Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH2:23][C:22]1=[O:31].[Al+3].[Cl-].[Cl-].[Cl-].Cl>O1CCCC1.ClCCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:28]1[CH:29]=[CH:30][C:25]2[O:24][CH2:23][C:22](=[O:31])[N:21]([CH3:20])[C:26]=2[CH:27]=1)=[O:13]
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Reactant: CN1C(=O)COc2ccccc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc3c(c2)N(C)C(=O)CO3)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2-chloro-4-methoxy-phenyl)-acetic acid (CAS Reg. No. 91367-09-8) (20 g, 100 mmol) in tetrahydrofuran (400 ml) were added N,N-dimethylformamide (1 ml) and oxalylchloride (20.2 g, 160 mmol) dropwise (15 min). The mixture was stirred overnight at room temperature. The solvent was evaporated; toluene was added and again evaporated. The residue was dried under high vacuum to give the crude acid chloride. To a cooled solution (ice bath) of 4-methyl-2H-1,4-benzoxazin-3(4H)-one (16.6 g, 100 mmol) in 1,2-dichloroethane (110 ml) was added AlCl3 (39.9 g, 300 mmol). The mixture was stirred for 30 min and a solution of the acid chloride in 1, 2-dichloroethane (110 ml) was added dropwise during 1.2 h at 2° C. The mixture was stirred at 0° C. for 4.5 h. The mixture was poured into ice water and hydrochloric acid and extracted three times with dichloromethane. The organic phases were dried (MgSO4), filtered and concentrated. The residue was dried under high vacuum for 17 h. The solid product was stirred with ethanol (180 ml) for 1.5 h at r.t., filtered off and dried under high vacuum to give the title compound (26.1 g) as an off-white solid. MS (m/e)=346.1 [M+H+].
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:37])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:31]3[CH2:35][CH2:34][O:33]C3=O)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[OH-].[K+]>O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:37])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][CH2:35][CH2:34][OH:33])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1N1CCOC1=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccccc1NCCO)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
N-Cyclopropyl-N-{1-[2-(2-oxo-oxazolidin-3-yl)-benzoyl]-piperidin-4-yl}-3-trifluoromethyl-benzenesulfonamide (12) (0.110 g, 0.20 mmol) was taken up in 3 ml of ETOH and 0.5 ml of water. To the mixture, KOH (0.046 g, 0.82 mmol) was added. The mixture was heated at 100° C. and stirred for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure. Then residue was dissolved in EtOAc (30 ml) and the mixture was washed with H2O (15 ml) and brine (15 ml). The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 90% to 100% EtOAc in hexane to afford the title compound 13 (pale yellow solid, 81 mg, 83%). LC: 100%. MS: m/z=511.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][CH2:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]=2[CH3:20])=O)[CH:5]=1.[C:28]([S-:30])#[N:29].[K+]>CC(O)=O>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:12]=[C:13]([C:15]3[CH:16]=[N:17][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:19]=3[CH3:20])[N:29]=[C:28]2[SH:30])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(NCC(=O)c2cnn(-c3ccccc3)c2C)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C)c(-n2cc(-c3cnn(-c4ccccc4)c3C)nc2S)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
A suspension of 380 mg (1.05 mmol) of 4-methyl-3-[2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-benzoic acid methyl ester and 203 mg (2.09 mmol) of KSCN in 4 mL of HOAc was stirred at 100° C. for 4 h, when a precipitate formed. The mixture was cooled to room temperature, filtered, and washed with cold MeOH to provide 283 mg of 3-[2-mercapto-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (0.70 mmol; 67%). ESI MS m/z 405 [C22H20N4O2S+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5]Cl.C1(C)C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[O:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[C:25]3[C:21](=[C:22]([CH2:33][OH:34])[S:23][CH:24]=3)[C:20]=2[CH:35]=1>[OH-].[Na+].[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[O:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[C:25]3[C:21](=[C:22]([CH2:33][O:34][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])[S:23][CH:24]=3)[C:20]=2[CH:35]=1
Reactant: OCc1scc2c1-c1cc(Cl)ccc1Oc1ccccc1-2
Reactant: CN(C)CCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCOCc1scc2c1-c1cc(Cl)ccc1Oc1ccccc1-2
Temperature: 25 °C

