Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[NH:22][C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=1)[CH2:8][CH2:9][CH3:10]>O1CCCC1>[CH2:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[NH:25][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:22]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCNC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCNCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
Part B. To a solution of lithium aluminum hydride (0.46 g, 0.012 mol) in dry tetrahydrofuran (15 mL) was added, dropwise, a solution of N-butyl-8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanamide (1.20 g, 0.0027 mol) in tetrahydrofuran (8 mL) and the reaction mixture was stirred at reflux for 18 hours. The reaction mixture was cooled to 0° C. and quenched by the slow and careful sequential addition of water (0.46 mL), 15% sodium hydroxide (1.38 mL), and water (1.38 mL) and then the reaction mixture was stirred at 0° for 30 minutes. The solution was dried over magnesium sulfate and concentrated under vacuum, and the residue was chromatographed with 1:1 hexane-ethyl acetate and then with a gradient of 1:0 to 8:2 to 1:1 ethyl acetatemethanol. The resulting solid was triturated with hexane to give N-butyl-8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanamine (0.45 g, 0.001 mol) as a white solid, mp 75°-78°. 1H NMR (CDCl3) δ 7.6-7.1 (m, 10H), 3.1(t,2H, J=7Hz), 2.5(t,2H, J=7Hz), 1.7-1.0(m, 16H), 0.9 (t, 3H, J=8Hz).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[F:36].[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[C@@H:4]([F:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](F)C1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1F

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f62) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:10]([N:15]1C(=O)C2=CC=CC=C2C1=O)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.NN.Cl>C(O)C>[CH3:1][O:2][C@@H:3]([C@@H:10]([NH2:15])[CH2:11][CH:12]([CH3:13])[CH3:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CO[C@H](c1ccccc1)[C@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CO[C@H](c1ccccc1)[C@@H](N)CC(C)C
Temperature: 5 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
The N-[1-(S)-[α-(R)-methoxybenzyl]-3-methyl-butyl]phthalimide (25.6 g, 75.9 mmol.) obtained above was suspended in ethanol (250 mL). To the suspension was added hydrazine hydrate (7.5 mL), and the resulting mixture was heated under reflux for 15 hours. The reaction mixture was chilled in an ice bath, and stirred at 5° C. for one hour after addition of 4N hydrochloric acid (200 mL). The insoluble material was removed by filtration and washed with 4N hydrochloric acid. The filtrate and washings were combined, and placed under reduced pressure to distill off ethanol. The residue was made basic to reach pH approx. 11, by addition of 10N aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The dried extract was placed under reduced pressure to give the titled compound as pale yellow oil (15.5 g, purity: 91%, yield. 81%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8](=[CH:11]Cl)[CH:9]=O.[NH2:13][C:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH:15]=1>C(Cl)Cl.CN(C)C=O.C([O-])(O)=O.[Na+]>[Cl:7][C:8]1[CH:9]=[N:13][C:14]2[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[C:15]=2[CH:11]=1
Reactant: NC1=CC(=O)CCC1
Reactant: O=CC(Cl)=CCl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCc2ncc(Cl)cc21
Temperature: 25 °C

Procedure:
Chloromalondialdehyde (19 grams, 0.178 mol) was suspended in methylene chloride (100 ml) with dry dimethylformamide (DMF) (2.5 ml). This was mechanically stirred under a nitrogen atmosphere while a solution of oxalyl chloride (23.7 grams/16.3 ml, 0.185 mol) in methylene chloride (50 ml) was added dropwise over 20 minutes. The reaction mixture at first started to warm from 22° to 28°, but as the evolution of gases increased the temperature fell to 18°. The reaction was stirred at room temperature and was followed by thin layer chromatography (ethyl acetate/hexanes, 1:1) until conversion to 2,3-dichloroacrolein was complete. A solution of 1-amino-cyclohexen-3-one (19.85 grams, 0.18 mol) in DMF (125 ml) was added dropwise and the reaction was heated to 70° C. overnight. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO3, and twice extracted with ethyl acetate (400 ml and 200 ml). The combined organic layers were washed with water (3×) and brine (1×). The organic solution was stirred with MgSO4 and decolorizing carbon (Darco (trademark)); then filtered through Super Cel (trademark)) and concentrated to a brown solid. Yield 21 grams (65%); mp 90°-91° C. NMR (CDCl3, 300 MHz) δ8.6 (d, 1), 8.24 (d, 1), 3.1 (t, 2), 2.7 (m, 2), 2.15 (m, 2).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[S:9][CH:10]=1>C(O)(=O)C>[CH:2]([C:6]1[CH:7]=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[S:9][CH:10]=1)=[O:1]
