Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([S:13][CH2:14][C:15](OCC)=[O:16])=[CH:6][C:5]=1[Br:20].COC(=O)C1C=C([N+]([O-])=O)C(F)=CC=1Br.CCN(CC)CC.C(OC(=O)CS)C>C(Cl)Cl.CCOC(C)=O>[Br:20][C:5]1[C:4]([C:3]([OH:2])=[O:21])=[CH:9][C:8]2[NH:10][C:15](=[O:16])[CH2:14][S:13][C:7]=2[CH:6]=1
Reactant: CCOC(=O)CSc1cc(Br)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: CCOC(=O)CS
Agent: COC(=O)c1cc([N+](=O)[O-])c(F)cc1Br
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CSc2cc(Br)c(C(=O)O)cc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
2-Bromo-4-ethoxycarbonylmethylsulfanyl-5-nitro-benzoic acid methyl ester. To a 0° C. solution of 2-bromo-4-fluoro-5-nitro-benzoic acid methyl ester (4.8 g, 17.3 mmol) in CH2Cl2 (87 mL) was added Et3N, followed by mercapto-acetic acid ethyl ester, and the resulting mixture was stirred at RT for 4 h. The mixture was diluted with EtOAc (250 mL), washed with brine (50 mL), dried (MgSO4), and concentrated. The crude material was purified on SiO2 (0-35% EtOAc/hexanes) to provide 5 g (77%) of the title compound. 1H NMR (500 MHz, CDCl3): 8.75 (s, 1H), 7.79 (s, 1H), 4.24 (q, J=7.2, 2H), 3.96 (s, 3H), 3.78 (s, 2H), 1.30 (t, J=7.2, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][CH:9]2[NH:12][C:11](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][CH:9]2[N:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11](=[O:13])[CH2:10]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CSC2CC(=O)N2)cc1
Reactant: COC(=O)CBr
Product: COC(=O)CN1C(=O)CC1SCc1ccc(OC)cc1

Procedure:
Treatment of 4-(4-methoxybenzylthio)-azetidin-2-one (7 g) with methyl bromoacetate (5.3 g) under the conditions described for Example 29a gave the title compound as a colourless solid, m.p. 45-46° C., (5.9 g, 64%)
Reaction SMILES: C(OC(=O)N(CCCC1C=CC([Cl:38])=CC=1)[C@@H]1CCC[C@H]1NC(NC1C=C(OC)C(OC)=C(OC)C=1)=O)(C)(C)C.C(OC(=O)[N:46]([CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[C@@H:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[NH:52][C:53](=[O:64])[C:54]1[CH:59]=[CH:58][C:57]([S:60]([CH3:63])(=[O:62])=[O:61])=[CH:56][CH:55]=1)(C)(C)C>>[ClH:38].[Cl:73][C:70]1[CH:71]=[CH:72][C:67]([CH2:66][CH2:65][NH:46][C@@H:47]2[CH2:51][CH2:50][CH2:49][C@H:48]2[NH:52][C:53](=[O:64])[C:54]2[CH:55]=[CH:56][C:57]([S:60]([CH3:63])(=[O:61])=[O:62])=[CH:58][CH:59]=2)=[CH:68][CH:69]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Cl)cc1)[C@@H]1CCC[C@H]1NC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: COc1cc(NC(=O)N[C@@H]2CCC[C@H]2N(CCCc2ccc(Cl)cc2)C(=O)OC(C)(C)C)cc(OC)c1OC
Product: CS(=O)(=O)c1ccc(C(=O)N[C@@H]2CCC[C@H]2NCCc2ccc(Cl)cc2)cc1
Product: Cl

