Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(O)(C(F)(F)F)=O.OS(O)(=O)=O>[Br:8][C:18]1[CH:17]=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:14][C:13]=1[C:9]([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 24 h

Procedure:
NBS (125.0 g, 697.5 mmol) was slowly added to a solution of TFA:H2SO4 (5:1, 750 mL) and tert-butyl-4-nitrobenzene (100.0 g, 558.0 mmol) at RT. The solution was stirred for 24 h then poured over 5 kg of ice. The resulting suspension was filtered and washed with a 1:1 MeOH:H2O solution (200 mL) and dried in a vacuum oven. MS (ES+): 258.1, 260.1 (M+H)+. Calc'd for C10H12BrNO2: 257.01.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:28]=[C:29]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([CH:49]4[CH2:52][O:51][CH2:50]4)[CH2:45][CH2:44]3)=[CH:39][N:38]=2)[C:30]2[N:31]([N:33]=[CH:34][N:35]=2)[CH:32]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[CH:28]=[C:29]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([N:43]4[CH2:44][CH2:45][N:46]([CH:49]5[CH2:50][O:51][CH2:52]5)[CH2:47][CH2:48]4)=[CH:39][N:38]=3)[C:30]3[N:31]([N:33]=[CH:34][N:35]=3)[CH:32]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c3ncnn3c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C1c2cc3c(n2CCN1c1cc(F)cc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4ncnn4c2)c1CO)CCCC3
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
A mixture of 108e (250 mg, 0.35 mmol) and LiOH (300 mg, 10 mmol) in iPrOH/THF (1:1, 3.5 mL) and H2O (1 mL) was stirred at 50° C. for 0.5 h. The mixture was evaporated in vacuo and the residue was extracted with Ethyl acetate (5 mL×2). The combined Ethyl acetate extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 108 (110 mg, 25%). LCMS: [M+H]+ 664. 1H NMR (500 MHz, DMSO) δ 9.33 (s, 1H), 8.67 (s, 1H), 8.55-8.54 (m, 2H), 7.95 (d, J=3.0, 1H), 7.44-7.41 (m, 2H), 7.37-7.33 (m, 2H), 6.53 (s, 1H), 4.98 (t, J=5.0, 1H), 4.55-4.54 (m, 2H), 4.45-4.44 (m, 2H), 4.13-4.32 (m, 5H), 3.91 (s, 1H), 3.43-3.41 (m, 1H), 3.10 (s, 4H), 2.60-2.38 (m, 8H), 1.78-1.76 (m, 2H), 1.69-1.67 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)(=O)=O)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:32][CH:33]4[CH2:38][CH2:37][CH2:36][C@H:35]([OH:39])[CH2:34]4)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: NC1CCCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)(=O)=O)n3)c3cc(Cl)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCC[C@H](O)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 130 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-(methylsulfonyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 1a, (1.09 g, 2.34 mmol) and 3-aminocyclohexanol (0.32 g, 2.82 mmol) in THF was added DIEA (0.60 g, 4.69 mmol). The reaction mixture was heated at 130° C. in microwave for 10 min. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography to afford 550 mg of the desired product, 27a.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](N)[CH:5]=[C:4]([Cl:12])[N:3]=1.[ClH:13].N([O-])=O.[Na+].[OH-].[Na+]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:13])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1c(Cl)cc(Cl)nc1Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
2,6-dichloro-3-nitropyridine-4-amine (2.27 g, 10.9 mmol) was added to 48 mL concentrated hydrochloric acid, and cooled to 0-5° C. To the solution was added sodium nitrite (2.26 g, 32.7 mmol) in batches. After the addition of sodium nitrite, the reaction solution was stirred for 1 h at 0-5° C., and then stirred for 2 h at 25° C., adjusted to pH=7 with 40% sodium hydroxide solution, and extracted with ethyl ether. After the organic phase was dried (Na2SO4) and concentrated, it was subjected to column chromatography eluted with petroleum ether to afford 2 g white solid with a yield of 80.7%.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.CN(C=O)C.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][C@H:44]2[CH3:49])=[N:35][N:34]=1>C(OCC)(=O)C.C(N(CC)CC)C>[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([N:43]2[CH2:48][CH2:47][N:46]([C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:11])[CH2:7][CH2:6]3)=[O:10])[CH2:45][C@H:44]2[CH3:49])=[N:35][N:34]=1
Reactant: C[C@@H]1CNCCN1c1nnc(Cl)c2ccccc12
Reactant: O=C(O)C1CCC(F)(F)CC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)C2CCC(F)(F)CC2)CCN1c1nnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4,4-difluorocyclohexanecarboxylic acid (386 mg, 2.35 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (624 mg, 2.45 mmol), DMF (4 mL), and triethylamine (0.57 mL) were stirred at RT for 2 minutes. (R)-1-chloro-4-(2-methylpiperazin-1-yl)phthalazine (JK-2) (537 mg, 2.04 mmol) was added and the reaction stirred at rt for 24 hours. The reaction was then taken up in ethyl acetate (80 mL), washed with aqueous K2CO3 (10%), water, and then saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a brown oil. Chromatography over silica gel with a gradient of hexanes/0-70% ethyl acetate gave an off-white solid, JK-27. MS (M+H)+=409.1
