Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8](OC)=[O:9])=[CH:6][N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:4]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(-c2cccc(OC)c2)cc1C(=O)OC
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1nn(-c2cccc(OC)c2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A solution (5 mL) of methyl 3-ethyl-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxylate (2.3 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (15 mL) of lithium aluminum hydride (0.34 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr, ice-cooled again, and water (0.88 mL), 1N aqueous sodium hydroxide solution (4.4 mL), water (0.88 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (2.3 g) of 3-ethyl-1-(3-methoxyphenyl)-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (50 mL), manganese dioxide (4.0 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, manganese dioxide was collected by filtration, and the solvent was evaporated under reduced pressure to give the title object compound (1.9 g, 94%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:12].C1(C)C=CC=CC=1.Cl>N1C=CC=CC=1>[CH2:14]([O:13][C:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 65.8 %

Procedure:
Commercially available p-hydroxybenzaldehyde (50 g) was dissolved in pyridine (400 ml), followed by dropwise adding octyl chloroformate (85 g) under ice cooling, heating on a water bath, allowing to stand overnight, adding toluene (300 ml), further adding 6N-hydrochloric acid, separating the liquid layer, further washing with 2N-NaOH aqueous solution, washing with water, drying, and distilling off toluene to obtain a raw product of p-octyloxycarbonyloxybenzaldehyde (75 g).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])/[CH:13]=[CH:14]/[C:15](OC)=[O:16])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:13]2[CH2:14][C:15](=[O:16])[NH:3][NH:2]2)=[O:19])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1
Reactant: NN
Reactant: COC(=O)/C=C/C(=O)Nc1ccc(Cl)cc1C(=O)NC(C)C1CC1
Solvent: O
Solvent: CCO
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Yield: 28.6 %

Procedure:
A mixed liquid comprising 90 mg of hydrazine monohydrate and 3 ml of ethanol was added to a mixed liquid comprising 0.56 g of methyl 4-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylamino)-4-oxocrotonate and 3 ml of ethanol, followed by rinsing with 2 ml of ethanol, and reflux under heating for 6 hours. The reaction liquid was stood to cool, the precipitated crystals were subjected to suction filtration, and the obtained crystals were washed with ethanol and air dried to obtain 0.16 g of the desired product (melting point: 248° C.).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:41]=[CH:40][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:31](=[O:39])[N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[C:20]([CH:30]=2)[O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][CH:6]=1.[C:42](OC1C=CC=CC=1)(=[O:44])[CH3:43].C(N(CC)CC)C>C(Cl)Cl>[C:42]([N:2]=[N:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:31](=[O:39])[N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[C:20]([CH:30]=2)[O:21][C:22]([CH3:28])([CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:40][CH:41]=1)(=[O:44])[CH3:43]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(C=NN)cc2)ccc1C(=O)N(C(C)C)C(C)C
Reactant: CC(=O)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(CN=NC(C)=O)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 0.85 g (1.4 mmol) of ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride in 10 ml of methylene chloride is added 0.39 g (2.8 mmol) of phenyl acetate and 1 ml of triethylamine. The mixture is stirred at room temperature for 2 days and then poured onto a silica gel column and eluted with 80% ethyl acetate/hexane, and then pure ethyl acetate to give ethyl 5-[5-[4-[(acetylimino)aminomethyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate as a foam; CHN calculated for C33H47N3O7.0.5H2O:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][N:7]=[C:6]2[C:14]([O:16][CH2:17][CH3:18])=[O:15].C[O-].[Li+].Cl[CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:28]=1)[N:7]=[C:6]2[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1n[nH]c2cc(OC)c(OC)cc12
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: CCOC(=O)c1nn(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
In 5000 ml of dimethyl sulfoxide was suspended 250.2 g of ethyl 5,6-dimethoxyindazole-3-carboxylate, and 40.2 g of lithium methoxide was added to the suspension, followed by stirring at room temperature for 1 hour. A solution of 447.8 g of 4-chloromethyl-1-tritylimidazole in 2000 ml of dimethyl sulfoxide was added dropwise thereto at room temperature over 10 minutes. After stirring at room temperature for 2 hours, 4.2 g of lithium methoxide and 44.8 g of 4-chloromethyl-1-tritylimidazole were further added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into 30000 ml of ice-water while stirring. A precipitated crystal was collected, washed with three 2000 ml portions of water, and dried. The solid was dissolved in 10000 ml of chloroform, and the solution was dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:ethanol=50:1) and recrystallized from chloroform/isopropyl alcohol to yield 222.0 g of the title compound as a colorless prism crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:21]([C:22](OCC)=[O:23])=[CH:20][N:19]=[C:18]([S:27][CH3:28])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:23][CH2:22][C:21]1[C:16]([NH:15][C:11]2[CH:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:14]=[CH:13][CH:12]=2)=[N:17][C:18]([S:27][CH3:28])=[N:19][CH:20]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1cccc(NC(=O)OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc(CO)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Temperature: 0 °C
Reaction time: 13 h
Yield: 92 %

