Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[N:6]1([CH:12]([CH3:26])[CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH2:25])=[N:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Br.Br[CH2:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[N:6]1([CH:12]([CH3:26])[CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH:25][CH2:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[N:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCN(CC)CCCBr
Reactant: CC(CCn1nc(N)c2cc(Cl)ccc21)N1CCCCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCNc1nn(CCC(C)N2CCCCC2)c2ccc(Cl)cc12
Temperature: 180 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 9.90 g of the 1-(3-piperidinobutyl)-3-amino-5-chloroindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 180° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried with anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 6.90 g of 1-(3-piperidinobutyl)-3-(3-diethylaminopropylamino)-5-chloroindazole having the following analytical values in a yield of 51 %.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22]>CN1C(=O)CCC1.CCOC(C)=O.O>[NH2:15][C:14]1[O:22][C:21]([C:20]2[C:19]([F:18])=[CH:27][CH:26]=[CH:25][C:24]=2[F:28])=[N:12][C:13]=1[C:16]#[N:17]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: N#CC(N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1nc(-c2c(F)cccc2F)oc1N
Temperature: 120 °C
Yield: 70 %

Procedure:
To a solution of aminomalononitrile p-toluenesulfonate (0.050 g, 0.2 mmol) in NMP (0.5 mL) was added 2,6-difluorobenzoyl chloride (27 ul, 0.21 mmol) and the resulting solution heated in the microwave at 120° C. for 5 minutes. The solution was diluted with EtOAc and water. The organic phase was washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to afford 5-amino-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.030 g, 0.14 mmol, 69%) as an off-white solid. 1H NMR (DMSO) δ 7.30 (2H, t), 7.61 (1H, m), 8.14 (2H, br. s). LCMS (1) Rt: 1.59 min; m/z (ES+) 222.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].O[C:13](=[C:20]1[S:24][C:23](=[O:25])[NH:22][C:21]1=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C[O:30]CC1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:30][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]=[C:20]1[S:24][C:23](=[O:25])[NH:22][C:21]1=[O:26])=[O:6]
Reactant: O=C1NC(=O)C(=C(O)c2ccccc2)S1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(=Cc2ccccc2OC(=O)c2ccc(Cl)c(Cl)c2)S1
Reaction time: 1.5 h

Procedure:
A solution of 3,4-dichlorobenzoylchloride in THF was slowly added to a solution of 5-(hydroxybenzylidene)thiazolidine-2,4-dione (1.5 eq.) and TEA (1.5 eq.) in THF. The resulting reaction was stirred for 1-2 h at which time the solid was filtered and filtrate was concentrated under reduced pressure to yield light yellow solid. The solid was dissolved in EtOAc followed by washing with sat. aq. K2CO3. The organic phase was separated, and dried over Na2SO4 followed by concentration under reduced pressure to yield pure compound.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH2:30])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@H](N(C)C)C1
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of acryloyl chloride (0.042 mL, 0.52 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of (S)—N1-[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]-4-[3-(dimethylamino)pyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 61, 250 mg, 0.52 mmol) and DIPEA (0.099 mL, 0.57 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (194 mg, 70%) as a yellow solid; 1H NMR: 1.69-1.83 (1H, m), 2.05-2.16 (1H, m), 2.19 (6H, s), 2.65-2.78 (1H, m), 3.18-3.29 (3H, m), 3.35-3.46 (1H, m), 3.77 (3H, s), 5.67 (1H, dd), 6.16 (1H, dd), 6.48 (1H, dd), 6.54 (1H, s), 7.12 (1H, t), 7.37 (1H, t), 7.43 (1H, s), 8.3-8.46 (2H, m), 8.55 (1H, s), 8.83 (1H, d), 8.94 (1H, s), 9.37 (1H, s); m/z: ES+ MH+ 533.5.
Reaction SMILES: [CH:1]1([NH:8][CH2:9][CH2:10]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:14]>>[Cl-:14].[CH:1]1([NH2+:8][CH2:9][CH2:10][Cl:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCNC1CCCCCC1
Reactant: O=S(Cl)Cl
Product: ClCC[NH2+]C1CCCCCC1
Product: [Cl-]

