Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(N(C(C)C)C(C)C)C.Cl.[Na+].[Cl-]>C(Cl)Cl>[C:1]1([S:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCC1CCCCN1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCCC1CCCCN1S(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
Naphthalene-1-sulfonyl chloride (13.7 g, 60.55 mmol) was added to a solution of methyl 4-(piperidine-2-yl)butanoate hydrochloride (2) (3.74 g, 20.2 mmol) in methylene chloride (143 ml). N-Ethyl-diisopropylamine (10.2 ml, 60.55 mmol) was then added dropwise. The reaction mixture was stirred overnight at room temperature. The completeness of the reaction was checked by means of TLC. When the reaction was complete, the reaction mixture was acidified with 1 M HCl (aqueous) and the aqueous phase was saturated with NaCl solution and then extracted 4× with methylene chloride. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. Purification via column chromatography (aluminium oxide; hexane/ethyl acetate 97.3→9:1) gave the desired product methyl 4-(1-(naphthalen-1-ylsulfonyl)piperidin-2-yl)butanoate 3 (4.95 g, 65%).
Reaction SMILES: Cl.[NH2:2]O.[F:4][C:5]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([Cl:14])[C:6]=1[CH:7]=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[F:4][C:5]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([Cl:14])[C:6]=1[C:7]#[N:2]
Reactant: NO
Reactant: Cc1ccc(F)c(C=O)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(F)c(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (1.1 parts) is added to a solution of 2-fluoro-5-methyl-6-chlorobenzaldehyde in pyridine, and the mixture is stirred for 15 minutes at room temperature. Acetic anhydride (1.3 parts) is then added and the mixture stirred at ambient temperature overnight to effect complete dehydration of the oxime to the nitrile. Most of the pyridine is removed by concentration under vacuum, then the residue is partitioned between ether and water. The organic phase is washed with brine, dried (MgSO4), filtered through silica gel, concentrated, then triturated in hexane to afford 2-fluoro-5-methyl-6-chlorobenzonitrile as light yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2nc[nH]c(=O)c2cc1O
Solvent: c1ccncc1
Product: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a suspension of 6-hydroxy-7-methoxyquinazolin-4(3H)-one (0.57 g) and pyridine (4 mL) was added acetic anhydride (10 mL) at room temperature. The reaction mixture was stirred at 100° C. for 3 hours, and then poured into ice-water. The resulting mixture was filtered to give the title compound (0.40 g, 53.00%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, d6-DMSO) δ: 2.30 (s, 3H), 3.92 (s, 3H), 7.28 (s, 1H), 7.75 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([F:27])[CH2:26][O:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:48][CH:49]1[CH2:52][NH:51][CH2:50]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:27][C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[N:13]=[C:12]([C:8]4[CH:9]=[C:10]([CH3:11])[N:6]([CH2:5][C:4]5[CH:3]=[C:2]([N:51]6[CH2:52][CH:49]([OH:48])[CH2:50]6)[CH:30]=[CH:29][CH:28]=5)[N:7]=4)[O:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:26][O:25][CH2:24]1
Reactant: Cc1cc(-c2nc(-c3ccc(C4(F)COC4)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Product: Cc1cc(-c2nc(-c3ccc(C4(F)COC4)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1