Procedure:
To a solution of 2-dimethylaminoethylchloride-hydrochloride (1.8 mmoles) in 50% sodium hydroxide (3 ml), benzyltriethylammonium chloride (0.3 mmole) and toluene solution of the alcohol 14 (0.18 mmole) were added. The reaction mixture was heated under vigorous stirring and refluxing for 5 hours. Then it was cooled to room temperature, diluted with water and extracted by dichloromethane. After purifiaction by column chromatograpy an oily product was isolated.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:11])[C@@H:4]([CH3:10])[C:5]([O:7]CC)=[O:6].Cl.O>O1CCOCC1>[CH3:1][O:2][C@@H:3]([CH3:11])[C@@H:4]([CH3:10])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)[C@H](C)[C@H](C)OC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CO[C@@H](C)[C@@H](C)C(=O)O
Temperature: 90 °C
Yield: 70.8 %

Procedure:
This methyl ether (2.55 g) was dissolved in dioxane (50 ml) and conc. hydrochloric acid (36 %, 10 ml) and water (50 ml) were added to the solution. The solution was heated at 90° C. for 5 hours. The reaction mixture was poured into water (100 ml) and the mixture was extracted 4 times with ethyl acetate. The combined extract was dehydrated, concentrated and distilled under reduced pressure (b.p. 105° C./1 mmHg) to obtain (2R, 3S)-3-methoxy-2-methylbutyric acid (1.49 g).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([NH2:10])(=[O:9])[CH:7]=[CH2:8].[C:11]([O-:15])(=[O:14])[CH:12]=[CH2:13].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].S([O-])(O[CH2:32]CCCCCCCCCCC)(=O)=O.[Na+:45].[OH-].[Na+]>CO.CC(C)=O>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Na+:45].[C:11]([O:15][CH2:32][CH:6]([OH:9])[CH3:7])(=[O:14])[CH:12]=[CH2:13].[C:6]([NH2:10])(=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)O
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: C=CC(=O)[O-]
Agent: C=CC(N)=O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: CC(C)=O
Solvent: CO
Product: C=CC(=O)OCC(C)O
Reaction time: 3 h

Procedure:
A terpolymer of sodium acrylate-2-hydroxypropyl acrylate and acrylamide was prepared utilizing an emulsion polymerization process. The mole ratios of acrylic acid to acrylamide, mole percent of 2-hydroxypropyl, acrylate and molecular size were varied by controlling the reaction parameters. Six representative samples of the terpolymer were prepared with the compositions of the various terpolymers being estimated based upon their total nitrogen content. In the reaction, ammonium persulfate was utilized as the polymerization initiator or catalyst. Reagent grade acetone and reagent grade anhydrous methanol were utilized to form the solvent. The emulsifier was sodium lauryl sulfate, and 2N aqueous sodium hydroxide was utilized to neutralize the reactants. The dried products were thereafter milled and passed through a number 30 mesh screen. The reaction was conducted over a period of three hours at a reaction temperature of about 60° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[O:14][C:8]1([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH2:7][C:6]2=[O:18].[C:19]([O:24][C@@H:25]([C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(O)(C)C>[C:19]([O:24][C@@H:25]([C:27]1[N:28]=[C:29]([N:11]2[CH2:12][CH2:13][C:8]3([CH2:7][C:6](=[O:18])[C:5]4[C:15](=[CH:16][CH:17]=[C:3]([Cl:2])[CH:4]=4)[O:14]3)[CH2:9][CH2:10]2)[CH:30]=[CH:31][N:32]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(Cl)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCC3(CC2)CC(=O)c2cc(Cl)ccc2O3)n1
Yield: 100 %

