Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH2:5][N:4]1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].[H-].[Na+].[CH3:20]I>CN(C=O)C>[CH3:20][O:1][CH2:2][C@H:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH2:5][N:4]1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13]
Reactant: CI
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC)[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CC=C(C(=O)OC)[C@@H]1COC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of 1-allyl 3-methyl (2R)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (234 mg, 0.97 mmol) in DMF (4.7 ml) was added at 0° C. sodium hydride (60% suspension in oil, 39 mg, 0.98 mmol) and the mixture was stirred for 30 minutes. Then thereto was added at 0° C. methyl iodide (0.95 ml, 9.7 mmol) and the mixture was stirred at room temperature for 1 hour. After cooled to 0° C., the reaction mixture was poured into ice water and extracted three times with ethyl acetate. The organic layer was washed with water and then a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified with silica gel chromatography to give 1-allyl 3-methyl (2R)-2-(methoxymethyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (55 mg, 15%).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]([CH:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH3:21])[C:9]1=[O:29])=O)(C)(C)C>C(Cl)Cl>[C:25]([O:24][C:22](=[O:23])[CH:19]([N:10]1[C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=2[NH:8][C:9]1=[O:29])[CH2:20][CH3:21])([CH3:26])([CH3:27])[CH3:28]
Reactant: CCC(C(=O)OC(C)(C)C)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Solvent: ClCCl
Product: CCC(C(=O)OC(C)(C)C)n1c(=O)[nH]c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a stirred solution of 3-(1-tert-butoxycarbonyl-propyl)-5-cyano-2-oxo-2,3-dihydrobenzoimidazole-1-carboxylic acid tert-butyl ester (55 mg, 0.14 mmol) in CH2Cl2 (5 mL) trifluoroacetic acid (0.10 mL) was added. The reaction mixture was stirred at room temperature for 4 hours, concentrated in vacuo and co-evaporated the solvent with toluene (3×). The residue was purified by flash chromatography in silica gel using 40% ethyl acetate in n-heptane as eluent to afford 2-(6-cyano-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-butyric acid tert-butyl ester (28 mg, 68%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].[O:38]1[CH2:50][CH:39]1[CH2:40][O:41][C:42]1[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=1[C:44]#[N:45]>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][CH2:50][CH:39]([OH:38])[CH2:40][O:41][C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3[C:44]#[N:45])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCCN)cc2)C1c1cccc([N+](=O)[O-])c1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCCNCC(O)COc3ccccc3C#N)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 3.5 g (6.8 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-aminoethoxy)-phenoxy]-ethyl}-ester 5-methyl ester and 1.55 g (8.9 mmol) of 2-(2,3-epoxypropoxy)-benzonitrile in 20 ml of isopropanol is heated under reflux for 2 hours. The oil obtained after concentration by evaporation (approximately 6 g) is purified by "flash" chromatography analogously to Example 1 and yields 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{{{2-{{p-{2-[3-(o-cyanophenoxy)-2-hydroxypropylamino]-ethoxy}-phenoxy}}-ethyl}}}-ester 5-methyl ester in the form of an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=CCOc1ccc(C(=O)O)cc1

