Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].CCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:13]([C:19]([OH:18])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:26]=[N:12]2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(SCc2ccccc2)c1
Solvent: CCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(SCc3ccccc3)ccc2c1O
Temperature: 265 °C
Reaction time: 0.75 h
Yield: 71.3 %

Procedure:
A mixture of 7.40 g of 3-(benzylsulfanyl)aniline from Preparation No. 28 and 7.70 g of diethyl ethoxymethylene malonate is heated at 135° C. under a gentle flow of argon for 2 h, then diluted with 30 mL of diphenyl ether and heated to 260-270° C. After 45 min, the solution was added to 500 mL of stirred heptane. The resulting solid was filtered, washed well with hexane, and dried under vacuum to afford 8.32 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH3:25].CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH3:25])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CNCCOC
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.07 g, 10 mmol), N-(2-methoxyethyl)methylamine (2.43 mL, 23 mmol) and Et3N (4.2 mL, 30 mmol) in DMSO (20 mL) at 23° C. according to the general procedure C. Obtained as a brown oil (3.57 g).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1.[CH3:12][SH:13]>C(N(CC)CC)C>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1.[CH3:12][S:13][CH:3]1[CH:2]([CH3:1])[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4]1
Reactant: CS
Solvent: C=C(C)C1CC=C(C)C(=O)C1
Solvent: CCN(CC)CC
Product: C=C(C)C1CC(=O)C(C)C(SC)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
15.0 g of carvone are mixed with 0.5 g of triethylamine. 20 ml of methyl mercaptan are condensed in this mixture at room temperature. After standing overnight in the autoclave, the mixture is heated to 50° C for a further 2 hours. After removal of the excess methyl mercaptan, the reaction product is fractionally distilled in vacuum. After a small fore-run of unreacted carvone, there are obtained 14.9 g of 6-methylthio-p-menth-8-en-2-one in the form of a mixture of two isomers in the ratio 1:4 (boiling point 105°-107°/0.2 mm Hg, nD20 1.5067), corresponding to a yield of 78% of the theory. The odour of the mixture is reminiscent of boiled white cabbage with a caraway and onion peel note.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@@H:21]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[N:22]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:18](O)=[O:19])=[CH:13][C:12]=1[F:35].Cl.Cl.[CH3:38][C@H:39]1[C:47]2[C:46]([N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[N:45][CH:44]=[N:43][C:42]=2[C@@H:41]([OH:54])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@H:21]2[N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C:23]([CH3:26])([CH3:27])[CH2:24][CH2:25]2)[C:18]([N:51]2[CH2:52][CH2:53][N:48]([C:46]3[C:47]4[C@H:39]([CH3:38])[CH2:40][C@@H:41]([OH:54])[C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:49][CH2:50]2)=[O:19])=[CH:13][C:12]=1[F:35]
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)c(F)c2)CCC1(C)C
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)c(F)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (0.045 mL, 0.26 mmol) was added to a solution of (S)-2-(4-bromo-3-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.035 g, 0.081 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.025 g, 0.081 mmol; see Example 3, Step 12), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.031 g, 0.081 mmol) in DCM (5 mL). The reaction was stirred overnight at room temperature. The reaction was then quenched with H2O, washed with H2O (3×30 mL), dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography to give (S)-tert-butyl 5-((S)-1-(4-bromo-3-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (23% yield). LCMS (APCI+) 648.2 m/z [M+H]+; Retention time=4.28 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)[CH:10]=[C:9]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:8]2=[O:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:1][C:2]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH2:17][OH:18])[CH:10]=[C:9]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:8]2=[O:31]
Reactant: CCOC(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(CCO)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate (350 mg, 0.63 mmol) obtained in Step 5 was dissolved in THF (25 ml) and tetrabutylammonium fluoride (1M THF solution; 1.9 ml, 1.9 mmol) was added. The mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution and the precipitate was collected by filtration, washed with water and vacuum-dried to give an object product (279 mg, yield quant) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].BrN1C(=O)[CH2:16][CH2:15][C:14]1=O.ClC(C)=C.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH:14]=[C:15]([CH3:16])[O:8][N:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C=NO)ccc1Br
Agent: C=C(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc(Br)c(C)c2)no1
Temperature: -15 °C
Reaction time: 2.5 h
Yield: 27.3 %

