Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:47]3[CH2:48][CH2:49][CH2:50][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:45][CH2:46]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)CCN1CCCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-[1,4]diazepan-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 1-(2-methanesulfonyl-ethyl)-[1,4]diazepane (example 19) in an analogous manner as described in example 25. LR-MS: 699.4 [(M+H)+]
Reaction SMILES: B.O1CCCC1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])O.[Na+].O>O1CCCC1>[OH:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A 1M-borane/tetrahydrofuran solution (4.36 ml, 4.36 mmol) was added dropwise to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.0 g, 4.36 mmol) in tetrahydrofuran (20 ml) at 0° C. After 1 hour, the mixture thus obtained was warmed up to room temperature. After another 6 hours, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the resulting mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (715 mg, 76%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(N)c1
Yield: 93.9 %

Procedure:
10 g of 5-chloro-2-nitroaniline are dissolved in 100 ml of methanol, and 32.3 g of sodium methoxide are added. The reaction mixture is heated at the boil under reflux for 18 hours. After cooling, the mixture is evaporated to dryness, 500 ml of water are added, and the crude product is isolated by filtration. Drying gives 9.15 g of 5-methoxy-2-nitroaniline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:57])=[C:4]([C@@H: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])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:54]=[CH:53][C:34]([C:35]([O:37][CH2:38][CH2:39][O:40][P:41]([O:48]C(C)(C)C)([O:43]C(C)(C)C)=[O:42])=[O:36])=[CH:33][C:32]=2[O:55][CH3:56])=[O:29])[CH:5]=[CH:6][CH:7]=1.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>C(Cl)Cl>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[Cl:1][C:2]1[C:3]([F:57])=[C:4]([C@@H: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])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:54]=[CH:53][C:34]([C:35]([O:37][CH2:38][CH2:39][O:40][P:41]([OH:48])([OH:43])=[O:42])=[O:36])=[CH:33][C:32]=2[O:55][CH3:56])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)OCCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)OCCOP(=O)(O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
A solution of chiral 2-(di-tert-butoxyphosphoryloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 12, 89.1 mg, 0.104 mmol) in methylene chloride (2 mL) was treated with trifluoroacetic acid (1 mL) and stirred for 45 min at 0° C. The reaction mixture was concentrated and the product was lyophilized to give chiral 2-(phosphonooxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate trifluoroacetate as a white solid (80.7 mg, 90% yield). MS (ES+) m/z calcd. for C33H35Cl2F2N3O8P: [(M+H)+]: 740. found: 740.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1.[C:23](Br)(=[O:25])[CH3:24]>FC(F)(F)C(O)=O>[C:23]([O:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Br
Reactant: COc1c(O)cc2c(c1Sc1ccccc1)CCN(C)CC2
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OC(C)=O)cc2c(c1Sc1ccccc1)CCN(C)CC2

Procedure:
Reaction of 8-hydroxy-7-methoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine with acetyl bromide in trifluoroacetic acid gave 8-acetoxy-7-methoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine; hydrochloride salt m.p. 240°-241° C.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[C:10]([N+:15]([O-])=O)=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.Cl[Ni]Cl>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[C:10]([NH2:15])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(F)c([N+](=O)[O-])ccc2[nH]1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc2c(F)c(N)ccc2[nH]1
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a solution of 2-tert-butyl-4-fluoro-5-nitro-1H-indole (2.1 g, 9.0 mmol) in methanol (50 mL) was added NiCl2 (4.2 g, 18 mmol) and NaBH4 (1.0 g, 27 mmol) at 0° C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na2SO4, evaporated under vacuum to give 2-tert-butyl-4-fluoro-1H-indol-5-amine (900 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 7.80 (brs, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.64 (dd, J=0.9, 2.4 Hz, 1H), 6.23 (s, 1H), 1.38 (s, 9H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[CH2:9][C:10]#[CH:11])(=O)=O.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[CH2:9][C:10]#[CH:11])([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CCC(C)(C)CCOS(C)(=O)=O
Reactant: CC(C)(C)N
Product: C#CCC(C)(C)CCNC(C)(C)C

