Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([CH3:21])([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:22])=[CH:4][N:3]=1>CO.CN(C=O)C.CCOC(C)=O.O=[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([CH3:20])([CH3:21])[C:17]([NH2:19])=[O:18])[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: CC(C)(C(N)=O)c1ccccc1C#Cc1nc(Cl)ncc1Cl
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Reaction time: 64 h

Procedure:
A mixture of 2-(2-((2,5-dichloropyrimidin-4-yl)ethynyl)phenyl)-2-methylpropanamide A37 (0.067 g, 0.20 mmol) and PtO2 (0.014 g, 0.060 mmol) in MeOH (3.0 mL) and DMF (3.0 mL) was stirred in an atmosphere of H2 for 64 hours. The mixture was diluted with EtOAc, filtered through Celite and the filtrate solvent was removed in vacuo. The residue was purified by column chromatography (Biotage Isolera, 12 g SiO2, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A38 as an off-white solid (0.042 g, 62%). LCMS-D: rt 3.37 min; m/z 338 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH:27]=O)=[CH:21]2)[CH3:13].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:27][C:22]1[NH:23][C:24]2[C:20]([CH:21]=1)=[CH:19][C:18]([CH2:17][CH2:16][CH2:15][N:14]([CH2:29][CH3:30])[CH2:12][CH3:13])=[CH:26][CH:25]=2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4ccc(Br)cc43)cc2c1
Temperature: 95 °C
Yield: 60.5 %

Procedure:
A mixture of 5-bromo-2-oxindole (41 mg, 0.19 mmol), 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine(0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 52 mg (59%) of the title compound as a red-orange solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N[C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+].IC1C=CC=CC=1>O1CCOCC1.[Cu]I>[C:11]1([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: c1cc2[nH]ccc2cn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: C1COCCO1
Product: c1ccc(-n2ccc3cnccc32)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-azaindole (780 mg, 6.60 mmol), copper(I) iodide (25.1 mg, 132 μmol), (1S,2S)-(+)-1,2-diaminocyclohexane (162 μl, 1.35 mmol) and potassium phosphate (2.52 g, 11.9 mmol) in dioxane (24 ml) was added iodobenzene (739 μl, 6.60 mmol). The reaction mixture was stirred overnight at 110° C. The mixture was then cooled to room temperature, filtered through silica gel, and the silica gel washed with EA. The combined filtrates was evaporated under reduced pressure, and the resulting solid was purified by preparative HPLC. The fractions containing the title compound were combined and lyophilized overnight. Yield: 1.28 g.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[O:45]1[C:49]2[CH:50]=[CH:51][C:52]([S:54]([N:57]([CH2:82][CH:83]([CH3:85])[CH3:84])[CH2:58][C@@H:59]([OH:81])[C@@H:60]([NH:69][C:70](=[O:80])[O:71][C@@H:72]3[C@H:79]4[C@H:75]([O:76][CH2:77][CH2:78]4)[O:74][CH2:73]3)[CH2:61][C:62]3[CH:67]=[CH:66][C:65](O)=[CH:64][CH:63]=3)(=[O:56])=[O:55])=[CH:53][C:48]=2[O:47][CH2:46]1>C(Cl)Cl>[O:45]1[C:49]2[CH:50]=[CH:51][C:52]([S:54]([N:57]([CH2:82][CH:83]([CH3:85])[CH3:84])[CH2:58][C@@H:59]([OH:81])[C@@H:60]([NH:69][C:70](=[O:80])[O:71][C@@H:72]3[C@H:79]4[C@H:75]([O:76][CH2:77][CH2:78]4)[O:74][CH2:73]3)[CH2:61][C:62]3[CH:63]=[CH:64][C:65]([O:28][CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:66][CH:67]=3)(=[O:55])=[O:56])=[CH:53][C:48]=2[O:47][CH2:46]1
Reactant: OCCc1ccccc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCc2ccccc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of 66 mg (0.25 mmol) of triphenylphosphine and 30 μL (0.25 mmol) of phenethyl alcohol in 3 mL of anhydrous CH2Cl2 was added 58 mg (0.25 mmol) of di-tert-butyl azodicarboxylate. The resulting solution was stirred at RT for 5 minutes and was then treated with a solution of 50 mg (0.084 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate in 2 mL of CH2Cl2. After stirring at RT for 1.5 hours the solution was concentrated to dryness and the residue purified by flash chromatography (SiO2, 4:6 hexane/EtOAc) to give the desired product as a white foam in 72% yield, 1H NMR (CDCl3): 7.34-7.17 (m, 6H), 7.15 (s, 1H), 7.07 (d, 2H), 6.86 (d, 1H), 6.78 (d, 2H), 6.03 (s, 2H), 5.61 (d, 1H) 4.98 (m, 1H), 4.86 (d, 1H), 4.09 (t, 2H), 3.92 (m, 1H), 3.84-3.56 (m, 6H), 3.17-3.01 (m, 3H), 3.00-2.81 (m, 4H), 2.80-2.64 (m, 2H), 1.78 (m, 1H), 1.56 (m, 1H), 1.47 (m, 1H), 0.91 (d, 3H), 0.85 (d, 3H). MS(ESI): 697(M+H).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].[NH3:11]>CO>[N+:1]([CH2:4][CH2:5][CH2:6][C:7]([NH2:11])=[O:9])([O-:3])=[O:2]
Reactant: N
Reactant: COC(=O)CCC[N+](=O)[O-]
Solvent: CO
Product: NC(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
To a solution of methyl 4-nitrobutyrate (8.83 g, 60 mmol) in methanol (20 mL) at 0° C. was added a solution of ammonia in methanol (7N, 30 mL). The solution was then warmed to room temperature and stirred at for 72 h. The solvent was evaporated and the residue was re-crystallized from ethyl acetate to give the title product (6.2 g, 78%). 1H NMR (acetone-d6): 6.86 (bs, NH, 1H), 6.28 (bs, NH, 1H), 4.59 (t, J=6.9 Hz, 2H), 2.36-2.30 (m, 2H), 2.28-2.20 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]2[C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][N:18]=[C:17]([Cl:26])[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]2[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=[C:17]([Cl:26])[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)nc1NCC1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2nc(Cl)ncc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of ethyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylate (544 mg, 1.41 mmol) in THF (8 mL), aq. 1N NaOH (8 mL, 8.0 mmol) was added. The mixture was stirred at room temperature for 18 h. It was acidified to pH 1-2 with 6N HCl. Water and EtOAc were added. The organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid (503 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1.[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>C1COCC1>[CH2:19]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([Br:3])[CH:12]=2)[CH:8]=[N:9]1)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1.[CH2:19]([N:9]1[CH:8]=[C:7]2[C:11]([CH:12]=[C:4]([Br:3])[CH:5]=[CH:6]2)=[N:10]1)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc2cn(Cc3ccccc3)nc2c1
Product: Brc1ccc2cnn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %
Yield: 20 %