Procedure:
A solution of 4-bromo-3-methylbenzaldehyde oxime (D81) (2.68 g, 0.0125 mol) in dry dimethylformamide (30 ml) was treated over 15 minutes with N-bromosuccinimide (636 mg, 0.00357 mol), and reaction mixture stirred for 2.5 hours, then cooled to -15° C. 2-Chloropropene (3.45 ml, 0.0405 mol) was added in a single portion, followed by dropwise addition of triethylamine (1.35 ml, 0.0097 mol) in dry dimethylformamide (10 ml) over 0.5 hours maintaining the temp. at -10° C. The mixture was stirred at 0° C. for 1 hour, then stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue partitioned between K2CO3 solution and chloroform. The organic phase was dried (Na2SO4) and evaporated under reduced pressure and the residue purified by chromatography on silica gel eluting with 60-80 petroleum-ether and ethyl acetate, to afford the title compound (246 mg, 8%).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(C2C(O)=C[C:19]3[O:20]COC=3C=2)C1=O)CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:38]1[C:46]([OH:47])=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=1)[C:31](=[O:37])[NH:32]2.BrCC(OCC)=O.C=O>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:38]1[C:46]([OH:47])=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=1)([CH2:19][OH:20])[C:31](=[O:37])[NH:32]2
Reactant: O=C1Nc2cccc(Br)c2C1c1cc2c(cc1O)OCO2
Reactant: CCCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: C=O
Agent: CCOC(=O)CBr
Product: O=C1Nc2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 31D, and making non-critical variations to replace 1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, and ethyl bromoacetate with para-formaldehyde, the title compound was obtained (70%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.00 (br, 1H), 7.13-6.95 (m, 3H), 6.84 (d, 1H), 6.16 (d, 1H), 5.90-5.84 (m, 2H), 5.16-4.83 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.8, 150.4, 147.1, 146.8, 139.8, 130.2, 129.3, 125.8, 117.7, 115.8, 109.3, 107.9, 101.2, 97.6, 63.5, 57.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)=[C:6]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:36]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:7]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]3[C:5]([C:6]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:16]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc2c(=O)n(C)c(C3CCCNC3)c(-c3ccccc3)c2c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(=O)n(C)c(C3CCCN(C(=O)c4ccccc4)C3)c(-c3ccccc3)c2c1

Procedure:
To a dichloromethane (0.100 mL) solution of (±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one (30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol) was added benzoyl chloride (0.011 mL, 0.095 mmol). After 24 hours saturated sodium bicarbonate and additional dichloromethane were added. The layers were separated and the organic phase dried with anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by trituration with ether-EtOAc gave a white solid which was isolated by vacuum filtration to give the titled product. ESI+MS: 453.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:7]=1[O:14][CH3:15])(=[O:4])=[O:3].S(=O)(=O)([OH:18])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:15][O:14][C:7]1[CH:8]=[CH:9][C:10]([C:12]([OH:18])=[O:13])=[CH:11][C:6]=1[O:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COc1ccc(C=O)cc1OS(C)(=O)=O
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)O)cc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 268.1 %