Procedure:
A solution of 1.3 g of 24b in 15 ml of tert.butylamine, was heated in a closed vessel at an oil bath at 70° C. for 4 days. The reaction was concentrated (rotavap, 150 mB, 40° C.) and then diluted with water and acidified with 1N HCl. The organic layer was washed twice with ether. The aqueous phase was made alkaline (2N NaOH) and extracted with diethylether. The organic material was dried and concentrated (100 mm, 40° C.) to give 960 mg of amine 24c, as a colorless oil. NMR (CDCl3) δ 1.00 (s, 6, 2×CH3), 1.11 (s, 9, tertC4H9), 1.47 (m, 2, CH2), 1.98 (t, 1, acetylene), 2.10 (d, 2, CH2), 2.55 (m, 2, CH2).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:41]([O:44][CH2:45][CH2:46]Br)(=[O:43])[CH3:42].O>CN(C=O)C>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:46][CH2:45][O:44][C:41](=[O:43])[CH3:42])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OCCBr
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCOC(C)=O)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To a solution of N-(1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-N'-(2,6-diisopropylphenyl)urea (300 mg, 0.59 mmol) in DMF (10 ml) was added sodium hydride (NaH, 23 mg, 0.59 mmol), and the mixture was stirred at room temperature for 0.5 hour. To the mixture was added 2-bromoethyl acetate (98 mg, 0.59 mmol), and the mixture was stirred at 40°-50° C. for 6 hours. After allowed to stand for cooling, the mixture was poured into water, extracted with ethyl acetate, and the extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (3% methanol in chloroform) to give the title compound (209 mg, 0.35 mmol) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][C:3]=1[CH3:17].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: O=C1CCCCC1
Reactant: Cc1cc(C(=O)c2ccc(O)cc2)ccc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
Titanium tetrachloride (2.70 mL, 24.5 mmol) was added dropwise to a suspension of zinc powder (3.24 g, 49.5 mmol) in anhydrous THF (60 mL) at RT. After refluxing for 1 h, a mixture of 66 (1.78 g, 6.11 mmol) and cyclohexanone (1.80 g, 18.3 mmol) dissolved in THF (20 mL) was added dropwise. Refluxing was continued for 30 min. The reaction mixture was cooled to RT and filtered through Celite. Water (250 mL) was added and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.85 g (85%) of 67 as an orange solid. 1H NMR (400 MHz, CDCl3): δ 1.58 (m, 6H), 2.20 (m, 4H), 2.32 (s, 3H), 5.95 (br s, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.79 (dd, J=8.1 Hz, 2.0 Hz, 1H), 6.95 (m, 3H), 7.40 (d, J=8.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]([CH3:18])[C:11]([O:13]C(C)(C)C)=[O:12])=[O:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]([CH3:18])[C:11]([OH:13])=[O:12])=[O:8])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1ccc(Cl)s1)C(=O)O

