Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4].[I-:42].[Na+].CCCCCC>CC(C)=O>[I:42][CH2:2][C:3]([N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: [I-]
Reactant: CCCCCCCC/C=C\CCCCCCCCN(CCCCCCCC/C=C\CCCCCCCC)C(=O)CBr
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCCN(CCCCCCCC/C=C\CCCCCCCC)C(=O)CI

Procedure:
A solution of 2-bromo-N,N-dioleylacetamide (0.81 g; 1.27 mmol) and sodium iodide (0.76 g; 5.08 mmol) in acetone is refluxed overnight. Hexane (10 ml) is added and the precipitate is filtered off to give, after evaporating the filtrate under reduced pressure, 2-iodo-N,N-dioleylacetamide (0.87 g; 100%) in the form of a yellowish liquid.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:6]([CH2:7]O)[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2].C(N(S(F)(F)[F:26])CC)C>C(Cl)Cl>[CH2:1]([C@H:3]1[C@@H:6]([CH2:7][F:26])[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1CO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1CF
Reaction time: 8 h

Procedure:
To (±)-cis-3-Ethyl-4-hydroxymethyl-N-toluenesulfonyl-2-azetidinone (3.9 mg) in CH2Cl2 (0.5 ml) was added diethylaminosulfur trifluoride (DAST) (15μl). The mixture was stirred overnight under nitrogen. The mixture was purified by preparative TLC on a silica gel plate (1000μ) and developed with CH2Cl2 to give the titled compound. NMR(CDCl3): δ1.06(3H, t), 1.6-2.0(2H, m), 2.45(3H, s), 3.26(1H, dt), 4.27(1H, dm), 4.65(1H, m), 4.88(1H, m), 7.37(2H, d), 7.88(2H, d)
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][C:6]1[C:7]([NH2:16])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.B(Br)(Br)Br.O>ClCCl>[NH2:16][C:7]1[C:6]([CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[OH:2])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COc1ccccc1Cc1cc2ccccc2nc1N
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Nc1nc2ccccc2cc1Cc1ccccc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-(2-Methoxybenzyl)quinolin-2-amine (53 mg, 0.2 mmol) was mixed with boron tribromide solution in dichloromethane (1M, 0.4 mL, 0.4 mmol) in dichloromethane [sic; duplication] at −78° C. After thawing, the mixture was stirred for 12 hours at room temperature. The batch was mixed with water, extracted with dichloromethane and the combined organic phases were washed with sodium hydroxide solution (1M), water and saturated saline solution until neutral. After drying (sodium sulfate), the crude product was stirred with methyl tert-butyl ether and recrystallized from methanol/water (yield: 28 mg, 56%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH2:6][C:5](=[O:10])[CH2:4]1)[CH3:2].[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])=[CH:13][CH:12]=1>C1C=CC=CC=1>[CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH:6]([C:21](=[O:22])[NH:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:23])=[CH:12][CH:13]=2)(=[O:18])=[O:19])[C:5](=[O:10])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(=O)CC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: CCC1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C(=O)C1

Procedure:
Reaction of 5-ethyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-ETHYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 86°-87° C. (corr.).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[C:16]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:24]=2)=[N:15][C:14]([CH2:36][OH:37])=[N:13]1>ClCCl>[CH3:11][N:12]1[C:16]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[CH:24]=2)=[N:15][C:14]([CH:36]=[O:37])=[N:13]1
Reactant: Cn1nc(CO)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cn1nc(C=O)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
Dimethyl sulphoxide (304 mg) was added to a solution of oxalyl chloride (254 mg) in dichloromethane (20 ml) at -60° under nitrogen for 2 min. and a solution of 1-methyl-5-[[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino]-1H-1,2,4-triazole-3-methanol (0.5 g) in dichloromethane (10 ml) was added. The mixture was stirred at -50° to -60° for 15 min. and then quenched with triethylamine (657 mg). The solution was allowed to warm to 25° and was diluted with water. The aqueous phase was extracted with dichloromethane and the combined organic extracts were dried and evaporated to leave the title compound as a pale yellow oil (0.4 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:10]([CH3:11])[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C:10]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:11])[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: CC1=CC(=O)N(Cc2ccccc2)C1=O
Solvent: C1CCOC1
Product: CC1(NCc2ccccc2)CC(=O)N(Cc2ccccc2)C1=O
Yield: 38 %

Procedure:
120.6 g (0.6 mol) of N-benzylcitraconimide and 65.2 g (0.6 mol) of benzylamine are heated to reflux in 600 ml of tetrahydrofuran for 16 hours. The solvent is then distilled off, and the residue is chromatographed on silica gel using ethyl acetate-petrol ether 1:1. This gives 76.2 g of an oil, which is 93% strength after analysis by gas chromatography (yield 38% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=O)[CH:12]=[O:13].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:12](=[O:13])[CH:11]=[N:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(=O)C=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1