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][CH2:21][C@@H:22]3[C:26]([O:28][CH3:29])=[O:27])[C@H:18]3[C@H:9]2[C@:10]2([CH3:31])[C@@H:15]([CH2:16][CH2:17]3)[CH2:14][C@H:13]([OH:30])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:43][C:44](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:45].[CH2:67]([OH:69])C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:44]([O:30][C@@H:13]1[C@@H:12]([O:69][CH3:67])[CH2:11][C@@:10]2([CH3:31])[C@@H:15]([CH2:16][CH2:17][C@@H:18]3[C@@H:9]2[C@H:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C:26]([O:28][CH3:29])=[O:27])[CH2:14]1)(=[O:45])[CH3:43]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Reactant: CCO
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OC)C[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Reaction time: 0.33 h

Procedure:
Methyl 11α-cyclohexylamino-3α-hydroxy-5α-androstane-17β-carboxylate (740 mg) in chloroform (8 ml) containing dry PTSA (640 mg) was stirred for 20 min then treated with acetic anhyride (1.9 ml) and left for 20 h. The reaction mixture was diluted with ethanol and evaporated to give an oil. This was dissolved in ethyl acetate, washed with dilute ammonia solution (2×) and water (1×), dried and evaporated to give a foam. This was purified by preparative t.l.c. in chloroform/methanol (9:1) to give a foam which was crystallised from acetonitrile to give the title compound, m.p. 87°-89° [α]D +16.9°.
Reaction SMILES: [H][H].[C:3]1(P([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C2C=CC=CC=2)[CH:8]=CC=[CH:5][CH:4]=1.[C:22]1(C)C=CC=C[CH:23]=1>>[CH2:8]=[CH:3][CH:4]=[CH2:5].[CH2:22]=[CH:23][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1
Reactant: [H][H]
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
A 13 weight percent butadiene styrene copolymer (50 grams), which was prepared by following the suspension polymerization procedure described above, was hydrogenated in toluene (250 milliliters) under 1,000 psi hydrogen using tris(triphenyl)phosphine rhodium chloride (0.9 gram) and triphenylphosphine (7 grams) at 100° C. for 3 days. The polymer was precipitated into methanol, filtered and then vacuum dried. The Tg of the resultant polymer was 60.3° C. compared with 58.1° C. of the starting polymer. The FTIR-, the 1H- and --C- NMR spectra were consistent with complete hydrogenation and disappearance of butadienyl double bonds. The olefinic bonds attributed to styrene aromatic groups were unchanged by this treatment. Thus, the butadienyl groups in the product were completely hydrogenated as evidenced by FTIR spectroscopy and NMR spectrometry.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CN1CCOCC1.[N:13]1([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1[C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23](O)=[O:24])=[O:20]>C(Cl)Cl>[N:13]1([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1[C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:24])=[O:20]
Reactant: NCC(=O)O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Two solutions were prepared before the peptide coupling. Solution A: H-Gly-OH (1.2 eq.) was dissolved in MSA (3.0 eq.) at maximum 60° C. The suspension was cooled down to 25° C., diluted with DCM and stirred for at least 8 hours before being cooled to −15° C. In solution B, the carboxylic function of the Z-Glp-Pro-OH was dissolved with DCM and NMM (1.05 eq.). The solution was cooled to −15° C. The carboxylic acid was activated with IBCF (1.05 eq.) and the silylated solution A was then added to the slurry. The slurry was stirred for at least 0.5 h and left to warm to 25° C. The mixture was quenched with water and the addition of a solution of KHSO4 under stirring precipitated the peptide. The solid was filtered and washed with water. After drying under vacuum, 80% of Z-Glp-Pro-Gly-OH was recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[CH3:9][C:10](N(C)C)=[O:11].O.[O:16]1CC[CH2:18][CH2:17]1>C([Li])CCC.CCCCCC>[C:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][C:17](=[O:16])[CH3:18])=[N:3][CH:4]=1)(=[O:11])[CH3:9]
Reactant: CC(=O)N(C)C
Reactant: Cc1ccc(O)cn1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CC(=O)Cc1ccc(OC(C)=O)cn1

Procedure:
