Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][CH2:8]1.[OH:15][NH:16][C:17](=N)[CH:18]([CH3:20])[CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:18]([C:17]1[N:14]=[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C@H:5]3[CH2:6][C@H:4]3[CH2:3][CH2:2][OH:1])[CH2:12][CH2:11]2)[O:15][N:16]=1)([CH3:20])[CH3:19]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC([C@H]2C[C@H]2CCO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml RBF was added a solution of 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carbonitrile (15.3 g, 85 mmol) in 1:1 THF:EtOAc (150 ml). To this solution was added N-hydroxy-2-methylpropanimidamide (9.93 g, 97 mmol) as a solid and the resulting mixture was stirred to yield a clear solution. An addition funnel was added to the flask and the whole set up was set under nitrogen atmosphere. The solution was placed in an oil bath heated to 70° C. A 0.5M solution of zinc chloride (204 ml, 102 mmol) in THF was placed in the addition funnel and added over a 5 minute period to the reaction mixture. Upon complete addition, the resulting mixture was stirred at 70° C. for 2 hours. After 30 minutes the clear solution became cloudy. After 1 hour at 70° C., a thick white precipitate formed. TLC indicates consumption of the all starting material. The mixture was cooled to RT and the white solid was filtered off and washed with 1:1 THF:EtOAc (200 mL) and dried. The white solid in the fitted funnel was dissolved in 100 mL of DMF and drawn through by vacuum into a 250 ml RBF. To this solution was then added Tosic Acid (8.07 g, 42.4 mmol) and the resulting mixture stirred at 80° C. overnight. (LCMS after 2.5 hrs showed the reaction was ˜30-40% complete with no other by-products forming.) The mixture was allow to cool to room temperature and then was diluted with 150 mL of ethyl acetate. The mixture was placed in a separatory funnel and washed with sat'd sodium bicarbonate solution (150 mL). The aqueous was extracted once with ethyl acetate (100 mL) and the organics were combined. The organics were washed with 1M Na2CO3 (50 mL), followed by water (2×100 mL), and then brine (100 mL). The organics were dried over sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The residue was taken up in 50 mL DCM and loaded onto a Flash 75 system (silica gel column). Biotage Flash 75 purification was done eluting with 20-70% ethyl acetate/hexane for 4 column volumes followed by 70% ethyl acetate for 4 column volumes (total solvent 16 L). The fractions containing the product were collected and concentrated under reduced pressure to afford the pure product. LC/MS (m/z): 280 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>O1CCCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:17])=[O:9])[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C

Procedure:
In 30.0 ml of tetrahydrofuran (THF), 10.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 6.97 g of oxalyl chloride at 5° C. to a mixture of 100 ml of THF and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 250 ml of ice water to precipitate crystals. The crystals were collected by filtration and washed with 100 ml of ice water. The resulting crystals were thereafter suspended in water and the suspension was adjusted to pH 4.0 with a 1M aqueous solution of sodium acetate. The resulting solution was extracted with 250 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, followed by filtration. The filtrate was concentrated and, under reduced pressure, was then dried, whereby the title compound was obtained. Yield: 7.5 g (68.7%). Purity: 98.7 %.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:34][CH2:35][N:30]([C:24]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:22])[CH2:31][CH2:32]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3c(C)cccc3C)CC2)c(OC)nc1C
Yield: 80 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:13]([O:20][N:21]1[C:30](=[O:31])[C:29]2[CH:32]=[C:33]([C:36]#[N:37])[C:34](Cl)=[C:27]3[C:28]=2[C:23](=[CH:24][CH:25]=[CH:26]3)[C:22]1=[O:38])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([O:20][N:21]1[C:30](=[O:31])[C:29]2[CH:32]=[C:33]([C:36]#[N:37])[C:34]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:27]3[C:28]=2[C:23](=[CH:24][CH:25]=[CH:26]3)[C:22]1=[O:38])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1cc2c3c(cccc3c1Cl)C(=O)N(OCc1ccccc1)C2=O
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(OCc1ccccc1)C2=O
Temperature: 0 °C
Yield: 68.6 %

