Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.C([Li])CCC.CON(C)[C:18](=[O:27])[C:19]1[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=1[CH3:26].[Cl-].[NH4+]>C(OCC)C>[S:9]1[C:8]([C:18]([C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[CH3:26])=[O:27])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: c1ccc2sccc2c1
Reactant: CON(C)C(=O)c1cc(Br)ccc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccc(Br)cc1C(=O)c1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
A solution of thianaphthene (543 mg) in diethyl ether (20 ml) was cooled to 0° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 1.74 ml). The reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was added dropwise to a solution of N-methoxy-N-methyl-5-bromo-2-methylbenzamide (1.15 g) obtained in Reference Example 4-(2) in diethyl ether (10 ml) cooled to −78° C. The mixture was warmed to room temperature and stirred for one hour. Added thereto was a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-95:5) to give 5-bromo2-methylphenyl benzo[b]thiophen-2-yl ketone (995 mg) as a pale yellow syrup. APCI-Mass m/Z 331/333 (M+H). (2) The above 5-bromo2-methylphenyl benzo[b]thiophen-2-yl ketone was treated in a manner similar to Reference Example 5-(2) to give 1-(benzo[b]thiophen-2-ylmethyl)-5-bromo-2-methylbenzene as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH:5]=O.Cl.[NH2:21][OH:22].C([BH3-])#N.[Na+].[C:27]([OH:30])(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][N:21]([OH:22])[CH:27]=[O:30]
Reactant: COc1ccc(Oc2c(Cl)cc(C=O)cc2Cl)cc1
Reactant: NO
Reactant: CC(=O)O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(Oc2c(Cl)cc(CN(O)C=O)cc2Cl)cc1

