Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:19][CH:20]1[CH2:25][N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[O:21]1.O>CN(C)C=O>[C:1]1([N:7]2[C:11]3([CH2:12][CH2:13][N:14]([C:20]4([CH3:19])[CH2:25][N:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:23]5[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=5[O:21]4)[CH2:15][CH2:16]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCC1CN(c2ccccc2)c2ccccc2O1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Solvent: O
Solvent: CN(C)C=O
Product: CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CN(c2ccccc2)c2ccccc2O1
Temperature: 90 °C
Yield: 38.5 %

Procedure:
1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (2.03 g; 8.8 mmol) is added to a stirred solution of 2-chloromethyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine (1.29 g; 4 mmol) in dimethylformamide (20 ml). The reacting mixture is heated at 90° C. for 8 hours. After cooling, water (100 ml) is added and the product is extracted twice with ethyl acetate (80 ml). The organic layer is washed twice with water (30 ml) and dried over anhydrous sodium sulphate. The solid residue, obtained after evaporation of the solvent under reduced pressure, is purified by flash column chromatography on silica gel by using hexane/acetone=9/1 as eluant, thus obtaining 0.7 g of pure 2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine, yield 37%; m.p. 191°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:14]1COCC1>C(OCC)(=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: C1CCOC1
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of compound 1 (10.05 g, 64.04 mmol, 1.0 eq.) in THF (30 ml) was added dropwise to a suspension NaH (1.84 g, 76.85 mmol, 1.2 eq.) in THF (90 ml) at 0° C. and the mixture was stirred at same temperature for 1 h. Triethyl phosphonoacetate (16.5 ml, 83.25 mmol, 1.3 eq.) was added to the reaction mixture at −20° C. and the reaction mixture was allowed to warm to RT and stir for 2 h. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (2×100 ml) and the organic layer dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel; 5% ethyl acetate/hexanes) to yield compound 2. Yield: 94% (17.28 g, 60.2 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 87 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 2.42-2.48 (m, 3H), 3.20-3.28 (m, 4H), 3.75-3.80 (m, 3H), 4.10-4.13 (m, 4H), 6.59 (s, 3H), 7.00-7.12 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.48-7.65 (m, 2H).
Reaction SMILES: CI.[Cl:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[C:9]([CH2:20]N(C)C)=[C:8]1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1.C[C:43](C)=[O:44]>>[Cl:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[C:9]([CH2:20][O:44][CH3:43])=[C:8]1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:25]1
Reactant: CC(C)=O
Reactant: CN(C)Cc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Solvent: CI
Product: COCc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (25 μl) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (112 mg) in acetone (5 ml), and the resulting mixture was stirred overnight in a sealed tube at room temperature. The reaction solution was concentrated under reduced pressure, and to a solution of the resulting residue in methanol (2 ml) was added 28% methanol methoxide (2 ml), followed by stirring with heating at 60° C. for 4 hours. The methanol was distilled off under reduced pressure and the residue was adjusted to pH 2 with an aqueous potassium hydrogensulfate solution and extracted with ethyl acetate (100 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a thin-layer silica gel column chromatography (hexane/ethyl acetate=1/5) to obtain the title compound (26 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=3)[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>C(#N)C.CCOC(C)=O>[CH:20]([N:19]([CH2:18][C:17]1[CH:23]=[CH:24][CH:25]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:16]=1)[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COCc1cc(-c2nc(-c3cccc(CNC(C)C)c3)no2)ccc1-c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCc1cc(-c2nc(-c3cccc(CN(CC(=O)OC(C)(C)C)C(C)C)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
