Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:2]1[O:10][C@@H:9]([CH3:11])[C@@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:18]([O:4][C@H:3]1[C@H:5]([O:6][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:7]([O:8][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:9]([CH3:11])[O:10][C@@H:2]1[S:1][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 100 °C

Procedure:
To a solution of crude phenyl 6-deoxy-1-thio-β-L-galactopyranoside 3 in 15 mL of pyridine is added pivaloyl chloride (4.0 mL, 3.90 g, 32.5 mmol) and DMAP (0.33 g, 2.71 mmol). The reaction mixture is heated at 100° C. for 12 h, cooled, diluted with 50 mL of CH2Cl2, washed with H2O (100 mL) and saturated NaCl (100 mL), dried over Na2SO4, filtered and concentrated to afford 3.25 g of phenyl 6-deoxy-2,3,4-tri-O-pivaloyl-1-thio-β-L-galactopyranoside 4 as a brown oil. This oil is purified by flash chromatography (15% EtOAc/petroleum ether) to afford 0.53 g (48%) of the pure compound. An additional 0.81 g of a brown oil, which that appeared to be a mixture of incompletely acylated products, is also isolated. This material is resubjected to the reaction conditions for 48 h and provided an additional 0.21 g (19%, total yield 67% for 2 steps): Rf 0.48 (15% EtOAc/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 7.50-7.59 (m, 2H), 7.23-7.35 (m, 3H), 5.16-5.30 (m, 2H), 5.08 (dd, J=9.9, 3.0 Hz, 1H, H-3), 4.66 (d, J=9.6 Hz, 1H, H-1), 3.90 (q, J=6.3 Hz, 1H, H-5), 1.21 (s, 9H), 1.18 (s, 9H), 1.21 (s, 9H), 1.21 (d, J=6.6 Hz, 3H, H-6); 13C NMR (CDCl3, 68 MHz) δ 177.2, 177.4, 177.1, 133.5, 131.1, 128.6, 128.4, 128.1, 127.7, 85.1, 73.3, 72.6, 69.9, 66.3, 38.9, 38.6, 26.9, 27.0, 16.4; FABMS C27H39O7S (MNa+) calcd 531.2392, found 531.2404.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25].CCN(CC)CC>C(Cl)Cl>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CCS(=O)(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCC4N)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CCCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Yield: 125.2 %

Procedure:
A cooled (0° C.) brown solution of (rac)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (intermediate A-2) (61.5 mg, 200 μmol) in CH2Cl2 (3.0 ml) was treated with ethanesulfonyl chloride (65.6 mg, 48.3 μL, 500 μmol) and Et3N (40.5 mg, 55.8 μL, 400 μmol). After ½ h the mixture was concentrated in vacuo and purified by flash chromatography (20 g SiO2, Telos-cartridge, CH2Cl2/MeOH (1 to 5%)) to give 100 mg of the title compound together with Et3N×HCl as impurity. Extraction with H2O/EtOAc (3×), and precipitation CH2Cl2/n-pentane gave the pure title compound (46 mg, 58%) as a yellow powder. MS: 400.2 (M+H+).
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[C:22]1([CH3:36])[CH:27]=[CH:26][C:25]([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])=[CH:24][CH:23]=1.[Cl:37][CH2:38][CH2:39][CH2:40][C:41]#[CH:42]>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH3:36])=[CH:27][CH:26]=2)[CH:42]=[C:41]([CH2:40][CH2:39][CH2:38][Cl:37])[O:35]1)[CH3:33]
Reactant: C#CCCCCl
Reactant: CCOP(=O)(O)C#Cc1ccc(C)cc1
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccc(C)cc2)C=C(CCCCl)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
Method 2—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tent-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen p-tolylethynylphosphonate (67.3 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, 5-chloropent-1-yne (61.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-p-tolyl-6-chloropropyl-1,2-oxaphosphorin 2-oxide (68.5 mg, 70%) which is a title compound.
Reaction SMILES: ClC1N=CC(C2CC2)=CN=1.Cl.ClC1C=C(N2C(=O)C=C(OC3CCNCC3)C(C#N)=N2)C=CC=1Cl.[Br:36][C:37]1[CH:38]=[N:39][C:40](Cl)=[N:41][CH:42]=1.Cl.[C:45]([C:47]1[CH:52]=[CH:51][C:50]([N:53]2[C:58](=[O:59])[CH:57]=[C:56]([O:60][CH:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)[C:55]([C:67]#[N:68])=[N:54]2)=[CH:49][C:48]=1[F:69])#[N:46]>>[Br:36][C:37]1[CH:38]=[N:39][C:40]([N:64]2[CH2:65][CH2:66][CH:61]([O:60][C:56]3[C:55]([C:67]#[N:68])=[N:54][N:53]([C:50]4[CH:51]=[CH:52][C:47]([C:45]#[N:46])=[C:48]([F:69])[CH:49]=4)[C:58](=[O:59])[CH:57]=3)[CH2:62][CH2:63]2)=[N:41][CH:42]=1
Reactant: Clc1ncc(Br)cn1
Reactant: N#Cc1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1F
Agent: Cl
Agent: Clc1ncc(C2CC2)cn1
Agent: N#Cc1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCNCC1
Product: N#Cc1ccc(-n2nc(C#N)c(OC3CCN(c4ncc(Br)cn4)CC3)cc2=O)cc1F
Yield: 89 %