Procedure:
A solution of 3,5-dichloro-4-(4-methoxyphenoxy)benzaldehyde (170 mg, 0.572 mmol) and hydroxylamine hydrochloride (48 mg, 0.687 mmol) in 1 ml of pyridine was stirred for 1 h then all volatiles were removed in vacuo. The resulting imine intermediate was treated with sodium cyanoborohydride (122 mg, 1.944 mmol) in 2 ml of glacial acetic acid for 5 h. The reaction mixture was then quenched with water and neutralized with sodium bicarbonate powder, extracted with ethyl acetate and dried (sodium sulfate). The resulting 3,5-dichloro-N-hydroxy-4-(4-methoxyphenoxy)benzyl amine was converted to the title compound using the method described in example 1c (50 mg, 26%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.34 (s, 2H), 6.82 (d, j=8.8 Hz, 2H), 6.76 (d, j=8.8 Hz, 2H), 4.64 (s, 2H), 3.76 (s, 3H). M+1=342.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[O:15][CH3:16].[CH2:17](N(C(C)C)C(C)C)C.C=O>ClCCl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH3:17])[CH2:13][CH2:14]2)=[CH:5][C:4]=1[O:15][CH3:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(N2CCNCC2)ccc1Br
Agent: C=O
Agent: [Na]
Solvent: ClCCl
Product: COc1cc(N2CCN(C)CC2)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyhydroborate (25.9 mg) was added to 1-(4-bromo-3-methoxy-phenyl)piperazine (30 mg), N-ethyl-N-isopropyl-propan-2-amine (0.030 ml) and 37% aqueous formaldehyde (8.01 μl) dissolved in dichloromethane (1 ml). The resulting mixture was stirred at 25° C. for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate (5 ml) and extracted with ethyl acetate (2×10 ml). The combined organic phases were dried over magnesium sulfate and concentrated to afford the crude 1-(4-bromo-3-methoxy-phenyl)-4-methyl-piperazine (25.00 mg). NMR Spectrum: (CDCl3) 2.38 (s, 3H), 2.60 (bs, 4H), 3.17-3.28 (m, 4H), 3.88 (s, 3H), 6.41 (dd, 1H), 6.47 (d, 1H), 7.36 (d, 1H); Mass spectrum: M+H+ 286
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.CCN(C(C)C)C(C)C.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>C(Cl)Cl.O>[O:23]=[C:14]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:1]34[CH2:6][CH:5]3[CH2:4][N:3]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH2:2]4)=[CH:12][CH:11]=2)[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15]1
Reactant: Brc1ccccn1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(c3ccccn3)C4)cc2)C(=O)O1
Temperature: 90 °C
Yield: 69.5 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (0.4 g, 1.1 mmol) in DCM (5 mL) were added DIPEA (0.5 mL, 3.4 mmol) and 2-bromopyridine (0.9 mL, 5.7 mmol) at r.t. The reaction mixture was stirred at 90° C. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 0.2:9.8 MeOH:CHCl3) to provide the title compound (0.3 g, 67%) as white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33](Cl)(=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:33](=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CC(C)C)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 mmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, isovaleryl chloride (24 mg, 197 mmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 20×50 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (22.4 mg, 68% of theory).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:40][CH2:39][N:30]2[C:31]3[CH:32]=[C:33](I)[CH:34]=[CH:35][C:36]=3[CH2:37][CH:29]2[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH3:41][S:42][Sn](CCCC)(CCCC)CCCC.O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:40][CH2:39][N:30]2[C:31]3[CH:32]=[C:33]([S:42][CH3:41])[CH:34]=[CH:35][C:36]=3[CH2:37][CH:29]2[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN2c3cc(I)ccc3CC2C1
Reactant: CCCC[Sn](CCCC)(CCCC)SC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc2c(c1)N1CCN(C(=O)OC(C)(C)C)CC1C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
Triphenylphosphine (28 mg) was added in 1 portion to a stirred solution of palladium(II) acetate (6 mg) in THF (2.5 mL) at room temperate under Ar. After stirring at room temperature under Ar for 10 min a solution of 2-tert-butoxycarbonyl-7-iodo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole (0.20 g, 0.5 mmol) in THF (5 mL) was added. The reaction was stirred at room temperature for 10 min then a solution of (methylthio)tributyltin (035 g, 1 mmol) in THF (2.5 mL) was added. The reaction was heated to reflux and stirred for 2 days. After allowing to cool to room temperature the mixture was poured into water (50 mL) and extracted. with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (r×50 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-heptane (1:20)] to give the product as a yellow oil (0.08 g, 50%). NMR δH (400 MHz; CDCl3) 6.97 (1H, d, J 7.5 Hz), 6.56 (1H, dd, J 7.5, 1.5 Hz), 6.36 (1H, d, J 1l Hz), 3.94-4.26 (2H, m), 3.35-3.49 (2H, m), 2.78-2.96 (41, m), 2.49-2.55 (1H, m), 2.44 (311, s), 1.46 (9H, s).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:26][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl chloroformate (7.15 g, 50 mmol) and 1-octadecanol (13.53 g, 50 mmol) were suspended in chloroform (100 ml) at 0° C. Pyridine (3.96 g, 50 mmol) was added dropwise during 20 minutes, maintaining the temperature below 10° C. After stirring at room temperature for 24 hours the reaction mixture was washed four times with 1N hydrochloric acid, once with a saturated sodium bicarbonate solution and finally twice with water. The organic solution was dried with magnesium sulphate and the solvent was removed at reduced pressure. Yield: 19 g.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@H:13]([CH:15]3[CH2:17][CH2:16]3)[OH:14])[O:11]C(C)(C)[N:9]2C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl.[OH-].[Na+]>CO.CCOCC>[NH2:9][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@@H:12]([OH:11])[C@H:13]([CH:15]1[CH2:17][CH2:16]1)[OH:14]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)C2CC2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 3 h
Yield: 66.1 %

Procedure:
1.42 g (3.86 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-cyclopropylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate dissolved in 15 ml of methanol and 10 ml of water are treated with 4 ml of 7.5N hydrochloric acid and stirred at 50° for 3 hours. The reaction solution is cooled to 3° in an ice bath, treated dropwise with 4 ml of 7.5N sodium hydroxide solution and stirred for 1 hour. The suspension obtained is evaporated under reduced pressure, the water is removed azeotropically twice with 10 ml of toluene and the residue is stirred three times with 10 ml of a 95:5 mixture of methylene chloride and methanol. The insoluble residue is filtered off and the filtrate is evaporated under reduced pressure. The crude product obtained (1.14 g) is suspended in 15 ml of ether and then filtered. There is obtained 0.58 g of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol as a colourless crystals, m.p. 141°-142°.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH2:17])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:18][CH2:19][CH3:20])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=3)[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:7]2[CH2:18][CH2:19][CH3:20])=[CH:24][CH:23]=1
Reactant: CCCc1[nH]c2cc(C(N)=O)ccc2c1C(=O)C(C)C
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 66.6 %