Procedure:
To a solution of pyrrolidine (0.070 g, 0.98 mmol) and triethyl amine (0.11 g, 1.1 mmol) in acetonitrile (5 mL) at reflux was added 2-benzyloxy-6-chloro-5-cyano-benzo[de]isoquinoline-1,3-dione (0.20 g, 0.55 mmol, from Example A2). The reaction was heated at reflux for 20 minutes, then cooled to 0° C. The resulting precipitate was removed by filtration, washed with cold acetonitrile, and dried to give 0.15 g of the title compound.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[N:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[H-].[Na+]>O1CCOCC1>[CH2:24]([NH:23][C:21](=[O:22])[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]#[C:12][C:9]2[CH:8]=[N:7][C:6]([O:4][CH2:3][CH2:2][F:1])=[N:11][CH:10]=2)=[CH:19][CH:18]=1)[CH3:26])[CH3:25]
Reactant: OCCF
Reactant: CCNC(=O)C(C)c1ccc(C#Cc2cnc(Cl)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)C(C)c1ccc(C#Cc2cnc(OCCF)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 13 mg (0.21 mmol) 2-fluoro-ethanol in 0.5 mL 1,4-dioxane are added 34 mg (0.10 mmol) 2-[4-(2-chloro-pyrimidin-5-ylethynyl)-phenyl]-N-ethyl-propionamide (XVIII.1) in 1 mL 1,4-dioxane, followed by 12 mg (0.30 mmol) sodium hydride (60% in mineral oil). The mixture is stirred at rt for 12 h. After that time, the solvent is evaporated and the residue s purified by HPLC (preparative column: Sunfire, eluent A: water+0.1% TFA, eluent B: MeOH) to yield the desired product.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>CCO>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:15][CH:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: C1CNCCNC1
Solvent: CCO
Solvent: CC(=O)Cl
Product: Clc1ccc(CN2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
Acetyl chloride (11.7 mL, 0.165 mol) was added to anhydrous EtOH (500 mL) and the mixture was stirred for 30 min at 25° C. Homopiperazine (15.0 g, 0.150 mol) was added and the mixture was heated to reflux for 4 h. 4-Chlorobenzyl chloride (13.96 g, 0.087 mol) was added and the reaction mixture was heated to reflux for 16 h before concentrating. The residue was dissolved in EtOAc (500 mL) and washed with 1N aqueous KOH (50 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (double separation. SiO2, 20×7 cm, 1PrOH—H2O—NH4OH, 80:12:6 to 70:20:10 gradient elution) afforded the desired product (10.6 g, 53.4%) and the dialkylated homopiperazine (2.36 g, 16.5%). GC/MS m/e 224 (M+, C12H17N2Cl).10% CH3OH—CH2Cl2); RPLC tR=5.96 min (>85%), 220 nm (Mm (Method B): ESI/MS m/e 498.3 (MH++H, C31H35N3O3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH:10]=[O:11].O1CCOCC1.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:18][CH:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH:10]=[O:11]
Reactant: BrBr
Reactant: Cc1cccc(C)c1CC=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccc(C)c1C(Br)C=O
Reaction time: 0.17 h
Yield: 103.8 %

Procedure:
2-(2,6-dimethylphenyl)-acetaldehyde (4.4 g, 29.7 mmol) was dissolved in DCM (30 mL) and dioxane (50 mL) and a solution of bromine (1.7 mL, 32.7 mmol) in DCM (30 mL) was added dropwise at room temperature. Completion of reaction was determined by GC/MS. Upon completion, sodium thiosulfate aqueous solution was added and stirred for 10 minutes. The layers were separated, and washed twice with DCM (100 mL) and combined organics with 10% aqueous LiCl solution (100 mL). The organic layers were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give 7 g (93%) of 2-bromo-2-(2,6-dimethylphenyl)acetaldehyde as an orange oil. NMR confirmed the product, which was used without further purification.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6]Cl)[CH2:2]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[O:16]=[C:17]([CH3:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>O.CN(C)C=O>[C:17]([C:18]1([C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][O:4][CH2:1][CH2:2]1)(=[O:16])[CH3:23]
Reactant: COC(=O)CC(C)=O
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(C(C)=O)CCOCC1
Temperature: 80 °C
Yield: 51 %