N-(3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)propan-2-amine (64 mg, 0.15 mmol) was dissolved in ACN (2 mL). K2CO3 (83 mg, 0.60 mmol) and tert-butyl bromoacetate (48 μl, 0.32 mmol) were added and the mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, and then dried over MgSO4. After concentration under vacuum, the crude product was purified by flash chromatography (silica, cHex/EtOAc) to give the title compound as a colorless oil (58 mg, 72%). HPLC (Method A) Rt 5.54 min (Purity: 97.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])CCC.CON(C)[C:26](=[O:42])[CH:27]([O:40][CH3:41])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]([CH3:39])=[N:37][N:38]=2)=[CH:30][CH:29]=1>C1COCC1>[CH3:41][O:40][CH:27]([C:28]1[CH:29]=[CH:30][C:31]([C:34]2[O:35][C:36]([CH3:39])=[N:37][N:38]=2)=[CH:32][CH:33]=1)[C:26]([C:15]1[O:14][C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17][CH:16]=1)=[O:42]
Reactant: COc1cc(-c2ccco2)cc(OC)c1OC
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a solution of 2-(3,4,5-trimethoxyphenyl)furan (1.4 g, 5.98 mmol) in anhydr THF (70 mL) under argon in an oven-dried flask cooled to −78° C. was added n-butyl lithium (2.5 M in hexanes; 2.63 mL, 6.28 mmol) dropwise. After stirring for 1 hr at −78° C., a solution of N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide (1.75 g, 6.0 mmol) in THF (5 mL) was added dropwise. After stirring for 25 min, the mixture was allowed to warm to room temp while stirring for 2 hrs. The reaction was quenched with the addition of saturated aqueous NH4Cl then brine and EtOAc were added. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (60% EtOAc-hexanes) gave 2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)ethanone as a fluffy yellow solid (0.81 g, 29% yield). MS: m/z 465.3 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:45])[C:10]([CH3:44])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[S:28]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)(=[O:30])=[O:29])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[C:9]([F:45])[C:10]([CH3:44])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[S:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)(=[O:30])=[O:29])[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(S(=O)(=O)N3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of tert-butyl 4-({6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfonyl)piperazine-1-carboxylate (Example 47c, 0.141 g) dissolved in DCM (10 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction was purified by SCX, flushing with methanol (impurities), and eluting the product with 0.7 N methanolic ammonia. Purification by preparative HPLC (Xbridge column using a 95-5% gradient of aqueous ammonia in acetonitrile as eluent) followed by concentration under reduced pressure gave a white solid. This was combined with material from another reaction (scale: 0.097 g of starting material) to give the title compound (0.034 g) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:28][N:29](C)[C:30](=O)OC(C)(C)C)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[O:21][CH2:22][C:23]([N:25]([CH3:26])[CH3:27])=[O:24])(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:28][NH:29][CH3:30])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(C)C(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2C2=CCCCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OCC(=O)N(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl ((5-(cyclohex-1-en-1-yl)-1-((3-(2-(dimethylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 8c (69 mg, 0.13 mmol) was dissolved in 8 mL of dichloromethane, and the reaction solution was cooled in an ice bath, followed by dropwise addition of 2 mL of trifluoroacetic acid. After removing the ice bath, the reaction solution was stirred at room temperature for 2 h. A saturated sodium bicarbonate solution was added dropwise until the pH of the reaction solution was 7 to 8, and then it was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system A to obtain the title product 2-(3-((2-(cyclohex-1-en-1-yl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N,N-dimethylacetamide 8 (39 mg, a colorless oil) in 69% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl[Si](C)(C)C.[CH3:17][CH2:18]O>>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH2:17][CH3:18])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CCO
Agent: C[Si](C)(C)Cl
Product: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reaction time: 72 h

Procedure:
To a solution of 5,6-dichloronicotinic acid (20.01 g, 104 mmol) in EtOH (500 mL) at 20° C. was added chlorotrimethylsilane (132 mL, 1042 mmol). The reaction was stirred for 72 hours. The reaction mixture was then concentrated and diluted with EtOAc (500 mL), and washed with saturated NaHCO3 (2×100 mL) and brine (100 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (21.25 g). LCMS m/z 220.1 (M+H)+, Rt 0.94 min.