The starting material is prepared as follows: To the suspension of 32.7 g of 2-methyl-5-pyridinol in 400 ml of tetrahydrofuran, 400 ml of 1.6 molar n-butyllithium in hexane are added during 1 hour while stirring under nitrogen and cooling with ice to maintain the temperature below 10°. Thereupon 29 g of dimethylacetamide in 50 ml of tetrahydrofuran are added during 15 minutes, the mixture is stirred for 2 hours at room temperature and poured into 700 ml of water. It is thoroughly shaken, the aqueous layer separated, washed with diethyl ether, acidified with hydrochloric acid and again washed with diethyl ether. Its pH is adjusted to 5.0 with aqueous sodium bicarbonate and after saturation with sodium chloride the mixture is extracted with ethyl acetate-isopropanol (1:1). The extract is evaporated azeotropically with the aid of benzene and the residue is taken up in 100 ml of acetic anhydride. The mixture is stirred for 30 minutes at the steam bath, evaporated, the residue distilled and the fraction boiling at 130°-138°/0.9 mmHg collected, to yield the 5-acetoxy-2-pyridylacetone; its hydrochloride melts at 69°-72° and the oxime thereof at 149°-150°.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][S:23]1(=[O:33])=[O:32])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1.O>[O:33]=[S:23]1(=[O:32])[N:22]([CH2:21][CH2:20][CH2:19][OH:18])[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24]1
Reactant: CC(C)(C)[Si](OCCCN1Cc2ccccc2NS1(=O)=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2ccccc2CN1CCCO
Temperature: 23 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of 3-(3-{[tert-butyl(diphenyl)silyl]oxy}propyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.44 g, 0.92 mmol) in tetrahydrofuran (4 mL) was treated with tetrabutylammonium fluoride (1.4 mL of a 1 M solution in tetrahydrofuran, 1.4 mmol) and acetic acid (0.16 mL, 2.8 mmol), and stirred at 23° C. for 18 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with dichloromethane (2×50 mL), dried (Na2SO4), and evaporated. Flash chromatography (SiO2, 2.5-100% ethyl acetate/hexanes) provided 3-(2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl)propan-1-ol (0.20 g, 90%) as a colorless oil:
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24](=[O:35])[N:25]([CH2:30][C:31](OC)=[O:32])[CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[BH4-].[Na+]>C1COCC1>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([C:23]5[C:24](=[O:35])[N:25]([CH2:30][CH2:31][OH:32])[CH:26]=[C:27]([CH3:29])[CH:28]=5)[N:22]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)Cn1cc(C)cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c(=O)n(CCO)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 33459.5 %

Procedure:
To a solution of methyl 2-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-5-methyl-2-oxopyridin-1(2H)-yl)acetate (17 mg, 0.034 mmol) in THF (1.6 mL) was added NaBH4 (7 mg, 0.17 mmol) and stirred at 50° C. for 3 hours and 15 minutes. The reaction was filtered using ethyl acetate and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(1-(2-hydroxyethyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide as a white solid (5.5 g, 33.6%). ESI-MS m/z calc. 483.46. found 484.5 (M+1)+, retention time 1.49 minutes
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][CH2:25][CH:26]=[CH2:27].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C(OCC)C>[C:16]1([C:9](=[N:8][CH:7]([CH2:27][CH2:26][CH:25]=[CH2:24])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CCCBr
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
While under an atmosphere of argon, a solution of N-(diphenylmethylene)glycine tert-butyl ester (6.30 g, 21.33 mmol) and 4-bromo-butene (3.45 g, 25.56 mmol) in freshly distilled THF (50 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (23.4 mL, 1.0 M in THF). Once the addition was complete, the reaction was warmed to room temperature and stirred for 16 h, cooled to 0° C., diluted with ethyl ether and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Rapid purification by MPLC (1-25% ethyl acetate in heptane over 8 CV) gave product tert-butyl 2-(diphenylmethyleneamino)hex-5-enoate as a colorless oil (7.00 g, 94%). Rf 0.50 (30% ethyl acetate in heptane).