Procedure:
2-Hydroxyethylamine was reacted with cycloheptyl bromide according to Method B2a to give N-cycloheptyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-cycloheptyl-1,3-thiazolidine.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][S:15][CH3:16])(C1C=CC(C)=CC=1)(=O)=O.[SH:17][CH2:18][CH2:19][CH2:20][OH:21].CC(C)([O-])C.[K+].O>C1COCC1>[CH2:20]([OH:21])[CH2:19][CH2:18][S:17][CH2:12][CH2:13][CH2:14][S:15][CH3:16]
Reactant: OCCCS
Reactant: CSCCCOS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSCCCSCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
To a mixture of 3-methylthio-1-propanol tosylate (14.14 g, 54.3 mmol), and 3-mercapto-1-propanol (5.0 g, 54.3 mmol) in dry THF (300 mL) was added potassium tert-butoxide (8.51 g, 80.0 mmol) in one portion under a blanket of nitrogen, and the resulting mixture was stirred at room temperature for 24 hours. Water (10 mL) was added drop-wise to the reaction mixture to quench excess potassium tert-butoxide, and solvent was evaporated under reduced pressure. The resulting solid was washed with ether (3×100 mL), and filtered. The ether layer was washed with water (3×100 mL) and dried (Na2SO4). Solvent evaporation produced 8.7 g of a light yellow oil. This product was used for acryloylation without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([N:57]1[CH:61]=[C:60]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)[CH:59]=[N:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH2:50]([N:57]1[CH:61]=[C:60]([C:62]2[CH:63]=[C:64]([NH:68][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:65]=[CH:66][CH:67]=2)[CH:59]=[N:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cnn(Cc5ccccc5)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 61.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-benzyl-1H-pyrazol-4-yl)-phenylamine (0.016 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 62% yield: LCMS (ESI) m/z 452 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Product: O=C(O)c1cc(NC(=O)C2CCCCC2)ccc1Cl
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A solution of 5-amino-2-chlorobenzoic acid (0.34 g, 2.0 mmol) in THF (10 mL) was charged with cyclohexanecarbonyl chloride (0.27 mL, 1.7 mmol). The reaction was stirred for 16 h and then concentrated in vacuo. The residue was suspended in DCM and filtered to afford the title compounds as a white solid (0.47 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1)C(=O)O

Procedure:
A solution of 3.7 g of ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate, 30 ml of 15% sodium hydroxide solution and 30 ml of methanol, is stirred under reflux for 3 hr. The methanol is evaporated and the aqueous solution poured into ice/dilute hydrochloric acid. The precipitate is collected, dried and recrystallized from toluene to afford 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionic acid, mp 176°-7° C.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([S:16]([NH:19][C@@H:20]([CH3:24])[C:21]([OH:23])=O)(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[NH2:71][CH2:72][C:73]([NH2:75])=[O:74].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:73]([CH2:72][NH:71][C:21](=[O:23])[C@@H:20]([NH:19][S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:35]=[CH:36][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:34])[C:9](=[O:33])[N:10]([C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)[C:11]2=[N:15][CH:14]=1)(=[O:17])=[O:18])[CH3:24])(=[O:74])[NH2:75]
Reactant: NCC(N)=O
Reactant: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
The above carboxylic acid (0.05 g, 0.091 mmol) was dissolved in anhydrous DMF (2 mL) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (0.071 g, 0.137 mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature for 10 min and glycinamide hydrochloride (0.015 g, 0.137 mmol) was added to the mixture followed by N,N-diisopropylethylamine (0.039 mL, 0.227 mmol). The reaction mixture was stirred at room temperature for another 15 min. The mixture was then diluted with EtOAc (10 mL) and washed with water (×2), 1N HCl, saturated NaHCO3 and then water (×1). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica gel preparative thin layer chromatography using CH2Cl2—MeOH (95:5) as an eluent to afford 0.043 g of the title compound as a white foam (M+1, 604.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.[NH2:11][C@H:12]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[CH:26][CH:25]=1)[CH2:13][C@:14]([CH2:19][O:20][CH2:21][CH3:22])([CH3:18])[C:15]([OH:17])=[O:16]>>[Cl:36][C:32]1[CH:31]=[C:30]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C@@H:12]([NH:11][C:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)=[O:10])[CH2:13][C@:14]([CH2:19][O:20][CH2:21][CH3:22])([CH3:18])[C:15]([OH:17])=[O:16])=[CH:29][CH:28]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CCOC[C@](C)(C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Reactant: COc1cc(C(=O)O)on1
Product: CCOC[C@](C)(C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(OC)no1)C(=O)O