Reactant: COC(=O)/C=C/c1cc(C2OCCO2)cs1
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1cc(C=O)cs1
Temperature: 37.5 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To methyl (2E)-3-[4-(1,3-dioxolan-2-yl)thiophen-2-yl]prop-2-enoate (2.200 g, 9.156 mmol) was added 50% acetic acid aqueous solution (22 ml), and the mixture was stirred at 35 to 40° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure, and water (50 ml) was added. The mixture was concentrated again under reduced pressure, and water (100 ml) was added. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give methyl (2E)-3-(4-formylthiophen-2-yl)prop-2-enoate (1.701 g, yield 94.7%) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2([CH3:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:23][CH:24]=1.O>CN(C)C=O>[CH3:31][C:25]1([C:22]2[O:23][CH:24]=[C:20]([CH2:19][O:3][C:4]3[CH:17]=[CH:16][C:7]([CH2:8][CH:9]4[S:13][C:12](=[O:14])[NH:11][C:10]4=[O:15])=[CH:6][CH:5]=3)[N:21]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: CC1(c2nc(CCl)co2)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)co2)CCCCC1
Reaction time: 0.5 h

Procedure:
60% sodium hydride in oil (1.32 g) was added to solution of 5-(4-hydroxybenzyl)-2,4-thiazolidinedione (3.35 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred for 30 minutes. Then, solution of 4-chloromethyl-2-(1-methylcyclohexyl)oxazole (3.85 g) in N,N-dimethylformamide (5 ml) was added dropwise thereto at room temperature. After being stirred at 60° C. for 1 hour, the reaction solution was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The oily residue was chromatographed on a column of silica gel (70 g). Elution with hexaneethyl acetate (2:1, V/V) gave 5-{4-[2-(1-methylcyclohexyl)-4-oxazolylmethoxy]benzyl}-2,4-thiazolidinedione as an oily substance. A solution of sodium 2-ethylhexanoate in isopropanol (2N, 3 ml) was added to the oily substance, and treated with ether. The crystals which separated out were collected by filtration to give 5- {4-[2-(1-methylcyclohexyl)-4-oxazolylmethoxy]benzyl}-2,4-thiazolidinedione.sodium salt (2.3 g, 36.3%). Recrystallization from methanol afforded colorless plates. m.p. 285°-287° C. (decomp.) Elemental analysis for C21H23N2O4SNa, Calcd.: C, 59.70; H, 5.49; N, 6.63. Found: C, 59.76; H, 5.56; N, 6.82.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25]([C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:25]([C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:42])=[O:41])(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CCCCCCCCCCN
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7 ml of anhydrous triethylamine are added to 5.3 g of ethyl 11-aminoundecanoate hydrochloride in 30 ml of anhydrous methylene chloride and, after stirring for one hour at ambient temperature, 6.3 g of 2-benzoyl-4-chlorobenzenesulphonyl chloride are added dropwise. After stirring for 12 hours, the reaction medium is evaporated to dryness under vacuum, taken up with water and extracted with ethyl acetate. The organic phase which is washed with water until the washings are free of Cl- ions is dried over sodium sulphate and evaporated to dryness under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([Cl:20])=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[O:22]>>[Cl:20][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10](/[CH:9]=[CH:8]/[C:4]3[CH:3]=[C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH:21]=[O:22])[CH:7]=[CH:6][CH:5]=3)=[N:11]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2ccc(/C=C/c3cccc(Br)c3)nc2c1
Reactant: O=Cc1ccccc1B(O)O
Product: O=Cc1ccccc1-c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
Prepared as described in Example 1 (step 1) from (E)-2-[2-(3-bromophenyl)vinyl]-7-chloroquinoline (prepared as described Example 8 (step 6), from 3-bromobenzaldehyde) and 2-formyl benzeneboronic acid (1.5 eq.). Title compound was purified by swish (Hex: CH2Cl2). 1H NMR (CDCl3) δ 7.3-7.6 (6H, m), 7.6-7.8 (6H, m), 8.0-8.1 (3H, m), 10.03 (1H, d).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.CCN(CC)CC.