Procedure:
4,5-Dichlorophenylenediamine (26.0 g, 147 mmol) and 50% ethyl glyoxylate in toluene (32 mL, 161 mmol) in ethanol (250 mL) was refluxed for 18 h. The reaction was cooled and the crystallized brown product was collected by filtration, then washed with ethanol (50 mL). The obtained product (25.5 g, 81%) was 96% pure via LC/MS. MS (ES) m/e 215[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:21]([N:25]=[C:26]=[S:27])([O:23][CH3:24])=[O:22]>C(OCC)C>[C:21]([NH:25][C:26](=[S:27])[NH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])([O:23][CH3:24])=[O:22]
Reactant: CCCCNc1ccc(C(=O)c2ccccc2)cc1N
Reactant: COC(=O)N=C=S
Solvent: CCOCC
Product: CCCCNc1ccc(C(=O)c2ccccc2)cc1NC(=S)NC(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.2 %

Procedure:
To a solution of 3-amino-4-n-butylaminobenzophenone (2.38 g.) in diethyl ether (200 ml.) is added carbomethoxy isothiocyanate (1.4 g.). The reaction mixture is stirred at room temperature for three hours. The product is collected by filtration and dried to afford 0.2 g. of product, m.p. 160°-162° C., dec. The filtrate is allowed to stand overnight at room temperature and a second crop is collected amounting to 0.15 g., m.p. 162° C., dec. The total amount of 3-(3-carbomethoxythioureido)-4-n-butylaminobenzophenone obtained is 0.35 g. (10.2% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1cccc(C(=O)O)c1
Reactant: NCc1ccccc1
Product: CC(C)Cc1cccc(C(=O)NCc2ccccc2)c1
Yield: 0.8 %

Procedure:
Using preparation method 1, 94B (131 mg, 0.74 mmol) was reacted with benzylamine (120 μL, 118 mg, 1.1 mmol). Purification by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100% afforded white crystals (1.60 mg, 81%). NMR 1H (ppm, CDCl3): 7.58-7.54 (m, 2H), 7.36-7.24 (m, 7H), 6.35 (br. s, 1H), 4.64 (d, J3=5.7 Hz, 2H), 2.50 (d, J3=7.2 Hz, 2H), 1.92-1.82 (m, 1H), 0.88 (t, J3=6.6 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1c[nH]c2ccc(N)cc12
Temperature: 15 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 3-tert-butyl-5-nitro-1H-indole (2.5 g, 12 mmol) in MeOH (30 mL) was added Raney Nickel (0.2 g) under N2 protection. The mixture was stirred under hydrogen atmosphere (1 atm) at 15° C. for 1 h. The catalyst was filtered off and the filtrate was concentrated to dryness under vacuum. The residue was purified by preparative HLPC to afford 3-tert-butyl-1H-indol-5-amine (0.43 g, 19%). 1H NMR (CDCl3, 400 MHz) δ 7.72 (br.s, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.59 (dd, J=2.0, 8.4 Hz, 1H), 6.09 (d, J=1.6 Hz, 1H), 1.37 (s, 9H); MS (ESI) m/e (M+H+) 189.1.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([O:62][Si](C(C)(C)C)(C)C)[CH3:61])=[CH:54]4)[CH:46]([OH:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([OH:62])[CH3:61])=[CH:54]4)[CH:46]([OH:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)O[Si](C)(C)C(C)(C)C)cc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)O)cc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(1-t-butyl-dimethylsilyloxyethylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (74mg) in CH2Cl2 (2 mL.) at rt was added a solution of p-toluene sulfonic acid (10 mg.) in CH3OH (2 mL.). The reaction mixture was stirred for 3 hr., quenched with saturated NaHCO3, then extracted with CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give 44.8 mg of the title compound. Partial 1H NMR (CDCl, 200 MHz) d: 7.24 (d, J=9 Hz, 1H); 7.15 (d, J=3 Hz, 1H); 7.12 (d, J=3.5 Hz, 1H); 6.86 (dd, J=3 and J=9 Hz, 1H); 6.39 (d, J=3.5, 1H); 4.20 (t, J=5, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:3]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:13]=2)[CH:3]=1
Reactant: Cc1ccc(N)c(-c2nc(C(F)(F)F)cs2)c1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2CC2)c(-c2nc(C(F)(F)F)cs2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a stirred solution of the product obtained in Step E (0.46 g, 1.8 mmol) and triethylamine (250 μL, 1.8 mmol) in anhydrous tetrahydrofuran (THF, 15 mL) cooled to 0° C. was added dropwise a solution of cyclopropanecarbonyl chloride (160 μL, 1.8 mmol) in THF (5 mL). The mixture was stirred at 0° C. for 30 min and then at room temperature overnight. The reaction mixture was filtered and the solids were washed with ethyl acetate. The filtrate was evaporated to dryness and the residue purified by recrystallization from hexane to yield 0.41 g (71% yield) of the title compound as a white solid melting at 155°-156° C. 1H NMR (400 MHz, CDCl3) δ 11.75 (s,1H), 8.61-8.63 (m,1H), 7.76 (s, 1H), 7.55 (s,1H), 7.26-7.27 (m,1H), 2.37 (s,3H), 1.56-1.62 (m,2H), 1.07-1.13 (m,2H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+]>O>[C:13]1([NH:12][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ncnc2ncccc12
Reactant: Nc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc(Nc2ncnc3ncccc23)cc1
Yield: 26.7 %