Procedure:
In a flask made of glass having an inner volume of 1000 ml and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 143 g (1.0 mol) of 2,2′-dichloroethyl ether, 276 g (2.0 mol) of anhydrous potassium carbonate, 10 g (0.06 mol) of potassium iodide and 600 ml of N,N-dimethylformamide, and the temperature of the mixture was raised to up to 80° C. with stirring. Then, 139 g (1.2 mol) of methyl 3-oxobutanoate was gently added dropwise to the mixture, and the mixture was reacted at the same temperature for 8 hours. After completion of the reaction, 1000 ml of water was added to the reaction mixture, and the resulting mixture was extracted three times with 600 ml of ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure (125 to 127° C., 1.3 kPa) to give 95 g (Isolation yield: 50%) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 98% (areal percentage by gas chromatography) as a pale yellow liquid.
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[C:29]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccccc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC[C@@H](C)OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (725 mg, 2.76 mmol), benzoic acid (338 mg, 2.76 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (649 mg, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for two hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 10% ethyl acetate-hexane solution) to give (R)-2-benzoyloxyoctane as a colorless liquid substance (490 mg, yield: 91%/(S)-2-octanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]1([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:23][CH2:24]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCC(c2ccc(F)cc2)CC1
Product: Fc1ccc([C@H]2CC[C@H](N3CCN(Cc4ccccc4)CC3)CC2)cc1

Procedure:
A mixture of 4-(4-fluorophenyl)cyclohexanone (7.8 mmole) and 1-(phenylmethyl)piperazine (7.8 mmole) were reacted as described in Example 8. The crude isomer mixture was purified as described in Example 62. Concentration of the fractions containing the more polar isomer gave the trans product (22%, mp: 106-106° C.). Calc'd for C23H29FN2 : C, 78.38%; H, 8.30%; N, 7.95%. Found: C, 78.02; H, 8.20%; N, 7.90%.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:15](O)(=O)(=O)=O.II.S(=O)(=O)(O)O>C(O)(=O)C.O>[I:15][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: c1ccc2c(c1)CCc1ccccc1-2
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Ic1ccc2c(c1)CCc1ccccc1-2
Temperature: 0 °C

Procedure:
25.0 g (0.139 mol) of 9,10-dihydrophenanthrene, 6.30 g (27.6 mmol) of periodic acid and 17.0 g (67.0 mmol) of iodine are heated at 70° C. for 1 h in a solution of 4 ml of conc. sulfuric acid and 28 ml of water in 140 ml of glacial acetic acid. The solution is subsequently added to ice-water and extracted three times with ethyl acetate. The combined org. phases are washed with sat. sodium hydrogencarbonate soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is distilled in a bulb tube at 170° C. and 0.3 mbar, giving 2-iodo-9,10-dihydrophenanthrene as yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][CH3:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1)=[O:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[O:29][CH3:30]>CN(C)C=O>[CH3:30][O:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[CH2:18][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[O:2])[CH:11]=2)[C:7]([CH2:12][CH2:13][CH3:14])=[CH:8]1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CCCc1c[nH]c2cc(C=O)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cn(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc12
Reaction time: 1 h
Yield: 97.6 %

Procedure:
6-Formyl-3-propylindole (1.0 g) in N,N-dimethylformamide (DMF) (10 ml) was added slowly to a stirred suspension of sodium hydride (0.128 g, oil-free) in dry DMF (30 ml) at 0° under an atmosphere of nitrogen. The mixture was stirred at 0° for 60 min and methyl 4-bromomethyl-3-methoxybenzoate (1.38 g) in dry DMF (10 ml) was added dropwise. The cooling bath was removed, the mixture stirred for 3.5 hr, then poured into 1N hydrochloric acid (75 ml), and extracted with ethyl acetate (15 ml). The organic extract was washed (water (twice), brine), dried (MgSO4) and evaporated to give a dark oil. The product was purified by flash chromatography, eluting with 55:40:5 hexane:methylene chloride:ethyl acetate, to give methyl 3-methoxy-4-(6-formyl-3-propylindol-1-ylmethyl)benzoate (1.9 g, 97%) as a yellow oil; partial NMR(250 MHz, DMSO-d6): 0.95(t, 3H, CH2CH3), 1.65(m, 2H, CH2CH3), 2.70(t, 2H, CH2CH2CH3), 3.83(s, 3H, OCH3), 3.95(s, 3H, OCH3), 5.50(s, 2H, NCH2), 9.96(s, 1H, CHO).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:13])[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:3].F[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:2]([O:4][C:5](=[O:13])[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)[CH3:3]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 90 °C

