Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH2:8]([C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:32])[CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl>CO>[CH2:8]([C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:32])[CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC/C=C/Cc1nc2ccc(F)cc2c(OC(C)=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCC/C=C/CC1=Nc2ccc(F)cc2C(=O)C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
A solution of 24 mg (0.17 mmols) of potassium carbonate and 1 ml of water was added to a solution of 60 mg (0.17 mmols) of 2-(trans-2-nonenyl)-3-methyl-4-acetoxy-6-fluoroquinoline in 8 ml of methanol and stirred at room temperature for 10 minutes. This solution was neutralized with 1N hydrochloric acid, after which the solvent was distilled off under reduced pressure, followed by addition of 10 ml of chloroform, washing with water and drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (solvent: n-hexane : ethyl acetate=1:1) to obtain 46 mg (yield 87 %) of 2-(trans-2-nonenyl)-3-methyl-6-fluoro-4-quinolone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[N:15]1[NH:16][C:17](=[O:21])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][N:12]([CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:16]2[C:17](=[O:21])[CH:18]=[CH:19][CH:20]=[N:15]2)=[CH:3][CH:4]=1)[CH3:14]
Reactant: O=c1cccn[nH]1
Reactant: CN(C)C[C@H]1C[C@@H]1c1ccc(Br)cc1
Product: CN(C)C[C@H]1C[C@@H]1c1ccc(-n2ncccc2=O)cc1

Procedure:
Following the general procedure, reaction of 7d (2.13 g assayed, 8.37 mmol) with 3(2H)-pyridazinone (1.05 g, 10.5 mmol) afforded a solution of the free base of 8d in an assayed yield of 1.57 g (5.8 mmol, 70% assay yield, 93% peak area).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:49]([CH2:51][NH2:52])[OH:50]>CN(C=O)C.CC(=O)OCC>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:52][CH2:51][CH2:49][OH:50])=[O:22])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: NCCO
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)NCCO)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid ethyl ester (1.42 g) is prepared starting from 4-(N-hydroxycarbamimidoyl)-benzoic acid ethyl ester (1.01 g, 4.84 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (1.00 g, 4.40 mmol) according to Method A; LC-MS: tR=0.63 min; [M+1]+=400.12; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 1.45 (t, J=7.0 Hz, 3H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.73 (s, 2H), 4.44 (q, J=7.3 Hz, 2H), 7.69 (s, 1H), 8.16-8.20 (m, 2H), 8.22-8.25 (m, 2H). This material (1.42 g, 3.58 mmol) is dissolved in 2 M LiOH in methanol (50 mL) and the mixture is stirred at rt for 20 h before it is acidified by adding aq. HCl. The mixture is extracted twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (710 mg) as a white solid; LC-MS: tR=0.52 min; [M+1]+=372.14. b) To a solution of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (400 mg, 1.08 mmol) in DMF (5 mL), HOBt (160 mg, 1.19 mmol) followed by EDC HCl (227 mg, 1.19 mmol) is added. The mixture is stirred at rt for 5 min before ethanolamine (72 mg, 1.19 mmol) is added. The reaction mixture is stirred at rt for 1 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3. The washing is extracted back twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with DCM containing 4% of methanol to give the title compound (290 mg) as a white solid; LC-MS: tR=0.47 min; [M+1]+=415.14; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.67-3.72 (m, 2H), 3.73 (s, 2H), 3.90 (t, J=4.8 Hz, 2H), 6.69 (t br, J=5.3 Hz, 1H), 7.68 (s, 1H), 7.91-7.95 (m, 2H), 8.22-8.26 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[CH:27]=[C:26]([CH3:28])[N:25]([CH3:29])[N:24]=1)=[O:4].[OH-].[Li+]>>[CH3:29][N:25]1[C:26]([CH3:28])=[CH:27][C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:21])([F:22])[F:20])(=[O:11])=[O:12])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[N:24]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)n(C)n1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)nn1C

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(1,5-dimethyl-1H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid. MS (ESI): m/z=418.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
m-Nitrobenzyl bromide (500 mg, 2.31 mmol) was added to a mixture of 1-methylpiperazine (277 mg, 2.77 mmol) and potassium carbonate (414 g, 3.0 mmol) in 5 mL of DMF. The mixture was stirred at 90° C. for 16 hours. After cooling to room temperature, the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with EtOAc/CH3OH/NH4OH (10:1:0.1, v/v), gave 510 mg of 1-methyl-4-(3-nitro-benzyl)-piperazine, which was converted to the title compound under normal hydrogenation conditions. The titled compound was obtained as a yellow solid (450 mg, 95%). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.02 (t, J=7.6 Hz, 1H), 6.62 (s, 1H), 6.60 (d, J=7.6 Hz, 1H), 6.54 (d, J=7.6 Hz, 1H), 3.43 (s, 2H), 2.76 (br, 4H), 2.65 (br, 4H), 2.82 (m, 4H), 2.46 (s, 3H).
Reaction SMILES: [OH-].[Na+].CS(C)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]#[N:16])=[CH:10][CH:9]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(CCCc1ccccc1)c1ccc(Cl)cc1