Procedure:
The reaction of ethyl 4-hydroxybenzoate and 3,3-dimethylallyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 4-(3-Methyl-but-2-enyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.54 (s, —CO2H); 7.81 (d-like, 2 arom.H); 6.95 (d-like, 2 arom.H); 5.38 (m, CH═C(CH3)2); 4.54 (d-like, CH2CH═C(CH3)2); 1.69, 1.64 (2s, CH═C(CH3)2). 13C-NMR (100 MHz, d6-DMSO): 166.96 (C═O); 162.05; 137.66; 131.25 (2 arom. C); 122.78; 119.38; 114.36 (2 arom.C); 64.58; 25.37; 17.99.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[I:13]Cl>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([I:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClI
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(O)c(I)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
Charge a 10 L double jacketed reactor with a mechanical stirrer and a reflux condenser with 4-hydroxy benzoic acid ethyl ester (967 g, 8.81 mol) and acetic acid (5.8 L). Heat the mixture to 65° C. and add a solution of ICl (1010 g) in acetic acid (1 L) in ½ h. Stir the resulting mixture at 60-62° C. for 16 h. Cool the black solution to 20° C. and transfer on water (5 L) and ice (7.5 kg). Stir the resulting suspension over 1 h at 20° C., filter and wash the cake with water (2 L) and cyclohexane (6 L). Dry the solid under vacuum at 55° C. till constant weight to give 4-hydroxy-3-iodo-benzoic acid ethyl ester (1372.8 g, 4.70 mol). 11H NMR (250 MHz, CDCl3): 1.38 (t, J=7.1 Hz, 3H), 4.35 (quartet, J=7.1 Hz, 2H), 5.8 (s, 1 H), 7.01 (d, J=8.5 Hz, 1H), 7.95 (dd, J=8.5 Hz, 2.0 Hz, 1H), 8.37 (d, J=2 Hz, 1 H).
Reaction SMILES: [C:1]1([S:7]([CH:10]([CH3:25])[CH:11]([CH3:24])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26]I>>[C:1]1([S:7]([C:10]([CH3:26])([CH3:25])[CH:11]([CH3:24])[CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:18][CH2:19]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: CC(CCN1CCC(C(F)(F)F)CC1)C(C)S(=O)(=O)c1ccccc1
Product: CC(CCN1CCC(C(F)(F)F)CC1)C(C)(C)S(=O)(=O)c1ccccc1

Procedure:
Prepared from 1-(4-benzenesulfonyl-3-methylpentyl)-4-trifluoromethylpiperidine (example 126) and methyl iodide by the method of Example 187.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][C:3]([C:4]=23)=[CH:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:29])C=1Cl>C1COCC1.O>[O:29]=[C:13]1[C:3]2=[CH:2][NH:1][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:4]=32)[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]c3cccc(c23)C1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)c2c[nH]c3cccc(c23)C1

Procedure:
tert-butyl 1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 12 (100 mg, 0.37 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (167 mg, 0.73 mmol) in THF/water 9/1 (8 ml) was stirred under N2 over night at room temperature. The compound was purified on a Biotage preparative flash column eluting with 15-100% EtOAc in petroleum ether 40-65° C. Obtained 58 mg of the title compound. MS (ESI+) m/z 231 [M+H-isobutene]+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2OC(=O)N[C:6]=2[CH:11]=1.N1C=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH3:16][CH2:15][CH:14]=[CH:13][CH2:11][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Reactant: c1ccncc1
Solvent: O
Product: C=CCCCCC=CCC

Procedure:
A mixture of anti-tricyclo[4.2.2.02,5 ]dec-3,9-diene-endo-7,endo-8-dicarboxylic anhydride (2.02 g., 0.01 mole), 5-aminobenzoxazolin-2-one (1.50 g., 0.01 mole) and pyridine (20 ml.) is heated under reflux for six hours. The cooled solution (25° C.) is diluted with water (200 ml.) and the precipitate is collected by filtration, 2.60 g., m.p. 252°-257° C. Recrystallization from 2-propanol provides N-(5-benzoxazolinyl-2-one)-antitricyclo[4.2.2.02,5 ]dec-3,9-diene-endo-7,endo-8-dicarboximide, m.p. 287.5°-290° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([C:14]([O:16]C)=[O:15])=[CH:6]2.[OH-].[Na+]>C1COCC1.CO>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][C:7]([C:14]([OH:16])=[O:15])=[CH:8]2
Reactant: COC(=O)C1=Cc2cc(OC)c(OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CC(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
To a stirred solution of methyl 5,6-dimethoxy-1H-indene-2-carboxylate (330 mg, 1.41 mmol) in THF (8 mL) and MeOH (4 mL) was added 2 N NaOH solution (3.5 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours and the reaction was quenched with 1N HCl solution. Then mixture was diluted with water and the resulting suspension was filtered and the solid was dried under vacuum to give 5,6-dimethoxy-1H-indene-2-carboxylic acid (150 mg, 48%). LC-MS (ES-API); rt 8.44 min; m/z calculated for C12H12O4 [M−H]− 219.1, found 219.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[C:35]([F:37])[C:34](O)=[C:33]([F:39])[CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:32]=[C:33]([F:39])[C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:35]([F:37])[CH:36]=1
Reactant: COC(=O)c1cc(F)c(O)c(F)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1
Yield: 59 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), 3,5-difluoro-4-hydroxy-benzoic acid methyl ester (commercially available) and di-tert-butyl azodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the desired compound as a light yellow foam (59%). MS (Turbo Spray): m/z=561.2 [M+H].
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCCl>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([C:17](=[O:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc2c(F)cccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(F)c2ccc(F)cc12
Temperature: 0 °C
Yield: 80 %

