Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].N1C=CC=CC=1.[Br:24][CH2:25][C:26](Br)=[O:27]>C(Cl)Cl.C(OCC)(=O)C>[Br:24][CH2:25][C:26]([NH:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5])=[O:27]
Reactant: Nc1c(Cl)cccc1C(=O)c1ccccc1F
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CBr)Nc1c(Cl)cccc1C(=O)c1ccccc1F
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a solution of 2-amino-3-chloro-2′-fluorobenzophenone (4.80 g) and pyridine (3.04 g) in methylene chloride (100 ml) was added dropwise bromoacetyl bromide (3.42 ml) under stirring and cooling in an ice-bath. After the addition was completed, the mixture was stirred at ambient temperature for 0.5 hour and refluxed for 0.5 hour. The mixture was allowed to stand to cool to ambient temperature and evaporated in vacuo to give a residue, which was dissolved in ethyl acetate and washed with water three times and brine successively. After drying over magnesium sulfate and treating with active carbon, the solvent was removed in vacuo to give a crystalline mass. Pulverization in diisopropyl ether and collection by filtration afforded 2-(bromoacetylamino)-3-chloro-2′-fluorobenzophenone (5.86 g, 82.4% yield) as a white crystalline powder.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:31][NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Si:24]([O:23][CH2:22][CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][N:32]([CH3:31])[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCC(CO)c1ccccc1
Reactant: CNS(=O)(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(CC(CO[Si](C)(C)C(C)(C)C)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
Diethyl azodicarboxylate (0.059 mL, 65 mg, 0.37 mmol) was added to a solution of 2-phenyl-3-(tert-butyldimethylsilyloxy)-1-propanol (100 mg, 0.375 mmol), N-methylbenzenesulfonamide (77 mg, 0.45 mmol), and triphenylphosphine (98.4 mg, 0.38 mmol) in 1.0 mL of dry THEF, and the mixture was stirred 4 h at room temperature. Additional triphenylphosphine (48 mg, 0.18 mmol) and diethyl azodicarboxylate (0.030 mL, 33 mg, 0.19 mmol) were added and stirring was continued overnight at room temperature. After concentrating in vacuo, the residue was dissolved in 50 mL of dichloromethane and washed with 25 mL of 10% aqueous sodium hydroxide and 25 mL of brine. The organic layer was dried over sodium sulfate, decanted, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 5% ethyl ether in hexane to give 83 mg of the title compound as a colorless syrup. 1NMR (400 MHz, CDCl3): δ 7.73 (d, 2H, J=7 Hz), 7.57 (tt, 1H, J=7, 1 Hz), 7.49 (t, 2H, J=7 Hz), 7.33-7.20 (m, 5H), 3.84 (dd, 1H, J=10, 6 Hz), 3.77 (dd, 1H, J=10, 6 Hz), 3.48 (dd, 1H, J=13, 7 Hz), 3.20 (dd, 1H, J=13, 8 Hz), 3.08 (quintet, 1H, J=7 Hz), 2.64 (s, 3H), 0.84 (s, 9H),-0.05 (s, 3H),-0.06 (s, 3H). Mass spectrum (ESI): m/z=420 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)(OC)[CH3:9])=[C:5]([CH3:7])[N:6]=1.[ClH:17]>C(OCC)C>[ClH:17].[CH3:1][C:2]1[O:3][C:4]([C:8]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[CH2:9])=[C:5]([CH3:7])[N:6]=1
Reactant: COC(C)(c1ccoc1)c1oc(C)nc1C
Agent: Cl
Solvent: CCOCC
Product: C=C(c1ccoc1)c1oc(C)nc1C

Procedure:
1-(2,4-Dimethyl-5-oxazolyl)-1-(3-furyl)-1-methoxyethane (790 mg) in dry diethylether was treated with 1M anhydrous hydrogen chloride in diethylether (1.2 equivalents). The title compound was obtained as a white solid which was filtered off, washed and dried. M.p. 128.5°-130° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[CH2:16]([O:18][CH2:19][CH2:20][O:21]CCO)[CH3:17]>[O-]CC.[Na+].C(O)C>[CH:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14][CH2:15][O:21][CH2:20][CH2:19][O:18][CH2:16][CH3:17])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2]
Reactant: C=CC1CC1(C(=O)OCC)C(=O)OCC
Reactant: CCOCCOCCO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CC1CC1(C(=O)OCC)C(=O)OCCOCCOCC