Procedure:
Example 41 was prepared in 89% yield according to procedures described in Example 21 substituting 2-chloro-5-cyclopropylpyrimidine and 1-(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl for 5-bromo-2-chloropyrimidine and 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt. 1H NMR (400 MHz, CDCl3) δ ppm 0 1.90-2.01 (m, 2H) 2.01-2.19 (m, 2H) 3.78-3.91 (m, 2H) 3.99-4.19 (m, 2H) 4.52-4.93 (m, 1H) 6.32 (s, 1H) 7.60-7.71 (m, 2H) 7.71-7.82 (m, 1H) 8.31 (s, 2H). MS (ESI) 497 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:17]2[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]2=[CH:15][N:14]=1.[O:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>>[O:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[N:17]([C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:14][CH:15]=3)[CH:18]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1-c1ncc2ccc(C(=O)O)cn12
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1-c1ncc2ccc(C(=O)NC3CCOCC3)cn12
Yield: 55.2 %

Procedure:
As described for example 4b, 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine-6-carboxylic acid (58 mg, 0.18 mmol), was converted, using tetrahydropyran-4-ylamine (28 mg, 0.27 mmol) instead of cyclopropyl methylamine, to the title compound (40 mg, 55%) which was obtained as a light yellow solid. MS: m/e (ESI): 403.3 [M+H]+.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[C-:11]#[N:12].[Na+]>O>[C:11]([C:4]1([OH:10])[CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH2:3]1)#[N:12]
Reactant: O=C1CN2CCC1CC2
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CC1(O)CN2CCC1CC2
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a cooled (ice bath), stirred solution of 3-quinuclidinone hydrochloride (300 g) in water (400 ml) was added dropwise a solution of sodium cyanide (90.97 g) in water (400 ml). After stirring at ice bath temperature for three hours the precipitate was collected by filtration, washed with water and dried under vacuum to afford the title compound (282 g); m.p. 153°-157° C. (lit m.p. 152°-155° C.; Helv. Chim. Acta., 1954, 37, 1689).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:43])=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[CH:17]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH:26]=O)=[CH:24][CH:25]=2)[CH:19]=1)=[O:13].[NH:44]1[CH2:49]COC[CH2:45]1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:13])[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH2:26][N:44]([CH3:49])[CH3:45])=[CH:24][CH:25]=2)[CH:17]=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)[C:15]=1[CH3:43]
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a stirred solution of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-formylpyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (1 equiv.) and morpholine (5 equiv.) in methanol (5 mL for 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 4 h. Then reducing agent NaBH3CN (1 equiv.) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and residue purified by column chromatography over silica gel affording desired tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-((dimethylamino)methyl)pyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate. This compound was then dissolved in DCM (5 mL) and cooled to 0° C. TFA (2 mL) was added to it. The reaction mixture was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was purified by solvent washings to afford the title compound (0.06 g, 40%). LCMS: 517.25 (M+1)+; HPLC: 99.07% (@254 