Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C@@H:7]2[CH2:12][C@H:11]([N:13]([C:18]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]4[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=4[N:21]=3)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCCl>[N:1]1([C:5]([C@H:7]2[CH2:8][NH:9][CH2:10][C@@H:11]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]4[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=4[N:21]=3)=[O:19])[CH2:12]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCC3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To tert-butyl (3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (230 mg) in 1,2-dichloroethane (3 ml) was added TFA (3 ml) and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate-water, and neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the object product (100 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[H-].[Na+].Cl[CH:15](Cl)[C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]2[O:8][CH:15]([C:16]([O:18][CH3:19])=[O:17])[O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1Oc2ccc([N+](=O)[O-])cc2O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
31.0 g of 4-nitrocatechol was added to 17.6 g of 60% NaH in suspension in 300 ml of DMF over 1 hour, with cooling to keep the temperature below 30° C. Stirring was continued for 15 minutes then 104 ml of methyl dichloroacetate was added over 1 hour, and stirring was continued for 4 hours at 90° C. The reaction medium was poured over a mixture of 2 liters of ice/water then extracted 4 times with 400 ml of AcOEt. The combined organic phases were washed once with a saturated NaCl solution then dried and concentrated under vacuum (DMF evaporated off). The residue was taken up in a AcOEt/H20 mixture and the pH was brought to 8.6 using Na2CO3; the organic phase was decanted, washed with saturated NaHCO3, H2O, 5% KHSO4/K2SO4, H2O, saturated NaCl then dried and vacuum evaporated; a semi-solid residue was obtained which was taken up then triturated in heptane to produce a solid.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26](B3OC(C)(C)C(C)(C)C3)=[CH:27][CH:28]=2)[N:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=5)=[N:23]4)=[CH:28][CH:27]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccn4)nc3c2)OC1(C)C
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccn5)nc4c3)c12
Temperature: 80 °C

Procedure:
The mixture of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-ylamine (62.8 mg 0.200 mmol), 2-pyridin-2-yl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline(79.1 mg, 1.2 eq.), Pd(PPh3)4 (14.0 mg, 6% eq.) and Na2CO3 (53.0 mg, 2.5 eq.) in DMF (5 ml)/H2O (1 ml) was flushed with N2 for 30 min at rt and heated at 80° C. for 16 h under N2. After that time, the reaction mixture was treated with H2O (20 ml), and was then extracted with CH2Cl2 (2×25 ml). The extracts were washed with H2O (2×20 ml), and dried over MgSO4. After the solid was filtered off and the solvent was removed in vacuo, the crude yellow oil (105 mg) was purified by MS directed purification system to obtain a yellow solid of 3-cyclobutyl-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine; 1H NMR (CDCl3, 400 MHz) δ 2.05-2.09 (m, 1H), 2.15-2.22 (m, 1H), 2.48-2.56 (m, 2H), 2.62-2.72 (m, 2H), 3.85 (quintet, 1H, J=8.4 Hz), 5.27 (s, 2H), 7.09-7.10 (d, 1H, J=4.8 Hz), 7.15-7.16 (d, 1H, J=4.8 Hz), 7.36-7.39 (m, 1H), 7.86-7.90 (m, 1H), 7.97(m, 2H), 8.31-8.33 (d, 1H, J=8.8 Hz), 8.43 (s, 1H), 8.59-8.61 (d, 1H, J=8.8 Hz), 8.67-8.69 (d, 1H, J=7.6 Hz), 8.75-8.76 (d, 1H, J=4.0 Hz); MS(ES+): 393.4 (M+1), tR(polar-5 min)=2.2 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl.[N:33]1([C:38](=N)[NH2:39])C=CC=N1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:38]([NH2:39])=[NH:33])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: N=C(N)n1cccn1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=N)N)CC4)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.193 g, 0.65 mmol) in dichloromethane (10 mL) and Hunig's Base (0.34 mL, 1.95 mmol) was added 1H-pyrazole-1-carboximidamide hydrochloride (0.100 g, 0.69 mmol). The reaction mixture was stirred at room temperature for 2 hours. A white precipitates was formed, which was filtered, washed with dichloromethane and hexane to give the desired product, 3-(4-methoxy-benzyl)-3,6,8,9-tetrahydro-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamidine as a white solid (0.088 g, 40%). M.p.=255-256° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.35 (s, 1H), 8.26 (s, 1H), 7.63 (s, 4H), 7.22-7.16 (m, 2H), 6.88-6.82 (m, 2H), 5.60 (s, 2H), 4.75 (s, 2H), 3.76 (t, J=6.4 Hz, 2H), 3.69 (s, 3H), 3.21 (t, J=6 Hz, 2H); LCMS [M+H]: 337.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:42]12[CH2:49][CH2:48][CH:45]([CH2:46][CH2:47]1)[C@@H:44](O)[CH2:43]2>C1COCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:10][C@@H:44]1[CH:45]2[CH2:48][CH2:49][N:42]([CH2:47][CH2:46]2)[CH2:43]1)=[O:9]
