3.30 (bm, 1H), 3.16-2.92 (bm, 2H), 2.85-2.83 (d, 6H), 2.68-2.41 (dt, 1H), 2.24-1.97 (m, 1H), 1.57-0.76 (m, 3 H), 0.16-0.08 (m, 1H); 13C NMR (CDCl3) ppm 168.50, 156.40, 151.62, 136.50, 135.00, 134.70, 130.56, 130.44, 129.80, 129.35, 129.18, 128.50, 128.41, 128.07, 128.00, 123.01, 122.93, 119.33, 115.58, 115.47, 66.60, 52.29, 52.19, 45.70, 45.43, 45.37, 45.13, 42.02, 42.21, 40.35, 40.18, 37.48, 37.34, 32.17, 31.92, 31.06, 30.79, 30.65, 29.67, 28.77, 28.58, 25.12, 11.08; IR (KBR, cm-1) 33,50 2975, 2975, 2950, 1725, 1650, 1550, 1475, 1350, 1275, 1180, 1160; MS m/z (MH+) 595.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)[C:36]2=[O:51])[S:28][C:29]=1[C:30]([O:32]CC)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)[C:36]2=[O:51])[S:28][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Yield: 85 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 85% yield: mp 195-197° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.74 (d, J=11.4 Hz, 2H), 7.60 (d, J=11.4 Hz, 2H), 4.51 (s, 2H), 4.00 (t, J=8.1 Hz, 2H), 3.47 (t, J=8.1 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 386.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[O:12])[NH:9][C:10]=1[CH3:11])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CN(C)C=O>[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[O:12])[NH:9][C:10]=2[CH3:11])[N:15]=1
Reactant: NC(N)=S
Reactant: Cc1[nH]c(=O)c(C#N)cc1C(=O)CBr
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
C-2. 5-(2-Amino-4-thiazolyl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile--A mixture containing 25.4 g of 5-bromoacetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 7.9 g of thiourea and 100 ml of dimethylformamide was heated on a steam bath for 3 hours and then evaporated to dryness. The residual material was diluted with 100 ml of water followed by the addition of 10 ml of concentrated aqueous ammonium hydroxide. The resulting mixture was reacidified with acetic acid and the solid that separated was collected, washed with water and dried. The solid (15.8 g) was suspended in 400 ml of water and the mixture treated with 25 ml of concentrated ammonium hydroxide. The resulting mixture was stirred for 30 minutes and a small quantity of insoluble material was filtered off. The filtrate was concentrated on a rotary evaporator to a volume of about 200 ml and allowed to cool to room temperature. The crystalline precipitate was collected, washed with distilled water and dried in a vacuum oven at 90° C. to produce 7.3 g of 5-(2-amino-4-thiazolyl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, m.p. 294°-296° C. with decomposition.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].O[CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:5][CH:15]1[CH2:16][CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
Methanesulfonic anhydride (996 mg, 5.72 mmol) was added to a mixture of 3-hydroxy-N-t-butoxycarbonylpiperidine (959 mg, 4.76 mmol) and triethylamine (0.86 ml, 6.19 mmol) in methylene chloride (30 ml) at 0° C. After stirring for 1 h, the reaction mixture was washed with saturated NaHCO3 and dried (Na2SO4). Concentration gave the title compound. 1H NMR (CDCl3) d 1.46 (s, 9 H), 1.77-2.17 (m, 4 H), 3.05 (s, 3 H), 3.14-3.49 (m, 2 H), 3.62 (m, 2 H), 4.72 (br s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.[N:21]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CS(C)=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.5 %

