Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24](O)=[O:25])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)([NH:20][C:21]3[CH:29]=[CH:28][CH:27]=[C:23]([C:24]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:25])[CH:22]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cccc(NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CN1CCN(C(=O)c2cccc(NC3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid (60 mg, 0.14 mmol), 1-methyl-piperazine (56 mg, 0.56 mmol) and EDCl (54 mg, 0.28 mmol) in dichlorometahne (2 mL) was stirred at room temperature for overnight. The reaction mixture was purified by preparative HPLC to give rac-6-chloro-3-(3-chloro-benzyl)-3-[3-(4-methyl-piperazine-1-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one as a powder. 1H NMR (CDCl3, 400 MHz): δ 7.21-6.74 (m, 9H), 6.49 (d, 1H), 6.17 (s, 1H), 4.70 (s, 1H), 3.80-3.45 (br, 8H), 3.28-3.15 (q, 2H), 2.66 (s, 3H). MS: [M+H]+=509
Reaction SMILES: I.[C:2](=[S:5])(S)[NH2:3].[CH3:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH2:12][S:13][CH2:14][CH2:15][NH2:16].[Na]>C(O)C>[CH3:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH2:12][S:13][CH2:14][CH2:15][NH:16][C:2]([NH:3][CH2:15][CH2:14][S:13][CH2:12][C:11]1[NH:10][CH:9]=[N:8][C:7]=1[CH3:6])=[S:5]
Reactant: NC(=S)S
Reactant: Cc1nc[nH]c1CSCCN
Agent: I
Agent: [Na]
Solvent: CCO
Product: Cc1nc[nH]c1CSCCNC(=S)NCCSCc1[nH]cnc1C

Procedure:
A solution prepared from S-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio))ethyl]dithiocarbamate hydriodide (15.6 g.), 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (6.8 g.) in ethanol (200 ml.) containing sodium (0.9 g.) was heated under reflux for 8 hours. Concentration followed by chromatographic purification of the product on a column of silica gel with ethyl acetate-isopropyl alcohol (5:1) as eluant gave the title compound which was converted to the dihydrochloride (2.5 g., m.p. 115°-120° ) with ethanolic hydrogen chloride.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O.C(=O)(O)[O-].[Na+]>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]2[CH2:34][CH2:35][N:30]([C:25]3[N:24]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:31][CH2:32]2)[S:7][C:8]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: O=C(CCl)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CN1CCN(c2ncccn2)CC1)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
Compound 262 (300 mg, 0.860 mmol) was dissolved in THF (5.0 mL), and 1-(2-pyrimidinyl)piperazine (0.370 mL, 2.58 mmol) was added thereto, followed by stirring at room temperature for 16 hours. Further, 1-(2-pyrimidinyl)piperazine (0.370 mL, 2.58 mmol) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Water and aqueous saturated sodium bicarbonate solution were added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (hexane:ethyl acetate=1:2) to afford the entitled Compound 278 (345 mg, 84%) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[N:6][CH:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.O.O.O.C([O-])(=O)C.[Na+].O>C(O)C>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(Br)cn1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A mixture of the product of Example 364A (24.2 g, 0.0678 mol), 4-amino-benzenethiol (12.7 g, 0.102 mol, 1.5 equiv.), and sodium acetate trihydrate (46.1 g, 0.339 mol, 5.0 equiv.) in 500 mL of ethanol was heated under reflux under nitrogen with stirring for 2 hours. The reaction mixture was then allowed to cool to room temperature and 200 mL of water added. The mixture was stirred for 30 minutes, filtered, and dried in vacuo to give the title compound (29.8 g, 99%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.CC1C=CC(S(O[CH2:31][CH2:32][Cl:33])(=O)=O)=CC=1>O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:31][CH2:32][Cl:33])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCOc1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
With reference to the document (J. Org. Chem., (2002), 67, 1093-1101), potassium carbonate (83.0 g, 600 mmol) was added to a solution of DMF (500 mL) containing 4-bromophenol (50.4 g, 291 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes, and then 2-chloroethyl 4-methylbenzenesulfonate (70.2 g, 299 mmol) was added thereto. The mixture was stirred at 50° C. for 24 hours. The reaction solution was cooled to 10° C., and water (500 mL) was added thereto to precipitate a white solid. This white solid was collected by filtration, washed with water (500 mL), and dried at 50° C. under reduced pressure to give 58.6 g of the title compound (yield: 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCO)cc1
Reaction time: 18 h
Yield: 96.9 %