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:41][C:31]1[CH:36]=[CH:35][C:34]([S:37]([O:1][CH2:2][CH2:3][N:4]2[CH:8]=[C:7]([NH:9][C:10]([C:12]3[N:13]=[CH:14][O:15][C:16]=3[C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[O:11])[CH:6]=[N:5]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCO)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (2.57 g, 8.23 mmol) in DCM (70 mL), Et3N (3.44 mL, 24.69 mmol) was added. After stirring for 20 min at 0° C., p-toluenesulfonyl chloride (1.73 g, 9.05 mmol), was added dropwise, and the resulting suspension was stirred at 0° C. for 3 h, then quenched with water and extracted with DCM (2×). The combined org. layers were washed with 1 N aq. HCl-solution and brine, dried (MgSO4), filtered and concentrated in vacuo to obtain the title compound as an oil. LC-MS conditions A: tR=0.93 min, [M+H]+=467.46.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Cl:15])=[CH:10][N:9]=1.C1OCCOCCOCCOCCOCCOC1.[CH2:34]([O:36][C:37]([C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=2)[N:41]([C:49]2[CH:54]=[CH:53][C:52]([O:55][C:56]([F:59])([F:58])[F:57])=[CH:51][CH:50]=2)[C:40]=1[CH2:60][C:61]([O:63][CH2:64][CH3:65])=[O:62])=[O:38])[CH3:35]>CCOC(C)=O.CN(C=O)C>[CH2:34]([O:36][C:37]([C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][C:8]3[CH:13]=[CH:12][C:11]([CH2:14][Cl:15])=[CH:10][N:9]=3)[CH:46]=2)[N:41]([C:49]2[CH:50]=[CH:51][C:52]([O:55][C:56]([F:59])([F:57])[F:58])=[CH:53][CH:54]=2)[C:40]=1[CH2:60][C:61]([O:63][CH2:64][CH3:65])=[O:62])=[O:38])[CH3:35]
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(CCl)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
K2CO3 (138 mg, 1.0 mmol), 2-chloro-5-chloromethylpyridine (32 mg, 0.2 mmol) and 18-crown-6 (5 mg) were added to a mixture of 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (90 mg, 0.2 mmol, see step (b) Example 9) and DMF (5 mL). The mixture was stirred for 48 h at 70° C., cooled, diluted with EtOAc, filtered through Celite®, concentrated and purified by chromatography. Yield 60 mg (520%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH2:16])=[O:10])[CH:5]=[CH:4][N:3]=1.[CH:18]1([CH:21]=O)[CH2:20][CH2:19]1.C(O)C.C([BH3-])#N.[Na+]>O>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:16][CH2:21][CH:18]2[CH2:20][CH2:19]2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)sc2N)ccn1
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(NC(=O)c2nc(C)sc2NCC2CC2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
5-Amino-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide (0.200 g, 0.806 mmol) was treated with cyclopropanecarboxaldehyde (0.230 g, 3.22 mmol) and tetraisopropyl-orthotitanate (0.916 g, 3.22 mmol) and stirred at room temperature overnight. Ethanol (5 mL) and sodium cyanoborohydride (0.213 g, 3.22 mmol) were added and the reaction mixture was stirred for 5 h. Water (0.5 mL) was added to the reaction mixture and the solvent was evaporated. The residue was purified by flash chromatography on silica gel with ethyl acetate/methanol 100:0→90:10 gradient to yield the title compound (0.110 g, 45%) as a light yellow solid, MS (ISP): m/e=303.1 (M+H+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1)(=O)=O>CN(C)C=O>[N:1]([CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([CH2:26][CH2:27][O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:18]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCOS(C)(=O)=O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCN=[N+]=[N-])cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Sodium azide (0.29 g) was added to a solution of ethyl 3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-(2-phenoxyethyl)propionate, which is the product of Reference example 3(g), in dimethylformamide (8 ml). The mixture was stirred at 70° C. for 2 hours. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and then concentrated to afford the desired compound (546 mg) as a syrup.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[N:9]([CH2:11][C:12](=[O:19])[NH:13][CH2:14][C:15](=O)[CH2:16][CH3:17])[N:8]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=2[CH2:5][CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:16]([C:15]1[O:19][C:12]([CH2:11][N:9]2[C:10]3[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=3[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:8]2)=[N:13][CH:14]=1)[CH3:17]
Reactant: CCOC(=O)c1nn(CC(=O)NCC(=O)CC)c2c1CCCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ncc(CC)o2)c2c1CCCC2=O
Temperature: 90 °C
Yield: 59.5 %

Procedure:
A solution of 506 mg (1.51 mmol) of ethyl 7-oxo-1-{2-oxo-2-[(2-oxobutyl)amino]ethyl}-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in toluene (45 mL) was treated with 0.422 mL (4.53 mmol) of phosphoric trichloride and heated at 90° C. for 15 hours. The mixture was cooled to room temperature, poured into ice and neutralized with NaOH 5N. The aqueous phase was extracted with dichloromethane and the organic layer afforded 425 mg of crude that was purified on silica gel (eluant hexane/ethylacetate 7/3). 285 mg of the title compound were thus isolated (60% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23]N1C(=O)CCC1=O>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[CH2:10][CH:9]1[Cl:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1Cl