Procedure:
Employing a procedure similar to that of Example IV diethyl 2-vinylcyclopropane-1,1-dicarboxylate was reacted with a polyalkoxylated alcohol in the presence of sodium ethoxide catalyst. For the process 33.77 g (0.159 mol) diethyl 2-vinylcyclopropane-1,1-dicarboxylate and 7.12 g (0.053 mol) 2-(2-ethoxyethoxy)ethanol were heated at reflux until the theoretical amount of ethanol was recovered. After removal of unreacted diethyl 2-vinylcyclopropane-1,1-dicarboxylate (19.63 g), 8.4 g crude ethyl 2-(2-ethoxyethoxy)ethyl 2-vinylcyclopropane-1,1-dicarboxylate was obtained. Redistillation of the crude product provided 4.9 g high purity 2-(2-ethoxyethoxy)ethyl 2-vinylcyclopropane-1,1-dicarboxylate. B.p. 110°-112° C. at 0.01 mm Hg; nD24.5 1.4608. Infrared and nuclear magnetic resonance spectra were consistent with the desired structure.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([C:16]([O:18]C)=[O:17])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:22].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:22]
Reactant: COC(=O)c1cc(C(=O)NCc2ccc(F)c(C)c2)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(CNC(=O)c2cc(C(=O)O)ncn2)ccc1F
Reaction time: 3 h

Procedure:
8.75 g (0.02 mol) of methyl 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylate (70%) were taken up in 150 ml of ethanol, after which 1.89 g (0.022 mol) of NaOH in 6 ml of water were added. After 3 hours (h) at room temperature, the solvent was removed under reduced pressure and water was added to the residue; the solution was then brought to pH <2 with conc. HCl. The precipitate was filtered off with suction and dried. This resulted in 5.5 g (94%) of 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylic acid. MS (ES+): m/e=289.09.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:18])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(-c2ccccc2)c(-c2ccccc2)s1)c1ccccc1

Procedure:
4,5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and benzoyl chloride (28.1 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was subjected to microwave irradiation for 5 minutes at 200° C. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (7.21 mg, 0.0202 mmol, 10.1%). ESI-MS m/z calc. 356.1, found 357.2 (M+1)+ Retention time 3.95 minutes.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19])=[N:7][N:6]=[CH:5]2.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25]([CH:27]=1)[NH2:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:26][C:25]4[CH:27]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=4[CH3:28])=[CH:11][CH:10]=3)[CH:5]=[N:6][N:7]=2)=[C:13]([CH3:19])[CH:14]=1
Reactant: Cc1cc(F)ccc1-c1nncc2cc(Cl)ccc12
Reactant: Cc1ccc(F)cc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1Nc1ccc2c(-c3ccc(F)cc3C)nncc2c1
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-1-(4-fluoro-2-methylphenyl)phthalazine (200 mg, 0.73 mmol), 5-fluoro-2-methylaniline (138 mg, 1.1 mmol), tris(dibenzylideneacetone)dipalladium (0) (34 mg, 0.037 μmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (35 mg, 0.073 mmol), and sodium tert-butoxide (211 mg, 2.2 mmol) in toluene (2 mL) was heated at 100° C. in an oil bath for 18 h. The mixture was cooled to room temperature, diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated over silica gel and purified using column chromatography (0-40% acetone in hexanes) to afford a tan solid that was about 90% pure. The material was dissolved in MeOH and loaded onto an Agilent AccuBOND II SCX solid phase extraction column. It was washed with MeOH followed by 2 M NH3 in MeOH. The title compound was obtained as a tan solid. MS (ESI, pos. ion) m/z: 362.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:29][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[C:12]([O:11][C:9]([N:5]1[CH2:6][C:7](=[O:29])[CH2:8][CH:4]1[C:3]([O:2][CH3:1])=[O:16])=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 57 %