Procedure:
A mixture of 3-isobutyryl-2-propylindole-6-carboxamide (100 mg), 4-chlorobenzyl bromine (113 mg) and potassium carbonate (152 mg) in dimethylformamide (2 ml) was heated at 60° C. or 2 hours, and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was crystallized from a mixture of ethyl acetate and hexane. The crude crystals were recrystallized from a mixture of ethyl acetate and hexane to give 1-(4-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide (97 mg) as colorless crystals.
Reaction SMILES: [OH-:1].[K+].C([C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:6]1[CH:11]=[CH:10][C:9](=[N:12][OH:13])[C:8]([C:14]([OH:16])=[O:15])=[CH:7]1)#N.[OH:23]O.Cl>O>[C:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:13])=[O:23])=[C:8]([CH:7]=1)[C:14]([OH:16])=[O:15])(=[O:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OO
Reactant: [OH-]
Reactant: N#CC(=C1C=CC(=NO)C(C(=O)O)=C1)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 16.2 parts of potassium hydroxide, 150 parts of water and 5.72 parts of intermediate 17, namely 3-(cyanophenylmethylene)-6-(hydroxyimino)-1,4-cyclohexadiene-1-carboxylic acid, was added a solution of 16.25 parts of hydrogen peroxide in 16 parts of water. After stirring for 1 hour at room temperature, the reaction mixture was acidified with HCl while cooling on ice. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was recrystallized from methylbenzene, yielding 3.7 parts (63.5%) of 5-benzoyl-2-nitrobenzoic acid; mp. 168.6° C. (interm. 18).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:14]>C(Cl)Cl>[CH:13]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:2]([CH2:3][CH2:4][OH:5])[CH3:1])(=[O:23])=[O:22])=[CH:19][CH:20]=1)=[O:14]
Reactant: CNCCO
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCO)S(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 80 h
Yield: 92.3 %

Procedure:
To an ice-cooled solution of 2-(methylamino)ethanol (0.196 mL, 2.44 mmol) and triethylamine (0.407 mL, 2.93 mmol) in DCM (10 mL) was added 4-formylbenzenesulfonyl chloride (0.500 g, 2.44 mmol). The reaction mixture was warmed slowly to RT and stirred at RT for 80 hours. The reaction mixture was diluted with DCM and was washed with 10% aqueous potassium hydrogen sulfate and dried (magnesium sulfate). The mixture filtered and the solvent evaporated at reduced pressure to afford the title compound (0.548 g, 92%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24][NH2:25]>O1CCOCC1.CC#N>[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24][NH:25][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: NCc1c(F)cccc1Cl
Reactant: COc1ncc(N)cn1
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ncc(NS(=O)(=O)c2ccccc2NCc2c(F)cccc2Cl)cn1
Yield: 9 %

Procedure:
The title compound (106 mg, impure, used without further purification) was prepared in two steps from 2-fluorobenzenesulfonyl chloride (0.46 mL, 3.5 mmol) and 5-amino-2-methoxypyrimidine (482 mg, 3.85 mmol) in 1,4-dioxane at 100° C.; followed by 2-chloro-6-fluorobenzyl amine (0.36 mL, 2.8 mmol) in MeCN (1.5 mL) at 180° C. in a Biotage Initiator microwave reactor using the methods of (IntB1).
Reaction SMILES: C[O-].[Na+].CO[C:6]([C:8]1([NH:16][C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]([CH3:28])=[CH:21][C:20]=2[CH3:29])[CH2:13][CH2:12][N:11]([O:14][CH3:15])[CH2:10][CH2:9]1)=[O:7]>CN(C)C=O>[CH:25]1([C:23]2[C:22]([CH3:28])=[CH:21][C:20]([CH3:29])=[C:19]([C:18]3[C:17](=[O:30])[NH:16][C:8]4([CH2:9][CH2:10][N:11]([O:14][CH3:15])[CH2:12][CH2:13]4)[C:6]=3[OH:7])[CH:24]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)C1(NC(=O)Cc2cc(C3CC3)c(C)cc2C)CCN(OC)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON1CCC2(CC1)NC(=O)C(c1cc(C3CC3)c(C)cc1C)=C2O
Temperature: 65 °C
Yield: 23.9 %

Procedure:
To 1.3 g of sodium methoxide in 10 ml of dimethylformamide was added a solution of 3.2 g of crude 4-[2-(5-cyclopropyl-2,4-dimethyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester in 10 ml of dimethylformamide and the reaction mixture was heated to 65° C. for 2 hours. The mixture was poured into ice water, extracted with dichloromethane, the combined organic phases dried with sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (dichloromethane/methanol 95:5) to yield 700 mg of 3-(5-cyclopropyl-2,4-dimethyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound C16) as a wax. LC-MS (EI, ES+): 343 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.Cl.[I-:47].[NH2:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N+:59]=2[CH3:64])=[CH:53][CH:52]=1>ClCCCl>[I-:47].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:48][CH2:49][CH2:50][C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][N+:59]=4[CH3:64])=[CH:55][CH:56]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: C[n+]1ccccc1Nc1ccc(CCN)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [I-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(Nc4cccc[n+]4C)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AD using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (50 mg, 0.13 mmol), CDI (33 mg, 0.2 mmol), DIPEA (0.14 mL, 0.81 mmol) and 2-{[4-(2-aminoethyl)phenyl]amino}-1-methylpyridinium iodide hydrochloride (55 mg, 0.14 mmol) in DCE (1.0 mL).
Reaction SMILES: O[C:2]1C(C(O)=O)=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1.[C:12](Cl)(=O)[C:13]([Cl:15])=[O:14].C(Cl)[Cl:19]>CN(C=O)C>[Cl:19][C:2]1[C:12]([C:13]([Cl:15])=[O:14])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(O)c(C(=O)O)cn1
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(C(=O)Cl)cn1
Reaction time: 4 h