Procedure:
2 ml of an aqueous sodium hydroxide (1.08 g) solution was added to a 10 ml solution of dimethylsulfoxide containing 1.0 g (6.6 mmole) of 4-chlorophenylacetonitrile and 1.3 g (6.6 mmole) of 1-bromo-3-phenylpropane at room temperature. After stirring for 2 hours under the same conditions, water was added to the reaction mixture and the mixture was extracted with 10 ml of n-hexane, dried, and condensed under reduced pressure to obtain 1.78 g (yield: quantitative) of 2-(4-chlorophenyl)-5-phenylvaleronitrile.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[C:7](O)[C:6]([CH3:11])=[CH:5][N:4]=1.P(Br)(Br)([Br:14])=O.[OH-].[K+]>C(Cl)(Cl)Cl>[Br:14][C:7]1[C:6]([CH3:11])=[CH:5][N:4]=[C:3]([CH2:2][Cl:1])[C:8]=1[CH3:9]
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cnc(CCl)c(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cnc(CCl)c(C)c1Br
Temperature: 130 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of 2-chloromethyl-3,5-dimethyl-pyridin-4-ol (8.2 g, 47.8 mmol) and POBr3 (60 g, 209 mmol) was stirred at 130° C. for 3 h. The resulting viscous oil was cooled to r.t. and poured onto ice water. The pH was adjusted to 10 with solid KOH. Work-up (CHCl3), drying (MgSO4) and evaporation afforded the title compound as a purple solid (8.7 g, 78% yield) which was used without purification. R.t.: 6.03 min. 1H-NMR (CDCl3): 8.20 (s, 1H), 4.62 (s, 2H), 2.50 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[O:12])=[C:6]([CH3:35])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[CH:29]1([N:13]([C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)[C:11](=[O:12])[NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:36])=[O:2])=[CH:5][C:6]=2[CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1NC(=O)N(c1c2ccccc2nn1-c1ccccc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 2.2, 4-[3-cyclohexyl-3-(2-phenyl-2H-indazol-3-yl)-ureido]-3-methyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as off-white solid. MS: m/e=469.4 [M+H+].
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][N:13](C)C=O.[Cu](C#N)C#N.O>C(Cl)Cl>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:12]#[N:13])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN(C)C=O
Reactant: O=C1CCc2ccc(Br)cc21
Agent: N#C[Cu]C#N
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C(=O)CC2
Reaction time: 0.25 h