nm) (Rt; 3.913; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.48 (s, 1H), 10.08 (bs, 1H), 8.97 (s, 1H), 8.57 (bs, 1H), 8.23 (d, 2H, J=7.6 Hz), 8.18 (s, 1H), 7.60 (d, 1H, J=8 Hz), 7.50 (s, 1H), 7.34 (s, 1H), 5.87 (s, 1H), 4.49 (d, 2H), 4.30 (s, 2H), 3.25 (d, 2H), 3.16 (s, 1H), 2.89 (m, 2H), 2.83 (s, 6H), 2.64 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.81 (bs, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:34])[N:14]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:34])[N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1c(CCc2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(CCc2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3-benzyloxycarbonylamino-2-oxo-6-phenethyl-1,2-dihydro-1-pyridyl)acetate (0.554 g) in dichloromethane (distilled from CaH) was added trifluoroacetic acid (1.50 ml); and the mixture was stirred overnight, evaporated, and dried under vacuum to afford (3-benzyloxycarbonylamino-2-oxo-6-phenethyl-1,2-dihydro-1-pyridyl)acetic acid; MS: m/z=407(M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[C:4]([CH3:14])[CH:3]=1.B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[CH3:27])(O)O>>[CH3:27][C:19]1[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[CH:25]=[CH:26][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1nnc(-c2ccc(Br)cc2C)o1
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3C)cc2C)o1

Procedure:
The title compound was prepared from 2-(4-bromo-2-methylphenyl)-5-methyl-1,3,4-oxadiazole (D35) and 4-borono-3-methylbenzoic acid (D33) using a similar procedure to Description 11 as a white solid (24%).
Reaction SMILES: [C@@H:1]12[N:8]([C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.C1(C2C=CC=CC=2)C=CC=CC=1C(N1C2C(CCNC2)C1)=O.Cl[C:45]1[N:50]=[C:49]([CH3:51])[CH:48]=[C:47]([CH3:52])[N:46]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[CH3:52][C:47]1[CH:48]=[C:49]([CH3:51])[N:50]=[C:45]([N:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:1]([N:8]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:7]3)[CH2:2]2)[N:46]=1
Reactant: O=C(c1ccccc1-c1cccs1)N1C[C@@H]2CCNC[C@@H]21
Reactant: Cc1cc(C)nc(Cl)n1
Agent: Clc1cnc2ccccc2n1
Agent: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Product: Cc1cc(C)nc(N2CC[C@H]3CN(C(=O)c4ccccc4-c4cccs4)[C@H]3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S) (3,8-diaza-bicyclo[4.2.0]oct-8-yl)-(2-thiophen-2-yl-phenyl)-methanone (Intermediate 7) for biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone and 2-chloro-4,6-dimethyl-pyrimidine for 2-chloro quinoxaline. MS (ESI) mass calcd. for C23H24N4OS, 404.53; m/z found 405.2 [M+H]+. 1H NMR (CDCl3) 7.54-7.27 (m, 4H), 7.25-7.12 (m, 2H), 7.07 (dd, J=5.1, 3.6, 0.7H), 6.81-6.75 (m, 0.3H), 6.29 (d, J=17.6, 1H), 4.78-4.54 (m, 0.75H), 4.10-3.55 (m, 4.5H), 3.52-3.33 (m, 0.75H), 3.01-2.90 (m, 0.6H), 2.73-2.56 (m, 1H), 2.30 (d, J=23.8, 6H), 2.10-1.50 (m, 2.4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.I[C:26]1[CH:39]=[N:38][C:29]2[NH:30][C:31]3[CH:36]=[N:35][C:34]([Br:37])=[CH:33][C:32]=3[C:28]=2[CH:27]=1>C(=O)([O-])[O-].[Na+].[Na+].CC1CCCO1.C(Cl)Cl>[Br:37][C:34]1[N:35]=[CH:36][C:31]2[NH:30][C:29]3[N:38]=[CH:39][C:26]([C:14]4[CH:13]=[CH:12][C:4]([CH2:5][N:6]5[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]5)=[C:3]([O:2][CH3:1])[CH:15]=4)=[CH:27][C:28]=3[C:32]=2[CH:33]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1CN1CCCCC1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)ccc1CN1CCCCC1
Temperature: 85 °C
Yield: 60.8 %

