Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][C:4]#[CH:5].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl.Cl>[CH2:2]([NH:6][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3][C:4]#[CH:5]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCNS(C)(=O)=O
Reaction time: 3 h

Procedure:
To a 5-10° C. solution of tert-butyl but-3-yn-1-ylcarbamate (115 g, 0.675 mol) in dichloromethane (500 mL) was added 4N hydrochloric acid in dioxane (650 mL, 2.60 mol). After 3 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was washed with dichloromethane, then with diethyl ether, and then dried in vacuo to afford but-3-yn-1-amine hydrochloride as an intermediate. To a −5 to −10° C. solution of but-3-yn-1-amine hydrochloride and triethylamine (206 mL, 1.47 mol) in dichloromethane (500 mL) was added methanesulfonyl chloride (68.4 mL, 0.88 mol). After 3 hours at ambient temperature, the reaction mixture was diluted with 1N hydrochloric acid (150 mL). The organics were separated, washed with saturated aqueous sodium bicarbonate (150 mL) and with brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford N-but-3-yn-1-ylmethanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([I:9])[CH:3]=1.[CH:10](O)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(#N)C.C1(S(O)(=O)=O)C=CC=CC=1>[CH:10]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[I:9])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Cl)cc1I
Agent: O=S(=O)(O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a nitrogen purged 2 L three necked flask equipped with addition funnel, overhead stirrer and reflux condenser was charged 150 g(0.591 mol) 4-Chloro-2-iodo-phenylamine, 3 g(0.018 mol, 0.03 eq) benzenesulfonic acid and 500 mL acetontrile. The mixture was warmed to 70 C and 120 g (0.652 mol, 1.1 eq) benzhydrol dissolved in 500 mL acetonitrile was added to the stirred warm solution over a period of 7.5 h. After another 4 h, LC analysis showed 95% product and 5% starting material remaining. The mixture was cooled to 25 C and 290 mL water was added dropwise over a period of 30-40 min. Stirring was continued over night at 23 C. The dark purple solid was collected by filtration, washed with 2× withMeCN/water 1/1 dried at 50 C in vacuo for 15 h to give 218.5 g (88%) product.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:4]2[O:23][CH:24]=[CH:25][C:3]=12.[Si:26]([O:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([N:40]2[CH:44]=[C:43](B(O)O)[CH:42]=[N:41]2)[CH2:36][CH2:35]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Si:26]([O:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([N:40]2[CH:44]=[C:43]([C:2]3[CH:7]=[N:6][C:5]([N:8]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[C:4]4[O:23][CH:24]=[CH:25][C:3]=34)[CH:42]=[N:41]2)[CH2:36][CH2:35]1)([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(B(O)O)cn2)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(I)c2ccoc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2ccoc12
Temperature: 70 °C

Procedure:
A mixture of di-tert-butyl (4-iodofuro[2,3-c]pyridin-7-yl)imidodicarbonate (1.2 g, 2.6 mmol), [1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]boronic acid (1.06 g, 3.26 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane complex (213 mg, 0.261 mmol) and potassium carbonate (0.901 g, 6.52 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was degassed with nitrogen for 10 min. The mixture was then heated to 70° C. for 20 min. Ethyl acetate was added, and the layers separated. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by ISCO chromatography (0% to 35% EtOAc:heptane) afforded 1.15 g (72%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.38 (s, 1 H), 7.89 (s, 1 H), 7.82-7.77 (m, 2 H), 7.02 (d, J=2.0 Hz, 1 H), 4.21 (tdd, J=3.9, 7.7, 11.5 Hz, 1 H), 3.82-3.66 (m, 1 H), 2.33-2.17 (m, 2 H), 2.09-2.01 (m, 2 H), 2.00-1.87 (m, 2 H), 1.59-1.49 (m, 2 H), 1.40 (s, 18 H), 0.91 (s, 9 H), 0.09 (s, 6 H); MS (ESI): 613.46 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[C:20]1C=CC=C[CH:21]=1.[Na]>C(O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][CH2:20][CH3:21])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)c1ccccc1
Reactant: O=c1[nH]cnc2cc(O)ccc12
Agent: [Na]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1ncnc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-hydroxyquinazolin-4-one (105 mg, 648 μmol), phosphorous oxychloride (2 ml), and dimethylaniline (85 μl, 671 μmol) was heated at reflux for 15 minutes in an argon atmosphere. The cooled mixture was concentrated under vacuum, and kept in an argon atmosphere to avoid hydrolysis. This residue was dissolved in ethanol (anhydrous, 3 mL), and a solution of sodium (283 mg, 12.34 mmol) in ethanol (3 ml) was added dropwise. The resulting yellow mixture was stirred at room temperature under argon for 2 hours, acidified to pH 6 using NaH2PO4 and extracted with ethyl acetate (3×50 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The white solid (156 mg) was used without further purification.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:30]=[CH:29][C:11]([CH2:12][N:13]3[CH:21]=[C:20]4[C:15]([N:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:17](=[O:24])[N:18]([CH3:23])[C:19]4=[O:22])=[CH:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Cl:31][C:14]1[N:13]([CH2:12][C:11]2[CH:29]=[CH:30][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=3)=[CH:9][CH:10]=2)[CH:21]=[C:20]2[C:19](=[O:22])[N:18]([CH3:23])[C:17](=[O:24])[N:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:15]=12
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)c(Cl)c21
Temperature: 100 °C
Yield: 56.7 %