Procedure:
3-Methoxyisoxazole-5-carboxylic acid and (2S,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-ethoxymethyl-2-methylpentanoic acid were reacted as described herein to yield the title compound (2 mg). MS m/z [M+H]+ calc'd for C26H29ClN2O6, 501.17. found 501.2.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:13][C:14]([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].[Si](OC(C)(C)CC1[S:34]C(N)=C(C2C=C(Cl)C=CC=2OC)N=1)(C(C)(C)C)(C)C>>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([C:3]2[N:13]=[C:14]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[S:34][C:2]=2[NH2:1])[CH:9]=1
Reactant: COc1ccc(Cl)cc1C(NC(=O)C1CCOCC1)C(N)=O
Reactant: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O[Si](C)(C)C(C)(C)C)sc1N
Product: COc1ccc(Cl)cc1-c1nc(C2CCOCC2)sc1N

Procedure:
Using N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)tetrahydro-2H-pyran-4-carboxamide, the title compound was prepared following the synthetic procedures described for 2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine to give 4-(5-chloro-2-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)thiazol-5-amine as a white gum. LCMS (ESI) m+H=325.2; 1H NMR (400 MHz, DMSO-d6): δ 7.38 (d, 1H); 7.31 (dd, 1H); 7.09 (d, 1H); 5.31 (s, br, 2H); 3.90 (d, 2H); 3.84 (s, 3H); 3.43 (m, 2H); 3.04-2.99 (m, 1H); 1.90 (d, 2H); 1.66-1.66 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7]1([OH:19])[CH:14]2[CH2:15][CH:10]3[CH2:11][C:12]([OH:17])([CH2:16][C:8]1([OH:18])[CH2:9]3)[CH2:13]2.C(N(CC)CC)C.C1COCC1>O>[C:1]([O:19][C:7]1([CH3:6])[CH:14]2[CH2:15][CH:10]3[CH2:11][C:12]([OH:17])([CH2:16][C:8]1([OH:18])[CH2:9]3)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CC1(O)C2CC3CC(O)(C2)CC1(O)C3
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC1(C)C2CC3CC(O)(C2)CC1(O)C3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A total of 6.5 mmole of acryloyl chloride was added dropwise to a mixture of 5 mmole of 2-methyl-1,2,5-adamantanetriol, 7.5 mmole of triethylamine and 50 ml of THF over about 15 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 1.5 hours. After the addition of water, the reaction mixture was extracted with ethyl acetate, the organic layer was concentrated, and the concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound.
Reaction SMILES: CC1(C)[O:7][C:6]2[C:8]([O:12][CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:9][CH:10]=[CH:11][C:5]=2[C:4](=[O:26])C1.[OH-].[K+].[OH:30]S([O-])(=O)=O.[K+]>CS(C)=O>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[CH2:13][O:12][C:8]1[C:6]([OH:7])=[C:5]([CH:11]=[CH:10][CH:9]=1)[C:4]([OH:30])=[O:26])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cccc2c1OC(C)(C)CC2=O
Reactant: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1COc1cccc(C(=O)O)c1O
Temperature: 60 °C
Yield: 93 %

Procedure:
tert-butyl-2-(2, 2-dimethyl-4-oxo-4,4-benzo[1,3]dioxin-8-yloxymethyl)pyrrolidine-1-carboxylate 47 (1.65 g, 4.54 mmol) was dissolved in DMSO (9.5 mL) and then 49% aqueous KOH (1.5 mL) was added to the solution to form a basic reaction mixture. This basic reaction mixture was heated at 60° C. for 40 min. After cooling to room temperature and addition of 0.5 M aqueous KHSO4 (100 mL) gave an acidic suspension. The suspension was extracted with ether (4×250 mL) and the combined extracts were washed with brine (2×50 mL) and dried (Na2SO4). Evaporation of the ether gave 1.26 g (93%) of 3-(1-tert-butoxycarbonyl pyrrolidin-2-ylmethoxy)-2-hydroxy benzoic acid 48 as a brown solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1.C1(C(C2CCCCC2)N2CCNCC2)CCCCC1.C1[O:44]C1>>[OH:44][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1
Reactant: C1CO1
Reactant: ClCCN1CCN(C(C2CCCCC2)C2CCCCC2)CC1
Agent: C1CCC(C(C2CCCCC2)N2CCNCC2)CC1
Product: OCCN1CCN(C(C2CCCCC2)C2CCCCC2)CC1