Procedure:
To a solution of piperidin-4-yl-acetic acid ethyl ester hydrochloride (24 mmol) in anhydrous DMSO (20 mL) is added 1-(4-fluoro-phenyl)-ethanone (24 mmol) and potassium carbonate (24 mmol). The resulting mixture is heated at 90° C. for 36 hr. The reaction mixture is allowed to cool to rt, poured into cold water (100 mL), and extracted with EtOAc (40 mL×3). The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified through silica gel flash chromatography (hexane/ethyl acetate 2:1) to give the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.86 (2H, d), 6.85 (2H, d), 4.15 (2H, q), 3.89 (2H, br, d), 2.90 (2H, dt), 2.51 (3H, s), 2.27 (2H, d), 2.04 (1H, m), 1.83 (2H, br, d), 1.38 (2H, dt), 1.27 (3H, t); LC-MS (M+1): 290.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH3:13].O>C1COCC1>[CH2:12]([N:14]([CH2:18][CH3:19])[C:15]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:16])[CH3:13]
Reactant: CCN(CC)C(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.4 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 1.2 g, 30 mmol, 1.5 eq., Aldrich) in THF (20 mL) at 0° C. was slowly added a solution of indole (2.4 g, 20 mmol, Aldrich) in THF (20 mL). The resulting mixture was stirred at 0° C. for 20 min, after which N,N-diethylcarbamoyl chloride (2.9 mL, 22 mmol, 1.1 eq., Aldrich) was added. Then, the reaction mixture was stirred at 0° C. for 30 min. H2O (10 mL) was added to quench the reaction and the mixture was transferred to a separatory funnel. The organic and aqueous layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under reduced pressure. After purification of the residue by a short silica gel column (silica gel 60, 230-400 mesh) with EtOAc/hexanes as eluent, the product N,N-diethyl-1H-indole-1-carboxamide (4.3 g, 99% yield) was obtained as a light yellow oil. Further purification using flash column chromatography was deemed unnecessary. 1H NMR (400 MHz, CDCl3) δ ppm: 7.67 (d, J=8.17 Hz, 1H), 7.63 (d, J=7.65 Hz, 1H), 7.36-7.26 (m, 2H), 7.21 (t, J=7.24 Hz, 1H), 6.62 (d, J=2.77 Hz, 1H), 3.51 (q, J=7.10 Hz, 4H), 1.27 (t, J=7.11 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ ppm: 154.39, 135.51, 129.27, 125.89, 123.36, 121.55, 120.90, 112.98, 105.35, 42.41, 13.46.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.ClC1C(C2C=CC=CC=2)=NN=[C:30]2[N:40]([CH2:49][C:50]([NH:52][CH3:53])=O)N=C(C3C=CC=CC=3)[C:29]=12.CN1CCNCC1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:40]3[CH2:30][CH2:29][N:52]([CH3:53])[CH2:50][CH2:49]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CNC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN1CCNCC1
Product: CN1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
Compound 1 was synthesised from 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid following a similar procedure outlined in Example 16 (Compound 5), using N-methylpiperazine instead of methylamine hydrochloride in the final step. The residue in the final step was purified by preparative HPLC, followed by column chromatography (silica gel, gradient 0 to 5% triethylamine/acetone), yielding the Compound 1 as an off-white solid (6 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([Cl:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:21]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[C:13]([Cl:17])=[CH:12][C:11]=3[O:18][CH3:19])=[C:2]([NH2:1])[N:3]=2)[CH2:30][CH2:31]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: COc1cc(Cl)c(F)cc1C(=O)c1ccc(Cl)nc1N
Product: CCOC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)c(Cl)cc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(4-chloro-5-fluoro-2-methoxy-phenyl)-methanone (Example 47) and ethyl4-amino-1-piperidine carboxylate (Aldrich 96%) using the procedure described in Step B. Example 6. HRMS, observed: 451.1545, Calcd for (M+H)+: 451.1543.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34]3)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])/[C:34]/3=[CH:21]\[C:3]2[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]4)[C:7](=[O:20])[C:6]=3[C:2]=2[CH3:1])=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2ccc3c(c2)CC(=O)N3)cc1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: COc1ccc(-c2ccc3c(c2)/C(=C/c2[nH]c4c(c2C)C(=O)N(CCN2CCCCC2)CCC4)C(=O)N3)cc1
Yield: 68.7 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 5-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-[5-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 34 (68 mg, yield 68.7%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11](Cl)[C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1.ClC1C=CC(Cl)=CC=1CO>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Agent: OCc1cc(Cl)ccc1Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)nc(N)c1-c1cc(Cl)ccc1Cl

Procedure:
This compound was made in an analogous manner to the compound of Example 6 from 2,5-dichlorobenzylalcohol (Lancaster Synthesis). Mp. 226°-228° C.: TLC (SiO2 : CHCl3 /MeOH, 9.1) Rf=0.24.