Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.C(N(CC)CC)C.[C:18]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)#[N:19].O>C(Cl)Cl.C(OCC)(=O)C>[C:18]([C:20]1[CH:21]=[C:22]([S:26]([N:5]2[CH2:6][C@@H:2]([OH:1])[CH2:3][C@H:4]2[C:7]([O:9][CH3:10])=[O:8])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)#[N:19]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](O)CN1S(=O)(=O)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Methyl (4S)-4-hydroxyprolinate (52.0 g, 0.286 mol) was dissolved in 500 mL CH2Cl2 and cooled to 0° C. Triethylamine (83.6 mL, 0.600 mol) was added, followed by 3-cyanobenzenesulfonyl chloride (55.0, 0.273 mol) slowly. The reaction mixture was stirred at room temperature overnight. Water was added, and the aqueous layer was extracted three times with CH2Cl2. The combined organic layers were washed with 1N HCl, H2O, 1N NaOH, and brine, dried over MgSO4, and concentrated to give a viscous residue. Ethyl acetate (300 mL) was added to completely dissolve the residue. Approximately 100 mL hexanes was added slowly until the solution became slightly cloudy. The mixture was then stirred overnight to allow the product to precipitate. The solid was filtered and rinsed two times with 30% EtOAc/hexanes to give the desired product as an off-white powder (66.2 g, 78%). 1H-NMR (CDCl3, 500 MHz) δ 8.20-8.18 (m, 1H), 8.15-8.12 (m, 1H), 7.92-7.89 (m, 1H), 7.72 (t, 1H), 4.51-4.47 (m, 1H), 4.42 (br s, 1H), 3.74 (s, 3H), 3.53-3.49 (m, 1H), 3.46-3.43 (m, 1H), 3.39 (br s, 1H), 2.29-2.25 (m, 1H), 2.21-2.02 (m, 1H). MS (ESI) calculated for C13H14N2O5S 310.3, observed m/e 311.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:42]=[CH:41][C:36]([O:37][CH2:38][CH2:39][OH:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:40][CH2:39][CH2:38][O:37][C:36]1[CH:41]=[CH:42][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])=[CH:34][CH:35]=1
Reactant: Nc1ccc(OCCO)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(OCCO)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 77.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.4 g, 0.86 mmol) was reacted with 2-(4-amino-phenoxy)-ethanol (0.24 g, 1.5 mmol), HATU (0.58 g, 1.5 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide as a white solid (0.4 g, 78%).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[CH:7]=[C:8]([OH:17])[CH:9]=[C:10]2[C:15]=1[O:14][C:13](=[O:16])[CH:12]=[CH:11]2.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[Br:5][C:6]1[CH:7]=[C:8]([O:17][CH2:1][O:2][CH3:3])[CH:9]=[C:10]2[C:15]=1[O:14][C:13](=[O:16])[CH:12]=[CH:11]2
Reactant: O=c1ccc2cc(O)cc(Br)c2o1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(Br)c2oc(=O)ccc2c1
Reaction time: 8 h

Procedure:
Add BBr3 (0.75 mL, 8 mmol) to preparation 3(662 mg, 2.0 mmol) in 20 mL of dichloromethane at 0° C. Let stir for 15 min. Add 8 mL of methanol and then concentrate. Adsorb to 6 g of silica gel and purify by flash chromatography (40 g, 10-50% A/B, A=10% MeOH in EtOAc, B=hexanes) to give 476 mg of 8-Bromo-6-hydroxy-chromen-2-one (3). Add chloromethyl methyl ether (0.18 mL) to a solution of 8-bromo-6-hydroxy-chromen-2-one (476 mg, 1.97 mmol) and K2CO3 (660 mg, 4.77 mmol) in 10 of DMF. Let the solution stir overnight, add 0.09 mL more chloromethyl methyl ether, let stir 2 hrs, dilute with EtOAc, wash with water, 1:1 water:brine, brine, dry (Na2SO4), filter and concentrate to yield 524 mg (1.84 mmol, 93%) of preparation 5. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, 1H, J=9.2 Hz), 7.50 (d, 1H, J=2.6 Hz), 7.12 (d, 1H, J=2.6 Hz), 6.46 (d, 1H, J=9.7 Hz), 5.20 (s, 2H), 3.50 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15]1.N1CCCCC1>C(O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11](=[O:13])/[CH:12]=[CH:23]/[C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:14][CH:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)=O)c1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(OC)cc(C(=O)/C=C/c2c[nH]c3ccccc23)c1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
3',5'-Dimethoxyacetophenone (1.10 g) and indole-3-carboxaldehyde (1.45 g) were dissolved in ethanol (20 ml), and piperidine (0.85 g) was added thereto, followed by heating under reflux for 32 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration, followed by recrystallization from ethanol to give Compound 69 (1.79 g).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](S)=[N:10][C:9]=2[CH:14]=1.O>C(Cl)(Cl)Cl.CCOCC>[Br:1][C:11]1[S:12][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:14][C:9]=2[N:10]=1
Reactant: COc1ccc2sc(S)nc2c1
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc2sc(Br)nc2c1
Reaction time: 0.5 h