Procedure:
To a suspension of ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (50c) (340 g, 0.84 mol) in THF (200 mL) at −40° C. was added LiAlH4 (2.57 L of 1.0 M solution in THF, 2.57 mol) dropwise. The reaction mixture was stirred at 0° C. for 13 h, then cooled to −20° C. and carefully quenched with solid Na2SO4.10H2O. The reaction mixture was filtered and rinsed with 2×150 mL of EtOAc. The filtrate was concentrated affording crude tert-butyl (3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50d) (280 g, 92% yield). m/z (ESI, +ve ion) 363.0 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[O:36]1[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37]1>>[O:36]1[CH2:40][CH2:39][CH:38]([C:41]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:42])[CH2:37]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=C(O)C1CCOC1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)C6CCOC6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and tetrahydrofuran-3-carboxylic acid (Aldrich, Cat. No. 339954). LCMS (M+H)+: m/z=583.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[Si](C#N)(C)(C)C.CC([O:23][C:24](OC(OC(C)(C)C)=O)=[O:25])(C)C>C1COCC1.[Zn+2].[I-].[I-]>[C:9]([O:8][C:6]([N:4]1[CH2:5][C:2]([OH:1])([C:24]([OH:25])=[O:23])[CH2:3]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 3-oxoazetidine-1-carboxylate LII (2.0 g, 11.7 mmol) in THF (50 mL) under an argon atmosphere was added ZnI2 (0.11 mg, cat) followed by TMSCN (1.62 g, 16.4 mmol). The mixture was stirred at room temperature for 18 h, and was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with aqueous NaHCO3 and water and then concentrated to dryness. The residue was dissolved in HOAc (25 mL) and treated with concentrated aqueous HCl (25 mL). The mixture was heated at reflux for 3 h and was concentrated to dryness. The residue was dissolved in iPrOH (20 mL) and 2 M aqueous NaOH (20 mL) followed by Boc2O (1.66 g, 8.0 mmol) were added. The iPrOH was removed with a rotary evaporator, water (30 mL) was then added to the residue and the mixture was extracted with Et2O (2×30 mL). The aqueous phase was acidified with 1 N aqueous HCl to pH=2 and extracted with EtOAc (3×30 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100% EtOAc→1:1 EtOAc:MeOH) affording 1-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-carboxylic acid LIII (0.17 g, 0.79 mmol, 7%). ESIMS found for C9H15NO5 m/z 216 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(N)cc2)CC1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
4-Methyl-1-(4-nitro-phenyl)-piperazine (1.50 g, 6.78 mmol) is dissolved in MeOH (50 mL), and to this solution is added 10% Pd/C (0.145 g, 6.78 mmol). The reaction mixture is stirred under an atmosphere of H2 for 18 h. The resulting mixture is filtered through celite, and the filtered catalyst is washed with excess EtOAc. The filtrate is concentrated under high vacuum to afford the product as a purple solid (1.28 g, 98%); 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.37-2.40 (m, 4H), 2.83-2.87 (m, 4H), 4.48 (s, 2H), 6.43 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H); mass spectrum [(+) ESI], m/z 192 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Br[C:44]1[C:49]2[CH:50]=[CH:51][NH:52][C:48]=2[CH:47]=[CH:46][N:45]=1>>[CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([C:44]1[C:49]3[CH:50]=[CH:51][NH:52][C:48]=3[CH:47]=[CH:46][N:45]=1)=[N:6][C:7]=2[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(N4CCOCC4)CC3)n(C)c2n1
Reactant: Brc1nccc2[nH]ccc12
Product: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(-c3nccc4[nH]ccc34)nc21

