Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][C:8]2=[O:13])[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30](O)=[O:31])(=[O:27])=[O:26])[CH:19]=[CH:18]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][C:8]3=[O:13])[CH2:3][CH2:2]1)=[O:31])(=[O:26])=[O:27])[CH:19]=[CH:18]2
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=C1COCCN1C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCOCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.6 %

Procedure:
4-(Piperidin-4-yl)morpholin-3-one (0.18 g) obtained in Example 7c), (2S)-3[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropionic acid (0.31 g) and HOBt (0.23 g) were dissolved in DMF (10 mL), WSC (0.29 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed successively with water, an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (form ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound (0.20 g, 42%) as a colorless powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].NC(N)=[S:14].[OH-].[Na+].S(=O)(=O)(O)O>O>[SH:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCCCCCCBr
Reactant: NC(N)=S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCCCS
Yield: 63.8 %

Procedure:
5.0 g 8-bromooctanoic acid (22.4 mmol), 2.24 g thiourea (29.4 mmol) and 22 ml water were placed in a round botton flask, and the mixture was refluxed for 3 hours. 15.1 ml 3M sodium hydroxide was then added and the mixture was refluxed for one additional hour. The reaction mixture was cooled in an ice bath, and dilute sulfuric acid was added dropwise until the solution had a pH of about 2. The cloudy solution was then extracted with ether (2×25 ml), dried over anhydrous MgSO4, and concentrated under reduced pressure to give a white solid (2.52 g, 64%). 1H-NMR (300 MHz, CDCl3) 1.37, (m, 7 H); 1.60, (m, 4 H); 2.35, (t, J=7.4 Hz, 2 H); 2.52, (q, J=7.4 Hz, 2 H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[OH-].[Na+].[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(OCC)C.O>[C:16]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: C=C(C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mechanically stirred mixture of L-proline (42.0 grams, g), NaHCO3 (148 g), H2O (680 milliliters, ml) and diethyl ether (280 ml) was maintained in an ambient temperature bath at pH 10.5-10.7 (adjusted by the addition of concentrated aqueous NaOH), then treated portionwise over 20 minutes with a solution of redistilled methacryloyl chloride (40 ml) in diethyl ether (20 ml). Additional concentrated aqueous NaOH was added as needed to keep the pH at 10.5-10.7. Upon addition of all of the methacryloyl chloride (and pH stabilization), the mixture was stirred for 20 minutes at ambient temperature. The resulting immiscible phases were separated and the aqueous phase was extracted with two 250 ml portions of diethyl ether. The combined organic extracts were washed with H2O (50 ml), and the aqueous extract was added to the aqueous phase which phase was then acidified to pH 1 with concentrated aqueous HCl and then extracted with four 250 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with about 100 ml of brine (saturated aqueous sodium chloride solution) and then dried over Na2SO4. The resulting solution was filtered and concentrated in vacuo to about 230 ml and then heated to boiling, diluted with hexane (80 ml) and allowed to cool. Upon cooling, the desired N-methacryloyl-L-proline spontaneously crystallized as chunky white prisms (51.3 g). The concentrated mother liquor yielded a second crop of crystals (4.26 g) when crystallized as described above. A portion of the first crop was recrystallized twice from ethyl acetate to give an analytical sample, m.p. 102°-104.5° C., having the following spectral characteristics:
Reaction SMILES: [C:1]([C:3]1([CH2:22][CH:23]([CH3:26])[CH2:24][CH3:25])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[N:2].CCOCC.[Cl:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35].C1CCC(N=C=NC2CCCCC2)CC1>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH:6]3[CH2:7][CH2:8][C:3]([C:1]#[N:2])([CH2:22][CH:23]([CH3:26])[CH2:24][CH3:25])[CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)=[O:35]
Reactant: CCC(C)CC1(C#N)CCC(c2ccc(-c3ccc(O)cc3)cc2)CC1
Reactant: CC(C)C(Cl)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCC(C)CC1(C#N)CCC(c2ccc(-c3ccc(OC(=O)C(Cl)C(C)C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 5.3 g of p-[p-(4-cyano-4-(2-methylbutyl)-cyclohexyl)-phenyl]-phenol (obtainable by alkaline ether cleavage from r-1-cyano-cis-4-(4'-propyloxybiphenyl-4-yl)-1-(2-methylbutyl)-cyclohexane with potassium tert.-butylate in NMP at 180°), 1.9 g of optically active 2-chloro-3-methyl-butyric acid and 170 g of DMAP are suspended in 40 ml of CH2Cl2. 3.1 g of DCC in 5 ml of CH2Cl2 are then added dropwise and the mixture is stirred at room temperature for 12 hours. After removal of the dicyclohexylurea and customary working up, optically active 4'-(4-cyano-4-(2-methylbutyl)-cyclohexyl)-biphenyl-4-yl 2-chloro-3-methyl-butyrate is obtained.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=O)[CH3:28].C([N:48](CC)[C:49]([CH2:51]P(=O)([O-])[O-])=[O:50])C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[C:35]1([C:33]([C:32]2[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:30]([O:29][CH2:27][CH3:28])[CH:31]=2)=[CH:51][C:49]([NH2:48])=[O:50])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCN(CC)C(=O)CP(=O)([O-])[O-]
Reactant: CCOc1cc(C(=O)c2ccccc2)ccc1OC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOc1cc(C(=CC(N)=O)c2ccccc2)ccc1OC