Procedure:
6-(4-(6-fluoropyridin-2-yl)benzyl)-1-isobutyl-3-methyl-1H-pyrrolo [3,4-d]pyrimidine-2,4(3H,6H)-dione (81 mg, 0.2 mmol) is dissolved in a mixture of CCl4 and DMF (3/1, v/v), and then N-chlorosuccinimide (27 mg, 0.2 mmol) is added. The reaction mixture is heated in a Biotage microwave at 100° C. for 30 minutes. Solvents are removed under vacuum, and the residue is purified by a semi-preparative HPLC to give pure product as off white solids (50 mg, yield 70%). MS (ESI) m/z 441.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][CH:22]=[C:23]([F:25])[F:24])[CH:16]=[CH:17][C:7]2=1.[Br:34]N1C(=O)CCC1=O>C(#N)C>[Br:34][C:16]1[C:15]([O:18][CH2:19][C@@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:21][CH:22]=[C:23]([F:25])[F:24])=[CH:14][C:8]2[N:9]([CH3:13])[C:10](=[O:12])[C:11]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][CH:4]=[N:3][C:2]=3[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC=C(F)F)NC(=O)OC(C)(C)C)ccc21
Solvent: CC#N
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC=C(F)F)NC(=O)OC(C)(C)C)c(Br)cc21
Temperature: 80 °C
Yield: 67.4 %

Procedure:
A solution of (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-5,5-difluoropent-4-en-2-yl)carbamate (1.03 g, 2.24 mmol) in acetonitrile (22 mL) was treated with N-bromosuccinimide (0.44 g, 2.5 mmol), heated to 80° C. for 45 min, and then concentrated under reduced pressure. The crude material was purified over SiO2 (1-4% 2M ammonia in methanol/dichloromethane gradient elution) to afford (S)-tert-butyl (1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-5,5-difluoropent-4-en-2-yl)carbamate (0.81 g, 1.51 mmol, 67% yield) as a white solid. LC/MS, (ESI) m/z 537.9 [(M+H)+, calcd for C24H27BrF2N3O4, 538.1]; 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (d, J=5.8 Hz, 1H), 8.22 (s, 1H), 7.65 (d, J=5.5 Hz, 1H), 6.75 (s, 1H), 5.01 (d, J=8.3 Hz, 1H), 4.41-4.26 (m, 1H), 4.24-4.04 (m, 3H), 3.67 (s, 3H), 3.12 (s, 3H), 2.64-2.34 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.Cl.[CH2:38]1[C:43]2([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][N:39]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C(N(C(C)C)CC)(C)C>C(O)CCCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:46]4[CH2:45][CH2:44][C:43]5([CH2:38][N:39]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:40][CH2:41][CH2:42]5)[CH2:48][CH2:47]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCNCC2)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(Cl)nn45)ccnc32)cc1
Agent: Cl
Solvent: CCCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCC7(CCCN(C(=O)OC(C)(C)C)C7)CC6)nn45)ccnc32)cc1
Temperature: 140 °C
Yield: 0.1 %