Procedure:
1,6-Difluoronaphthalene (0.164 g, 1.0 mmol) was dissolved in 1,2-dichloroethane (5 mL) and cooled to 0° C. Aluminum trichloride (0.264 g, 2.0 mmol) was added as a solid to the solution. Acetic anhydride (0.1 mL, 1.0 mmol) was added slowly over 20 minutes to the solution while maintaining a temperature of 0° C. The reaction was poured onto ice-cold 10% aqueous hydrochloric acid and extracted with methylene chloride (2×10 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by column chromatography to give 1-(4,7-difluoronaphth-1-yl)-ethanone as an oil (0.165 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=O)[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([NH:27][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:14])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: NC1CCCC1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)NC2CCCC2)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and cyclopentylamine (1 ml) was heated at 120° C. for 15 h to obtain 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-N-cyclopentylacetamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:28]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:29])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(-c2cncc(CNC(=O)N3CCOCC3)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e, 0.060 g, 0.202 mmol) in dichloromethane (2 mL) are added morpholine-4-carbonyl chloride (0.026 g, 0.222 mmol) and triethylamine (0.056 mL, 0.405 mmol) and the reaction is stirred at room temperature overnight. The mixture is then washed with water and extracted with dichloromethane twice. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford morpholine-4-carboxylic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide as a solid. 1H NMR (400 MHz, MeOD) δ ppm 3.41-3.47 (m, 4H), 3.66-3.72 (m, 4H), 3.84 (s, 3H), 4.55 (s, 2H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 8.11 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). MS (ESI) m/z 410.00 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24]O)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[BrH:26].C1COCC1.[OH-].[Na+]>CC(O)=O>[Br:26][CH2:24][C:20]1[CH:19]=[C:18]([C:16]2[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(c1cc(-c2cccc(CO)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(c1cc(-c2cccc(CBr)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 0 °C

Procedure:
A suspension of the {3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-methanol compound from Step 3 above (30 g, 85 mmol) in AcOH (140 mL) and HBr (48 mL, 48% aq) was stirred for 18 h at 80° C. The resulting mixture was cooled to 0° C. and poured into 2L of cold NaOH (0.3N). The pH of the resulting solution was adjusted to 5 and filtered. The resulting solid was dissolved in EtOAc, washed with saturated NaHCO3 solution, brine, dried (MgSO4), filtered and concentrated. Stirring the solid in ether/EtOAc, followed by filtration gave desired 8-(3-Bromomethyl-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline as a pale brown solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][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.[NH2:67][CH:68]1[CH:73]2[CH2:74][CH2:75][N:70]([CH2:71][CH2:72]2)[CH2:69]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14][CH2:15]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:67][CH:68]5[CH:73]6[CH2:74][CH2:75][N:70]([CH2:71][CH2:72]6)[CH2:69]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CN2CCC1CC2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)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)CC1(CCC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 7) (15 mg, 0.033 mmol), DIPEA (12 μl, 0.066 mmol, 2 eq) and TBTU (12 mg, 0.036 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 (8 mg, 0.04 mmol, 1.2 eq) and DIPEA (13 μL). The RM was then stirred at rt for 3 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide (±)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:26])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[OH:26][CH2:3][CH:2]1[CH2:1][C:4]2=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[C:13]2[O:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(C(=O)OC)ccc([N+](=O)[O-])c1O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(CO)O2
Reaction time: 24 h
Yield: 86.9 %