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (5.00 g, 27.47 mmol) in DMSO (30 mL) were added BOP (18.21 g, 41.21 mmol), NH4Cl (4.41 g, 82.41 mmol) and DIPEA (10.63 g, 82.41 mmol) and the reaction mixture was stirred at rt for 14 h and it was quenched with ice-water and the precipitate obtained was filtered, washed with Et2O and dried to afford 4.90 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.48 (br s, 2H), 8.19-8.17 (m, 2H), 7.96-7.94 (d, J=7.2 Hz, 1H), 7.62 (br s, 1H), 6.71-6.65 (t, J=7.8 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:33](=[O:36])[CH:34]=[CH2:35])[CH:11]([C:14]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:31])[C:21]2[C:16](=[CH:17][C:18]([Cl:32])=[CH:19][CH:20]=2)[N:15]=1)[CH2:12][CH3:13])(C)(C)C.C(OC(=O)N)(C)(C)C>>[CH2:24]([N:23]1[C:22](=[O:31])[C:21]2[C:16](=[CH:17][C:18]([Cl:32])=[CH:19][CH:20]=2)[N:15]=[C:14]1[CH:11]([N:10]1[C:33](=[O:36])[CH2:34][CH2:35][NH:7][CH2:8][CH2:9]1)[CH2:12][CH3:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=CC(=O)N(CCNC(=O)OC(C)(C)C)C(CC)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(C)(C)OC(N)=O
Product: CCC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O

Procedure:
Preparation of (2-{acryloyl-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-propyl]-amino}-ethyl)-carbamic acid tert-butyl ester: Following the procedure of Example of 1c, 2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-propylamino]-ethyl}-carbamic acid tert-butyl ester (940 mg, 2 mmol) was converted to the title compound as a white solid: MS (ES) m/e 525.4 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[C:8]([N+:14]([O-])=O)[CH:7]=1)(=[O:5])=[O:4]>C(O)C.[NH4+].[Cl-].[Zn]>[NH2:14][C:8]1[CH:7]=[C:6]([S:3]([NH:2][CH3:1])(=[O:4])=[O:5])[CH:11]=[CH:10][C:9]=1[S:12][CH3:13]
Reactant: CNS(=O)(=O)c1ccc(SC)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(SC)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of N-methyl-4-(methylthio)-3-nitrobenzenesulfonamide (1.0 g, 3.81 mmol) in 10 mL of ethanol and 10 mL of NH4Cl, zinc dust (2.5 g, 3.81 mmol) was added. The reaction mixture was stirred overnight at room temperature. The mixture was then filtered and diluted with ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to afford 3-amino-N-methyl-4-(methylthio)benzenesulfonamide (0.500 g, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.06 (d, J=8.03 Hz, 1H), 6.86 (s, 1H), 6.67-6.76 (m, 1H), 5.28 (br. s., 2H), 2.17 (s, 3H), 2.21 (s, 3H); MS (m/z) 232.7 (M+H+)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:3]1.CN(CCN(C)C)C.[Li]CCCC.CN(C)[C:33](=O)[O:34]CC.[NH4+].[Cl-]>CCOCC.CCCCCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[C:11]3[C:12]([C:33](=[O:34])[C:3]1=2)=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3
Reactant: Cc1ccc(-c2cn(C)c3ccccc23)cc1
Reactant: CCOC(=O)N(C)C
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1ccc2c(c1)C(=O)c1c-2c2ccccc2n1C
Temperature: -40 °C

Procedure:
A solution of 2.19 g (0.00991 mol) of 1-methyl-3-(4-methylphenyl)-1H-indole and 3.24 mL (0.0218 mol) of TMEDA in 30 mL of ether was treated with 13.6 mL (0.0218 mol) of 1.6M BuLi in hexane under stirring at −40° C. Then the reaction mixture was allowed to warm up to r.t. and stirred for 4 h. The reaction mixture was cooled to −60° C. and treated with 1.16 g (0.00991 mol) ethyl N,N-dimethylcarbamate in 5 mL of ether. Then the reaction mixture was allowed to warm up to r.t. and was stirred overnight. Resulting mixture was treated with 50 mL of 10% aqueous NH4Cl. The violet precipitate was separated, washed twice with water and dried. Yield 1.04 g (42%).