Procedure:
A mixture of 0.15 g (0.29 mmol) of 6-chloro-2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared according to the method described in step 3.2 of Example 3, 0.337 g (1.15 mmol) of tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate hydrochloride (1:1) (CAS 1023301-88-3) and 0.224 g (1.7 mmol) of diisopropylethylamine in 2 ml of pentanol is heated under reflux for 40 hours at 140° C. The solvent is then evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column by eluting with a gradient of dichloromethane, methanol and aqueous ammonia (of 100/0/0 to 90/10/1) in order to give 0.190 mg of tert-butyl 9-{2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazin-6-yl}-2,9-diazaspiro[5.5]undecane-2-carboxylate after crystallization in methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>C1(C(C)C)C=CC=CC=1.P(O)(O)O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=O
Agent: OP(O)O
Solvent: CC(C)c1ccccc1
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
83.5 g (0.5 mol) of 4-nitrobenzoic acid, 33.0 g (0.55 mol) of urea and 0.5 g of phosphorous acid are heated in 250 ml of cumene with stirring at 150° C. for 8 h. After cooling to 25° C. the solid is filtered off with suction and washed with 50 ml of cumene. The filter cake is introduced into 250 ml of water, the mixture is adjusted to a pH of 12 using aqueous sodium hydroxide solution, and is subjected to steam distillation. Subsequently the solid is filtered off with suction and dried at 100° C. 71.3 g of 4-nitrobenzamide are obtained having a melting point of from 192° to 193° C. This corresponds to a yield of 85.9% of theory. By acidification of the aqueous mother liquor to pH 2, 4.9 g of 4-nitrobenzoic acid (5.9% of theory) are obtained which can be employed again in a subsequent batch.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([NH:25]CC4C=CC(OC)=CC=4)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:25][C:18]([C:35]1[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:42][CH:43]1[CH2:44][CH2:45]1)[C:10](=[O:46])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(CNC(c2ccc(Cl)nc2)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)c2cncn2C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1

Procedure:
To a solution of the title compound of Example 48 (the slower moving enantiomer), (−)4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-(4-methoxy-benzyl-amino)-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (1.07 g, 1.64 mmol) in dichloromethane (6.5 ml) was added trifluoroacetic acid (TFA, 6.5 ml) slowly at 0° C. The reaction mixture was stirred at ambient temperature for 80 minutes after which time it was diluted with DCM (10 ml) and was poured into a chilled aqueous solution of potassium carbonate. After separation, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (1.5:98.5:0.15) as the eluents to afford the title compound as a white solid ( 0.588 g, 1.11 mmol, 68% yield). It is the faster eluting enantiomer of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one with >99% optical purity.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)([F:12])[F:11].FC(F)(C1C=CC=CC=1)COCCCCCC[N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>>[F:11][C:10]([F:12])([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]
Reactant: Cc1cccc(C(F)(F)COCCCCCCBr)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCOCC(F)(F)c1ccccc1
Product: Cc1cccc(C(F)(F)COCCCCCCN2C(=O)c3ccccc3C2=O)c1
Yield: 40 %