Procedure:
A solution of bromine (3.6 eq) in chloroform (0.75M) was added dropwise over a of 1 hr to a stirred suspension of 5-methoxy-2-mercaptobenzothiazole (1 eq) in form at 0° C. The mixture was stirred for 30 min before it was added slowly to water and stirred for further 20 min. The mixture was filtered to remove a cream solid. The organic phase was dried and evaporated to leave a brown solid. The brown solid was dissolved in ether and filtered. The residue was washed with ether and the filtrate and washings were combined and evaporated, chromatographed (4:1 hexanes and ethyl acetate) to give the title compound as a pale yellow solid. MS: MH+=244
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=O.ClC1C(OC)=C(Cl)C(OC)=C2C=1C[N:16]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:17]1=N2>C1(C)C=CC=CC=1>[Cl:1][CH:2]1[CH2:3][CH2:4][CH2:5][C:6]2[N:11]=[C:32]3[CH2:31][CH:30]=[CH:29][CH:28]=[CH:17][N:16]3[C:8](=[O:10])[C:7]1=2
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: COc1c(Cl)c2c(c(OC)c1Cl)N=C1CCCCCN1C2
Solvent: Cc1ccccc1
Product: O=c1c2c(nc3n1C=CC=CC3)CCCC2Cl

Procedure:
18.01 g 6-chloroanthranilic acid suspended in 100 mL toluene was treated with 14 mL 1-aza-2-methoxy-1-cycloheptene (1) and refluxed with stirring under a Dean-Stark trap to remove the forming water and methanol for 1 hour. An exothermic reaction ensued, forming a two-layer mixture and foaming considerably. This gradually dissolved, giving a brown solution. Then 9 mL of (1) was added and the mixture was refluxed for 18 more hours. The toluene was removed in vacuo and excess of (1) was distilled out at 11 mmHg at 140° C. bath. The residue was chromatographed (6:1 chloroform-ethyl acetate) and recrystallized from hexane-ethyl acetate. The product, 1-chloro-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one, was obtained as a white, crystalline solid, m.p. 128° C.-129° C.; yield 16.5 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]=[CH:5][CH:6]([NH:24][C:25](=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C@H:6]([NH:24][C:25](=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:9]=1
Reactant: COC(=O)C=CC(Cc1cn(Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC[C@@H](Cc1cn(Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Yield: 83.4 %