Procedure:
A suspension of NaH (60 wt % in mineral oil, 5.6 g, 140.0 mmol) in dry THF (150 mL) was cooled in an ice bath, and a suspension of 6-bromo-1H-indazole (27.6 g, 140 mmol) in dry THF (150 mL) was added slowly. The liquid portion became red, but some solids remained. After 30 min, BnBr (17.1 mL, 147.4 mmol) was added, the cooling bath removed, and the mixture left to stir for 3 h at RT. 1H NMR of a sample showed a product ration of 1:1.7 (N1:N2) and incomplete conversion; additional NaH (1.0 g, 25.0 mmol) was added. After a further 1 h at RT and 1 h at 50° C., the mixture was concentrated and chromatographed directly on silica using a 4 cm diameter column with 1:3 EtOAc/cyclohexane as eluent. Only partial separation was achieved, and so the mixed fractions were re-purified on an 8 cm diameter column using approx. 0.5 kg of silica. Samples of both N1-Benzyl-6-bromo-1H-indazole (Rf 0.5, 7.9 g, 20%) and N2-benzyl-6-bromo-2H-indazole (Rf 0.45, 14.2 g, 35%) were isolated, along with some mixed fractions that were retained against future requirements. N1-Benzyl-6-bromo-1H-indazole: 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=0.6 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.52 (s, 1H), 7.36-7.20 (m, 4H), 7.20-7.15 (m, 2H), 5.53 (s, 2H). MS (ES+): 287 (79Br, [M+H]+), 289 (81Br, [M+H]+) calcd for [C14H11BrN2+H]+ 287.0 (79Br). N2-benzyl-6-bromo-2H-indazole: 1H NMR (300 MHz, CDCl3) δ 7.92-7.88 (m, 1H), 7.85 (s, 1H), 7.52-7.46 (m, 1H), 7.41-7.32 (m, 3H), 7.31-7.24 (m, 2H), 7.14 (dd, J=8.9, 1.6 Hz, 1H), 5.56 (s, 2H). MS (ES+): 287 (79Br, [M+H]+), 289 (81Br, [M+H]+); calcd for [C14H11BrN2+H]+ 287.0 (79Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2(=[O:21])=[O:20])=[CH:5][C:4]=1[CH3:22].[F:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([F:34])[C:25]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[F:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([F:34])[C:25]=1[CH2:26][N:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10](=[O:21])(=[O:20])[N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[C:4]([CH3:22])[CH:5]=2)[C:14]1=[O:15]
Reactant: COc1cc(F)c(CBr)c(F)c1
Reactant: COc1ncc(N2C(=O)Nc3ccccc3S2(=O)=O)cc1C
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3cnc(OC)c(C)c3)S(=O)(=O)c3ccccc32)c(F)c1
Yield: 26 %