Reaction SMILES: [C@@H:1]1([N:10]2C3N=C(N)[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH:21]1C=NC(C(N)=O)=N1.[OH-].[K+]>>[CH:11]1[N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[N:21]=[C:13]([C:14]([NH2:16])=[O:15])[N:12]=1
Reactant: NC(=O)c1nc[nH]n1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1

Procedure:
Bioconversion media were prepared as in Example 1, except the initial amounts of guanosine and 1,2,4-triazole-3-carboxamide were 40 millimoles. The initial pH of each flask was adjusted to pH 7.2 with potassium hydroxide. The bioconversions were initiated as in Example 1. The cells were added promptly as the temperature reached 70° C. to avoid gelling of the bioconversion mixture. Forty millimole additions of both guanosine and 1,2,4-triazole-3-carboxamide were made at 6 and 12 hours into the bioconversion. Thus after the second addition, a total of 120 millimoles of the two reactants had been added. Potassium hydroxide was added at 6 hours to adjust the pH from 6.7 to 7.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]2)=[N:6][CH:7]=1.Cl.[F:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([N:22]3[CH2:23][CH2:24][C@@H:20]([F:19])[CH2:21]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: F[C@@H]1CCNC1
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2ccc(Br)cn2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: F[C@@H]1CCN([C@H]2CCN(c3ccc(Br)cn3)C2)C1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
Dissolve methanesulfonic acid (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl ester (0.23 g, 0.71 mmol) and (R)-3-fluoro-pyrrolidine hydrochloride (107 mg, 0.85 mmol) in DMF (5 mL) and add Cs2CO3 (0.69 g, 2.13 mmol). Warm to 70° C. overnight. Dilute with EtOAc (100 mL) and wash with H2O (3×100 mL). Dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 75-100% EtOAc/hexane to give 0.22g (100%) of the title compound. 1H-NMR (CDCl3), δ 1.87-2.00 (m, 1H), 2.00-2.09 (m, 1H), 2.18-2.30 (m, 2H), 3.40-3.80 (m, 9H), 5.10-5.28 (m, 1H), 5.34-5.40 (m, 1H), 6.28 (d, J=9.0 Hz, 1H), 7.51 (dd, J=9.0, 2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Cl-].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:39]=[CH:38][C:17]([CH2:18][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:16][CH:15]=1.[H-].[Na+].[OH:42][C:43]1[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=1>CN(C=O)C>[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:47][C:46]2[CH:49]=[CH:50][C:43]([OH:42])=[CH:44][CH:45]=2)=[CH:38][CH:39]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: c1ccc([P+](Cc2ccc(OCc3ccc4ccccc4n3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of (13.29 mmol) of 4-(2-quinolinylmethyloxy)benzyl triphenylphosphonium chloride in 100 ml of dry DMF under positive nitrogen atmosphere is cooled to 0° C. and 0.50 g (20.77 mmol), of an 80% NaH in oil dispersion is added in small portions. The suspension is aged for 15 minutes at 0° C. followed by 45 minutes at room temperature to assure complete anion formation. The flask is cooled back to 0° C. and (13.29 mmol) of 4-hydroxybenzaldehyde in 20 ml of DMF is dropped in over a period of 15 minutes. The reaction is allowed to equilibrate to room temperature and stirred for 2 hours. The resultant mixture is poured into ice water and filtered. The precipitate is dissolved in CH2Cl2, dried, and concentrated in vacuo. The crude product is recrystallized from ether to give 4-(4-(2-quinolinylmethyloxy)styryl)phenol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH2:17])[CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[O:8][N:7]=1.CCN(C(C)C)C(C)C.[CH2:28]([C:30]1[C:35]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C:37]2=[O:42])=[CH:34][CH:33]=[CH:32][C:31]=1[S:43](Cl)(=[O:45])=[O:44])[CH3:29]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH:17][S:43]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C:37]2=[O:42])[C:30]=1[CH2:28][CH3:29])(=[O:45])=[O:44])[CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[O:8][N:7]=1