Procedure:
5-formyl-2-methoxyphenyl methanesulfonate (3.3 g, 14 mmol) was dissolved in acetic acid (50 ml) and sulfamic acid (500 mg, 5.15 mmol) was added. Sodium chlorite (3 g, 33.2 mmol) was dissolved in H2O (20 ml) and added dropwise. The reaction was stirred at RT overnight, then the precipitate was filtered and washed with HCl 1 M, MeOH and dried in the vacuum oven, to give 3.4 g of the desired product (Yield: 99%).
Reaction SMILES: OC1(C)C2CCC1CC([C:10]1[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=1)C2.[Li]CCCC.[CH:33]12[O:40][CH:37]([CH:38]=[CH:39]1)[CH2:36][C:35](=[O:41])[CH2:34]2>C1COCC1>[OH:41][C:35]1([C:10]2[NH:11][C:12]3[N:13]([CH2:24][CH2:25][CH3:26])[C:14](=[O:23])[N:15]([CH2:20][CH2:21][CH3:22])[C:16](=[O:19])[C:17]=3[N:18]=2)[CH2:34][CH:33]2[O:40][CH:37]([CH:38]=[CH:39]2)[CH2:36]1
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4(C)O)nc2n(CCC)c1=O
Reactant: O=C1CC2C=CC(C1)O2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCn1c(=O)c2nc(C3(O)CC4C=CC(C3)O4)[nH]c2n(CCC)c1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dipropyl-7-pyrrolidin-1-ylmethyl-3,7-dihydro-purine-2,6-dione (Example 48) (522 mg, 1.63 mmol) in THF (50 ml) at −78° C. was added n-BuLi (1.55 M in hexanes, 1.2 eq, 1.3 ml). The color of the resulting yellow mixture deepened to orange-red and was stirred at this temperature for 0.5 h. A solution of 8-oxa-bicyclo[3.2.1]oct-6-en-3-one (1.1 eq, 222 mg, 1.79 mmol) in THF (4 ml) was added via syringe over a period of 20 minutes. The mixture was held at −78° C. for 2 h and allowed to reach ambient temperature overnight (12 h). The reaction mixture was partitioned between saturated aqeuous NH4Cl (20 ml) and EtOAc (20 ml) and the aqueous phase was extracted with EtOAc (20 ml). The combined organic extracts were washed with saturated aqeuous NaCl (20 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting orange oil was purified by chromatography on silica using 5% MeOH in CH2Cl2 as eluent to give a clear oil that solidified upon standing (50 mg, 8%).
Reaction SMILES: Br[C:2]1[C:3]([Cl:29])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[F-].[Cs+].CO[CH2:34][CH2:35]OC.CO>C(OCC)(=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>[Cl:29][C:3]1[C:2]([CH:34]=[CH2:35])=[CH:17][CH:16]=[C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: COCCOC
Reactant: O=C(OCc1ccccc1)c1c(NS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OCc2ccccc2)c1Cl

Procedure:
A mixture of Example 226E (160 mg, 0.32 mmol), dibutyl vinylborate (88 mg, 0.48 mmol), CsF (146 mg, 0.96 mmol), Pd(PPh3)4 (37 mg, 0.03 mmol), DME (3.2 mL) and methanol (1.6 mL) was purged with argon, sealed in a vial and microwaved at 150° C. for 240 seconds. The mixture was diluted with ethyl acetate (50 mL), washed with brine, dried (Na2SO4), filtered, concentrated and purified on a Biotage silica gel cartridge (40 g) with 10% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 446 (M+H)+, 463 (M+NH)+, 468 (M+Na)+; (ESI(−)) m/e 444 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.76 (m, 3H), 7.38 (m, 7H), 7.10 (d, 1H), 6.93 (dd, 1H), 5.86 (d, 1H), 5.51 (d, 1H), 5.26 (s, 2H).
Reaction SMILES: [Na].[CH2:2]([O:9][P:10]([O-:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+].C(OP([O-])OCC1C=CC=CC=1)C1C=CC=CC=1.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CCOCC.C(O)C>[CH2:43]([O:42][C:40]([P:10](=[O:19])([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:41])[CH3:44]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)P(=O)(OCc1ccccc1)OCc1ccccc1

Procedure:
Ethanol (4.6 g) was added to a fine suspension of sodium metal (2.25 g) in dry ether (200 ml) under an atmosphere of nitrogen. The mixture was heated for 8 hours, after which dibenzylphosphite (25.7 g) in dry ether (50 ml) was added. After standing over-night the dibenzylphosphite sodium salt was added over a period of 2 hours to a cold solution of ethyl chloroformate (10.8 g) in ether, under an atmosphere of nitrogen. The reaction was heated at reflux for 1 hour, cooled, washed with water, a NaCl solution and dried over Na2SO4. The ether was evaporated. After evaporating and discarding components volatile at 0.01 mm and 150° C. the residue was collected (13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc(Cc2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a solution of 4-(4-chloro-benzyl)-phenol (1.1 g, 5 mmol) in DMF (15 mL) at 0-5° C. was added 60% NaH (0.4 g, 10 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.14 g, 6 mmol) in DMF (5 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to it and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (1.58 g, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: Cc1cc(O)cc(O)c1C=O
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
To a mixture of 2,4-dihydroxy-6-methyl-benzaldehyde (6.37 g, 37.88 mmol) in dichloromethane (150 mL) was added 3,4-dihydro-2H-pyran (4.78 g, 56.82 mmol) and pyridium p-toluenesulfonic acid (1.90 g, 7.58 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hours then quenched by adding saturated NaHCO3 at 0° C. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane=1:3) to give pure product (8.78 g, 98.1%). 1H NMR (400 MHz, CDCl3) δ ppm 12.33 (s, 1H), 10.11 (s, 1H), 6.47 (s, 1H), 6.39 (s, 1H), 5.49 (t, J=3.13 Hz, 1H), 3.78-3.90 (m, 1H), 3.52-3.72 (m, 1H), 2.54 (s, 3H), 1.77-2.03 (m, 3H), 1.53-1.70 (m, 3H); MS (ESI) m/z=285 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C(O)C>[C:7]([O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])(=[O:10])[CH:8]=[CH2:9].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9]
Reactant: CN(C)CCO
Agent: C=CC(=O)OCC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCO
Product: C=CC(=O)OCCN(C)C