Procedure:
Sodium hydroxide (6.22 g) is added to a solution of p-nitrophenol (21.45 g) in DMF (300 mL) and stirred until the reagents are fully dissolved. After a dropwise addition of 2-chloroethanol (10.66 ml), the reaction mixture is heated to 100° C. for 72 hours. After filtering and evaporating the solvent under reduced pressure, the resulting oil is recrystallized in a methanol/water mixture and filtered to afford 21.62 g (92%) of 2-(4-nitrophenoxy)-1-ethanol. A mixture of 2-(4-nitrophenoxy)-1-ethanol (6.17 g) and palladium on carbon (0.08 g) in EtOH (120 mL) is hydrogenated in a 500 mL Parr jar at 33 psi for 18 hrs. Vacuum filtration through celite and evaporation under reduced pressure affords 5.00 g (96%) of 2-(4-aminophenoxy)-1-ethanol. This material is combined with diethyl ethoxymethylenemalonate (7 mL) and heated to 130° C. for 1 hr in a round bottom flask under a gentle stream of nitrogen. The mixture is cooled, diluted with 1:1 cyclohexane/toluene (20 mL), and filtered to afford 9.1 g (86%) of diethyl 2-{[4-(2-hydroxyethoxy)anilinorlmethylene}-malonate. A solution the resulting malonate (8.59 g) in acetic acid (15 mL) and acetic anhydride (4 mL) is heated to 60° C. for 36 hrs. The reaction mixture is diluted with water, extracted with ethyl acetate and washed with saturated sodium bicarbonate. Evaporation under reduced pressure leaves a brown oil which is recrystallized from 1:1 methanol/water and filtered to afford 7.09 g (73%) diethyl 2-({4-[2-(acetyloxy)ethoxy]anilino}methylene)malonate. Diethyl 2-({4-[2-(acetyloxy)ethoxy]anilino}methylene)malonate (6.55 g) is dissolved in diphenyl ether (75 mL) and refluxed at 250° C. for 1 hr. After the mixture is cooled and diluted with 250 mL toluene, the resulting precipitate is collected by filtration, washed with toluene and recrystallized from aqueous acetic acid. This procedure yielded 0.50 g (9%) of ethyl 6-[2-(acetyloxy)ethoxy]-4-hydroxy-3-quinolinecarboxylate. The resulting carboxylate ester (0.49 g) and 4-chlorobenzylamine (0.90 mL) are heated to 175° C. for 2 hrs. After the reaction mixture is cooled and diluted with xylenes, the dark solid is filtered. Recrystallization from acetic acid and water affords 0.150 g (26%) of the title compound as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[C:11]([F:15])[CH:10]=[CH:9][CH:8]=3.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[C:11]([F:15])[CH:10]=[CH:9][CH:8]=3
Reactant: Fc1ccc2[nH]c3cccc(F)c3c2c1
Reactant: BrCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)c1c(F)cccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a stirred solution of 3,5-difluoro-9H-carbazole (0.300 g, 1.5 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.117 g, 1.8 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.244 mL, 3.0 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 4 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as an off-white solid (0.36 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, 1H, J=8.7, 2.7 Hz), 7.46-7.36 (m, 2H), 7.29-7.20 (m, 2H), 6.92 (dd, 1H, J=9.9, 7.8 Hz), 4.68 (dd, 1H, J=15.9, 3.0 Hz), 4.35 (dd, 1H, J=15.9, 5.1 Hz), 3.36 (m, 1H), 2.85 (t, 1H, J=4.5 Hz), 2.56 (dd, 1H, J=4.5, 2.7 Hz).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14](=[O:22])[NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:22])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cnccn1)[C@@H]1C[C@@H](F)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,4R)-tert-butyl 4-fluoro-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 65A (4.1 g, 12.3 mmol) in CH2Cl2 (120 mL) was added TFA (10 mL). The reaction mixture was stirred at rt overnight. After concentration in vacuo, the residue was used for the next step without purification. LC/MS [M+H]+: 211; Ret time (Method F): 0.30 min.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]=1)([CH3:3])[CH3:2].O.[C:13]1(=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[C:14]1=[O:23]>C(Cl)(Cl)Cl>[OH:24][C:13]12[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[C:14]1([OH:23])[C:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=1[N:4]2[CH:1]([CH3:3])[CH3:2]
Reactant: O=c1c(=O)c2ccccc2c1=O
Reactant: CC(C)NC1=CC(=O)CCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)N1C2=C(C(=O)CCC2)C2(O)C(=O)c3ccccc3C12O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Equimolar amounts of 3-isopropylaminocyclohex-2-enone and indanetrione hydrate (ninhydrin) were dissolved in chloroform and stirred at room temperature for 12 h. The solvent was then stripped off, and the oily residue was crystallized from acetone.
Reaction SMILES: [CH:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)=[O:2].O1CCCC1.[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3cc(C=O)sc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3cc(CO)sc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of 4′-{[6-formyl-2,4-dioxo-3-(2-phenylethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), tetrahydrofuran (20 mL) and methanol (20 mL) was added sodium borohydride (0.088 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was extracted with chloroform and saturated aqueous ammonium chloride solution. The chloroform layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.45 g, 89%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:40]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:48]1[CH2:49][CH2:50][CH:45]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:46][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N4CCCC4)CC3)ccc2[nH]1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-(1-pyrrolidinyl)-piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a brown solid (67%).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:7])[CH2:5][CH3:6])[CH3:3].[C:8](O)(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:5]([CH:4]([O:7][C:8](=[O:12])[CH:9]=[CH:10][CH3:11])[CH:2]([CH3:3])[CH3:1])[CH3:6]
Reactant: CCC(O)C(C)C
Reactant: C/C=C/C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(CC)C(C)C
Yield: 79.4 %