Procedure:
5-(1-Benzyl-1H-indol-3-yl)-4-(7-phenyl-heptanoylamino)-pent-2-enoic acid methyl ester (67 mg, 0.128 mmol) in MeOH (40 mL) was hydrogenated at 15 psi for 15 min using 10% Pd/C. The solution was filtered and the solvent removed to afford the title compound (56 mg, 83%), mp 107.1-109.2° C. 1H NMR (CDCl3) δ 1.21-1.34 (4H, m), 1.47-1.77 (5H, m), 1.87-1.98 (1H, m), 2.04 (2H, t, J=7.53 Hz), 2.26-2.44 (2H, m), 2.57 (2H, t, J=7.69 Hz), 2.91 (1H, dd, J=6.53, 14.63 Hz), 2.98 (1H, dd, J=5.52, 14.63 Hz), 3.62 (3H, s), 4.22-4.33 (1H, m), 5.26 (2H, s), 5.42 (1H, d, J=5.42), 6.96 (1H, s), 7.08-7.18 (7H, m), 7.24-7.28 (6H, m), 7.64 (1H, 7.26 Hz). 13C NMR (CDCl3) δ 174.3, 172.8, 142.7, 137.5, 136.6, 128.7, 128.6, 128.4, 128.2, 127.6, 126.8, 126.8, 125.6, 121.9, 119.3, 119.2, 110.8, 109.7, 51.7, 49.9, 49.5, 36.9, 35.8, 31.2, 31.0, 30.6, 29.1, 29.1, 28.9, 25.5. ISMS: 525 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]1)[N:6]=[CH:5]2.[OH-].[Na+].Cl>CO.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]1)[N:6]=[CH:5]2
Reactant: COC(=O)C1CCN(c2ncc3cc(O)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)C1CCN(c2ncc3cc(O)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
To a solution of methyl 1-(6-hydroxyquinazolin-2-yl)piperidine-4-carboxylate (330 mg, crude from above) in MeOH (10 mL) was added aqueous NaOH (10 mL, 2M). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was acidified with 1N HCl to pH=1˜2, then concentrated to give a residue, which was diluted with EtOAc (100 mL), filtered and concentrated to give the crude product which was purified by prep-HPLC (0.1% TFA as additive). Most of the solvent was removed in vacuo followed by lyophilization to give the product (70 mg, 2-step yield: 19%) as a solid. 1H NMR (DMSO-d6 400 MHz): δ 9.15 (s, 1H), 7.51 (d, J=9.2 Hz, 1H), 7.37 (dd, J=9.2, 2.8 Hz, 1H), 7.13 (d, J=2.8 Hz, 1H), 4.59 (d, J=13.2 Hz, 2H), 3.16 (t, J=11.4 Hz, 2H), 2.68-2.52 (m, 1H), 1.93 (dd, J=13.2, 3.2 Hz, 2H), 1.62-1.48 (m, 2H). MS (ESI): m/z 274.1 [M+H]+.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]2=[O:24])[CH:9]=[CH:8][N:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccccc3[N+](=O)[O-])cc1C(C)=O)C2=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3[N+](=O)[O-])C=C1C(C)=O)C2=O

Procedure:
The title compound 158 is prepared according to the procedure reported in Example 39.1 with compound 125 (80 mg, 0.16 mmol) and BNAH (34 mg, 1 equiv) as reactants. Yellow solid. (Yield 28 mg, 40%).
Reaction SMILES: C(OC([CH:6]([C:21](=[O:23])[CH3:22])[CH2:7][C:8]1[C:9]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=2[O:11][C:12]=1[CH3:13])=O)C.[OH-].[Na+]>C(O)C>[CH3:13][C:12]1[O:11][C:10]2[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[CH2:7][CH2:6][C:21](=[O:23])[CH3:22]
Reactant: CCOC(=O)C(Cc1c(C)oc2c([N+](=O)[O-])cccc12)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)CCc1c(C)oc2c([N+](=O)[O-])cccc12
Yield: 79.8 %

Procedure:
A solution of 3-(2-ethoxycarbonyl-3-oxobutyl)-2-methyl-7-nitrobenzo[b]furan (170 mg) in a mixture of ethanol (5 ml) and aqueous 1N-sodium hydroxide (5 ml) was refluxed for 1 hour. The reaction mixture was cooled and the separated solid was collected, washed with water and dried to give 2-methyl-7-nitro-3-(3-oxobutyl)benzo[b]furan (105 mg).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[N:17]([C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[Cl:35])=[O:20])[CH3:18])C)(C)(C)C.[OH-].[Na+].C(#N)C>Cl>[Cl:35][C:29]1[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:28]=1[O:27][C:26]1[C:21]([C:19]([N:17]([C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[NH:7][CH3:6])[CH3:18])=[O:20])=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(F)c(F)cc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CNc1cc(F)c(F)cc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 22.1 %