Reactant: O=C(O)C(c1ccccc1)N1CCCC1=O
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
A mixture of 2-(2-oxopyrrolidin-1-yl)-2-phenylacetic acid (345 mg, 1.57 mmol), DCC (649 mg, 3.15 mmol), HOBT (425 mg, 3.15 mmol) and (R)-quinuclidin-3-ol (400 mg, 3.15 mmol) in dry THF (15.7 ml) was stirred at room temperature for 24 hours. The yellow suspension was filtered washing the white solid with THF. The yellow solution was evaporated and the crude was purified by flash chromatography (DCM/MeOH=96/4+0.4% NH4OH) to collect the title compound (482 mg, 93% yield) as a pale yellow oil.
Reaction SMILES: [ClH:1].O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[ClH:1].[CH2:4]1[C:5]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][C:6]=2[CH2:7][CH2:8][NH:3]1
Reactant: NNc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: c1ccc2c3c([nH]c2c1)CCNC3
Yield: 87.6 %

Procedure:
4-Piperidone monohydrate hydrochloride (10 g, 65.1 mmol) and phenylhydrazine hydrochloride (9.4 g, 65.1 mmol) are suspended in ethanol (200 ml) and stirred at reflux overnight. The resulting solid is filtered off and washed with diethyl ether to afford pure sub-title compound (11.9 g) in 88% yield. tR (LC-2) 0.89; ESI-MS (positive ion): m/z 173.34 [M+H]+ (calcd 172.23 for C11H12N2).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(Nc1ccc(F)c(CO)c1F)c1cccs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(NS(=O)(=O)c2cccs2)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To thiophene-2-sulfonic acid (2,4-difluoro-3-hydroxymethyl-phenyl)-amide (511, 0.46 g, 1.52 mmol) in tetrahydrofuran (5.0 mL) was added Dess-Martin periodinane (0.71 g, 1.67 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (512, 100 mg, 21%). MS (ESI) [M+H+]+=304.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+]>N1C=CC=CC=1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:24](=[O:26])(=[O:25])[N:23]2[CH3:22])=[CH:15][CH:16]=1
Reactant: CNS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)c2ccc3cccnc3c2N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)cc1
Yield: 6.6 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(4-methoxy-phenyl)-methanone (Intermediate 375) (95 mg, 0.34 mmol), N-methylsulfamoyl chloride (Intermediate 213) (133 mg, 1.02 mmol) and NaBH4 (13 mg, 0.34 mmol) in pyridine (5 ml) gave the title compound (8 mg, 7%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][O:4][CH2:3]1.CCN(C(C)C)C(C)C.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[S:23]([O:1][C:2]1[CH2:3][O:4][CH2:5][CH2:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:24])=[O:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C1CCOCC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)COCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (1.0 g, 5.81 mmol) in DCM (30 mL) was added DIPEA (1.22 mL, 6.97 mmol) and Tf2O (1.08 mL, 6.39 mmol) at −78° C., then it was warmed up to room temperature and stirred at room temperature for 2 h, the solution was diluted with DCM, washed with Sat. NaHCO3, brine, dried and concentrated to give ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate as crude product (2 g).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]([NH:42][NH:43][C:44](=O)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]1[S:10][C:44]([CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[N:43][N:42]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)s1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