Procedure:
Following the procedures to prepare 124, 4-(1-((9-Methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine and 4-bromo-1H-pyrrolo[3,2-c]pyridine were reacted to give 133. LCMS: M+H+=518.3. 1H-NMR (400 MHz, DMSO-d6): δ 11.55 (s, 1H), 8.30 (d, 1H), 7.51 (d, 1H), 7.48 (d, 1H), 7.20 (d, 1H), 4.30 (m, 4H), 3.80 (s, 3H), 3.78 (m, 6H), 3.55 (m, 4H), 2.88 (m, 2H), 2.44 (m, 4H), 2.09 (m, 2H), 1.77 (m, 2H), 1.40 (m, 3H)
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.Cl.[Cl:13][C:14]1[CH:15]=[N:16][C:17](=[O:20])[NH:18][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:9][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([S:3][CH2:2][N:18]2[CH:19]=[C:14]([Cl:13])[CH:15]=[N:16][C:17]2=[O:20])=[CH:5][CH:6]=1
Reactant: OCc1ccc(SCCl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1CSc1ccc(CO)cc1

Procedure:
4-(Chloromethylthio) benzyl alcohol (see Preparation 17) (5 mmol) in CH2Cl2 (2 ml) was added dropwise with stirring to a solution prepared from 5-chloropyrimidin-2-one hydrochloride (4 mmol) and triethylamine (8 mmol) in CH2Cl2 (20 ml). The resultant mixture was heated under reflux for 24 hours. The solvent was then distilled off, the residue triturated with water, dried (MgSO4), triturated with ether and the residual material recrystallized from ethanol/Pet. ether. Yield 0.17 g (15%). 1H NMR (DMSO-d6, δ) 4.50 (CH2O), 5.22 (CH2S), 7.22 (Ph), 8.03 or 8.50 (H-4, H-6, J3 Hz).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][CH2:16]O>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][CH2:16][Cl:3]
Reactant: O=[N+]([O-])c1cccc(Cl)c1CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(Cl)c1CCCl
Yield: 93.2 %