Procedure:
The acrylamide was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3-ethoxy-4-methoxybenzophenone (0.3 g, 1.2 mmol), diethylcarbamoylmethylphosphonate (0.25 g, 1.3 mmol) and lithium hexamethyldisilazide (1 mL, 1.3 mmol, 1.3M) with a reaction time of 54 hours at reflux. The crude mixture was purified by flash column chromatography (silica gel, 45% ethyl acetate/methylene chloride) to afford 0.06 g (17%) of a mixture of the E and Z isomers as an oil: 1H NMR (CDCl3) δ 7.54-7.19 (m, 10H), 7.00-6.65 (m, 6H), 6.34 (s, 2H), 5.54 (s, 1H), 5.55 (s, 1H), 5.24 (s, 1H ), 5.04 (s, 1H), 4.16 (m, 4H), 3.92 (s, 3H), 3.87 (s, 3H), 1.60-1.33 (m, 6H); 13C NMR (CDCl3) δ 168.7, 168.6, 150.8, 150.4, 149.7, 148.4, 148.0, 140.7, 138.2, 133.0, 130.2, 129.2, 129.1, 128.8, 128.3, 128.0, 121.9, 121.6, 120.0, 113.7, 111.9, 111.4, 110.8, 64.4, 64.3, 55.9, 14.6; Anal. Calcd for C18H19NO3.0.35H2O. Theoretical: C, 71.19; H, 6.54; N, 4.61. Found: C, 71.19; H, 6.68; N, 4.45.
Reaction SMILES: [C:1]([O:8][CH:9]([CH3:11])[CH3:10])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]1[O:34][CH:32]1[CH3:33]>>[C:1]([O:8][CH:9]([CH3:11])[CH3:10])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:33][CH2:32][CH2:31][OH:34])=[O:5]
Reactant: CC(C)OC(=O)/C=C\C(=O)[O-]
Reactant: CC1CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)OC(=O)/C=C\C(=O)OCCCO
Temperature: 85 °C
Reaction time: 3 h

Procedure:
2100 grams of 2-propyl maleate (Example 9), 8.12 grams of triphenylphosphine, and 8.12 grams of tri-2-ethylhexylphosphite were charged to a 4 liter stirred stainless steel pressure autoclave. The reactor was twice pressurized with nitrogen then depressurized, finally leaving 0.36 kPa nitrogen. The reactor contents were heated to 85° C., and 829.74 grams of propylene oxide were added over 3 hours. Then 270 grams of propylene oxide were added. After 3 hours, the pressure was lowered to remove residual propylene oxide. The product was a liquid containing less than 100 parts per million propylene oxide, having a viscosity of 75.7 centipoise at 25° C. and an acid number of 0.61 milligrams KOH/gram of solution.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH3:24])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Reactant: CC1CCCN1
Product: Cc1cc(Cl)cc2c(-c3ccccc3)c(C(=O)O)c(N3CCCC3C)nc12

Procedure:
The title compound was prepared in analogy to example 40 step D from 2,6-dichloro-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 40 step C) and 2-methylpyrrolidine. Yellow foam. MS (ESI): 381.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]1([C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12])[OH:10].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:10][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[OH:12])=[CH:6][CH:7]=1
Reactant: Oc1ccccc1O
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: Oc1ccccc1Oc1ccc(Cl)nn1
Reaction time: 2 h
Yield: 60.2 %