Procedure:
A solution of 100 mg (0.186 mmol) (2-{[4-(2,5-dichloro-phenoxy)-pyridine-3-carbonyl]-methyl-amino}-4,5-difluoro-phenyl)-methyl-carbamic acid tert-butyl ester in 1.5 mL 1M aqueous hydrochloric acid was stirred for 4 hours at 90° C. The reaction mixture was cooled down to room temperature and 2 mL 1M aqueous sodium hydroxide solution and 1 mL acetonitrile were added. The light yellow solution was directly purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 18 mg (22%) of the title compound as a colorless solid. MS (ESI): m/z=438.058 [M+H]+.
Reaction SMILES: CC1CC[N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=CC=CC=3)[C:11]2=O)C1=O.O.NN.[CH2:25]1COCC1.CO>>[NH2:4][CH2:7][CH2:8][CH2:9][N:10]1[CH:11]([CH3:25])[CH2:12][CH2:17][C:18]1=[O:19]
Reactant: C1CCOC1
Reactant: CC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CC1CCC(=O)N1CCCN
Temperature: 50 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
2-[3-(3-Methyl-2-oxo-pyrrolidin-1-yl)-propyl]-isoindole-1,3-dione (0.5 g, 1.74 mmol) was taken in a mixture of THF/MeOH (3.0 mL/3.0 mL). Hydrazine hydrate (0.44 g, 8.7 mmol) was added to this and the reaction was stirred at 50° C. for 16 h. The precipitate was filtered and the filtrate was concentrated to give the product 1-(3-amino-propyl)-5-methyl-pyrrolidin-2-one (0.12 g, 45%).
Reaction SMILES: [CH:1]([C:3]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4]1)=C.[OH-].[Na+].OO.Cl>O1CCCC1.C(O)C>[CH2:4]1[C:3]2([CH2:1][CH2:11][O:10][C:8](=[O:9])[CH2:7]2)[CH2:6][CH2:5]1
Reactant: C=CC1(CC(=O)OC)CCC1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1CC2(CCC2)CCO1
Temperature: 0 °C
Reaction time: 9 h
Yield: 50.9 %

Procedure:
To an ice-cooled solution of methyl (1-vinylcyclobutyl)acetate (0.67 g) in tetrahydrofuran (3 mL) was added 0.5M9-borabicyclo[3.3.1]nonane/tetrahydrofuran (17.5 mL) dropwise over 10 minutes. The reaction solution was then allowed for its temperature to rise to room temperature and it was stirred for additional 9 hours. The reaction solution was again ice-cooled and ethanol (4 mL), a 6N aqueous sodium hydroxide solution (8 mL) and 30% hydrogen peroxide (8 mL) were successively added thereto. The reaction solution was then allowed for its temperature to rise to room temperature and it was stirred for additional 30 minutes. The reaction solution was again ice-cooled. After conc. hydrochloric acid (5 mL) was added to the solution, it was stirred for additional 30 minutes. The reaction solution was extracted with tert-butyl methyl ether. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (9:1)] to give the title compound (0.31 g).
Reaction SMILES: C([O:9][C:10]1[C:11]([C:21]([O:23]C)=O)=[N:12][C:13]([Br:20])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=O)C1C=CC=CC=1.[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C1(C)C=CC=CC=1>[Br:20][C:13]1[N:12]=[C:11]([C:21]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:27]=2[O:26][CH3:25])=[O:23])[C:10]([OH:9])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: COc1cccc(CN)c1OC
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(CNC(=O)c2nc(Br)c3cccnc3c2O)c1OC

Procedure:
Into a round bottom flask fitted with a gas inlet, condenser and a magnetic stirring bar was placed methyl 8-(benzoyloxy)-5-bromo-1,6-naphthyridine-7-carboxylate (0.4 g, 1.03 mmol), 2,3-dimethoxybenzylamine (0.432 g, 0.38 mL, 2.58 mmol) and 10 mL toluene. This mixture was refluxed for 18 hours, after which the reaction was cooled and the solvent removed in vacuo. The resulting residue was triturated with diethyl ether and filtered to yield 5-bromo-N-(2,3-dimethoxybenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:4]=2[N:3]=1.C1COCC1.CCN(C(C)C)C(C)C.Cl[CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32]>CCOC(C)=O>[Cl:1][C:2]1[N:6]([CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:4]=2[N:3]=1
Reactant: Clc1nc2c(Cl)cccc2[nH]1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCn1c(Cl)nc2c(Cl)cccc21
Reaction time: 18 h