Procedure:
A reaction flask was charged with ethylmagnesium chloride (CH3CH2MgCl) (2 M, 2.17 L) and cooled to −10° C. Isobutyraldehyde ((CH3)2CHCHO) (295 g) was fed over about 1 hour while the temperature was kept under 15° C. The reaction mixture was aged to room temperature over about 6 hours and then poured into a mixture of ice and acetic acid (CH3COOH) (293 g). Hexanes (C6H14) (350 mL) were added and aqueous and organic layers were split. The organic layer was separated, washed sequentially with sodium bicarbonate (NaHCO3), brine, and water, and further distilled to provide 2-methyl-pentan-3-ol (336 g). 2-Methyl-pentan-3-ol (250 g), crotonic acid (CH3CH═CHCOOH) (198 g), toluene (250 mL), and para-toluenesulfonic acid (PTSA) (10 g) were then charged into to 2-L reaction flask fitted with a Bidwell-Sterling trap. The reaction mixture was heated to reflux. Water was collected and removed via the Bidwell-Sterling trap. The reaction mixture was aged at reflux for about 22-30 hours till the Gas Chromatography (“GC”) analysis showed completion of the reaction. The resulting reaction mixture was washed sequentially with brine, sodium carbonate (Na2CO3), and brine, and further purified by fractional distillation to provide but-2-enoic acid 1-ethyl-2-methyl-propyl ester (311 g) with a boiling point of 65° C. at 0.6 mmHg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:19]1[C:27]2[C:22](=[C:23]([CH2:28][NH2:29])[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[NH:19]1[C:27]2[C:22](=[C:23]([CH2:28][NH:29][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:13]=[C:12]([O:14][CH2:15][CH:16]5[CH2:18][CH2:17]5)[NH:11][N:10]=4)[CH:5]=[CH:4][N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: NCc1cccc2[nH]ccc12
Reactant: Clc1nccc(Nc2cc(OCC3CC3)[nH]n2)n1
Product: c1cc(CNc2nccc(Nc3cc(OCC4CC4)[nH]n3)n2)c2cc[nH]c2c1

Procedure:
N2-((1H-indol-4-yl)methyl)-N4(5-(cyclopropylmethoxy)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (I-42) was prepared analogously except 77 was replaced with (2-chloro-pyrimidin-4-yl)-(5-cyclopropylmethoxy-1H-pyrazol-3-yl)-amine and (1H-indol-4-yl)methanamine was replaced with 116.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:14][C:4]1[CH:3]=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(CO)cc2n1
Yield: 89.7 %

Procedure:
(4-Chloro-2-methyl-quinolin-7-yl)-methanol (750 mg, 3.61 mmol) was refluxed in pyrrolidine (6.42 g, 90.3 mmol) for 16 h. Most of the pyrrolidine was then removed under reduced pressure, the oily residue was taken up in toluene, evaporated, and the solid obtained triturated in ethyl acetate, filtered and dried to afford the title compound (785 mg, 90%). Light brown solid, ISP-MS: m/e==243.3 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29]CC2C=CC=CC=2)=[CH:25][C:24]=1[O:37][CH3:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=1[O:37][CH3:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(O)cc1OC