Procedure:
14.9 g of 3,6-dichloropyridazine and 14.3 g of catechol are dissolved in 40 ml of dimethyl sulfoxide, followed by addition of 15.2 g of anhydrous potassium carbonate. The mixture is heated gradually, and stirred at 80° to 90° C. for 2 hours. The reaction mixture, after cooling down, is poured into 300 ml of a 10% aqueous solution of sodium hydroxide. The resulting insoluble precipitates are filtered off and the filtrate is neutralized with concentrated hydrochloric acid. After the resulting crystals are filtrated, followed by drying to yield 13.4 g of title compound. When this product is subjected to treatment with activated charcoal and recrystallized from acetone, to yield colorless crystals of the title compound melting at 146.5°-148° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[CH3:10].[C:11](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=1)=[O:9]
Reactant: Cc1cc(C(=O)O)sc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C)c(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
5-Bromo-4-methyl-2-thiophenecarboxylic acid (3.33 g) was dissolved in dimethylformamide (50 ml), and potassium carbonate (4.0 g) and iodomethane (4.0 ml) were added. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (3.47 g). A mixture of 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (2.36 g), zinc powder (1.65 g), acetic acid (10 ml) and water (10 ml) was stirred under reflux for 3 hours. Zinc powder (1 g) and acetic acid (10 ml) were further added. The mixture was stirred under reflux for 1 day, cooled, poured into concentrated aqueous ammonia and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid methyl ester (1.42 g). 4-Methyl-2-thiophenecarboxylic acid methyl ester (1.42 g) was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (30 ml), and 1N aqueous sodium hydroxide (15 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid (1.16 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])[CH:5]=[CH:4][N:3]=1.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH3:29][C:28]1[CH:27]=[CH:26][C:10]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:25])=[CH:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[N:7]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1-c1ccnc(Cl)n1
Product: Cc1ccc(CN2CCNC[C@@H]2C)cc1-c1ccnc(NCCc2ccc(O)cc2)n1

Procedure:
Intermediate 158 from above was coupled with tyramine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.0 (d, 1H) 7.7 (d, 1H) 7.5 (d, 1H), 7.3 (d, 1H), 7.0 (d, 2H) 6.7 (d, 2H) 4.0 (t, 2H) 3.7 (m, 3H) 3.6-3.4 (m, 6H) 2.8 (t, 2H), 2.5 (s, 3H), 1.7 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1([CH2:6][C:7]([O:9]CC)=O)[CH2:5][O:4][CH2:3]1.[OH-].[NH4+:13]>C1(C)C=CC=CC=1>[NH2:1][C:2]1([CH2:6][C:7]([NH2:13])=[O:9])[CH2:5][O:4][CH2:3]1
Reactant: CCOC(=O)CC1(N)COC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NC(=O)CC1(N)COC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 88.8 %

Procedure:
To a microwave tube was added ethyl 2-(3-aminooxetan-3-yl)acetate (CAN 1207175-54-9, 400 mg, 2.51 mmol) followed by toluene (8.0 ml) and 25% ammonium hydroxide (7.2 g, 8.0 ml, 51.4 mmol). The tube was sealed and the reaction mixture was stirred vigorously at room temperature for 6 days. The reaction mixture was concentrated in vacuo and azeotroped several times with 20 ml toluene. The crude solid was dried under high-vacuum at 40° C. to dryness to yield the title compound (290 mg, 89%) as a white solid. MS (ESI, m/z): 131.1 (M+H+).
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1.C(N)[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1>>[CH2:4]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)[C:3]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)CCNc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1ccc2nc(NCc3ccccc3)sc2c1