Procedure:
Methyl 2-allyl-3-hydroxy-4-nitro-benzoate 1d (0.47 g, 2 mmol) was dissolved in 80 mL of dichloromethane followed by the addition of m-chloroperbenzoic acid (0.99 g, 4 mmol). The reaction solution was stirred for 24 hours. The resulting solution was added with 20 mL of saturated sodium thiosulfate solution and 20 mL of saturated sodium bicarbonate solution successively, stirred for 5 minutes and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 2-(hydroxymethyl)-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 40a (440 mg, yield: 87.0%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:7]=3[C:6]=2[C:5]=1[Cl:25].[F:26][C:27]1[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33]Br)=[CH:29][CH:28]=1>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:33][CH2:32][O:31][C:30]3[CH:35]=[CH:36][C:27]([F:26])=[CH:28][CH:29]=3)[C:8]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:7]=3[C:6]=2[C:5]=1[Cl:25]
Reactant: Fc1ccc(OCCBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Cl)c(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccc(F)cc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 84.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 68 mg, 1.7 mmol) was added to a solution of tert-butyl 9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.40 g, 1.1 mmol) in DMF (6 mL). After 25 min, 4-fluorophenoxy ethyl bromide (0.34 mL, 2.3 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 22 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (17:3) to give 0.46 g (82%) of a white solid: mp 163.5-165.5° C.; 1H NMR (300 MHz, CDCl3) δ 7.16 (m, 2H), 6.92 (m, 2H), 6.70 (m, 2H), 4.44 (m, 2H), 4.12 (m, 2H), 3.73 (m, 4H), 3.51 (m, 2H), 3.12 (m, 2H), 1.48 (s, 9H); IR (diffuse reflectance) 1675, 1507, 1449, 1405, 1365, 1354, 1298, 1249, 1242, 1221, 1209, 1170, 1120, 835, 828 cm−1; MS (FAB) m/z 493 (M+H+), 494, 493, 492, 439, 438, 437, 436, 435, 57, 42; HRMS (EI) calcd for C25H27Cl2FN2O3 492.1383, found 492.1385; Anal. Calcd for C25H27Cl2FN2O3: C, 60.86; H, 5.51; N, 5.68; found: C, 60.93; H, 5.60; N, 5.69.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: COC(=O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 74.8 %

Procedure:
{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid methyl ester (36 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), glycine methyl ester (27 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 481. 1H NMR (DMSO-d6, 400 MHz): δ 8.85 (br, 1H), 8.08 (s, 1H), 7.91 (m, 2H), 7.81-7.70 (m, 2H), 7.49 (d, 1H), 7.35 (d, 1H), 4.03 (d, 2H), 3.65 (s, 3H), and 3.62 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1)(=[S:14])[NH2:13]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:12]([CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[S:14][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(N)=S)C1
Product: CC(C)(C)OC(=O)N1CCCC(c2nc(-c3ccc(F)cc3)cs2)C1
Yield: 9 %

Procedure:
This compound was synthesized from 2-bromo-1-(4-fluorophenyl)ethanone and tert-butyl 3-carbamothioylpiperidine-1-carboxylate as described for example 59 step 5 (95 mg, yield 9%). 1H NMR (400 MHz, CDCl3) δ 7.90-7.87 (dd, J=8.8 Hz, 5.3 Hz, 2H), 7.31 (s, 1H), 7.13-7.09 (t, J=8.8 Hz, 2H), 4.05-4.02 (m, 1H), 3.24-3.18 (m, 2H), 2.96-2.89 (m, 1H), 2.30-2.25 (m, 2H), 1.85-1.80 (m, 2H), 1.64 (m, 1H), 1.49 (s, 9H). MS (ESI) m/z: Calculated for C19H23FN2O2S: 362.15. found: 363.2 (M+H)+