Procedure:
Prepared analogously to Example 2e from tert.-butyl(R)-2-[(5-chloro-thiophene-2-carbonyl)-amino]-propionate with TFA in dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[CH3:13][C:14]1([CH3:21])[CH2:19][O:18][PH:17](=[O:20])[O:16][CH2:15]1.CN(C)C(N(C)C)=N>C1(C)C=CC=CC=1.Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:17]2(=[O:20])[O:18][CH2:19][C:14]([CH3:21])([CH3:13])[CH2:15][O:16]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC1(C)CO[PH](=O)OC1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CP2(=O)OCC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Bromomethyl-benzoic acid methyl ester (0.50 g, 2.18 mmol) was made 2.0 M in anhydrous toluene and to this mixture was added 5,5-dimethyl-[1,3,2]dioxaphosphinane 2-oxide (0.66 g, 4.37 mmol) followed by N,N,N′,N′-tetramethyl-guanidine (0.25 g, 2.18 mmol). The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with 1N aq HCl and extracted with EtOAc. The organic layer was again washed with 1 N aqueous HCl, brine, dried (MgSO4) then concentrated in vacuo. The residue was purified by MPLC (0-70% EtOAc in CH2Cl2) to afford the title compound: MS: cal'd 299 (MH+), exp 299 (MH+)
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cn1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.5) (0.485 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.264 g, 1.2 mmol) according to the general procedure III. Obtained as a yellow solid (0.03 g, 7%). MS (ISP) 452.1 [(M+H)+]; mp 259° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][CH:12]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:37])[CH2:16][N:17]1[C:21](=[O:22])[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:19]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[N:18]1.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[C:48]([NH:11][CH:12]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:37])[CH2:16][N:17]1[C:21](=[O:22])[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:19]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[N:18]1)(=[O:50])[CH3:49]
Reactant: CC(=O)OC(C)=O
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 μl (0.11 mmol) of N,N-diisopropylethylamine were added to a solution of 60 mg (0.10 mmol) of the compound of Example 58A in 1 ml of dichloromethane. The mixture was cooled to 0° C., 10 μl (0.10 mmol) of acetic anhydride were then added and stirring was continued at 0° C. for 1 h. The volatile components were then removed on a rotary evaporator. The residue was dissolved in a little DMSO and separated by preparative HPLC [Method 8]. The product-containing fraction was freed from the solvent on a rotary evaporator and the residue was dried under high vacuum. This gave 50 mg (83% of theory) of the title compound.
Reaction SMILES: [Sn](Cl)Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[CH2:13][CH2:12][N:11]([CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 70 °C
Yield: 75.1 %

Procedure:
Tin (II) chloride (12.77 g, 67 mmol) was added to a solution of 1-benzyl-4-(2-nitrophenyl)piperazine (4.0 g, 13 mmol) in ethanol (50 mL) and the mixture was heated at 70° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate and washed with aqueous sodium hydroxide (2M, 4×). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (80:20 increasing to 75:25) to give the title compound as a pale yellow solid (2.61 g, 72%), δH (250 MHz, CDCl3) 7.38-7.25 (5H, m), 7.03-6.89 (2H, m), 6.77-6.70 (2H, m), 4.05-3.90 (2H, br s), 3.59 (2H, s), 2.96-2.92 (4H, m), and 2.65-2.55 (4H, br s).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:27])[CH:12]([NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:13](=O)[CH3:14])[CH3:9].II.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:8]([O:10][C:11]([C:12]1[N:16]=[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[O:26][C:13]=1[CH3:14])=[O:27])[CH3:9]
Reactant: CCOC(=O)C(NC(=O)c1ccc(OC)cc1)C(C)=O
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
23.2 ml Triethylamine and a solution of 11.3 g 2-(4-methoxy-benzoylamino)-3-oxo-butyric acid ethyl ester in 200 ml dichloromethane were added sequentially to a stirred solution of 20.5 g iodine and 21.2 g triphenylphosphine in 500 ml dry dichloromethane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the resulting residue purified by flash chromatography on silica gel to obtain 6.0 g 2-(4-methoxy-phenyl)-5-methyl-oxazole-4-carboxylic acid ethyl ester as pale yellow solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)(=[O:14])=[O:13])=[C:19]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)[CH:18]=1
Reactant: Nc1ccc(Cl)cc1-c1nccc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: O=S(=O)(Nc1ccc(Cl)cc1-c1nccc2ccccc12)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure using 4-oxazol-5-yl-benzenesulfonyl chloride and 4-chloro-2-isoquinolin-1-yl-phenylamine and purified by preparative HPLC. MS: (M+H)/z=462.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH3:10])=[O:4].B#B.[O:13]1CCCC1>C(OCC)C>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH:8]([OH:13])[CH2:9][CH3:10])=[O:4]
Reactant: C1CCOC1
Reactant: CC=CCCCC(=O)OC
Agent: B#B
Solvent: CCOCC
Product: CCC(O)CCCC(=O)OC