Procedure:
To a mixture of 2,4-dichloro-1H-benzoimidazole (0.550 g, 2.94 mmol) and THF (15 mL) was added DIPEA (1.54 mL, 8.82 mmol) followed by 1-chloromethoxy-2-methoxy-ethane (0.550 g, 4.41 mmol) at 23° C. After stirring for 18 h, EtOAc (100 mL) was added. The organic layer was washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-50% EtOAc/hexanes to yield the titled compound as a mixture of regioisomers (0.660 g, 82%). MS (ESI/CI): mass calcd. for C11H12Cl2N2O2, 274.0; m/z found, 275.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.61 (dd, J=8.0, 1.0 Hz, 1H), 7.41 (dd, J=8.1, 0.9 Hz, 1H), 7.33 (dd, J=7.9, 1.0 Hz, 1H), 7.31-7.20 (m, 3H), 5.98 (s, 2H), 5.66 (s, 2H), 3.76-3.69 (m, 2H), 3.67-3.60 (m, 2H), 3.55-3.46 (m, 4H), 3.37 (s, 3H), 3.36 (s, 3H).
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=1.[H-].[Na+]>CCOCC.CS(C)=O.O>[C:1]([C:2]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:22][NH:21][CH:20]=1)#[N:10]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: N#CC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#Cc1c[nH]cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cinnamonitrile (16.53 g) and (para-toluenesulfonyl)methylisocyanide (25 g) in a mixture of ether and dimethyl sulfoxide (450 mL, 2:1) was added dropwise to a stirred suspension of sodium hydride (6.14 g, 60% dispersion in mineral oil) in ether (50 mL). An exothermic reaction took place. The reaction mixture was then stirred at room temperature for 2 hours, then diluted with water (500 mL) and this mixture was extracted three times with ether (250 mL). The combined extracts were washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to filter chromatography on a pad of silica eluting with a mixture of ethyl acetate and pentane (1 L, 1:4, v/v) and then with a mixture of ethyl acetate and pentane (2 L, 2:3, v/v). Fractions containing the required material were evaporated and the residue was suspended in pentane (500 mL) with stirring, then filtered to give the title compound as a solid, m.p. 120-122° C. MS: 167 (MH−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=[O:14])[CH2:12][CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: CCC(=O)CCl
Product: CCC(=O)CSc1cccc(Br)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 3-bromothiophenol and 1-chloro-butan-2-one.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.C(=O)(O)[O-].[Na+].[CH2:20]([C:27]1[NH:28][C:29]2[CH:35]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:33]=[CH:32][C:30]=2[N:31]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.C(OCC)(=O)C>[CH2:20]([C:27]1[N:31]([CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[Cl:6])[C:30]2[CH:32]=[CH:33][C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:35][C:29]=2[N:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ccc2nc(Cc3ccccc3)[nH]c2c1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccccc1Cl
Temperature: 60 °C
Yield: 18.7 %

Procedure:
N,N-dimethylformamide (15 ml), 2-chlorobenzyl bromide (3.94 g) and sodium bicarbonate (1.23 g) are added to 2-benzyl-5-ethoxycarbonyl-benzimidazole (2.37 g) (example 11) and the solution is heated for one hour at 60° C. After adding ethyl acetate (70 ml) and water (70 ml) and separating the solution, the organic layer is washed with water three times and extraction is performed on the aqueous layer using ethyl acetate three times. By concentrating the obtained organic layer under reduced pressure, a mixture of 2-benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonylbenzimidazole (1.06 g) and 2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole (0.640 g) is obtained. Separation and purification is performed using medium pressure silica gel column chromatography (eluate: hexane/ethyl acetate=1/4˜0/100) produces medium pressure silica gel column chromatography (eluate: hexane/ethyl acetate=1/4˜0/100).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](Cl)=[N:12][CH:13]=1.[CH2:15]([OH:18])[CH2:16][CH3:17].O>C1COCC1.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:15][CH2:16][CH3:17])=[N:12][CH:13]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCOc1ccc(Br)cn1
Temperature: 120 °C
Yield: 96.6 %

Procedure:
Potassium tert-butoxide (1.85 g, 16.5 mmol) was added to a mixture of 5-bromo-2-chloropyridine (2.89 g, 15.0 mmol) and 1-propanol (1.230 mL, 16.5 mmol) in THF (15 mL). The reaction mixture was heated at 120° C. for 30 minutes in a microwave reactor. The mixture was poured into a mixture of water (50 mL) and EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4 and evaporated to dryness. Flash chromatography (silica, 0-20% EtOAc in heptanes) gave the title compound as a yellow oil (3.13 g, 97%) sufficiently pure for the next step.