Procedure:
A solution of 2.46 g (4.64 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(4-benzyloxy-2-methoxyphenyl)octanamide (prepared as described in Example 123) in 100 ml of ethanol was vigorously stirred at 40° C. under a stream of hydrogen in the presence of 10% palladium-on-charcoal for 1.5 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid to remove the catalyst, and the filtrate was concentrated to dryness by evaporation under reduced pressure. The residue was purified by column chromatography through 100 g of silica gel using a 49:1 by volume mixture of ethyl acetate and methanol as the eluent, to give a crude product containing the title compound. This product was further purified by column chromatography through silica gel under the same conditions as above to give 1.62 g (yield 79%) of the title compound as a foam-like substance.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]1=[O:18].Br[CH2:20][C:21]([C:23]1[C:24]([CH3:33])=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[O:27][CH2:26]2)=[O:22].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:33][C:24]1[C:23]([C:21](=[O:22])[CH2:20][N:15]2[CH2:16][CH2:17][C:10]3([C:9](=[O:18])[N:8]([C:3]4[CH2:4][O:5][C:6](=[O:7])[C:2]=4[CH3:1])[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:32]
Reactant: Cc1c(C(=O)CBr)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCN(CC(=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O

Procedure:
2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-17) (2 g, 7.99 mmol), 5-(2-Bromo-acetyl)-4-methyl-3H-isobenzofuran-1-one (I-4B, method 2, step F) (2.150 g, 7.99 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.48 mL, 19.98 mmol) in DCM (50 mL) were stirred overnight at rt. The mixture was washed with saturated ammonium chloride aqueous and brine, dried over MgSO4, and concentrated under reduced pressure. The crude material was used in the next step without further purification. 1H-NMR (500 MHz, CDCl3): δ ppm 7.83 (1H, d, J=7.8 Hz), 7.79 (1 H. , d, J=7.8 Hz), 5.34 (2 H, s), 5.32 (2 H, s), 5.26 (2 H, s), 4.03 (2 H, t, J=7.0 Hz), 3.71 (1 H, m), 3.15 (1 H, m), 2.94 (2 H, m), 2.47 (2 H, t, J=7.0 Hz), 2.42 (3 H, s), 2.17 (2 H, m), 2.07 (3 H, s), 2.02 (2 H, m), 1.58 (2 H, m). LCMS 438.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([OH:8])=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[N:7]=[N:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: Oc1ccc(Cl)nn1
Product: Oc1ccc(N2CCOCC2)nn1
Yield: 74 %

Procedure:
6-Chloro-3-hydroxypyridazine (25.0 g, 0.191 mol) was dissolved in morpholine (120 mol), under reflux condition for 24 hours. After cooling, the deposited crystal was filtered, to give 6-morpholino-3-hydroxypyridazine in white crystal (25.8 g as a yield of 74%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18]>>[NH2:22][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:25]=[CH:24][CH:23]=1
Reactant: C#Cc1cccc(N)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: Nc1cccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Yield: 74.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 3-ethynylaniline (0.07 mL, 0.65 mmol) to provide 260 (100 mg, 74% yield) as a brown solid. LC-MS (M+H=312 obsd.=312).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[CH2:14]([C@H:16]1[O:18][CH2:17]1)[Cl:15]>C(O)C.ClCCl>[Cl:15][CH2:14][C@@H:16]([OH:18])[CH2:17][N:11]1[CH2:10][CH2:9][N:8]([C:6]([C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:7])[CH2:13][CH2:12]1
Reactant: O=C([C@H]1CCCO1)N1CCNCC1
Reactant: ClC[C@@H]1CO1
Solvent: ClCCl
Solvent: CCO
Product: O=C([C@H]1CCCO1)N1CCN(C[C@H](O)CCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[(R)-tetrahydro-2-furoyl]piperazine (1.89 g, 10.26 mmol) in ethanol (25 mL) was added (S)-epichlorohydrin (1.09 g, 11.8 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo, yielding a pale yellow oil. The oil was dissolved in dichloromethane (100 mL), and washed with 1M H3PO4, dried and evaporated, to provide the title intermediate.