Procedure:
Using procedures similar to those described in Example 3, except replacing the (±)-trans-[3-(4-chlorophenyl)propyl]-{2-[3-(3,4,5-trimethoxyphenyl)ureido]-cyclopentyl}carbamic acid tert-butyl ester used therein with (±)-trans-[2-(4-chlorophenyl)ethyl]-[2-(4-methanesulfonylbenzoylamino)cyclopentyl]carbamic acid tert-butyl ester, the title compound was prepared; MS m/z 421 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]2=[N:5][CH:4]=[C:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:18]C(C)=O.C[I:23]>C(OCC)C>[I-:23].[CH2:16]([O:15][C:13]([C:3]1[C:2](=[O:1])[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]2=[N+:5]([CH3:18])[CH:4]=1)=[O:14])[CH3:17]
Reactant: CC(C)=O
Reactant: CI
Reactant: CCOC(=O)c1cnc2n(c1=O)CCCCC2
Solvent: CCOCC
Product: CCOC(=O)c1c[n+](C)c2n(c1=O)CCCCC2
Product: [I-]
Reaction time: 24 h
Yield: 43 %

Procedure:
1.18 g. of ethyl 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate is dissolved in 12 ml. of acetone and allowed to stand for 24 hours at room temperature in the presence of 1.25 ml. of methyl iodide. The reaction mixture is diluted with diethyl ether. The precipitated crystals are filtered. 0.8 g. (43%) of 3-ethoxycarbonyl-1-methyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepinium iodide is obtained melting at 202°-204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[N:8]=[CH:7][C:6]([C:16]#[N:17])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C1COCC1.C(=O)(O)[O-].[Na+]>[Br:25][C:21]1[CH:20]=[C:19]([NH:18][C:5]2[C:4]3[C:9](=[C:10]([CH2:12][N:13]([CH3:14])[CH3:15])[CH:11]=[C:2]([NH:1][C:35](=[O:38])[CH:36]=[CH2:37])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:16]#[N:17])[CH:24]=[CH:23][CH:22]=1
Reactant: C=CC(=O)Cl
Reactant: CN(C)Cc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(CN(C)C)c2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-amino-4-[(3-bromophenyl)amino]-8-dimethylaminomethyl-3-quinolinecarbonitrile (0.20 g, 0.50 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.75 mmol) in 3.4 ml of THF at 0° C. was added acryloyl chloride (0.045 ml, 0.55 mmol) during 5 m. After stirring for 3 h at 0° C. the mixture was diluted with sodium bicarbonate solution. The resulting solid was filtered off, washed with water, dried, and subjected to chromatography on silica gel with methylene chloride-ethyl acetate-methanol-triethylamine to give a yellow solid; mass spectrum (electrospray, m/e) M+H 449.9, 452.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[C:10]1=[O:18].FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:44][C:45]([F:56])([F:55])[C:46]1[CH:47]=[C:48]2[C:52](=[CH:53][CH:54]=1)[CH2:51][NH:50][CH2:49]2.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](=[O:17])[N:50]2[CH2:49][C:48]3[C:52](=[CH:53][CH:54]=[C:46]([C:45]([F:44])([F:56])[F:55])[CH:47]=3)[CH2:51]2)[C:10]1=[O:18]
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2Cl)C1=O
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2Cl)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(2-chloro-4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 268A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 5-(trifluoromethyl)isoindoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.59 (t, J=9.9, 2H), 7.48-7.30 (m, 2H), 7.13 (dd, J=2.7, 8.5, 1H), 7.06-6.94 (m, 1H), 4.92 (d, J=19.6, 4H), 4.36 (d, J=16.2, 1H), 4.24-4.10 (m, 2H), 3.77-3.60 (m, 2H), 2.77-2.56 (m, 1H), 2.04 (dq, J=8.1, 13.4, 1H); MS (DCI) m/z 441.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)CCCc1nccc2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCCC(=O)O)nccc34)no2)cc1Cl
Temperature: 80 °C
Yield: 56 %