Procedure:
Analogously to the process described in Example 3, 150 mg (0.320 mmol) of the compound from Example 6A and 149 mg (0.479 mmol) of the compound from Example 8A were used to obtain 60 mg (39% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[S:37])=[CH:31][CH:30]=1)([CH3:28])[CH3:27]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([CH:26]([CH3:28])[CH3:27])=[CH:30][CH:31]=4)=[S:37])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CC(C)c1ccc(N=C=S)cc1
Solvent: CC#N
Product: CC(C)c1ccc(NC(=S)Nc2cccc3cc4cccc5c4c(c23)C(=O)N(CCN(C)C)C5=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
300 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.90 mmole) were dissolved in 20 ml of acetonitrile. 309 μl (2 molar equivalents) of 4-isopropylphenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. Two more equivalents of 4-isopropylphenyl isothiocyanate was added and the reaction mixture was again stirred for 24 hours at room temperature. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 428 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=93%) which was characterized as follows:
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][C:12]([O:14]C)=[O:13])=[O:4].Br[CH2:25][C:26]1[C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:30]([O:39]C(OC(C)(C)C)=O)[C:29]([C:47]([F:50])([F:49])[F:48])=[CH:28][CH:27]=1>>[C:35]([O:34][C:32]([C:31]1[C:30]([OH:39])=[C:29]([C:47]([F:48])([F:49])[F:50])[CH:28]=[CH:27][C:26]=1[CH2:25][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][C:12]([OH:14])=[O:13])=[C:5]([C:3]([N:2]([CH3:23])[CH3:1])=[O:4])[CH:6]=2)=[CH:21][CH:20]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1C(=O)N(C)C
Product: CN(C)C(=O)c1cc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)ccc1CC(=O)O
Yield: 67 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl {3-[(dimethylamino)carbonyl]-4′-hydroxy-1,1′-biphenyl-4-yl}acetate (82 mg, 0.262 mmol) obtained in Example (89-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (131 mg, 0.288 mmol) obtained in Example (28-5), the title compound was obtained (100 mg, three-step total yield: 67%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[S:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[S:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nccs1
Reactant: S=C=NCCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCCCc1ccccc1)Nc1nccs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.5 %

Procedure:
A solution of 3-phenylpropyl isothiocyanate (500 mg, 2.82 mmol) and 2-aminothiazole (300 mg, 3.0 mmol) in N,N-dimethylformamide (10 mL) was heated to 100° C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with 1N hydrochloric acid, water (3×), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from ethyl acetate to provide 129 mg of the title product. A second crop was recrystallized from 1:1 ethyl acetate/hexanes to provide another 110 mg of the title product. Total yield of the title product: 239 mg (30%) as an off-white solid. A sample was recrystallized again from ethyl acetate:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)(=[O:3])[CH3:2].[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:32]1[C:28]([CH3:27])=[N:29][O:30][C:31]=1[CH3:36])(=[O:3])[CH3:2]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1Br
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1-c1c(C)noc1C
Yield: 76 %

Procedure:
By carrying out the operation analogously to example 3, starting from 2-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 3,5-dimethyl-4-isoxazoleboronic acid, the expected compound is obtained in the form of a white solid with a yield of 76%.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]1([C:15](=[C:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:40])[C:25]([C:27]3[C:35]4[C:30](=[C:31]([O:38][CH3:39])[N:32]=[CH:33][C:34]=4[O:36][CH3:37])[NH:29][CH:28]=3)=[O:26])[CH2:20][CH2:19]2)[C:16]#[CH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:41](=[O:43])=[O:42]>C1COCC1>[C:9]1([C:15](=[C:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:40])[C:25]([C:27]3[C:35]4[C:30](=[C:31]([O:38][CH3:39])[N:32]=[CH:33][C:34]=4[O:36][CH3:37])[NH:29][CH:28]=3)=[O:26])[CH2:22][CH2:23]2)[C:16]#[C:17][C:41]([OH:43])=[O:42])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(OC)ncc(OC)c23)CC1)c1ccccc1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(C#CC(=O)O)c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a solution of LDA [prepared from iPr2NH (0.15 mL, 1.070 mmol) and n-BuLi (0.52 mL, 0.936 mmol)] in THF (3 mL) at −78° C. under Ar was added 1-[4-(1-phenyl-1-ethynyl-methylene)-piperidin-1-yl]-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione (0.160 g, 0.373 mmol). The solution was allowed to stir for 30 min and then a large excess of powdered dry ice was added directly into the flask. The mixture was allowed to warm to room temperature overnight and was then quenched with 10% aqueous HCl. The mixture was extracted with EtOAc (×3) and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to afford the title compound as a colorless solid (0.026 g, 15%):
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]([OH:17])=O)[CH:11]=[N:12][C:6]=2[NH:5][CH2:4][C:3]1=[O:18].[CH3:19][NH:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][C:23]=1[CH3:31]>>[CH3:19][N:20]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][C:23]=1[CH3:31])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:10]1[CH:11]=[N:12][C:6]2[NH:5][CH2:4][C:3](=[O:18])[N:2]([CH3:1])[CH2:8][C:7]=2[CH:9]=1
Reactant: CN1Cc2cc(C=CC(=O)O)cnc2NCC1=O
Reactant: CNCc1c(C)[nH]c2ccccc12
Product: Cc1[nH]c2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)CN(C)C(=O)CN2