Procedure:
To a stirred solution of N-Boc proline methyl ester (2 .0 g, 8.15 mmol) in CH2Cl2 were added 3 A molecular sieves (2 g) and PDC (4.60 g, 12.2 mmol). The mixture was stirred for 3 days. The mixture was filtered through a Celiete pad and the filtrate was evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH (10:1) as eluent to give methyl 1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylate (1.13 g, 57%) as a colorless oil. 1H-NMR (CDCl3) δ 1.46–1.48 (m, 9 H), 2.56–2.61 (m, 1 H), 2.88–3.00 (m, 1 H), 3.77 (s, 3 H), 3.82–3.88 (m, 2 H), 4.71–4.83 (m, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Cl.[NH2:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(N(CC)CC)C>[CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH2:19][C:20]2([OH:26])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=1)(=[O:10])=[O:9])([CH3:13])[CH3:12]
Reactant: NCC1(O)CCOCC1
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccc(NCC2(O)CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-4-(isopropylsulfonyl)-2-nitrobenzene (Step C of Example 1), 4-(aminomethyl)tetrahydro-2H-pyran-4-ol hydrochloride (Step A of Example 19) and triethylamine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[Cl:29][CH2:30][C:31](Cl)=[O:32].[OH-].[Na+].[Cl-].[Na+]>O.O1CCCC1>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH2:2][NH:1][C:31](=[O:32])[CH2:30][Cl:29])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CNC(=O)CCl)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (30.0 g) in water (150 ml) and tetrahydrofuran (450 ml) was added chloroacetyl chloride (6.4 ml) below 10° C., keeping the pH between 8-9 with 4N aqueous sodium hydroxide. The reaction mixture was poured into saturated aqueous sodium chloride (150 ml), the organic layer was separated, and the aqueous solution was extracted twice with ethyl acetate (100 ml). The organic layer was combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give crude (2S,4R)-4-t-butyldimethylsilyloxy-2-(chloroacetamido)methyl-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].O.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH3:13][O:12][C:11]1[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(OC)c(-c2ccccc2)c1
Temperature: 95 °C
Yield: 95 %

Procedure:
To a solution of methyl 3-bromo-4-methoxybenzoate (13 g, 53 mmol) in toluene (500 mL), methanol (65 mL), and water (106 mL) was added phenyl boronic acid (7.8 g, 63.6 mmol) and potassium carbonate (14.6 g, 106 mmol) and bubbled with argon for 6 min. Tetrakis(triphenylphosphine)palladium(0) (370 mg) was added and bubbled with argon for another 2 min. The reaction mixture was then heated to 95° C. for 20 h with stirring. After cooling to RT, the two phases were separated and the aqueous layer was extracted with ether, dried with magnesium sulfate, and concentrated. Purification by MPLC (5% ethyl acetate in hexanes) gave 12.2 g of the desired product as an off white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]=[O:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1([CH2:28][C:29]2[CH:30]=[C:31]([Mg]Br)[CH:32]=[CH:33][CH:34]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:30]=2)[OH:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCc1cc(Cl)c2cccnc2c1OCc1ccccc1
Reactant: Br[Mg]c1cccc(CN2CCCC2)c1
Solvent: C1CCOC1
Product: OC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1cccc(CN2CCCC2)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (10.54 mmol) in tetrahydrofuran (75 mL) at −78° C. was slowly added a 0.25M solution of [3-(1-pyrrolidinylmethyl)phenyl]magnesium bromide in tetrahydrofuran (12.50 mmol, 1.2 eq.) and stirring at −78° C. was continued for 20 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (10 mL) and allowed to warm to room temperature. The mixture was then diluted with saturated aqueous ammonium chloride solution (65 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give 2-(8-benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethanol as a yellow oil that was purified by column chromatography using 70/29/1 dichloromethane/acetone/diisopropylethylamine. The 2-(8-benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethanol was subjected to the general conditions described above for conversion of alcohols to azides to give 7-[2-Azido-2-(3-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-8-benzyloxy-5-chloro-quinoline. 7-[2-Azido-2-(3-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-8-benzyloxy-5-chloro-quinoline (5.34 mmol) was subjected to the general conditions described above for Staudinger reduction of azides to give 2-(8-Benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethylamine an amber oil and was used directly in the ensuing step. 2-(8-Benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (0.675 mmol) was subjected to the general conditions described above for N-acylation with 4-biphenylcarbonyl chloride to give an off-white solid which was purified by twice recrystallizing from dichloromethane/hexanes to give the title compound as a white solid (0.311 mmol, 18% for 4 steps). MS (ESI) m/z 652.5; HRMS: calcd for C42H38ClN3O2+H+, 652.27253; found (ESI, [M+H]+ Obs'd), 652.2730.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[CH2:17]([N+:21]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O.CC(O)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[O-:13].[CH2:30]([N+:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32][CH3:33]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: [O-]c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a flask were added 11.0 g 3,5-bis(trifluoromethyl)phenol, 1.8 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 10 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 10 ml of 2-propanol were added and removed by distillation under reduced pressure. An oil was obtained which crystallized on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.CS(C)=O.C(N(CC)CC)C>O>[CH3:1][O:2][C:3]1[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH:9]=[O:10]
Reactant: CCCCCOc1c(CO)cccc1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CCCCCOc1c(C=O)cccc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
The crude product of (3-methoxy-2-pentyloxyphenyl)methanol (1.2 g), dimethyl sulfoxide (DMSO, 25 ml) and triethylamine (6.72 ml, 48.2 mmol) were mixed, and this solution was cooled to 0° C. Sulfur trioxide--pyridine complex (2.56 g, 16.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water to stop the reaction, and the aqueous layer was extracted 3 times with ethyl acetate (30 ml). The organic layers were combined, washed with 2N hydrochloric acid (30 ml), water (30 ml) and saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=15/1-10/1) to give 3-methoxy-2-pentyloxybenzaldehyde (1.16 g, 83% in 3 steps) as a colorless oil.
Reaction SMILES: C[CH2:2][N:3](C(C)C)[CH:4](C)C.[C:10]([O:14][C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([C:24]([OH:26])=O)[CH2:19]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CNC.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:10]([O:14][C:15](=[O:16])[NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([C:24](=[O:26])[N:3]([CH3:4])[CH3:2])[CH2:19]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.4 %