Procedure:
To a solution of 6-chloro-spiro[chroman-2,4′-piperidin]-4-one hydrochloride (prepared according to the method of Example 78, Step A, 175 mg, 0.61 mmol) in isopropanol (5 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 160 mg, 0.70 mmol) followed by triethylamine (0.29 mL, 2.1 mmol). This mixture was stirred at reflux for 1.5 h, concentrated, and purified by flash column chromatography (1% methanol/chloroform) to give 270 mg (100%) of the title compound of Example 78, Step B as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.19 (d, 1H), 7.83 (d, 1H), 7.44 (dd, 1H), 6.97 (d, 1H), 6.37 (d, 1H), 5.64 (q, 1H), 4.18 (app s, 2H), 3.34 (t, 2H), 2.72 (s, 2H), 2.37 (t, 2H), 2.10 (d, 2H), 1.71-1.60 (c, 4H), 1.55 (d, 3H), 0.94 (t, 3H); MS (APCI) 444, 446 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH3:23].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:36](=[O:37])[C:35]([C:38](O)=[O:39])=[CH:34][NH:33][C:32]2=[O:41])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:38]([C:35]2[C:36](=[O:37])[N:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[C:32](=[O:41])[NH:33][CH:34]=2)=[O:39])=[CH:18][C:17]=1[CH3:23]
Reactant: O=C(O)c1c[nH]c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c[nH]c(=O)n(-c5ccc(F)cc5)c4=O)cc3C)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methylphenylamine and 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=240-242° C.; LCMS m/z=543 (M+1); 1H NMR (CDCl3) δ: 10.74 (s, 1H), 8.61 (s, 1H), 8.45 (d, 1H, J=5 Hz), 7.63-7.61 (m, 1H), 7.60 (s, 1H), 7.58-7.53 (m, 1H), 7.44 (s, 1H), 7.29-7.26 (m, 3H), 7.08 (d, 1H, J=10 Hz), 6.30 (d, 1H, J=5 Hz), 5.30 (s, 1H), 4.05 (d, 6H, J=5 Hz), 2.05 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:16]([O:18]CC)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(O)C.[OH-].[Na+]>O.C(O)(=O)C>[C:21]1([C:13]2([C:16]([OH:18])=[O:17])[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:15][CH2:14]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1(c2ccccc2)CCN(CCCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)C1(c2ccccc2)CCN(CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
9.3 g Ethyl 1-(3-phenylpropyl)-4-phenyl-4-piperidine-carboxylate (Formula I: R1 =hydrogen, R2 =COOEt, X=Y=CH2), prepared according to the procedure described in U.S. Pat. No. 2,914,532, incorporated herein by reference, was taken up in 35 ml water and 12 ml ethanol with 2.3 g sodium hydroxide, then refluxed for 24 hours and stirred at room temperature for the next two days. The product mixture was poured into water, the solution was acidified with acetic acid, and a precipitate appeared. The precipitate was washed well with water. The product was recrystallized from 4 liters of water and was washed with water, ethanol and ether, yielding 4-phenyl-1-(3-phenylpropyl)-4-piperidinecarboxylic acid, as a white powder, which was used without further purification in the next preparation.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>C(Cl)Cl>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:16]3[CH:25]=[CH:24][C:19]([C:20]4[O:21][C:32](=[O:33])[NH:23][N:22]=4)=[CH:18][CH:17]=3)=[C:8]([C:12]([F:14])([F:15])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccc(-c3c(C(F)(F)F)oc4cc(O)ccc4c3=O)cc2)o1

Procedure:
4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzohydrazide (1 equiv.) and CDI (10 equiv.) in DCM is refluxed overnight. An aqueous/EtOAc workup followed by purification by prep-HPLC can give the desired product in Example 23.
Reaction SMILES: [NH2:1]N.ClC1C=C(Cl)C=C[C:5]=1[O:6][C:7]1[C:8](=[O:30])[C:9]2[C:14]([C:15](=[O:26])[C:16]=1[O:17][C:18]1C=CC(Cl)=CC=1Cl)=[CH:13][C:12]([N+]([O-])=O)=[CH:11][CH:10]=2>[Pd].C(O)C>[CH3:5][O:6][C:7]1[C:8](=[O:30])[C:9]2[C:14]([C:15](=[O:26])[C:16]=1[O:17][CH3:18])=[C:13]([NH2:1])[CH:12]=[CH:11][CH:10]=2
Reactant: NN
Reactant: O=C1C(Oc2ccc(Cl)cc2Cl)=C(Oc2ccc(Cl)cc2Cl)C(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Yield: 82.8 %