Procedure:
According to the method of example 35g, 3-(4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-acrylic acid (69 mg, 0.28 mmol) and methyl-(2-methyl-1H-indol-3-ylmethyl)amine (60 mg, 0.34 mmol) were coupled to yield the title compound as a white powder and as a mixture of amide rotomers (40 mg, 35%). 1H NMR (300 MHz, DMSO-d6) 10.86 (s, 1H), 8.12 (bs, 1H), 7.77 (bs, 1H), 7.49-7.41 (m, 2H), 7.34-7.30 (m, 1H), 7.25-7.22 (m, 1H), 7.00-6.85 (m, 3H), 4.84-4.71 (m, 2H), 4.53 (s, 2H), 4.09-4.07 (m, 2H), 2.93-2.91 (m, 6H), 2.40 (bs, 3H); ESI MS m/z 404.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([OH:23])[CH:6]=[C:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:8]=1.Cl.[CH3:25][N:26]([CH:33]([CH3:35])[CH3:34])[CH2:27]/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[Cl:2][C:3]1[CH:4]=[C:5]([OH:23])[CH:6]=[C:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:25])[CH:33]([CH3:35])[CH3:34])[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:8]=1
Reactant: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)cc(Cl)c4)c23)C1

Procedure:
The title compound was prepared in analogy to Example 122 from 3-chloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 65A (100 mg, 0.27 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (73 mg, 0.38 mmol) to yield 24 mg (19%) as tan crystals.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.[CH2:21]([N:23](CC)CC)C>C(Cl)Cl>[CH3:21][NH:23][C@@H:9]1[C:14]2[C:15](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][C@H:8]1[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O[C@@H]1Cc2ccccc2[C@H]1N1CCCC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1

Procedure:
A solution of methanesulfonyl chloride (6 g) in methylene chloride (50 ml) was added dropwise rapidly to a stirred and cooled (0-5°) solution of trans-2,3-dihydro-2-hydroxy-(pyrrolidin-I-yl)-1H-indene (5.5 g) and triethylamine (6 ml) in methylene chloride (200 ml). After the addition was complete, the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was treated with a 33% solution of methylamine in ethanol (100 ml) and the mixture was stirred at reflux for 3 hours and evaporated under reduced pressure. The residue was treated with water and extracted twice with ether. The combined ether extracts were washed successively with 2 N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated under reduced pressure to yield a liquid which was distilled under vacuum to give trans-2,3-dihydro-1-methylamino-2-(pyrrolidin-1-yl)-lH-indene (6.3 g) b.p. 118-120°/0.25 torr.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([Cl:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:14]#[N:15].[NH2:16][NH2:17]>CS(C)=O>[Cl:12][C:8]1[C:9]([CH3:11])=[C:10]2[C:2]3[NH:16][N:17]=[C:14]([NH2:15])[C:3]=3[S:4][C:5]2=[N:6][C:7]=1[CH3:13]
Reactant: NN
Reactant: Cc1nc2sc(C#N)c(Br)c2c(C)c1Cl
Solvent: CS(C)=O
Product: Cc1nc2sc3c(N)n[nH]c3c2c(C)c1Cl
Temperature: 25 °C
Yield: 95.7 %