Procedure:
4-Chloropyrido [2,3-d]pyrimidine (0.15 g, 0.91 mmol) was carefully added to a solution of aniline (0.15 g, 1.61 mmol) in water (1.5 mL). The solution was heated for 0.5 h on a steam bath, cooled, and then basified with conc. ammonium hydroxide. The crude precipitate was collected by filtration and recrystallized from 95% ethanol to give yellow crystals (0.054 g, 27%). MP 258° C.; LC-MS: 223 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:22]1([C:28](B(O)O)=[CH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC([O-])=O.[K+]>CCO>[C:22]1([C:28]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([C:12]4[NH:20][C:19]5[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=5[CH:13]=4)[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: C=C(B(O)O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: C=C(c1ccccc1)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 80 °C
Reaction time: 23 h
Yield: 77.1 %

Procedure:
A mixture of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 200 mg, 0.672 mmol), (1-phenylvinyl)boronic acid (Aldrich; 139.1 mg, 0.941 mmol), PdCl2(APhos)2 (23.8 mg, 0.034 mmol), and KOAc (131.8 mg, 1.34 mmol) in EtOH (3.4 mL) was stirred under argon in a sealed tube at 80° C. for 23 h. The mixture was concentrated onto silica gel, and chromatographically purified (silica gel, 0-10% MeOH/DCM) to provide 2-(2-(1-phenylvinyl)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (189.2 mg, 0.518 mmol, 77% yield) as an orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.05 (1H, br. s.), 8.23 (1H, d, J=8.8 Hz), 8.08 (1H, d, J=7.4 Hz), 7.81 (1H, d, J=8.6 Hz), 7.64 (1H, d, J=8.0 Hz), 7.54 (1H, d, J=7.8 Hz), 7.46-7.52 (2H, m), 7.41-7.46 (3H, m), 7.14 (1H, s), 6.01 (1H, s), 5.85 (1H, s), 5.47 (1H, br. s.), 3.47 (2H, td, J=6.9, 1.9 Hz), 2.33 (2H, t, J=6.8 Hz). m/z (ESI, +ve) 366.2 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:15]O>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:15])=[O:9])[CH2:4][CH2:3]1
Reactant: CO
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](O)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of (trans)-4-hydroxycyclohexanecarboxylic acid (4.32 g, 30 mmol) in MeOH (20 mL) was added SOCl2 (7.08 g, 60 mmol, 2.0 eq) dropwise at rt. Then the mixture was stirred at 70° C. for 18 h, and the solvent was removed in vacuo to give the title compound as a colorless oil (4.74 g, yield: 100%). 1H NMR (400 MHz, DMSO-d6) δ: 4.33 (br, 1H), 3.68-3.60 (m, 1H), 3.57 (s, 3H), 2.37-2.31 (m, 1H), 1.82-1.74 (m, 2H), 1.53-1.45 (m, 6H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[C@@H:17]12[CH2:23][C@@H:20]([CH:21]=[CH:22]1)[CH2:19][C@H:18]2[CH2:24][C:25](O)=[O:26]>>[C@@H:17]12[CH2:23][C@@H:20]([CH:21]=[CH:22]1)[CH2:19][C@H:18]2[CH2:24][C:25]([NH:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:26]
Reactant: Nn1nc(C2CCC2)c2ccccc2c1=O
Reactant: O=C(O)C[C@@H]1C[C@@H]2C=C[C@H]1C2
Product: O=C(C[C@@H]1C[C@@H]2C=C[C@H]1C2)Nn1nc(C2CCC2)c2ccccc2c1=O