Procedure:
Hydrazine (4.0 ml, 125 mmol of 97%) was added dropwise, over a 2 hour period, to a stirred mixture of the captioned compound of Preparation 2 (19.9 g, 75.6 mmol), 5% palladium on carbon (10 g) and ethanol (750 ml) in a nitrogen atmosphere. The catalyst was filtered off through a celite pad that was washed with hot ethanol (2×300 ml). The combined filtrate and washings were concentrated to dryness in vacuo and the residue recrystallized from water:ethanol (1.5:1) giving 14.6 g of 2,3-dimethoxy-5-amino-1,4-naphthoquinone, mp 116°-117°.
Reaction SMILES: C(O[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][S:13](=[O:16])[CH2:12][CH2:11]2)[C:7]([N+:17]([O-:19])=[O:18])=[C:6]([O:20][CH2:21][CH3:22])[N:5]=1)C.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH2:21]([O:20][C:6]1[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][S:13](=[O:16])[CH2:14][CH2:15]2)[C:7]=1[N+:17]([O-:19])=[O:18])[CH3:22]
Reactant: C1CNCCN1
Reactant: CCOc1nc(OCC)c([N+](=O)[O-])c(N2CCS(=O)CC2)n1
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
2 gm (6 millimols) of 2,6-di-ethoxy-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine (m.p. 130°-132°C) were heated together with 8.6 gm (100 millimols) of piperazine at 125°C for 4 hours. The reaction mixture was then poured over ice, and the crystals formed thereby were suction-filtered off and recrystallized from ethanol. Yield: 0.53 gm (23.6% of theory); m.p. 221°-222°C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([C:20](=O)[NH2:21])[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)(=[O:8])=[O:9])=[C:4]([C:20]#[N:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(N)=O)cc1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C#N)cc1
Yield: 94.9 %

Procedure:
To a solution of 4′-chloro-2′-carbamoyl-N-methyl-p-toluenesulfonanilide (0.70 g (2.07 mmol)) in pyridine (3.0 ml), under cooling with ice and with stirring, trifluoroacetic anhydride (0.40 ml (2.83 mmol)) was added dropwise. The temperature of the reaction mixture was brought to room temperature and the mixture was stirred at the same temperature for 2 hours. Then, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diisopropyl ether was added to the residue and crystals separated was filtered and washed to give 0.63 g (95%) of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])[CH:9]=O)=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[C:15]([NH:18][CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:17])[CH3:16].C[O-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1>[CH2:23]([O:22][C:20]([C:19]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N+:12]([O-:14])=[O:13])=[CH:11][N:18]1[C:15](=[O:17])[CH3:16])=[O:21])[CH3:24]
Reactant: C=C(C=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)CC(c2ccc(Cl)cc2[N+](=O)[O-])=CN1C(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 143.0 g (0.676 mol) of 2-(4-chloro-2-nitrophenyl) acrolein in 600 ml. of benzene was added over 1.5 hour to a stirred suspension of 148.5 g (0.684 mol) of diethyl acetamidomalonate and 0.80 g of sodium methoxide in 600 ml. of benzene. The Michael addition was complete after 30 minutes. 3.8 g of p-toluenesulfonic acid monohydrate was added and the mixture was heated at reflux for 40 minutes with constant removal of the water formed. The reaction mixture was washed with saturated sodium bicarbonate and brine. After drying with anhydrous NaSO4, the orange solution was concentrated to yield 278.5 g, m.p. 90°-95°. Crystallization from ethanol (500 ml) gave 264.6 g (95%) of deep yellow crystals, m.p. 96°-98°. A sample was recrystallized again from ethanol: m.p. 96.5°-98°.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].CN(C=O)C>CC#N.O>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([N:7]2[CH2:16][CH2:17][CH2:18][C:19]2=[O:20])=[CH:1][CH:2]=1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: O=C1CCCN1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 19.3 %