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of 1.25 g (4 mmol) of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 75c) in 10 ml of isopropanol are added 0.72 g (4.2 mmol) of N-chlorosuccinimide. The solution is stirred for 6 h at 50° C. After this time, the solution is evaporated to dryness and the residue is dissolved in 100 ml of EtOAc. The solution is extracted with water, dried over MgSO4 and evaporated to dryness to provide the title compound: ES-MS: 342.2, 344.2 (M+H)+; analytical HPLC: tret=5.70 minutes (Grad 2).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[OH:26][C:20](=[CH:12][C:11](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)=CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.6 %

Procedure:
To a solution of potassium bis(trimethylsilyl)amide (8.88 g, 44.5 mmol) in 400 mL of THF was added dropwise acetophenone (4.85 mL, 41.6 mmol) at 78° C. After 1 hour, diethyl oxalate (6.2 mL, 45.8 mmol) was added dropwise at the same temperature. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvent was removed in vacuo. The resulting yellowish solid was filtered and washed with Et2O to give the title compound 2 (10.5 g, 98%) as a sodium salt of Ethyl 2-hydroxy-4-oxo-4-phenyl-2-butenoate (2). To a solution of sodium salt of 2 in EtOH (300 mL) was added 4-amidosulfonylphenylhydrazine 1b (10 g, 44.7 mmol) at room temperature. The reaction mixture was stirred for 1 hour and then 2.4 mL of AcOH was added. The reaction mixture was refluxed for 2 hours. After cooling, the solvent was removed in vacuo. The resulting solid was purified by recrystallization with MeOH to afford the titled compound (13.5 g, 89% yield) as a white solid. mp 191.5-194.6° C. 1H NMR (300 MHz, DMSO-d6): δ 7.87 (d, J=8 Hz, 2H), 7.58-7.48 (m, 4H), 7.44-7.38 (m, 3H), 7.34-7.27 (m, 2H), 7.16 (s, 1H), 4.35 (q, J=7 Hz, 2H), 1.32 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH:13]([OH:15])[CH:12]([N:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C:31](OC(C)=O)=[O:32]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:14][CH:13]([OH:15])[CH:12]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[C:31](=[O:32])[CH3:30])[CH2:20][CH2:21]3)[CH2:11]2)=[O:9])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCC(Nc3ccc(Cl)cc3)CC2)C1
Solvent: c1ccncc1
Product: CC(=O)N(c1ccc(Cl)cc1)C1CCN(C2CN(C(=O)c3ccc(Cl)cc3)CC2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting materials (4-Chloro-phenyl)-{3-[4-(4-chloro-phenylamino)-piperidin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-methanone (48 mg, 0.11 mmol) and Ac2O (16 uL, 0.17 mmol) were added in pyridine (0.5 mL) and stirred at room temperature overnight. The reaction mixture was concentrated down to dryness. The resulting crude residue was purified by column chromatography on silica (Methanol\CH2Cl2: 0%-6%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:23]([O:27][C:28]1[CH:34]=[CH:33][C:31](O)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26]>O1CCCC1.C(N(CC)CC)C>[CH2:23]([O:27][C:28]1[CH:34]=[CH:33][C:31]([O:19][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:22][CH:21]=2)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26]
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCOc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.1 g of 4-(6-methacryloyloxyhexyloxy)benzoic acid were converted to the acid chloride in a manner similar to example 6. This substance was taken up in 100 ml of tetrahydrofuran (THF) and added dropwise at 0° to 5° C. to a stirred solution of 3.3 g of hydroquinone monobutyl ether in 100 ml of THF and 4 ml of triethylamine. The mixture was stirred for a further 3 hours at room temperature and the triethylamine hydrochloride was then filtered out. The filtrate was evaporated to dryness and the residue dissolved in 50 ml of dichloromethane. The solution was washed several times with water, dried with sodium sulphate and the solvent then distilled off. The crude product so obtained was purified by column chromatography and recrystallisation from n-hexane.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]2[N:30]=[CH:4][C:5]3[CH2:6][C:7](=[O:17])[NH:8][C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[C:11]=3[N:29]=2)=[CH:25][CH:26]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Reactant: COc1ccc(CC(=N)N)cc1
Agent: Cl
Product: COc1ccc(Cc2ncc3c(n2)-c2ccccc2NC(=O)C3)cc1
Yield: 31 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(4-methoxyphenyl)-acetamidine hydrochloride. Yield: 31%. White solid, m/z (ISP) 332 (MH).