Procedure:
Sodium hydroxide (50 mg) was added to a suspension of ethyl 4-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]butanoate (D44; 0.36 g) in isopropanol (5 ml) and water (5 ml). The reaction mixture was heated to 80° C. for 2 hours. After cooling, isopropanol was evaporated in vacuo and the remaining aqueous solution was acidified with aq. HCl (0.5 N) to pH=5. The solid was collected and washed with DMF (5 ml) and acetonitrile (5 ml) to afford the title compound (0.19 g). δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.05 (2H, m), 2.40 (2H, m), 3.37 (2H, m), 5.46 (1H, m), 7.88 (1H, dd), 8.57 (5H, m), 8.97 (1H, d), 12.04 (1H, s). MS (ES): C23H21ClN4O4 requires 452. found 453.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:10](Cl)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(Cl)Cl.CO.C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCCCCCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: NCCCCCCCNC(=O)OCc1ccccc1
Yield: 32.4 %

Procedure:
On an ice-water bath, to the solution of 1,7-diaminoheptane (1.433 g, 11 mmol) in CH2Cl2/MeOH (125 mL/125 mL) was added the solution of CbzCl (1.71 g, 10 mmol) in CH2Cl2 (250 mL) dropwise within 12 h while keeping the temperature below 5° C. The mixture was allowed to stir at the same temperature for another half of an hour before concentrated under reduced pressure to remove most of the MeOH. Water (150 mL) was then added, and the aqueous layer was adjusted to pH=2 using 6 N HCl. The layers were separated. The aqueous layer was washed with DCM (50 mL×3), then adjusted to pH=12 with 10 N NaOH and extracted with DCM (50 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by flash column using DCM/MeOH (9/1) to give 856 mg white solid in 32% yield. 1H NMR (400 MHz, CDCl3): δ 7.35-7.29 (m, 5H), 5.09 (s, 2H), 4.73 (brs, 1H), 3.18 (q, J=6.64 Hz, 2H), 2.67 (t, J=6.94 Hz, 2H), 1.55-1.44 (m, 2H), 1.44-0 (m, 2H), 1.32 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 156.40, 136.70, 128.50, 128.09, 128.06, 66.55, 42.18, 41.06, 33.71, 29.91, 29.09, 26.76, 26.68. mp 78-80° C. IR v (Diamond, cm−1): 3327, 1686, 1532, 1263, 1144. MS (ESI) found 264.8 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]1[C:8]2=[N:9][C:10]3[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:11]=3[CH:12]=[C:7]2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25].Cl>C(OC(=O)C)C>[ClH:1].[CH2:22]([NH:26][CH:2]1[C:8]2=[N:9][C:10]3[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:11]=3[CH:12]=[C:7]2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)[CH2:23][CH2:24][CH3:25]
Reactant: CCn1ncc2cc3c(nc21)C(Cl)c1ccccc1CC3
Reactant: CCCCN
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCNC1c2ccccc2CCc2cc3cnn(CC)c3nc21

Procedure:
11.8 g. of 11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine (0.04 mol.), from part (a), and 75 ml. of butylamine are refluxed for 5.5 hours. After evaporation of excessive butylamine, the residue is shaken with 100 ml. of water and 100 ml. of ether. The separated ethereal solution is washed twice with 50 ml. of water, treated with charcoal, dried with Na2SO4 and then evaporated to yield 8.7 g. of an oil. This material is dissolved in 125 ml. of ethylacetate and 5 ml. of ethereal hydrochloric acid (195 g./l.) are added to precipitate 8.4 g. of N-butyl-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-amine, hydrochloride (1:1); m.p. 231°-233° (dec.).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:25]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH:24][C:27]5[CH:28]=[CH:29][C:30]([N:33]6[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]6)=[CH:31][CH:32]=5)[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4cccc(-c5ccc(CN6CCS(=O)(=O)CC6)cc5)n4n3)cc2)CC1