Procedure:
To a solution of p-aminophenol (0.545 g, 5.00 mmol) in dry MeCN (5 mL) at 0° C. was added K2CO3 (1.38 g, 10.0 mmol), followed by dropwise addition of 4-chlorobutanoyl chloride (0.56 mL, 5.0 mmol). The mixture was stirred at rt for 40 min and then brought to reflux. Dry DMF (5 mL) was added after 90 min and heating was continued for an additional 2 h. The mixture was cooled, poured into water, and extracted with EtOAc (×8). Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.171 g of the title compound as a colorless solid: MS (APCI) m/z 177 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)=[O:4].[CH3:14][NH:15][CH3:16].[OH-].[Na+]>O1CCOCC1>[CH3:14][N:15]([CH3:16])[C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[CH:6][CH:7]=1)=[O:12]
Reactant: CNC
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 5 g (25.2 mmol) of methyl 4-chlorocarbonyl benzoate in 20 ml of dioxane was added to 30 ml of 50% aqueous dimethylamine solution under cooling with ice. After stirring for 30 minutes, 50 ml of 1 N aqueous sodium hydroxide solution was added to the resultant mixture, and they were stirred at room temperature for 2 days. The reaction liquid was washed with ethyl acetate and made acidic with hydrochloric acid. After the extraction with ethyl acetate, the extract was washed with saturated Aqueous NaCl solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was washed with hexane and dried to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(Cl)Cl>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:20][CH2:19][CH2:18][CH:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[ClH:1]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: c1ccc(C(CCNc2nc3ccccc3[nH]2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,3-diphenyl-propylamine by Procedure A. The reaction mixture was added dilute aqueous HCl and CH2Cl2. From the CH2Cl2 phase a precipitate was isolated by filtration yielding the title compound in pure form as its HCl salt (mp 136.5-137.5° C.). MS(ES+) m/z 328 ([M+1]+, 100). 1NMR (DMSO-d6) δ 2.43 (m, 2H), 3.28 (m, 2H), 4.15 (t, 1H), 7.15-7.35 (m, 14H), 9.00 (m, 1H), 12.7 (br s, 1H).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>[Ru].COCCOC>[CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1CC[C@H](CO)CC1
Agent: [Ru]
Solvent: COCCOC
Product: CC(C)C1CCC(CO)CC1

Procedure:
A mixture of 200 g of cuminic aldehyde, 200 g of 1,2-dimethoxy-ethane and 6 g of ruthenium -- 5% on charcoal; Doduco Chemie Werk, Sinsheim Elsenz, West Germany -- were heated in a stainless steel autoclave at 130° and at a pressure of 100 atm, for 25 h. The obtained reaction mixture was then filtered and subjected to a fractional distillation to yield 176 g (85%) of a 70 : 30 (parts by weight) mixture of cis and trans-4-isopropyl-cyclohexylmethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10][C@H:9]1[C:16](OCC1C=CC=CC=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10][C@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C[C@H]1C(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Alternatively Intermediate 18 was prepared from Intermediate 16. To a suspension of lithium aluminium hydride (0.57 g, 15 mmol) in anhydrous THF (30 ml) was added the solution of (S)-6-aza-spiro[2.5]octane-5,6-dicarboxylic acid 5-benzyl ester 6-tert-butyl ester (intermediate 16, 3.45 g, 10 mmol) in THF(20 ml) at 0° C., after the addition was completed, the reaction mixture was stirred at 0° C. for 2 hours. The resulting mixture was quenched with Na2SO4.10H2O, filtered and the filtration was dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1). (S)-5-Hydroxymethyl-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester was obtained as colourless oil (2.0 g), yield:83%.