Procedure:
2 g of 6-bromo-indanone, 10 ml of dimethylformamide and 3 g of copper cyanide are taken to reflux for 20 hours. At 20° C. the reaction mixture is poured into 40 ml of water and 30 ml of methylene chloride, agitated for 15 minutes and filtered on celite. The filtrate is decanted and re-extracted with methylene chloride. The organic phase is washed with water, dried, brought to dryness under reduced pressure and the residue is chromatographed on silica in a hexane-ethyl acetate mixture as eluant (7-3). 1.03 g of expected product is obtained, M.p.=109° C.
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:9]1[CH:37]([OH:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=O)C.Cl>C(OCC)C>[NH2:7][C@@H:8]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:9]1[CH:37]([OH:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCOC(=O)CC(O)[C@H]1[C@H](NC(=O)OC(C)(C)C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)CC(O)[C@H]1[C@H](N)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
Dissolve [1R,2S,3R,4S,5R]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-β-hydroxy-3,4,5-tris(phenylmethoxy)cyclopentanepropanoic acid, ethyl ester (160 mg, 0.258 mmol) in ethyl ether (20 mL) and cool to 0°-5° C. with an ice bath. Bubble hydrogen chloride gas into the solution for 25-30 minutes. Remove the ice bath and evaporate the ethyl ether to 1/2 volume with a stream of nitrogen. Add fresh ethyl ether and carefully add aqueous sodium hydrogen carbonate. Separate the organic phase and extract the aqeuous phase with ethyl acetate. Combine the organic phases, wash with aqueous sodium chloride, dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as a mixture of epimers (140 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH:12]([C:15]1[S:16][C:17]([C:20]([N:22]2[CH2:27][C:26]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[O:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][N:19]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>CC#N>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][C:26]2([O:25][CH2:24][CH2:23][N:22]([C:20]([C:17]3[S:16][C:15]([CH:12]([CH3:13])[CH3:14])=[N:19][CH:18]=3)=[O:21])[CH2:27]2)[CH2:28][CH2:29]1
Reactant: OCCCCCCCCCBr
Reactant: CC(C)c1ncc(C(=O)N2CCOC3(CCNCC3)C2)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 9-bromo-1-nonanol (0.446 g) in MeCN (3.9 mL) was added to solution of (2-isopropylthiazol-5-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 114, step b) (0.395 g) and triethylamine (0.36 mL) in MeCN (8.6 mL). The resulting mixture was stirred at 60° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM (25 mL), washed with brine (20 mL) and water (20 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the subtitled compound as a white solid. Yield 0.329 g.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H-].[Na+].[I-].[Na+].[CH3:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:18]Br>CC(=O)CC>[CH3:14][C:15]1[CH:22]=[C:21]([CH:20]=[C:17]([CH3:18])[CH:16]=1)[CH2:23][CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)CC(=O)CC
Reactant: Cc1cc(C)cc(CBr)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCC(=O)C(Cc1cc(C)cc(C)c1)C(=O)CC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
A solution of 3,5-heptanedione (1.24 ml, 9.13 mmol) in 2-butanone (40 ml) was treated with sodium hydride (60% dispersion in oil) (402 mg, 10.05 mmol) (added in portions) and stirred at room temperature for 10 minutes. Sodium iodide (1.5 g, 10.05 mmol) and then by 3,5-dimethylbenzyl bromide (2.0 g, 10.05 mmol) were added to the reaction mixture which was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (×3). The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane followed by cyclohexane:ethyl acetate (40:1, by volume) to afford the title compound as a yellow oil (995 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][N:16]([CH2:26][CH3:27])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1.[OH-].[Na+]>C(O)(=O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]([CH2:26][CH3:27])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cn(CC)c2nc(N3CCN(CCO)CC3)ncc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(CCO)CC3)nc21
Reaction time: 2 h
Yield: 53.3 %

Procedure:
5.14 g. of the ester are added to an aqueous-alcoholic solution of sodium hydroxide (N NaOH: 15 cm3, ethanol: 10 cm3); the mixture is stirred for 2 hours at ordinary temperature and is then brought to pH 6 by adding acetic acid. After concentration to dryness in vacuo, the residue is taken up in a saturated solution of sodium acetate (50 cm3) and is extracted with chloroform (3 × 50 cm3). After drying (MgSO4), the solvent is evaporated and the residue is recrystallised from 80 cm3 of ethanol. 2.4 g. (53.3%) of 2-(4'-β-hydroxyethyl-piperazino)-5-oxo-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid are obtained; melting point 222° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)(=[O:25])=[O:24]>C1COCC1>[N:35]1[C:36]2[C:31](=[CH:30][CH:29]=[CH:28][C:27]=2[NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:25])=[O:24])[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
Isobutyryl chloride (42 mg, 0.40 mmol) and DIPEA (100 mg, 0.83 mmol) were added to a solution of 2-amino-N-quinolin-8-yl-benzenesulfonamide (Example Compound 8) (100 mg, 0.33 mmol) in THF (3 ml) at 0° C. The reaction was stirred at room temperature for 1 h. The reaction was quenched water and extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (49:1) as the eluent to give the title compound (43 mg, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:6]([CH:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][C:17]2=[O:26])[CH2:12][CH2:11]1)[CH3:9])=[O:7].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH2:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[O:18][C:17]3=[O:26])[CH2:14][CH2:15]2)[CH3:9])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(C(=O)C(C)N2CCC(N3Cc4ccccc4OC3=O)CC2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)C(C)N2CCC(N3Cc4ccccc4OC3=O)CC2)cc1OC
Reaction time: 1 h
Yield: 59.4 %

Procedure:
In this example, 2.8 g of 1-[1-(3,4-dimethoxybenzoyl)-ethyl]-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine obtained in Example 5 is mixed with 150 ml of methanol. While the mixture is stirred at 0° to 10° C., 2 g of sodium borohydride is added thereto over a period of one hour. The mixture is further stirred for 3 hours at the same temperature and then stirred overnight at room temperature. The white crystals deposited are separated by filtration, washed with methanol and water and dried to obtain 1.90 g of a crude product. The crude product is recrystallized from ethanol to obtain 1.67 g of the desired product.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:17])=O.CN(C)C=O>CCOCC>[CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14])[CH2:3][CH2:2]1
Reactant: O=C(O)CCCCCCCCC1CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)CCCCCCCCC1CC1