Procedure:
The title compound was prepared following the procedure for N,N-dimethyl-N′-(6-nitrobenzothiazol-2-yl)-ethane-1,2-diamine, using benzylamine. Modified workup: Solid that had precipitated during course of reaction (amine salt) was filtered; no aqueous workup was conducted. 1H NMR (400 MHz, CDCl3): δ=4.70 (s, 2H), 6.07 (s, br, —NH), 7.33-7.39 (m, 1H), 7.39-7.42 (m, 4H), 7.51 (d, J=8.8 Hz, 1H), 8.21 (dd, J=8.8, 2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H). MS (ES+): m/z 286.03 (100) [MH+]. HPLC: tR=3.47 min (ZQ2000, polar—5 min).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:24]=[CH:23][S:22][C:21]=4[C:25]([NH2:27])=[O:26])[N:16]=[CH:15]3)=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][NH:3]1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH3:28][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:24]=[CH:23][S:22][C:21]=4[C:25]([NH2:27])=[O:26])[N:16]=[CH:15]3)=[CH:12][CH:13]=2)[C:2]1=[O:1]
Reactant: NC(=O)c1sccc1Cc1cn(-c2ccc(-c3ccc[nH]c3=O)cc2)cn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cccc(-c2ccc(-n3cnc(Cc4ccsc4C(N)=O)c3)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (0.02 g, 0.05 mmol) in DMF (0.5 mL) was added Cs2CO3 (0.049 g, 0.15 mmol) and MeI (0.01 mL, 0.15 mmol). After stirring for 30 min at ambient temperature, the mixture was purified by preparative HPLC to give 5-chloro-N-((1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (MS 425.1, 427.1 (M+H) Cl pattern).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:38]([C:35]2[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(-n3cccn3)cc2)Cc2cccc(OCC(=O)OC(C)(C)C)c2)cc1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13a, and 4-methoxybenzenesulfonyl chloride. MS 564 (M+1).
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:16])[CH3:15])[CH:11]=2)[N:6]([CH3:17])[C:5]1=[O:18])([CH3:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:19]([O-:21])=[O:20])=[C:10]([NH:13][C:14](=[O:16])[CH3:15])[CH:11]=2)[N:6]([CH3:17])[C:5]1=[O:18])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)C(C(C)C)C(=O)N2C
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)C2C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(rac)-N-(3-Isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide is dissolved in acetic acid (3 ml) and cooled to 0° C. Then nitric acid (fuming, 1.5 ml) is added drop-wise and the reaction mixture is stirred for 30 min at this temperature. After completion of the reaction the mixture is poured into ice-water and extracted with CH2Cl2. The combined organic layer is washed with water, dried over MgSO4 and evaporated. The residue is subjected to flash chromatography on silica gel eluting with light petroleum/EtOAc to give the pure compound (1.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:11][CH2:12][CH3:13])([CH3:10])[C:5](OCC)=[O:6])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH2:1]([O:3][C:4]([O:11][CH2:12][CH3:13])([CH3:10])[CH2:5][OH:6])[CH3:2]
Reactant: CCOC(=O)C(C)(OCC)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCOC(C)(CO)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A solution of ethyl pyruvate diethyl ketal (16.0 g, 0.084 moles) in ethyl ether (60 mL) was added dropwise during 30 min to a stirred solution of lithium aluminum hydride (1.90 g, 0.050 moles) in ethyl ether (150 mL). Next the mixture was stirred 1 h at room temperature under nitrogen atmosphere. Saturated solution of sodium sulfate (20 mL) was added and the mixture was stirred 15 min. Next the mixture was filtered, dried with anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to fractional vacuum distillation giving 9.5 g of pure 2,2-diethoxypropan-1-ol. NMR (d6-DMSO): 1.17 ppm (t, —CH3, ethyl (ketal), 6H), 1.31 ppm (s, —CH3—C—CH2OH, 3H), 3.37 ppm (q, —OCH2CH3, (ketal), 4H), 3.86 ppm (d, —CH2OH, 2H), 4.45 ppm (t, —OH, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29](OC(N1CCN(C(=O)C2C=CC(C=O)=CC=2)CC1)=O)([CH3:32])(C)[CH3:30].N1CCOCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH:32]1([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)=[O:28])[CH2:10][CH2:9]2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCN1
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Reaction time: 3 h
Yield: 48 %

Procedure:
4-(4-Morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester. A solution of 4-(4-formyl-benzoyl)piperazine-1-carboxylic acid tert-butyl ester (2.06 g) in methanol (100 mL) was treated with morpholine (4 mL) and NaB(OAc)3H (6.98 g, in portions over 1 h). After 3 h, the mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to give the title compound (1.22 g, 48%). MS (ESI): mass calcd. for C21H31N3O4, 389.23; m/z found, 390.4 [M+H]+. 1H NMR (CDCl3): 7.39-7.33 (m, 4H), 3.75-3.66 (m, 6H), 3.50 (s, 2H), 3.51-3.33 (m, 6H), 2.45-2.41 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][C:14]32[CH2:21][CH2:20][CH2:19][N:18]2[CH:22]=[N:23][CH:24]=[C:17]32)=[CH:9][CH:8]=1)(=O)=O.[CH3:27][N:28](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:14]12([CH2:21][CH2:20][CH2:19][N:18]3[CH:22]=[N:23][CH:24]=[C:17]13)[C:15]1[C:10](=[CH:9][CH:8]=[C:7]([C:27]#[N:28])[CH:16]=1)[CH2:11][CH2:12][CH2:13]2
Reactant: CN(C)C=O
Reactant: O=S(=O)(Oc1ccc2c(c1)C1(CCC2)CCCn2cncc21)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)C1(CCC2)CCCn2cncc21
Temperature: 120 °C
Reaction time: 20 h

Procedure:
An apparatus purified by baking is charged under argon with 1.160 mmol of 3′,4′,6,7-tetrahydro-2′H,5H-spiro[imidazo[1,5-a]pyridine-8,1′-naphthalen]-7′-yl trifluoromethanesulphonate together with 2.320 mmol zinc(II) cyanide in 15 ml of degassed N,N-dimethylformamide. 0.093 mmol of tetrakis(triphenylphosphine)palladium is added and the reaction mixture is stirred at 120° C. for 20 hours. The reaction mixture is cooled and poured into 100 ml of ice-water. It is extracted with ethyl acetate (3×). The combined organic phases are dried over magnesium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) as a white solid. Rf=0.165 (dichloromethane-2M ammonia in EtOH=95:5); Rt=5.64.