Procedure:
Compound XL is prepared by reacting endo-bicycle[3.1.0]hex-2-ene-6-carboxylic acid methyl ester with diborane in a mixture of tetrahydrofuran and diethyl ether, a reaction generally known in the art, to give endo-bicyclo[3.100]63 hexan-3-ol-6-carboxylic acid methyl ester which is then reacted with dihydropyran in the presence of a catalytic amount of POCl3 to give the desired compound. This is then used as described in said Belgian patent to produce the endo form of bicyclo-ketone XVI.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:22])=[C:8]([F:21])[CH:9]=2)[N:4]=1.O.[SH:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:22])=[C:8]([F:21])[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][NH:29]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2cc(F)c(F)cc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(F)c(F)cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 53.4 %

Procedure:
Prepared according to Procedure C using Intermediate 2q (200 mg, 0.586 mmol), 6-mercaptopurine monohydrate (110 mg, 0.645 mmol), K2CO3 (89 mg, 0.645 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 143 mg of a pale yellow crystalline solid (53%), mp 207.8° C. (discolors; sweats at 136(C). 1H NMR (DMSO-d6) δ: 13.57 (br s, 1H); 8.49 (s, 1H); 8.46 (s, 1H); 8.11 (t, J=9.4 Hz, 1H); 7.88 (dd, J=7.3, 11 Hz, 1H); 7.77 (dd, J=1.7, 7.3 Hz, 1H); 7.67 (d, J=7.4 Hz, 1H); 7.42-7.55 (m, 2H); 4.48 (s, 2H). 13C NMR (DMSO-d6) ppm: 159.5 (d, J=2.5 Hz), 154.6 (dd, J=14, 255 Hz), 154.0 (d, J=1.5 Hz), 151.5, 149.3 (dd, J=14, 250 Hz), 145.1 (d, J=12 Hz), 143.9, 133.9, 132.1, 131.8, 131.4, 130.5, 128.9, 118.0 (d, J=4.9 Hz), 115.8 (d, J=18 Hz), 114.6 (d, J=20 Hz), 32.0. MS (ES): m/z 457.0 (M+). Anal. calcd. for C20H11ClF2N6OS: C, 52.58; H, 2.43; Cl, 7.76; N, 18.40; S, 7.02. Found: C, 51.81; H, 2.37; Cl, 7.49; N, 18.04; S, 7.55.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4](P(OCC)(OCC)=O)[CH2:5][CH:6]([CH3:8])[CH3:7].[H-].[Na+].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:21]1([CH:20]=[C:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([O:2][CH3:1])=[O:17])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOP(=O)(OCC)C(CC(C)C)C(=O)OC
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccccc1)CC(C)C
Temperature: 25 °C
Yield: 79 %

Procedure:
To a stirred solution of 4-Methyl-2-(diethylphosphono) pentanoic acid methyl ester (25.72 g, 96.3 mmole) in dry tetrahydrofuran (250 ml) under nitrogen was added sodium hydride (4.2 g, 60% dispersion in oil) portionwise. After stirring for 30 min. at room temperature benzaldehyde (11.22 g, 96.3 mmole) was slowly added and the reaction mixture was then stirred for a further hour at room temperature. Volatiles were then removed in vacuo and the residue was dissolved in ethyl acetate, washed with saturated aqueous ammonium chloride solution (250 ml×2), dried (sodium sulphate), filtered and evaporated in vacuo to an oil. Distillation under reduced pressure gave the title compound as an oil (16.6 g, 79%); (Found: C, 75.83; H, 8.38. C14H18O2 +0.2H2O requires: C, 75.78; H, 8.36%); δ(CDCl3) 0.87 and 0.95 (together 6H, each d, each J=7 Hz, (CH3)2CH); 1.90 (1H, m, (CH3)2CH); 2.34 and 2.52 (together 2H, each d, each J=8 Hz, CH2CH(CH3 )2); 3.82 (3H, s, OCH3); 7.70 and 7.2-7.42 (together 6H, s, m, C6H5, vinyl CH).