Lawesson's reagent (0.68 g, 1.68 mol) was added to a solution of tert-butyl 2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethylcarbamate (0.50 g, 1.12 mmol) in THF (30 mL). The reaction mixture was heated at 70° C. for 0.5 h. The solution was cooled down to rt and saturated NaHCO3 was added. The organic layer was separated and the aqueous layer was exacted with EtOAc (2×). The combined organic layer was dried over Na2SO4, and concentrated. The crude sample was dissolved in THF (100 mL), and Hg(OAc)2 (1.68 g) was added. The mixture was stirred at rt overnight, filtered and concentrated. The residue was dissolved in EtOAc (100 mL), stirred for 30 min, filtered and concentrated. The crude material was purified by silica gel column chromatography (20% to 50% EtOAc/petroleum ether) to give tert-butyl ((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (230 mg, 45%) as a white solid. ESI-MS (EI+, m/z): 446.2 [M+H]+.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:17]=3[N:16]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([Cl:34])[CH:27]=3)[C:15]2=[O:35])[CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[Cl:34][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[O:32][CH3:33])[CH2:25][N:16]1[C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=2[N:14]([C@H:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)[C:15]1=[O:35]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CCN(C(=O)OC(C)(C)C)C3)c3ccc(C#N)cc32)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(=O)n([C@H]3CCNC3)c3ccc(C#N)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
4N-Hydrogen chloride solution in ethyl acetate (5 mL) was added to a suspension of 1-[(S)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (520 mg) in ethyl acetate (5 mL) at 0° C. The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo. To the residue was added an aqueous saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed successively with water and brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was triturated with diethyl ether to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-pyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (287 mg) as amorphous powders.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1ccc(F)cc1
Product: COC(=O)c1cc(Cl)ccc1COc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 4-fluorophenol:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([O:12][CH2:13][O:14][CH3:15])[CH:6]=1.CN(C)CCN(C)C.[Li]CCCC.C[O:30][C:31]1[CH2:35][CH2:34][C:33](=O)[CH:32]=1.Cl>C1COCC1>[CH3:15][O:14][CH2:13][O:12][C:7]1[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:9][C:8]=1[C:33]1[CH2:34][CH2:35][C:31](=[O:30])[CH:32]=1
Reactant: COCOc1ccc(Br)c(OCOC)c1
Reactant: COC1=CC(=O)CC1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2=CC(=O)CC2)c(OCOC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
1,3-Bis(methoxymethoxy)-4-bromobenzene (1.0 g) was dissolved in THF (20 ml) and cooled to −78° C. under argon. N,N,N′,N′-Tetramethylethylene diamine was added followed by dropwise addition of n-BuLi (3.4 ml of a 2.2M solution in hexanes) over 10 mins. After stirring at −78° C. for 1 hr, a solution of 3-methoxy-2-cyclopentene-1-one (605 mg) in THF (5 ml) was added slowly. The reaction mixture was stirred at −78° C. for 1 hr before warming to 0° C. 1 M HCl (20 ml) was added, and after 10 min the mixture was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as yellow oil (128 mg, 13%); m/z (ES+) 279 (M+1)+.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][Bi:11](Br)[CH3:12].CCCCCC>C(OCC)C.C1COCC1>[CH3:10][Bi:11]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: C[Bi](C)Br
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Bi](C)Cc1ccccc1
Yield: 32.8 %

Procedure:
A 40 ml (40 mmole) of 1.0 M solution of benzyl magnesium chloride in diethyl ether was cooled to 0° C., and thereto was added dropwise a solution of 10.2 g (32.1 mmole) of dimethylbismuthanyl bromide prepared in Preparation Example 2 in 20 ml of THF (45 minutes). The reaction mixture was further stirred at 0° C. for 2 hours qnd hexane was added. The supernatant liquid was extracted, concentrated and distilled in a vacuum, giving 3.5 g (yield 32.8%) of a yellow liquid product. b.p. 67-76° C./0.7 mmHg. 1H-NMR revealed that the product was the desired one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2O.C(=O)=O.CC(C)=O.CCN(S(F)(F)[F:33])CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2[F:33]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C(O)C1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C(F)C1
Temperature: 25 °C

Procedure:
To a flask containing tert-butyl 8-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-4) (622 mg, 1.895 mmol) was added anhydrous DCM (10 ml). The reaction mixture was then capped & cooled to −78 C (dry ice/acetone bath) while stirring under N2. Then added DAST (1.4 ml, 10.60 mmol) at −78 C. The reaction mixture was then stirred at −78 C. Followed by LC/MS. After 5 minutes at −78 C the reaction was quenched by dropwise addition of a saturated solution of NaHCO3 in water at −78 C (with a vent needle), then permitted to warm to room temperature, then the reaction mixture was suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated to yield. Purification by silica gel chromatography (0-15% EtOAc/Hex; 40 g ISCO); desired fractions concentrated to yield tert-butyl 8-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-5).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)#[N:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:4]([NH:3][C:1]#[N:2])=[N:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[S:29])=[CH:23][CH:22]=1
Reactant: N#CNC(=Nc1ccncc1)NCCCCCCO
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: N#CNC(=Nc1ccncc1)NCCCCCCOC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
N-Cyano-N′-(6-hydroxyhexyl)-N″-4-pyridylguanidine (0.5 g), 4-chlorophenyl isothiocyanate (0.4 g) and diisopropylethylamine (0.32 ml) was mixed in a two-necked flask with a three-way-tap and a septum. The air was exchanged with argon through the three-way-tap. Dry pyridine (10 ml) was added through the septum. The reaction mixture was stirred for 5 days at room temperature.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:22]([N:24]1[CH2:28][CH2:27][C@H:26]([F:29])[CH2:25]1)=[O:23])[C@H:9]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Rh]>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:22]([N:24]1[CH2:28][CH2:27][C@H:26]([F:29])[CH2:25]1)=[O:23])[C@H:9]([CH:15]1[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]1)[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CN(C)C(=O)[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: [Rh]
Solvent: CO
Product: CN(C)C(=O)[C@@H](C1CCC(O)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reaction time: 24 h

Procedure:
The material from Step B (0.33 g, 0.77 mmol) was hydrogenated at 50 psi hydrogen in the presence of 5% rhodium on alumina (0.33 g) in methanol (10 mL) using a Parr shaker. After 24 h, the reaction mixture was filtered by passage through a syringe filter. Concentration of the filtrate in vacuo afforded the title compound as a mixture of cis and trans isomers containing a small amount of the fully reduced cyclohexane. LC/MS 430.1 (M+1), 452.1 (M+Na).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=O)[O:9][CH:8]2O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19].C(O)(=O)C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=[O:9])[NH:19][N:18]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)c1cc(F)c2c(c1)C(O)OC2=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
1.2 g (5.4 mmol) of 5-tert-butyl-7-fluoro-3-hydroxy-3H-isobenzofuran-1-one was weighed into a 25 mL round bottom flask fitted with a stir bar, condenser, and nitrogen inlet. Added 7.5 mL (100 mmol) of hydrazine monohydrate. Added 10 mL of glacial acetic acid. Stirred under nitrogen at 100° overnight. Poured the reaction mixture into 100 ml, of stirred water. Extracted the aqueous mixture with 2×50 mL CH2Cl2. Dried the combined extracts over Na2SO4 and removed the solvent on the rotavap. Purified by silica gel flash chromatography using gradient elution with 0→100% EtOAc/CH2Cl2 to obtain 898 mg of the title compound as an off-white solid. MS (ESI) 221 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:13](Cl)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(COC)OC>[C:3]1([CH:9]([CH2:13][CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCC=Cc1ccccc1
Reactant: CC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(CC=Cc1ccccc1)c1ccccc1

Procedure:
Sodium hydride (10.5 g., 0.25 mole, oil dispersion) is suspended in glyme (200 ml.) and phenyl acetone (33.5 g., 0.25 mole) in glyme (25 ml.) is added dropwise with stirring. After complete addition, the mixture is heated to reflux for 0.5 hours. The mixture is cooled in a cold water bath and a solution of cinnamyl chloride (38 g., 0.25 mole) in glyme (25 ml.) is added dropwise. When addition is complete, the mixture is refluxed for 5 hours then allowed to cool. After filtration of inorganic salts and removal of solvent from the filtrate, vacuum distillation provides 44 g., b.p. 128°-134°/0.07-0.1 mm.