Procedure:
Obtained from Intermediate 30 (8.77 g, 26.2 mmol) by the procedure described in Intermediate 8. Purification by column chromatography with silica gel and methylene chloride as eluent gave the title compound (4.0 g, 40%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][CH3:19])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.[Cl-].[CH3:21][O:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][CH3:19])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:21][O:22][CH3:23]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Product: CCC(C(=COC)c1cccnc1)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-butanone and methoxymethyltriphenylphosphonium chloride there is obtained 3-(2,4-dichloro-β-ethyl-α-methoxymethylenephenethyl)-pyridine as an isomer mixture in the form of a yellow oil;
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[CH3:22][O:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:25]=1.N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C>[CH3:31][O:30][C:28]1[N:29]=[C:24]([O:23][CH3:22])[N:25]=[C:26]([NH:32][C:33]([NH:1][S:2]([C:5]2[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:19])([F:20])[F:21])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:3])=[O:4])=[O:34])[N:27]=1
Reactant: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(N)(=O)=O
Reactant: COc1nc(NC(=O)Oc2ccccc2)nc(OC)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At room temperature, 166 mg (0.5 mmol) of methyl 2-(aminosulfonyl)-4-[(2,2,2-trifluoroethlidene)hydrazino]benzoate and 138 mg (0.5 mmol) of phenyl (4,6-dimethoxy1,3,5-triazin-2-yl)carbamate were dissolved in 1.5 ml of N,N-dimethylacetamide. Then, 86.1 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene were added, followed by stirring for 5 minutes. The resultant mixture was allowed to stand for 6 hours. Thereafter, 0.2 ml of 35% hydrochloric acid was added to 30 ml of ice water, followed by the addition of the reaction mixture in 0.2 ml portions under stirring. After the reaction mixture was stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. Using as an eluent a 1:9 mixed solvent of methyl acetate and benzene, the crude product was purified by chromatography on a column of silica gel ("WAKO GEL C-300", trade name; product of Wako Pure Chemical Industries, Ltd.). The title compound was obtained as a white solid. Yield: 103 mg (41%). Melting point: 117°-119° C. (foamed). Its physicochemical properties are shown in Table 4.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)(C)(C)C.Cl.O1CCOCC1.C(OCC)C>O1CCOCC1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13]([C:9]3[C:8]([NH2:7])=[CH:12][O:11][N:10]=3)=[CH:18][CH:17]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCc2ccc(F)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1conc1-c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
{3-[4-(4-Fluoro-benzyloxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (1.97 g, 5.13 mmol) was dissolved in 30 mL of dioxane and 30 mL of 4 N HCl/dioxane was added. The reaction was stirred at rt for 4 h and allowed to stand overnight. The resulting crystalline mass was mixed with diethyl ether (20 mL) and stirred for 10 min. The suspension was filtered off and washed with a total of 20 mL of diethyl ether. The filter cake was partitioned between ethyl acetate and 5% NaHCO3 solution and the organic phase separated. The aqueous phase was extracted with once more with ethyl acetate. The combined organic phases were washed twice with brine and dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave 3-[4-(4-fluoro-benzyloxy)-phenyl]-isoxazol-4-ylamine (1.32 g, 91%) as an off-white solid. M+1=285.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=2[C:16]#[N:17])[CH2:8][CH2:7]1.C(=O)(O)O.[NH2:30][C:31]([NH2:33])=[NH:32].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:15]=2[C:16]([NH2:17])=[N:32][C:31]([NH2:33])=[N:30]3)[CH2:8][CH2:7]1
Reactant: N#Cc1c(F)cccc1OCC1CCC(Cc2cccc(Cl)c2)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCC3CCC(Cc4cccc(Cl)c4)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
2-[4-(3-Chlorobenzyl)cyclohexylmethoxy]-6-fluorobenzonitrile (150 mg; 0.42 mmol) was heated to 135° C. in the presence of guanidine carbonate (76 mg; 0.42 mmol) in 1.5 mLs of dimethylacetamide. After 6 hours, mixture was cooled to room temperature and 2 mLs of water added. After 30 minutes solids were collected by filtration. Solids were purified by trituration using a 3:1 mixture of ethyl alcohol and water. Solids collected by filtration to give title compound as a white solid. (128 mgs; 76% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1ccc2ocnc2c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2ocnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of benzo[d]oxazole-5-carboxylic acid (7.8 g, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (7.0 g, 1.5 eq), HOBt (7.76 g, 1.2 eq) and EDCI (11 g, 1.2 eq) in 100 mL CH2Cl2 was added Et3N (19 g, 4.0 eq) dropwise at 0° C. The mixture was then stirred at rt overnight, concentrated, and purified by column chromatography with petroleum ether:EtOAc=1:1 to give the desired product (6.0 g, 51%). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.16 (1H), 7.80 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 3.56 (s, 3H), 3.41 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[C:19](O)=[O:20]>>[O:20]=[C:19]1[C:18]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[N:1][C:2]2[C:7](=[CH:6][CH:5]=[C:4]([S:9]([OH:12])(=[O:10])=[O:11])[CH:3]=2)[NH:8]1
Reactant: Nc1ccc(S(=O)(=O)O)cc1N
Reactant: O=C(O)C(=O)c1cccs1
Product: O=c1[nH]c2ccc(S(=O)(=O)O)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with 3,4-Diamino-benzenesulfonic acid and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 2-Oxo-3-thiophen-2-yl-1,2-dihydro-quinoxaline-6-sulfonic acid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[H][H]>>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: [H][H]
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O

Procedure:
By means of a centrifugal pump, a circulation was conducted through the main reactor at a rate of about 500 g/h at a feed of L-isopulegol of 24.5 g/h (total amount 588 g) with a purity of 99.8% and 99.8% ee at a constant hydrogen pressure of 30 bar. The main reactor was operated at a temperature of 50° C. and the postreactor at 60° C. All pipelines were provided with electrical trace heating to prevent crystallization of the enantiomerically pure L-menthol (m.p. 44° C.). L-menthol (99.8% ee) was obtained in an amount of 597 g, corresponding to a rate of 24.9 g/h. The product thus obtained was analyzed by gas chromatography. The results are compiled in Table 4.