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2([CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)[N:14]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[O:17]=[C:16]1[C:15]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:14]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:13][N:12]1[CH2:11][C:10]1[CH:9]=[C:8]([CH:41]=[CH:40][CH:39]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of benzyl 3-(3-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (5 g, 9.0 mmol, 1 equiv) in a mixture of ethyl acetate and ethanol was charged with 10% palladium on carbon (1 g, 20%/wt) and the resulting mixture was stabilized to a hydrogen atmosphere. The reaction was stirred as such for 2 h, filtered through Celite and the filtrate was concentrated in vacuo to afford the title compound as a grey foam (3.69 g, 97%); 1H NMR (400 MHz, DMSO-d6): δ 1.52 (s, 9H); 1.54-1.56 (m, 2H); 2.43-2.49 (m, 2H); 2.88-2.93 (m, 2H); 3.18-3.24 (m, 2H); 4.58 (s, 2H); 4.62 (s, 2H); 6.74 (t, 2H, J=6.8 and 7.6 Hz); 6.88 (d, 2H, J=8 Hz); 7.18-7.22 (m, 2H); 7.49-7.55 (m, 2H); 7.79-7.85 (m, 2H); MS for C25H31N3O3 m/z 422.24 (M+H)+.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([NH2:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:26]([NH:12][C:4]12[CH2:10][CH:8]3[CH2:7][CH:6]([CH2:11][C:2]([OH:1])([CH2:9]3)[CH2:3]1)[CH2:5]2)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC12CC3CC(C1)CC(NC(c1ccccc1)(c1ccccc1)c1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 3-hydroxytricyclo[3.3.1.13,7 ]decan- 1-amine (5 g; 0.03 mole) dissolved in dichloromethane (140 ml) with gentle heating is added triethylamine (6 g; 0.06 mole) and cooled in an ice bath. Triphenylmethyl chloride (8.30 g; 0.03 mole) in CH2Cl2 (10 ml) is added all at once. The reaction is stirred in an ice bath for 10 minutes, warmed to room temperature and then refluxed for 3 hours. The reaction is then filtered and the filtrate evaporated to dryness. The reaction products are separated on HPLC, using 15% ethyl acetate/hexane and the product is then recrystallized from ethyl acetate/pet. ether to give N-trityl-3-hydroxytricyclo-[3.3.1.13,7 ]decan-1-amine (m.p. 184°-186° C.) which is used directly in step C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>C(#N)C>[CH:34]1([C:37]([O:16][NH:15][C:14]([CH2:13][C@@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)=[O:17])=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)C2CC2)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 65.6 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (500 mg, 1.11 mmol) in acetonitrile (5 mL) was added cyclopropanecarbonyl chloride (0.15 mL, 1.7 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (50 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[2-cyclopropanecarbonyloxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (380 mg, 66% yield): mp, 130-132° C.; 1H NMR (DMSO-d6) δ 0.81-1.01 (2 ms, 8H, 4CH2), 1.31 (t, J=7 Hz, 3H, CH3), 1.70-1.80 (m, 1H, CH), 2.97-3.05 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.97-4.04 (m, 2H, CH2), 4.17 (d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz, 1H, NCHH), 5.66 (t, J=8 Hz, 1H, NCH), 6.87-6.94 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.49 (d, J=8 Hz, 1H, Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.54 (s, 1H, NH), 12.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.77, 8.92, 10.28, 14.69, 15.46, 34.61, 46.60, 51.11, 55.48, 63.80, 111.94, 112.11, 116.81, 117.31, 117.49, 119.27, 131.22, 132.77, 136.96, 142.25, 147.94, 148.57, 166.59, 168.85, 171.72, 172.41; Anal Calcd for C28H31N3O7+0.7H2O: C, 62.96; H, 6.11; N, 7.87; Found: C, 62.64; H, 5.89; N, 7.78.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1CCOCC1.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[N:40][N:39]=[N:38]2)=[CH:33][C:29]=1[C:30](Cl)=[O:31]>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[N:40][N:39]=[N:38]2)=[CH:33][C:29]=1[C:30]([N:13]1[CH2:14][CH2:15][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:16][CH2:17][OH:18])[CH2:12]1)=[O:31]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Reactant: COc1ccc(C2(CCO)CCNC2)cc1OC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C2(CCO)CCN(C(=O)c3cc(-n4cnnn4)ccc3OC)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (2.27 g, 9.03 mmol) and N-methylmorpholine (2.48 mL, 22.6 mmol) in anhydrous dichloromethane (100 mL). Cool the reaction mixture to -5° C. with an salt-ice bath. Slowly, add 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (9.5 mmol) as a solution in dichloromethane (30 mL). Warm to ambient temperature. After 18 hours, extract the reaction mixture with a saturated solution of potassium carbonate. Dry the organic layer over Na2SO4, filter, and concentrate invacuo to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[S:9][CH2:11][C:12]2[NH:13][CH:14]=[CH:15][N:16]=2)(=[O:25])=[O:26])=[CH:20][C:19]=1[C:28]([F:31])([F:29])[F:30]
Reactant: ClCc1ncc[nH]1
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1ncc[nH]1)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, 2-chloromethyl-1H-imidazole and 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.