Reactant: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1cc(-c2ccc(Cl)s2)on1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](Cc1cc(-c2ccc(Cl)s2)on1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 2 (860 mg, 3 mmol) was dissolved in 15 ml DCM and DIPEA (2.041 ml, 12 mmol). 2-ethyl-3-(3-oxo-morpholin-4-yl)-benzenesulfonyl chloride, Intermediate 6 (911 mg, 3 mmol) in 10 ml DCM was slowly added and the reaction was stirred at RT overnight. After that 300 μl DIPEA were added and the reaction mixture was heated to 40° C. for 30 min. Then the solution was evaporated to dryness, dissolved in ethyl acetate, washed with 1 N HCl, sat. aq. NaHCO3 and brine. The combined organic layers were dried with MgSO4, filtered and evaporated to dryness. The crude product (1.5 g) was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][CH2:5]2.[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[Cl:12][C:10]1[CH:11]=[C:2]([CH:23]=[O:24])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][CH2:5]2
Reactant: CN(C)C=O
Reactant: CC1(C)CCc2cc(Br)cc(Cl)c2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCc2cc(C=O)cc(Cl)c2O1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
6-Bromo-8-chloro-2,2-dimethyl-3,4-dihydro-2H-chromene (483 mg, 1.75 mmol) in THF (8.76 mL) was cooled to −78° C. and n-BuLi (841 μL, 2.10 mmol) was added dropwise via a syringe. The reaction mixture was stirred at −78° C. for 10 minutes and then DMF (543 μL, 7.01 mmol) was added dropwise via a syringe. The resulting mixture was allowed to warm to room temperature, and wet silica gel (5.0 g/0.5 mL of water) was added. The mixture was allowed to stir at room temperature for 10 minutes before it was filtered. The silica gel was rinsed with EtOAc, and the filtrate was concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to obtain the desired product as a pale-yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C=O)C>[OH:1][CH:2]([CH3:6])[C:3]([O:5][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: CC(O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C(C)O)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of DL -2 hydroxypropionic acid (9.0 g, 100 mmole) in 100 ml dry DMF was added potassium tert-butoxide (12.34 g, 110 mmole) and the mixture was stirred for one hour at 60° C. 4-methoxybenzyl chloride (18.8 g 120 mmole) was added and the mixture was stirred for eight hours at 60° C. The mixture was evaporated under reduced pressure and 250 ml ethyl acatate was added. The organic phase was washed four times with water. The organic phase was dried with sodium sulfate and concentrated in vacuo. Yield: 16.8 g
Reaction SMILES: C[Mg]Br.Br[C:5]1[CH:6]=[C:7]([C:18]#[N:19])[N:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1.C([Li])CCC.CCCCCC.[CH2:31]=[O:32]>C1COCC1>[C:13]([O:12][C:11](=[O:17])[NH:10][N:8]1[CH:9]=[C:5]([CH2:31][OH:32])[CH:6]=[C:7]1[C:18]#[N:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)Nn1cc(Br)cc1C#N
Agent: C[Mg]Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nn1cc(CO)cc1C#N
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
Under argon, a 1 M solution of methylmagnesium bromide in THF (13.3 ml) was added over 15 min to a solution of tert-butyl (4-bromo-2-cyano-1H-pyrrol-1-yl)carbamate (3.7 g, 12.09 mmol; preparation described in PCT Int. Pat. Appl. WO 2007/064883, Intermediate AAE, Step 3) in THF (37 ml) cooled to −60° C. After 30 min, a 1.6 M solution of n-butyllithium in hexane (15.1 ml, 24.2 mmol) was added over 10 min to the reaction, and the resulting mixture was stirred between −60° C. and −40° C. for 1 h. Then, paraformaldehyde (1.09 g, 36.3 mmol) was added to the reaction, and the reaction mixture was slowly warmed to rt and stirred overnight. After quenching with sat. aq. ammonium chloride solution, the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with sat. aq. sodium chloride solution, dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate 2:1→1:1) afforded 2.04 g (69% of th.) of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])O.[Na+].[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21].O>C(#N)C>[CH2:19]([NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(NCC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 24.5 g (133.8 mM) of 1-(4-fluoro-3-nitrophenyl)ethanone in 100 ml of acetonitrile and 11.2 g (133.8 mM) of sodium hydrogen carbonate are added 26.6 ml (267.6 mM) of isobutylamine. The reaction is exothermic: the temperature of the reaction medium is maintained below 50° C. and the resulting mixture is then stirred for 1 hour at room temperature. Demineralised water is added, and a solid precipitates out. The solid is filtered off and washed with water to give after drying 31.6 g of 1-[4-(isobutylamino)-3-nitrophenyl]ethanone in quantitative yield.