Procedure:
In a stirred reactor provided with superposed distillation column (100 cm, 0.5 cm Raschig rings) and condenser a mixture of 223 g of dimethylaminoethanol, 500 g of ethyl acrylate (H2O content=0.02% by weight), 20.3 g of catalyst from Example 3 and 0.01 g of phenothiazine was heated to boiling under atmospheric pressure while stirring. The reaction temperature rose from 105° C. to 130° C. during the reaction time (3.5 hours). A mixture of ethanol and ethyl acrylate was taken off at the top of the column. The reflux ratio was initially 1:1 and was increased after 3 hours to 5:1. 230 g of distillate were separated off. After the transesterification was complete, the reaction mixture was subjected to a simple vacuum distillation (25 mbar, final temperature of 120° C.). 475 g of distillate (349 g of dimethylaminoethyl acrylate, 126 g of ethyl acrylate) were obtained. The distillation residue, mainly catalyst, inhibitor and polymers, amounted to 28 g. According to analysis of the distillate by gas chromatography, a yield of 97.5%, based on the alcohol, was achieved.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([OH:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)OCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc2c(c1)OCCC2O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
7-Cyano-4-chromanone (Step A) (7.7 g, 44 mmol) was dissolved in THF (75 mL) and MeOH (150 mL), and cooled to 10° C. NaBH4 (1.9 g, 49 mmol) was added and the reaction was warmed to RT and stirred overnight (14 h). The reaction was quenched with acetone (5 mL) and 2 N HCl (100 mL) was added. The reaction was concentrated in vacuo to approximately 75 mL in volume and the reaction was partitioned between 2N HCl (200 mL) and EtOAc (400 mL). The layers were separated and the aqueous layer was back extracted with EtOAc (200 mL). The organic layers were combined, washed successively with H2O (200 mL) and brine (200 mL). The solution was dried over MgSO4, filtered and concentrated in vacuo to provide the title compound which was used without further purification.
Reaction SMILES: Br.Br.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:5].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH3:5][N:4]([CH2:6][C:7]1([C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:3]
Reactant: CN(C)CC1NCCc2cc(O)ccc21
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)CC1(C(=O)Cc2ccc(Cl)c(Cl)c2)NCCc2cc(O)ccc21

Procedure:
Prepared as Ex. No. 5, from 5 g (13.58 mmoles) of 1-dimethylaminomethyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 3.7 g (18.13 mmoles) of 3,4-dichlorophenylacetic acid, 5 ml (35.57 mmoles) of triethylamine and 5.6 g (27.32 mmoles) of dicyclohexylcarbodiimide in 125 ml of dry chloroform.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.B(F)(F)F.C[CH2:18][O:19][CH2:20][CH3:21]>C(#N)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:3]2[C:4]3[C:21](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:20]([O:19][CH3:18])=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1cccc2ccccc12
Reactant: CCOCC
Agent: FB(F)F
Solvent: CC#N
Product: COc1ccc(-c2ccc(OC)c3ccccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In synthetic route `A3`, 1-methoxynaphthalene and a solution of tris(trifluoroacetato)thallium[III] in acetonitrile are charged to a reaction vessel. Boron trifluoride etherate is added and the reaction mixture stirred at room temperature for between approximately 1-2 h to provide the intermediate 4,4'-dimethoxy-1,1'-binaphthyl. The 4,4'-dimethoxy-1,1'-binaphthyl intermediate is subsequently demethylated using boron tribromide (BBr3) which is added slowly to a dichloromethane solution of the intermediate to maintain the temperature at about -78° C. The reaction mixture is then warmed to room temperature and stirred for approximately 16 h in an inert atmosphere, then poured into water. The white crystals that form are 4,4'-Dihydroxy-1,1'-binaphthyl.