Procedure:
A degassed mixture of 1-[2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine (885 mg, 2.7 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (500 mg, 1.3 mmol), 1,1′-[bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (163 mg, 0.2 mmol) in 2N aqueous sodium carbonate solution (10 mL) and 2-methyltetrahydrofuran (20 mL) was heated at 85° C. for 18 h. The cooled reaction mixture was diluted with DCM (100 mL) and washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue (357 mg, 61%) that was used in the next step without purification. 1H NMR (CDCl3, 300 MHz): 8.83 (d, J=2.0 Hz, 1H), 8.70 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 3.96 (s, 3H), 3.65 (s, 2H), 2.56-2.48 (m, 4H), 1.67-1.59 (m, 4H), 1.52-1.41 (m, 2H).
Reaction SMILES: [N:1]1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=3[S:8](=[O:20])(=[O:19])[N:7]=2)[CH:5]=[CH:4]N=C1.[CH2:21](N)CC>>[CH2:5]([NH:1][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=2[S:8](=[O:20])(=[O:19])[N:7]=1)[CH2:4][CH3:21]
Reactant: CCCN
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Product: CCCNC1=NS(=O)(=O)c2cc(C(=O)O)ccc2N1

Procedure:
3-(Imidazol-1-yl)-4H-1,2,4-benzothiadiazine-7-carboxylic acid 1,1-dioxide was treated with propylamine according to the general procedure Method A to give the title compound; m.p. >310° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][Al](C)C.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C1(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)C=CC=CC=1>[CH3:10][C:4]1[C:3]([CH3:11])=[C:2]([CH3:12])[C:7]([CH3:8])=[CH:6][N+:5]=1[O-:9]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Br
Reactant: C[Al](C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c[n+]([O-])c(C)c(C)c1C