Procedure:
15.60 9 g thionyl chloride (130 mmol) in 10 ml toluene (abs.) is added quickly in a drop-wise manner to 8.8 g 2-(2-chloro-6-nitrophenyl) ethanol (44 mmol) in 100 ml abs. toluene. The reaction solution is heated under reflux 1 h. After cooling, this is poured onto ice, diluted with 50 ml CH2Cl2 and the H2O phase is extracted 2× each with 50 ml CH2Cl2. The combined organic phases are dried over Na2SO4 and rotary evaporated. 9.08 g (41 mmol, 94%) 2-(2-chloro-6-nitrophenyl)ethyl chloride are obtained as a brown oil which crystallizes after storage for several days in a refrigerator.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:21]#[N:22].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:27][CH2:28][N:29]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:30][CH2:31]1)[C:21]#[N:22]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: Cc1cc(C#N)ccc1N1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cc(C#N)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCN32)CC1
Temperature: 105 °C
Yield: 49.1 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-methyl-4-(piperazin-1-yl)benzonitrile (92 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water (6 mL) and dried in vacuum to afford (S)-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile (90.1 mg, 0.224 mmol, 49.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.01 (m, 3 H) 2.12-2.21 (m, 1 H) 2.24 (s, 3 H) 2.43-2.55 (m, 4 H) 2.85-2.97 (m, 4 H) 3.35-3.44 (m, 3 H) 3.53-3.63 (m, 1 H) 3.95-4.03 (m, 1 H) 6.98 (d, J=2.02 Hz, 1 H) 7.05-7.12 (m, 1 H) 7.54-7.60 (m, 2 H) 7.62 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C23H26N6O, 403; found, 403.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:18]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21](O)[CH2:20][CH2:19]1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[N:15]([CH:21]1[C:22]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[O:18][CH2:19][CH2:20]1)=[N+:16]=[N-:17]
Reactant: OC1CCOc2ncccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC1CCOc2ncccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(Prep ref: Phompson, A. S. et. al. J. Org. Chem., 1993, 58, 5886-5888). Diphenyl phosphoryl azide (0.81 mL) was added to a suspension of 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol (0.37 g) in dry toluene (10 mL) then the mixture was cooled to 0° C. under an Ar atmosphere. Neat DBU (0.56 mL) was added and the resultant biphasic mixture was stirred at 0° C. for 2 hr and then at RT for 15 hr. The biphasic solution was diluted with sat. NaHCO3 and extracted with DCM (2×). The combined organics were concentrated and purified by silica gel chromatography using 10, 25 and 50% EtOAc/Hex elutants to afford the titled product (0.31 g) NMR CDCl3 1H δ 8.2 (dd, 1H), 7.6 (dd, 1H), 7.0 (dd, 1H), 4.7 (dd, 1H), 4.4 (m, 2H), 2.2 (m, 1H), 2.1 (m, 1H); MH+=177.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([NH2:11])=[CH:4][CH:3]=1.[N:12]#[C:13]Br.C(Cl)Cl.N>C(O)C.CO>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][CH3:10])[C:13]([NH2:12])=[N:11][C:5]2=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: CCNc1nc(Cl)ccc1N
Agent: N
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCn1c(N)nc2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
To a solution of 6-chloro-N2-ethylpyridine-2,3-diamine (401 mg, 2.34 mmol) in ethanol (10 mL) is added a 3M solution of cyanogen bromide in DCM (0.93 mL, 2.8 mmol). The solution is stirred for 6 h at room temperature. The solution is basified with ammonia in methanol and evaporated. The residue is purified via flash column chromatography using a gradient of 0-15% methanol in CH2Cl2 containing 1% NH4OH to afford the title compound (212 mg, 46%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]>C1COCC1.Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
N-(4-Ethoxycarbonylphenyl)-(4-chlorophenyl)-acetamide (8.91 g., 0.03 mole) was dissolved in dry THF (70 ml) under nitrogen and borane-dimethyl sulphide complex (3.8 ml; 0.03 mole) was added at room temperature. The mixture was stirred for 30 minutes at room temperature, boiled under reflux with stirring for 4 hours, cooled and IN hydrochloric acid (70 ml) was added. The organic phase was separated, the aqueous layer extracted with dichloromethane (2×80 ml), the combined organic phases washed with water (100 ml) and dried over anhydrous magnesium sulphate. Evaporation of the solvent gave an oil which was chromatographed on silica-gel (120 g.) in dichloromethane to give ethyl 4-[2-(4-chlorophenyl)ethylamino]benzoate (4.02 g, 44%) melting at 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.[NH:22]1[CH2:27][CH2:26][C:25]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:36])[NH:28]2)[CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:22]3[CH2:27][CH2:26][C:25]4([C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29](=[O:36])[NH:28]4)[CH2:24][CH2:23]3)=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Reactant: O=C1NC2(CCNCC2)c2ccccc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To a solution of 0.060 g (0.31 mmol) 6-chloro-1H-indole-3-carboxylic acid in 3 ml dichloromethane were added 0.045 ml (0.38 mmol) 1-chloro-N,N,2-trimethyl-propenylamine at room temperature. After stirring for 1 h the reaction mixture was concentrated in vacuo. The residue was redissolved in 2 ml dry N,N-dimethylformamide. A solution of 0.062 g (0.31 mmol) spiro[isoindole-1,4′-piperidin]-3(2H)-one and 0.064 ml (0.46 mmol) triethylamine in 1 ml dry N,N-dimethylformamide was added at room temperature. After stirring for 2 h the reaction mixture was quenched with 1 M aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×30 ml), 0.5 M aqueous hydrochloric acid solution (1×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was triturated in warm diethyl ether, filtrated and dried in vacuo to give the title compound (0.031 g, 22%) as light brown solid with a purity of approx. 80% by LC-.MS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1nccc(C(F)(F)F)n1

Procedure:
The title compound, MS: m/e=363.1 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloro-4-(trifluoromethyl)pyrimidine.