Procedure:
5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-N-[4-(4-methylpiperazin-1-yl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (75.0 mg, 0.210 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (65.0 mg, 0.255 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (22.0 mg, 0.0402 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.045 g, 40%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.00 (d, J=7.0 Hz, 2H), 7.52-7.43 (m, 6H), 6.98-6.91 (m, 3H), 6.67 (s, 1H), 3.76 (s, 2H), 3.18-3.03 (m, 12H), 2.62-2.56 (m, 4H), 2.36 (s, 3H). MS=532 (MH)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[N:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:38](Cl)=[O:39]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:38]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][N:32]=4)=[O:39])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=C(Cl)c1cnccn1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine was diluted to 0.40 M with anhydrous dichloromethane, then delivered to an 8 mL vial via pipette (0.2 mmol). To the amine solution was added base (0.4 M triethylamine in dichloromethane, 0.20 mmol). Pyrazine-2-carbonyl chloride was diluted to 0.40 M with dichloromethane, and added at rt (0.2 mmol). The reaction was shaken overnight at rt, then evaluated by MS. The reaction was concentrated using an HT-12 GeneVac, then purified by HPLC (30×100 mm ODS-A C(18) 5u column). Pyrazine-2-carboxylic acid {4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amide was isolated in 88% purity @ 254 nm, LCMS (APCI): 445 [M+H]+.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH:20]=[O:21])[C@H:11]1[O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:9][C@@H:10]1[C@H:15]2[N:16]([C:31](=[O:33])[CH3:32])[C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH:20]=[O:21])[C@H:11]1[O:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(=O)O[C@H]2C[C@H](C=O)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]21
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of (3aS,4R,5R,6S,7aS)-6-formyl-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (580 mg, 1.42 mmol) in dry DCM (10 mL) at 0° C. under N2 was added a solution of acetyl chloride (223 mg, 2.84 mmol) in dry DCM (2.84 mL) followed by a solution of DIPEA (330 mg, 2.56 mmol) in dry DCM (2.56 mL) dropwise. The mixture was stirred at 0° C. for 2 h. The reaction was further diluted with DCM (20 mL), washed with 0.1 N HCl and brine. The solvent was evaporated to give the crude (3aS,4R,5R,6S,7aS)-3-acetyl-6-formyl-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (614 mg, 96%) which was carried onto next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.90 (d, J=7.8 Hz, 2H), 7.54-7.59 (m, 2H), 7.40-7.44 (m, 4H), 5.79 (dd, J=5.7 Hz, 4.1 Hz, 1H), 5.68 (t, J=5.7 Hz, 1H), 5.01-5.04 (m, 1H), 4.82 (dd, J=7.7 Hz, 4.0 Hz, 1H), 3.13-3.19 (m, 1H), 2.54-2.60 (m, 1H), 2.50 (s, 3H), 2.26-2.34 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][Br:32])=[CH:29][CH:28]=1>>[Br-:32].[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N+:6]1[CH:10]=[CH:9][N:8]([CH2:26][C:27]2[CH:34]=[CH:33][C:30]([CH3:31])=[CH:29][CH:28]=2)[CH:7]=1
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(Cn2cc[n+](CC(OCc3ccc(Cl)cc3Cl)c3ccc(Cl)cc3Cl)c2)cc1
Product: [Br-]

Procedure:
mp. 152.2° C., by the reaction of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-imidazole and p-methylbenzyl bromide.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[C:12]1([CH:18]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:19]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC>C(OCC)(=O)C>[Br-:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N+:24]23[CH2:25][CH2:26][CH:27]([CH2:28][CH2:29]2)[C@@H:22]([O:21][C:19](=[O:20])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:23]3)=[CH:6][CH:7]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCC1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCCCC1)C2)c1ccc(Cl)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
2-Bromo-1-(4-chlorophenyl)ethanone (49.8 mg, 0.21 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(piperidin-1-yl)acetate (70 mg, 0.21 mmol) in ethyl acetate (2 ml). The reaction was stirred at room temperature overnight (UPLC-MS: complete conversion). Et2O (1 ml) was added and the white precipitate was collected by suction filtration and dried under vacuum to obtain (3R)-1-(2-(4-chlorophenyl)-2-oxoethyl)-3-(2-phenyl-2-(piperidin-1-yl)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (93.5 mg, 78% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[C:14]([NH2:16])=[O:15])[C:5]([Cl:17])=[CH:4][N:3]=1.[CH2:18]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1)[CH3:19].COCCO.Cl.O1CCOCC1>>[Cl:17][C:5]1[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[C:14]([NH2:16])=[O:15])=[N:7][C:2]([NH:31][C:28]2[CH:29]=[CH:30][C:23]3[CH2:22][CH2:21][N:20]([CH2:18][CH3:19])[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CCC[C@H]4C(N)=O)n3)cc2CC1
Reaction time: 0.17 h
Yield: 23.3 %