Procedure:
4-Bromo-2,3,5-trimethyl-pyridine 1-oxide (2 g, 9.2 mmole) and catalytic tetrakis(triphenylphosphino)-palladium (80 mg, 4% by wt) in 20 mL of dry THF before treating with trimethylaluminum (2M in toluene, 15.2 mmole) under nitrogen. The solution was heated to reflux for 3 h, diluted with toluene (20 mL) before quenching the reaction with 4 mL of methanol followed by ammonium chloride (15 mmole). The mixture was refluxed for 2 h and filtered, while hot, on Celite. See J. Med. Chem. 1999, 42(12), 2064–2086. HPLC Rt: 4.183 min. 1H-NMR (CDCl3): δ 8.05 (s, 1H), 2.55 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([OH:8])=[O:7])#[N:2].[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([O:8][CH3:13])=[O:7])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(F)c(C#N)c1
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a 100 mL rbf was added 3-cyano-4-fluoro-benzoic acid (2.6 g, 15.9 mmol), potassium carbonate (6.6 g, 47.6 mmol), and DMF (30 mL) and the reaction was allowed to stir for 10 minutes. Iodomethane (1.1 mL, 17.5 mmol) was added dropwise and the reaction was allowed to stir for 1 h. The reaction was complete by 1 cms. The reaction was quenched with brine and extracted with EtOAC. The organic layer was washed with brine 3 times and the organic layer was dried over sodium sulfate and evaporated. Methyl 3-cyano-4-fluoro-benzoate (2.5 g, 62%) was isolated as a white solid. ESI-MS m/z calc. 179.0, found 180.0 (M+1)+; Retention time: 1.15 minutes (3 min run).
Reaction SMILES: C(O[C:4](=[O:51])[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:50])[C@@H:15]([NH:17][C:18]([C:20]2[N:24]3[C@:25]([CH3:49])([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=4)[C:26](=[O:36])[N:27]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:23]3=[N:22][CH:21]=2)=[O:19])[CH3:16])[CH2:9]1)=O)C.[NH2:52][NH2:53]>C(O)C>[Cl:34][C:32]1[CH:33]=[C:28]([N:27]2[C:26](=[O:36])[C@@:25]([CH3:49])([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:42][CH:43]=3)[N:24]3[C:20]([C:18]([NH:17][CH:15]([CH3:16])[C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]5[NH:53][N:52]=[C:4]([OH:51])[CH:5]=5)[CH2:9]4)=[O:50])=[O:19])=[CH:21][N:22]=[C:23]23)[CH:29]=[C:30]([Cl:35])[CH:31]=1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)c2cnc3n2[C@](C)(Cc2ccc(OC(F)(F)F)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)C1
Reactant: NN
Solvent: CCO
Product: CC(NC(=O)c1cnc2n1[C@](C)(Cc1ccc(OC(F)(F)F)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N1CCC[C@@H](c2cc(O)n[nH]2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
To a solution of 3-[(R)-1-((S)-2-{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionyl)-piperidin-3-yl]-3-oxo-propionic acid ethyl ester (40 mg, 0.05 mmol) in ethanol (2 mL) was added hydrazine (8.5 μL, 0.26 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated in vacuo, and the residue was purified using reverse phase HPLC to afford the title compound (27 mg, 71%) as a white solid, m/z 720.6 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].FC(F)(F)C(O)=O.[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][S:24][C:25]1[N:30]=[C:29]([NH:31][S:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:28]=[C:27]([O:41][CH3:42])[N:26]=1>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([N:38]1[CH2:39][CH2:40][N:35]([S:32]([NH:31][C:29]2[CH:28]=[C:27]([O:41][CH3:42])[N:26]=[C:25]([S:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=3[F:15])[N:30]=2)(=[O:33])=[O:34])[CH2:36][CH2:37]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CCN(S(=O)(=O)N(C)C)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared by adding dimethyl sulfamoyl chloride to a solution of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, trifluoroacetate salt (the product from example 36) (0.25 g) in DCM (5 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then titurated with Toluene, DCM followed by Et2O to give the title compound as a white solid. Yield: 0.11 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:24]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
4-Fluoro phenylacetic acid (12.3 g, 79.79 mmoles) was dissolved in 30 ml dichloromethane. To this mixture, oxalylchloride (10.17 g, 79.79 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-bromoanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (10.6 g, 79.79 mmoles) was added and the reaction mixture was warmed to RT and stirred overnight. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as white solid (6.1 g, 37% yield. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 12.05 (s, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.58 (dd, J=8.9, 2.4 Hz, 1H), 7.24 (dt, J=5.4, 1.9 Hz, 2H), 7.09 (dt, J=8.6, 2.1 Hz, 2H), 6.79 (d, J=8.7 Hz, 1H), 4.27 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:13]1([N:19]=[C:20]=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]([CH3:9])[CH3:10])[C:20]([NH:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:21])=[CH:11][CH:12]=1
Reactant: CC(C)NCc1ccc(Br)cc1
Reactant: S=C=Nc1ccccc1
Product: CC(C)N(Cc1ccc(Br)cc1)C(=S)Nc1ccccc1
Yield: 87.4 %

Procedure:
Following the procedure described in Example 1, process variant (a), 23 g of N-(4-bromobenzyl)-N-isopropylamine were reacted with 14 g of phenyl isothiocyanate. 32 g of N-(4-bromobenzyl)-N-isopropyl-N'-phenylthiourea were obtained. Yield: 88%. Melting point: 133.5°-134.5° C.