Procedure:
The product of Example 67A and 2-((1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.34-8.28 (m, 1H), 8.00-7.93 (m, 1H), 7.92-7.83 (m, 2H), 6.22 (dd, J=5.7, 3.0, 1H), 6.07 (dd, J=5.7, 2.9, 1H), 4.10-3.99 (m, 1H), 2.91 (s, 1H), 2.79 (s, 1H), 2.49-2.42 (m, 1H), 2.41-2.22 (m, 4H), 2.14-2.02 (m, 3H), 1.95-1.87 (m, 1H), 1.86-1.77 (m, 1H), 1.39-1.31 (m, 1H), 1.26 (d, J=8.0, 1H), 0.61 (ddd, J=11.5, 4.2, 2.6, 1H); MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:12]1[S:16][N:15]=[C:14]([S:17][CH3:18])[N:13]=1.[Cl-].[Na+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:12]2[S:16][N:15]=[C:14]([S:17][CH3:18])[N:13]=2)=[CH:3][CH:2]=1
Reactant: OCc1ccncc1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccncc2)n1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Into 4 g of N,N-dimethylformamide was dissolved 218 mg of 4-pyridinemethanol, 96 mg of sodium hydride (60% in oil) was added thereto at room temperature. After stirring for 30 minutes, a solution of 334 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole in 1 g of N,N-dimethylformamide was added dropwise into the mixture and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 260 mg of 5-(4-pyridylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (34)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=O)[CH:6]=[CH:7][NH:8]2.P(Br)(Br)[Br:15].O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=[CH:7][CH:6]=1
Reactant: BrP(Br)Br
Reactant: COc1cccc2[nH]ccc(=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2nccc(Br)c12
Yield: 85 %

Procedure:
A solution of quinolone (c) (3.2 g, 18 mmol) in DMF (22 ml) was treated with phosphorous tribromide (2.2 ml). After 2 hours the mixture was added to water and neutralised with saturated aqueous sodium bicarbonate solution. Filtration and drying afforded a yellow solid (3.6 g, 85%).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=4)[N:30]=[C:29]([C:39]4[S:40][CH:41]=[C:42]([CH:44]([CH3:46])[CH3:45])[N:43]=4)[CH:28]=3)[CH2:12]1)[C:8](=[O:47])[NH:7]2)=[O:5])C.[Li+].[OH-].Cl>O1CCOCC1.CO>[CH:44]([C:42]1[N:43]=[C:39]([C:29]2[CH:28]=[C:27]([O:26][CH:11]3[CH2:10][CH:9]4[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:47])[CH2:23]5)[CH2:12]3)[C:36]3[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[N:30]=2)[S:40][CH:41]=1)([CH3:46])[CH3:45]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4nc(C(C)C)cs4)nc4cc(OC)ccc34)CC1C(=O)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reaction time: 72 h
Yield: 94.2 %

Procedure:
To a solution of 17-[2-(4-isopropyl-thiazol-2-yl)-7-methoxy-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid ethyl ester (34, 182 mg, 0.275 mmol) in dioxane (3 mL) and MeOH (1.5 mL) was added a 1 M aqueous solution of LiOH (3 mL). After 72 h, the reaction mixture was successively acidified to pH 2 with 1.7 M HCl and evaporated under vacuum. Then, 1 g of silica was added towards the end to adsorb the crude product. Purification by flash column chromatography (15 g YMC silica; gradient MeOH/CH2Cl2: 200 mL each 2%, 4%, 6%, 100 mL each 8%, 10%; forefraction 100 mL followed by 15-mL fractions, desired product fractions 33-42) gave 164 mg (94%) of the title product 35 as a yellow solid: Rf (10% MeOH—CH2Cl2)=0.38.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[CH3:6][C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:17])([CH3:16])[CH:14]=[O:15])[C:9](=[O:18])[C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:6][C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:16])([CH:14]([OH:15])[CH:1]([CH3:3])[CH3:2])[CH3:17])[C:9](=[O:18])[C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)[Mg]Cl
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)C(C)C)CO1
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (5 ml of a 2M solution in tetrahydrofuran) was added during 10 minutes to a stirred solution of 2-(2,3-dihydro-6-methyl-4-oxo-5 -phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (2 g) in tetrahydrofuran at 0° C. under an inert atmosphere. The mixture was allowed to warn to 10° C. over 1 hour, poured onto saturated ammonium chloride solution and extracted (ether). The organic phase was dried (magnesium sulphate) and evaporated to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2,4-dimethylpentan-3-ol (2.26 g) as a yellow gum, m.p. 42-54° C., NMR 1H δ0.85(d,3H), 0.95(d,3H), 1.4(s,3H), 1.5(s,3H), 1.65(m,1H), 1.85(s,3H), 3.25(dd,1H), 5.0(d,1H), 5.1(d,1H), 5.25(d,1H), 7.15-7.35(m,5H).