Procedure:
The title compound (60 mg, 0.13 mmol) was prepared from 2-(6-methoxy-5-methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (IntA28) (161 mg, 0.50 mmol), 2,6-difluoro-4-methoxybenzyl bromide (179 mg, 0.76 mmol) and K2CO3 (104 mg, 0.75 mmol) in DMF (3 mL) using the methods of (115).
Reaction SMILES: OC(C)(C)CNC(=O)C[N:7]1[CH2:10][CH:9]([C:11]2[CH:32]=[CH:31][C:14]3[C:15]4[N:16]=[C:17]([C:23]5[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=5)[S:18][C:19]=4[CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH2:8]1.[NH:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:37]([C:40]([OH:42])=O)([CH3:39])[CH3:38]>>[C:46]([O:45][C:43](=[O:44])[NH:36][C:37]([CH3:38])([CH3:39])[C:40]([N:7]1[CH2:10][CH:9]([C:11]2[CH:32]=[CH:31][C:14]3[C:15]4[N:16]=[C:17]([C:23]5[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=5)[S:18][C:19]=4[CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH2:8]1)=[O:42])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(=O)NCC(C)(C)O)C3)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)NC(=O)OC(C)(C)C)C3)ccc1-2

Procedure:
Following a similar method to N-(2-hydroxy-2-methyl-propyl)-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide using Boc-Aib-OH, (2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester was isolated as a colourless oil (203 mg, 59%). LCMS: RT=4.77 min, [M+H]+=553
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1>>[CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=1)[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:36][C:33]2[S:34][CH:35]=[C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[N:32]=2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: CN(c1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: CN(c1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid (6) (100 mg, 0.28 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (41 mg, 0.23 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 42 mg (35%). 1H-NMR: 8.60 (d, J=4.0 Hz, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=7.5 Hz, 1H), 7.89 (dt, J=7.5, 7.5, 1.5 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.33 (dd, J=7.0, 5.0 Hz, 1H), 3.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22]C=1Cl)[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][NH:18][CH3:19])[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].CCN(CC)CC.C[Si]([N:36]=[C:37]=[O:38])(C)C.[CH2:39]([Cl:41])Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:39]=1[Cl:41])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]([CH3:19])[C:37]([NH2:36])=[O:38])[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: C[Si](C)(C)N=C=O
Reactant: CNCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)C(N)=O
Reaction time: 2 h
Yield: 61 %

Procedure:
To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (Compound 15) (153 mg, 0.374 mmol) in CH2Cl2 (5 mL) was added Et3N (0.14 mL, 1.0 mmol) followed by trimethylsilyl isocyanate (68 μL, 0.5 mmol) at room temperature. After 2 h, the reaction mixture was concentrated and the resulting residue was dissolved in methanol and purified by preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as eluent. The fractions containing the product were combined, concentrated and lyophilized to yield the title compound as a white powder (120 mg, 61% yield). 1HNMR (500 MHz, CDCl3) δ: 10.37 (1H, br s), 7.41 (1H, d, J=8.2H), 7.34 (1H, s), 7.10 (1H, d, J=8.2 Hz), 5.78 (2H, br s), 4.56 (2H, s), 4.22 (2H, s), 3.64 (2H, t, J=5.2 Hz), 3.55 (2H, t, J=5.2 Hz), 2.99 (3H, s), 2.94 (3H, s). HRMS calcd for C17H21Cl2N4O4 (M+H): 415.094. found: 415.0941.
Reaction SMILES: C(O)(C)(C)C.[SH2:6].[N+:7]([C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[S:18])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].[SH-].[K+:20]>CCOCC>[N+:7]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[S:6])[S-:18])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].[K+:20]
Reactant: S
Reactant: O=[N+]([O-])c1cccc(N=C=S)c1
Agent: [K+]
Agent: [SH-]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cccc(NC(=S)[S-])c1
Reaction time: 2 h