Procedure:
The 3-bromo-5-chloro-4,6-dimethylthieno[2,3-b]pyridine-2-carbonitrile (0.273 g, 0.91 mmol) was added to a microwave reaction vial. The DMSO (4 mL) was added, followed by hydrazine (0.085 mL, 2.72 mmol). The vial was sealed and irradiated at 120 degrees for 10 minutes. LC\MS shows no remaining starting material. The reaction was cooled to RT, then poured into 50 mL of ice-water. The ice was allowed to melt and resulting slurry was poured through filter paper, washing the solid with cold water (3×). The solid was then dried under vacuum at 60° C. to give 220 mg (96%) of the product as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 5.53 (bs, 2H), 2.74 (s, 3H), 2.61 (s, 3H). LC/MS: RT=0.58 min., m/z=253.0 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[O:26][CH3:27].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39]>O1CCCC1>[OH:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:17]([C:18]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:42])[NH:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:20])=[CH:16][C:15]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reactant: CC(C)(C)NC(=O)OCCCCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCCCCCCOC(=O)NC(C)(C)C)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8.9 g of 1,1'-carbonyldiimidazole are added to a solution of 10.7 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 500 ml of dry tetrahydrofuran and the reaction mixture is subsequently heated to 65°-70° for 5 hours. It is then cooled to room temperature and a solution of 21.6 g of 6-aminohexyl-t-butylcarbamate in 50 ml of dry tetrahydrofuran is added dropwise thereto within 15 minutes. The reaction mixture is then heated to 65°-70° for 18 hours, evaporated, the residue is suspended in ethyl acetate, suction filtered and the suction filtered material is chromatographed on silica gel with acetone/methylene chloride (3:1). There is obtained [6-(4-hydroxy-5-nitro-m-anisamido)hexyl]-t-butylcarbamate of m.p. 145°-147° (from isopropanol).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:66][CH:67]1[CH:72]2[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]2)[CH2:68]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH:67]5[CH:72]6[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]6)[CH2:68]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CN2CCC1CC2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.8 %

Procedure:
4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (Intermediate 6) (20 mg, 0.046 mmol, 1 eq), DIPEA (16 μl, 0.091 mmol, 2 eq) and TBTU (16 mg, 0.05 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of 3-aminoquinuclidine dihydrochloride (11 mg, 0.055 mmol, 1.1 eq). The RM was then stirred at rt for 16 hours before purifying by preparative RP-HPLC-MS (Preparative—1) to provide (±)-4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide (8 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([O:22]C)=[C:16](I)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[CH:17]=[CH:16][C:15](=[O:22])[NH:14][C:13]=3[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: COc1nc2c(cc1I)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2ccc(=O)[nH]c21
Temperature: 200 °C
Yield: 56.3 %

Procedure:
N-(4-Chlorobenzyl)-6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide (150 mg) is mixed with pyridine hydrochloride (1.50 g). The resulting solid is heated at 200° C. for 1 h, then cooled to room temperature and washed with MeOH. The residue is then dissolved in CH2Cl2, washed with 1N HCl, brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by silica gel chromatography (CH2Cl2/MeOH 19/1, 9/1) to afford 60 mg (56%) of N-(4-chlorobenzyl)-1-methyl-4,7-dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamide. Physical characteristics are as follows: 1H NMR (DMSO-d6) δ8.85, 8.44, 7.42-7.33, 6.82, 4.55, 3.92; IR (diffuse reflectance) 3044, 2350, 2318, 1941, 1908, 1679, 1645, 1627, 1553, 1524, 1504, 1466, 803, 672, 656, cm−1.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CC(C)CN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CC(C)CNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 17.1 mg (0.23 mmol) of iso-butylamine are reacted together by general method E. 15.2 mg (26.9% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: O=C(c1cccnc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the general procedures for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone 5 g (21.5 mmol) and 4-bromo-benzenesulfonyl chloride 5.78 g (21.5 mmol), in 150 ml anhydrous pyridine, overnight at 80° C., followed by flash column chromatography on silica gel to yield a salmon color solid.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[O:13][CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1.Cl.Br[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[N:8]([CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:4]=2[C:3]=1[O:13][CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1
Reactant: BrCCN1CCOCC1
Reactant: Cn1c(=O)[nH]c2c(OCC3CCC3)c(Br)ccc21
Agent: Cl
Product: Cn1c(=O)n(CCN2CCOCC2)c2c(OCC3CCC3)c(Br)ccc21

Procedure:
This compound was synthesized according to the procedure of Example 44, Step 2, using 5-bromo-4-(cyclobutylmethoxy)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 4-(2-bromoethyl)morpholine hydrochloride as the starting materials. LCMS calculated for C19H27BrN3O3 (M+H)+: m/z=424.1, 426.1. found: 424.3, 426.3.