Procedure:
A mixture of 0.85 g. of 9-cyclopropylnonanoic acid, 0.45 ml. of thionyl chloride (density 1.656) and 0.10 ml. of dimethylformamide (density 0.945) in 10 ml. ether is stirred overnight at room temperature. The upper layer of the reaction mixture is then separated and the solvent removed by evaporation to yield 9-cyclopropylnonanoyl chloride to which is added at 0° under nitrogen 1.4 g. of 9-octadecen-1-ol and 40 ml. of ether. To this mixture is added dropwise 0.52 ml. of pyridine (density 0.98). The reaction mixture is then stirred 1/2 hour at 0° and overnight at room temperature. The mixture is filtered, 3 equivalents of water are added and then the mixture is stirred for one hour. Ether is added to dilute the reaction mixture which is washed in turn with 2N sulfuric acid (2 × 50 ml.), 10% aqueous sodium carbonate (2 × 50 ml.), water (2 × 50 ml.) saturated aqueous copper sulfate, water (2 × 50 ml.) and saturated aqueous sodium chloride (1 × 50 ml.). The solution is then dried over calcium sulfate and the solvent removed by evaporation to yield 9-octadecenyl 9-cyclopropylnonanoate which is purified by thin layer chromotography (15% ether/hexane solvent).
Reaction SMILES: Cl.[CH3:2][C:3]([NH:14][CH2:15][CH:16]([OH:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24]C1C=CC=CC=1)([CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C(O)C.C([O-])(=O)C([O-])=O.C(O)(=O)C(O)=O>[H][H].[C].[Pd]>[CH3:13][C:3]([NH:14][CH2:15][CH:16]([OH:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])([CH3:2])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)c2ccccc2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: COc1ccc(CC(C)(C)NCC(O)c2ccccc2OC)cc1
Yield: 73.8 %

Procedure:
A mixture of 442 mg of α-[(α,α-dimethyl-4-methoxyphenethylamino)methyl]-2-benzyloxybenzylalcohol hydrochloride, 250 mg of 10% palladium-carbon and 25 ml of 95% aqueous ethanol is shaken at room temperature in hydrogen gas atmosphere under atmospheric pressure. After the uptake of hydrogen is completed, insoluble materials are removed by filtration. The filtrate is evaporated to remove the solvent. The residue (colorless oil) is alkalized with an aqueous ammonia solution, whereby 300 mg of a pale yellow oil are obtained. Said oil is converted into its oxalate by using 45 mg of oxalic acid, and the oxalate is recrystallized from 95% aqueous methanol. 243 mg of α-[(α,α-dimethyl-4-methoxyphenethylamino)methyl]-2-hydroxybenzylalcohol 1/2 oxalate are thereby obtained as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.N([O-])=O.[Na+].O.O.O.[C:20]([O-])(=O)[CH3:21].[Na+]>O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([C:21]2[CH:20]=[CH:4][CH:3]=[CH:2][CH:8]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)[O-]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of 100 g (0.55 mole) of 97% purity 4-chloro-3-nitroaniline, 200 ml of concentrated hydrochloric acid and 130 ml of water was heated to reflux and then cooled to 0° C. To the resulting slurry was added dropwise a solution of 49 g (0.71 mole)of sodium nitrite in 70 ml of water over a 45 min period while maintaining the temperature at 0°-5° C. To this cold solution was added 1.3 liters of benzene (cooled to 5° C. and the mixture was stirred vigorously while a solution of 190 g sodium acetate trihydrate in 400 ml of water was added over a period of 1 hr. Vigorous stirring was continued first for 3 hr at 5° C. and then for 40 hr at ambient temperature. The organic layer was separated, washed with dilute sodium hydroxide and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 30% benzene in ligroin. Recrystallization of the isolated solid from cyclohexane-ligroin gave 71.3 g (56%) of the title product as pale yellow crystals, m.p. 43°-44° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl-].[NH4+]>CO.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:8])[CH:7]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cc(Br)cc(Br)c1
Yield: 87.1 %

Procedure:
A suspension of 3,5-dibromo nitrobenzene (J. Amer. Chem Soc., 1950, 72, 793) (1.0 g, 3.6 mmol) in methanol (30 ml) was added in portions to a stirred mixture of iron powder (0.52 g, 9.3 mmol) in a saturated solution of ammonium chloride (50 ml) at 60° C. The mixture was heated at reflux for 2 h, filtered and the filtrate extracted with dichloromethane (2×70 ml). The organic extract was dried (Na2SO4) and concentrated in vacuo to give the title compound (D7) as an oil (0.787 g, 87%), MH+ 250/252.