Procedure:
A mixture of 75.0 grams of potassium t-butylate in 500 ml. of t-butyl alcohol is saturated with hydrogen sulfide. With the temperature kept below 35°C. by cooling, a mixture of 120.0 grams of m-nitrophenyl isothiocyanate in 500 ml. of ether is added to the potassium hydrosulfide solution in three portions. After the mixture is stirred an additional two hours, the solids are collected by filtration, washed with ether, and dried under vacuum to give 162 grams of potassium m-nitrophenyldithiocarbamate. This salt is added portionwise over about 15 minutes to a stirred ice-cooled mixture of 174 grams of methylene bromide and 65 grams of triethylamine in 600 ml. of dimethylformamide with the reaction temperature at 25°C. to 30°C. After another five hours of stirring at room temperature, the mixture is poured into 3.5 liters of ice-water precipitating a light yellow solid. The solids, after drying, are taken up in benzene (ca. 2 liters), filtered free of some insoluble material, and the benzene mixture is saturated with dry hydrogen chloride. The precipitated solids are collected by filtration, washed with benzene, and then stirred vigorously with a water-benzene mixture at 60°C. to 70°C. The benzene layer is separated, washed with water and sodium bicarbonate solution, dried, and concentrated in vacuo to give 102 grams of crude product. The solids are dissolved in 800 ml. of ethanol. The mixture is filtered and diluted with 1200 ml. of ether. Then the mixture is cooled to -35°C. The resulting light yellow solids are collected and vacuum dried to give 84.0 grams of product, melting point 96.0°C. to 97.0°C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]1)[CH3:27]>CS(C)=O.CO>[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: CCN1CC[C@@H](N)C1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CO
Solvent: CS(C)=O
Product: CCN1CC[C@H](Nc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 120 °C
Yield: 65.4 %

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.13 g) and (R)-1-ethylpyrrolidin-3-ylamine (Intermediate 193, 1.22 g) in DMSO (0.7 mL) was stirred and heated in a sealed vessel at 120° C. for 22 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-yl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.107 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37].NN>O1CCCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][C:32]=2[Cl:37])[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)Cc2cccc(F)c2)sc1Cl
Reaction time: 24 h

Procedure:
To a 250 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide (9 g, 16.15 mmol) and hydrazine (15.69 ml, 323 mmol) in tetrahydrofuran (THF) (75 ml) and methanol (75 mL). After 24 h at RT, the precipitate was filtered, the filtrate was concentrated, and the crude product was purified on a silica gel column [CHCl3/MeOH/NH4OH, 90:9:1] to give the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[O:11]=[C:12]([O:30][C@@H:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1)[CH:13]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=[O:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C.CN(C=O)C>[Cl-:1].[C:24]([C:23]1[CH:22]=[C:21]([NH:20][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]([O:30][C@@H:31]2[CH:36]3[CH2:37][CH2:38][N+:33]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:34][CH2:35]3)[CH2:32]2)=[O:11])[CH:29]=[CH:28][CH:27]=1)([OH:26])=[O:25]
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(NC(C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)c2ccccc2)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 14 %

Procedure:
2-Chloro-1-phenylethanone (I19) (24.4 mg, 0.16 mmol) was added to a solution of 3-(2-oxo-1-phenyl-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoic acid (I5) (60 mg, 0.16 mmol) in acetonitrile (1 ml) and DMF (1 ml). The reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated, and the residue was purified by preparative HPLC (eluents CH3CN/H2O) to obtain (3R)-3-(2-(3-carboxyphenylamino)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (12 mg, 14.2% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH2:38]([O:40][C:41](Cl)=[O:42])[CH3:39]>O1CCCC1>[CH2:38]([O:40][C:41]([N:19]1[CH2:20][CH2:21][C:15]2[N:14]=[C:13]([C:11]3[S:12][C:8]4[C:7]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)[NH:22][C:16]=2[CH2:17][CH2:18]1)=[O:42])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCc2nc(-c3nc4c(OC)ccc(N5CCOCC5)c4s3)[nH]c2CC1
Yield: 64.6 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.011 g ethylchloroformate. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.028 g (62%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid ethyl ester as yellow solid; MS (ISP): m/e=458 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:11]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:21]I.Cl>CO>[CH3:19][CH:17]([CH3:18])[CH2:16][C@H:12]([N:11]1[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH3:21])[C:2]1=[O:1])[C:13]([OH:15])=[O:14]
Reactant: CI
Reactant: CC(C)C[C@@H](C(=O)O)n1c(=O)[nH]c2ccccc2c1=O
Agent: Cl
Solvent: CO
Product: CC(C)C[C@@H](C(=O)O)n1c(=O)c2ccccc2n(C)c1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of Compound 1 (0.5 g, 1.8 mmol) in 10 mL of MeOH/1N NaOH aq. solution (1:1) was added MeI (2 mL). The mixture was stirred at 80° C. in sealed tube overnight. The mixture was neutralized with concentrated HCl. Extracted by EtOAc and dried over MgSO4. Removing solvent gave the crude acid product, which used for next step without further purification. [M+H] calc'd for C15H18N2O4, 291; found, 291.