Procedure:
DIPEA (1.8 mL, 10.3 mmol) was added at RT to a mixture of racemic trans 3-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.00 g, 4.109 mmol), dimethylamine hydrochloride (0.0.503 g, 6.17 mmol), and EDCI (1.182 g, 6.17 mmol) in 13 mL of DCM. The resulting mixture was stirred at RT for 16 hours before being partitioned between H2O and DCM. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by SiO2 flash chromatography (DCM/MeOH 0 to 5% MeOH) to give 0.438 g (39%) of racemic trans 3-dimethylcarbamoyl-cyclohexyl carbamic acid tert-butyl ester.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][S:30][CH2:31][C@@H:3]12.C([N:34]([CH:38]([CH3:40])[CH3:39])C(C)C)C.C1(N)CC1>CN(C=O)C>[CH:38]1([NH:34][C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][S:30][CH2:31][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:18][CH2:17]3)=[CH:27][CH:26]=2)[CH2:40][CH2:39]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
In a vial equipped with a stir bar was charged (R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.114 mmol) was taken up in DMF (1.14 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (59 μl, 0.34 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (64.9 mg, 0.171 mmol), and cyclopropanamine (9.16 uL, 0.125 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were collected and lyophilized to yield 25.1 mg (49%) of the product as a white solid 1H NMR (CHLOROFORM-d) δ: 8.42 (br. s., 1H), 7.78 (d, J=1.5 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.13 (br. s., 1H), 6.85 (d, J=9.1 Hz, 2H), 6.17 (d, J=2.3 Hz, 1H), 5.05 (ddd, J=13.5, 2.7, 2.5 Hz, 1H), 4.42 (dd, J=10.4, 3.5 Hz, 1H), 3.53 (br. s., 2H), 3.34 (br. s., 4H), 3.14 (td, J=12.9, 2.3 Hz, 1H), 2.99 (td, J=12.8, 2.7 Hz, 1H), 2.78-2.93 (m, 3H), 2.68 (br. s., 4H), 2.39 (dd, J=13.6, 1.3 Hz, 1H), 0.80-0.90 (m, 2H), 0.54-0.67 (m, 2H). [M+H] calc'd for C, 23; H, 28; N, 6; O, 2; S, 479; found, 479.
Reaction SMILES: [Li][C:2](C)(C)C.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.C1COCC1.IC>CCOCC>[CH3:2][C:10]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=1
Reactant: [Li]C(C)(C)C
Reactant: c1ccc2sccc2c1
Solvent: CI
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc2ccccc2s1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
t-BuLi (1.7 M, 26 mmoles, 15 ml) was added to a stirred solution of benzo[b]thiophene (17 mmoles, 2.3 g) and THF (30 ml) at -50° C. The resulting bright yellow reaction mixture was warmed to -30° C., and iodomethane (26 mmoles, 1.6 ml) was added. After 10 min. at -30° C., the solution was warmed to ambient temperature and stirred an additional 30 min., then diluted with ether (100 ml) and washed with brine (2×100 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect 2.48 g (98%) of 2-methylbenzo[b]thiophene as a light yellow solid.