Procedure:
Into a microwave vial was added cis-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclopentane-carboxylic acid amide (80 mg, 0.0003 mol) and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (61 mg, 0.00032 mol) in 2-methoxyethanol (4 mL, 0.06 mol). To this reaction mixture was added 4N HCl-dioxane (0.04 g, 0.0003 mol) and the contents subjected to microwaves at 120° C. for 10 min. HPLC indicated no starting material remaining. A solid had precipitated out of the reaction mixture and was collected by filtration. The white solid was dried in vacuum at 50° C. overnight to give cis-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]-azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclopentanecarboxylic acid amide (30 mg, 20%). MP: 237-242° C.; 1HNMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.73 (s, 1H), 8.06 (s, 1H), 7.60 (s, 1H), 7.58 (d, 1H, J=), 7.46 (m, 1H), 7.16 (m, 2H), 4.43 (m, 1H), 3.62 (m, 5H), 3.18 (m, 2H), 2.87-2.98 (m, 4H), 1.59-1.75 (m, 5H), 1.59 (m, 1H), 1.27 (t, 3H, J=7.3 Hz); MS (m/e) 429 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24]([NH:27][CH:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:29][C:30](O)=[O:31])(=[O:26])=[O:25].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C(Cl)Cl>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH:28]([NH:27][S:24]([C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=3)(=[O:26])=[O:25])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:3][CH2:4][O:5]2)=[CH:10][CH:9]=1)#[N:13]
Reactant: N#Cc1ccc2c(c1)OCCC2N
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 23.5 °C
Reaction time: 8 h

Procedure:
4-Amino-chroman-7-carbonitrile (Step E) (50 mg, 0.28 mmol), 3-(naphthalen-2-ylsulfonylamino)-3-phenyl-propionic acid (100 mg, 0.28 mmol), HOBt (42 mg, 0.31 mmol), and DIEA (72 mg, 0.56 mmol) were dissolved in CH2Cl2 (10 mL). EDC (52 mg, 0.34 mmol) was added and the reaction was stirred at 22-25° C. overnight until completed. The reaction solution was washed with dilute (˜5%) NaHCO3—H2O and H2O, and solution was dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified by column chromatography (silica gel, 25% hexane in EtOAc) to provide the title compound as a white solid mixture of diastereomers (ca. 3:2 by 1H NMR after flash column chromotography).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH2:19]([S:23](Cl)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([S:23]([NH:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: CCCCS(=O)(=O)NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in example 1 but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and butanesulfonylchloride, the title compound was obtained in a similar yield as a solid foam:
Reaction SMILES: C(O[C:9]([N:11](C)[C@H:12]([CH2:21][O:22][C:23](=[O:35])[NH:24][C:25]1[N:26]=[CH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:25]([NH:24][C:23]([O:22][CH2:21][C@@H:12]([NH:11][CH3:9])[CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[O:35])[N:26]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)OC(C)(C)C
Yield: 99.1 %

Procedure:
To a solution of (S)-tert-butyl 3-((benzyloxycarbonyl)(methyl)amino)-4-(isoquinolin-3-ylcarbamoyloxy)butanoate (1.8 g, 3.65 mmol) and MeOH (5 mL) was added 10% Pd—C (500 mg). The resulting mixture was stirred under 12 psi of hydrogen for 1 h. The mixture was filtered and concentrated, and the remaining residue was dried in vacuo to give (S)-tert-butyl 4-(isoquinolin-3-ylcarbamoyloxy)-3-(methylamino)butanoate (1.3 g), which was used without further purification. LRMS (M+H+) m/z 360.1