Procedure:
4-Hydroxy-6-methylnicotinic acid (5 g) was dissolved in abs. DCM (30 ml) and treated with 10 drops of DMF. Oxalyl chloride (15 ml) was carefully added dropwise to this mixture. After stirring for four hours and allowing to stand overnight, the solvent was stripped off and for further drying the mixture was attached to the high vacuum. The 4-chloro-6-methylnicotinoyl chloride obtained (8 g) was dissolved in abs. DCM (160 ml). After cooling to 0° C., a 40% strength methanolic methylamine solution (66 ml) was added dropwise in the course of 15 min. After removal of the cooling, the mixture was additionally stirred at RT for 2 h. After addition of water (150 ml), it was extracted with DCM (three times). The combined organic phases were dried over sodium sulfate, filtered and concentrated. 4.4 g of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:11]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(O)C>[ClH:1].[O:11]([C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[C:3]3[S:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncnc2ccsc12
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CC(C)O
Product: Cl
Product: c1ccc(Oc2ccc(Nc3ncnc4ccsc34)cc2)cc1
Yield: 73.1 %

Procedure:
4-Chlorothieno[3,2-d]pyrimidine (0.085 g, 0.50 mmol) and 4-phenoxyaniline (0.105 g, 0.55 mmol) were reacted in 2-propanol (3.5 ml) for 3 hours according to Procedure A. The product was obtained as a cream solid (0.130 g, 73%), m.p. 236-240° C.; (Found: C, 60.61; H, 3.95, N, 11.93. C18H13N3OS.HCl requires: C, 60.76; H, 3.97; N, 11.81%); δH [2H6]-DMSO 10.93 (1H, br s, NH), 8.80 (1H, s, 2-H), 8.42 (1H, d, J 8, 6-H or 7-H), 7.69 (2H, d, J 9, 2′-H, 6′-H), 7.55 (1H, d, J 8, 6-H or 7-H), 7.41 (2H, t, J 9, 3″-H, 5″-H), 7.18 (1H, t, J 9, 4″-H), 7.04-7.15 (4H, m, 3′-H, 5′-H, 2″-H, 6″-H); m/z (%) 318 (100, M−1+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].Cl.[OH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[OH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22]1
Reactant: O[C@@H]1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](O)C3)s2)noc1C(F)(F)F
Yield: 45 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (R)-(+)-3-hydroxypiperidine hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine (containing and additional 1.1 eq. to neutralize the piperidinyl hydrochloride salt) and piperidine derivative. The reaction mixture was evaporated to an oil and partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2×5 mL), dried over MgSO4, filtered, and evaporated to an oil. The crude product was then chromatographed on silica gel with EtOAc/hexanes (50 then 75 then 100%) as eluant to afford product as a colorless solid (41 mg, 45%). 1H NMR (CDCl3) 1.56-1.62 (m, 1H), 1.62-1.80 (m, 1H), 1.83-2.10 (m, 2H), 2.36 (d, J=1.3, 3H), 2.86 (br, 1 H), 3.50-3.76 (m, 4H), 3.82-3.98 (m, 2H), 7.39 (br d, J=4.0, 1H), 7.44 (d, J=4.0, 1H). 13C NMR 7.9, 22.6, 32.5, ˜48 (br), ˜52 (br), 66.2, 114.7, 118.7 (q, J=271), 128.0, 129.6, 131.3, 140.1, 155.2 (q, J=40), 157.9, 163.5. 19F NMR −63.2. LC/MS 5.65 min, [M+1]+ 361.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1CCCC([Cl:24])C1=O)(C)(C)C>>[Cl:24][CH:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:13]
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Reactant: O=C1CCCCC1c1ccccc1
Product: O=C1C(Cl)CCCC1c1ccccc1

Procedure:
The chlorination of 2-phenylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.