Procedure:
For example, 1-(2-chloroethyl)-4-dicyclohexylmethylpiperazine can be prepared by reacting N-dicyclohexylmethylpiperazine with ethylene oxide, to form 1-(2-hydroxyethyl)-4-dicyclohexylmethylpiperazine, which is subsequently treated with a chlorinating agent, such as thionyl chloride, to produce the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]=O.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1/[CH:14]=[C:24]1\[C:25](=[O:29])[NH:26][C:27]2[C:23]\1=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=2
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)C(C)(C)COc1ccc(Br)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 53.8 %

Procedure:
In a manner similar to the method described in Example 227b, 3-(4-bromo-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester (3.4 g, 10.8 mmol) was reacted with 6-chlorooxindole (1.8 g, 10.8 mmol) and pyrrolidine (0.84 g, 11.8 mmol) in methanol to give E/Z-3-[4-Bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2,2-dimethyl-propionic acid methyl ester as a yellow solid (2.7 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:31][C@H:30]([O:32][CH2:33][C:34](OCC)=[O:35])[CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH2:40]([Mg]Br)[CH3:41].[Cl-].[NH4+].O1CC[CH2:48][CH2:47]1>>[CH2:47]([C:34]([OH:35])([CH2:40][CH3:41])[CH2:33][O:32][C@H:30]1[CH2:29][C@H:28]([N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:31]1)[CH3:48]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](OCC(=O)OCC)C2)c2ncnn12
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](OCC(O)(CC)CC)C2)c2ncnn12
Reaction time: 6 h

Procedure:
Ethyl [(trans-3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate (0.077 g) was dissolved in tetrahydrofuran (10 mL), and ethylmagnesium bromide (3.0 M diethyl ether solution, 0.15 mL) was added at room temperature. The reaction mixture was stirred for 6 hr, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium 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 solid (0.06 g, 76%).
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH2:14][C:15]1[O:16][C:17]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)C(OCC1C=CC=CC=1)=O.C(O)(=O)C>CO.[Pd]>[CH3:1][NH:2][CH2:13][CH2:14][C:15]1[O:16][C:17]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([NH2:35])(=[O:33])=[O:34])=[CH:30][CH:31]=2)=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1
Reactant: CN(CCc1nc(-c2ccccc2)c(-c2ccc(S(N)(=O)=O)cc2)o1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CNCCc1nc(-c2ccccc2)c(-c2ccc(S(N)(=O)=O)cc2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-[2-[2-(N-methyl-N-phenylmethoxycarbonylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide and 4-[2-[2-(N-methyl-N-phenyl-methoxycarbonylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamide (0.7 g, 1.4 mmol) from Step 3, in MeOH (15 mL) containing acetic acid (0.1 mL) was treated with 10% Pd on carbon (0.4 g) and stirred under an atmosphere of hydrogen at 50 psi at room temperature for 3 h. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting substance was purified by reverse-phase HPLC using a gradient of 5–70% CH3CN in water to give 0.42 g of 4-[2-[2-(N-methylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide and 4-[2-[2-(N-methylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamide trifluoroacetate salts as a white powder: 1H NMR (CD3OD/300 MHz) δ 7.88 (d, 2H, J=8.7 Hz), 7.74 (d, 2H, J=8.7 Hz), 7.6 (m, 2H), 7.43 (m, 3H), 3.55 (t, 2H, J=6.6 Hz), 3.36 (t, 2H, J=6.6 Hz), 2.82 (s, 3H); FABMS m/z=358 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>C(O)(C)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: COc1cccc(CN)c1
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: CC(C)O
Product: COc1cccc(CNc2ncnc3cc(N)ncc23)c1
Yield: 76.6 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (136 mg, 0.71 mmol) (described in a previous experimental) and 3-methoxybenzylamine (1.37 g, 10.0 mmol) in isopropanol (3 mL) is stirred under N2 at reflux for 3 h. Evaporation of the solvent and chromatography on silica gel (5-10% EtOH/EtOAc) gives 7-amino-4-(3-methoxybenzylamino)pyrido[4,3-d]pyrimidine (153 mg, 77%) as a white solid. 1H NMR (DMSO) δ 9.11 (1H, s), 8.83 (1H, t, J=5.7 Hz), 8.26 (1H, s), 7.24 (1H, dt, Jd =0.8 Hz, Jt =8.1 Hz), 6.92 (2H, m), 6.81 (1H, dr, Jd =8.2 Hz, Jt =1.2 Hz), 6.46 (2H, brs), 6.37 (1H, s), 4.71 (2H, d, J=5.8 Hz), 3.73 (3H, s).