Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[Cl:31].[CH3:32][C:33]1[O:37][C:36]([CH:38]=O)=[CH:35][CH:34]=1.[C:40]([OH:43])(=[O:42])[CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:40]([OH:43])(=[O:42])[CH3:41].[Cl:31][C:3]1[CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH:1][CH2:38][C:36]1[O:37][C:33]([CH3:32])=[CH:34][CH:35]=1
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(N)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Reactant: Cc1ccc(C=O)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(CNc2ccc(-c3nn([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2Cl)o1
Reaction time: 0.08 h

Procedure:
A mixture of 3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.00045 mol) in 1,2-dichloroethane (20 mL) was reacted with 5-methyl-2-furfural (0.052 g, 0.00048 mol), acetic acid (0.095 g, 0.00159 mol) and sodium triacetoxyborohydride (0.336 g, 0.00159 mol) at ambient temperature. An additional two equivalents of sodium triacetoxyborohydride (0.672 g, 0.00318 mol) were added in two 24 hour intervals. The solvents were removed in vacuo and the residue was partitioned between chloroform (25 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with chloroform (2×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 30% isocratic for five minutes, then 30%-60% acetonitrile—0.1M ammonium acetate over 15 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give trans 3-(3-chloro-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate as a white solid (0.129 g, 0.00022 mol):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8](I)[C:7]([CH2:11][CH3:12])=[CH:6][C:5]=1[NH2:13].[CH3:15][N:16]1[C:20]([Sn](CCCC)(CCCC)CCCC)=[CH:19][CH:18]=[N:17]1.O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:20]2[N:16]([CH3:15])[N:17]=[CH:18][CH:19]=2)[C:7]([CH2:11][CH3:12])=[CH:6][C:5]=1[NH2:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: CCc1cc(N)c(C(=O)OC)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1cc(N)c(C(=O)OC)cc1-c1ccnn1C
Temperature: 100 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
2-Amino-5-iodo-4-ethyl-benzoic acid methyl ester (280 mg, 0.92 mmol) and 1-methyl-5-tributylstannanyl-1H-pyrazole (409 mg, 1.2 equiv) were weighed in air and added to a flame-dried flask. [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (75 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred at 100° C. for 18 h (TLC control). The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to yield 2-amino-4-ethyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (163 mg, 68% yield) as a yellow solid. ESI-MS: m/z 260.3 [M+H]+, rt 6.37 min.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[NH:9][C:8]=2[CH3:22])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[NH2:56][CH2:57][C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([NH:56][CH2:57][C:58]4[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[NH:9][C:8]=2[CH3:22])=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2[nH]c(C)c(Cc3ccc(Cl)cc3)c2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-n2[nH]c(C)c(Cc3ccc(Cl)cc3)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-(4-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazole-5-carboxylic acid (0.05 g, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.04 g, 0.20 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.28 mmol) in N,N-dimethylformamide (2 mL) was added 1-hydroxy-benzotriazole (0.05 g, 0.37 mmol). The resulting mixture was stirred at ambient temperature for 15 minutes and 3-(aminomethyl)pyridine (0.02 mL, 0.02 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 hours, diluted with ethyl acetate (30 mL), washed with water and brine. The organic solution was dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by column chromatography to the title compound as a white powder (0.03 g, 48%): mp 215-217° C.: 1H NMR (300 MHz, DMSO-d6) δ 12.31 (br s, 1H), 8.71 (t, J=5.8 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.42 (dd, J=4.8, 1.6 Hz, 1H), 7.68 (td, J=7.8 Hz, 1.9 Hz, 1H), 7.36-7.19 (m, 5H), 4.38 (d, J=5.8 Hz, 2H), 3.52 (s, 2H), 2.52 (s, 3H), 2.13 (s, 3H); MS (ES+) m/z 454.3 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=1)=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:21])[NH2:20])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C[C:35]([OH:37])=[O:36]>>[NH:1]([C:35]([O:37][C:4]([CH3:6])([CH3:5])[CH3:3])=[O:36])[C@@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[CH:32][CH:33]=1)=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:21])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@@H](N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
MM-D-Leu-Gly-L-Arg-pNA.AcOH
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:39][CH2:38][O:37][CH2:36]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH:35]2[CH2:39][CH2:38][O:37][CH2:36]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCC1CCOC1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
N2-Butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (150 mg, 0.428 mmol) was heated in dry DMF (2.5 ml) at 60° C. for 1 hour with potassium carbonate (237 mg, 1.713 mmol). The reaction mixture was cooled to room temperature and 3-(3-bromopropyl)tetrahydrofuran (99 mg, 0.514 mmol) was added. The mixture was then heated at 50° C. overnight. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers were separated and then dried by passage through a hydrophobic frit and evaporated to dryness. The residue was dissolved in 1:1 MeOH:DMSO (2.8 ml) and purified by mass directed autopreparation. Product containing fractions were evaporated under a stream of nitrogen in a blowdown apparatus to give the title compound as a clear gum (84 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:35]1([N:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)N)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:22]=3[C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc([N+](=O)[O-])cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 601.6 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:8]2[C:13](=O)[O:12]C(C)(C)OC2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:27]1C=CC=C[CH:28]=1.CN>O>[CH:1]1([CH:7]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:8][C:13]([NH:27][CH3:28])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccncc1
Reactant: CC1(C)OC(=O)C(C(c2c[nH]c3ncccc23)C2CCCCC2)C(=O)O1
Agent: CN
Solvent: O
Product: CNC(=O)CC(c1c[nH]c2ncccc12)C1CCCCC1
Temperature: 120 °C

Procedure:
A mixture of 5-[cyclohexyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione (560 mg, 1.57 mmol), pyridine (8 mL) and MeNH2 (2 M in THF, 16 mL) heated to 120° C. in sealed vial for 3 h. The reaction was cooled to RT and poured into water. The pH was adjusted to 7. And the resulting solution was extracted 5 times with EtOAc (100 mL) and 3 times with DCM (200 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated, affording crude 3-Cyclohexyl-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide (270 mg), which was used in the next step without purification.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-:23].[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:23]
Reactant: CCCCCCCCCCI
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CCCCCCCCCCO)cc1

Procedure:
38.83 g (144.8 mmol) of decyl iodide is added to a mixture of 20 g (144.8 mmol) of 4-hydroxybenzoic acid and 46 g (434.4 mmol) of sodium carbonate in 400 ml of dimethylformamide, and it is heated for 4 hours to 70° C. Solid is filtered out, the filtrate is evaporated to the dry state in a vacuum, and the residue is taken up in 300 ml of methylene chloride, and 300 ml of 5% aqueous hydrochloric acid is added. It is thoroughly stirred, the organic phase is separated, and it is dried on magnesium sulfate. Then, the organic phase is evaporated to the dry state. The residue is chromatographed on silica gel (mobile solvent: n-hexane-acetone=20:1).
Reaction SMILES: [OH:1][C@H:2](/[CH:15]=[CH:16]/[CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][C:4](N1[C@H](C(C)C)CSC1=S)=[O:5].[Li+].[OH-].Cl.CC[O:44]C(C)=O>C1COCC1.O>[OH:1][C@H:2](/[CH:15]=[CH:16]/[CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][C:4]([OH:44])=[O:5]
Reactant: CCOC(C)=O
Reactant: CC(C)[C@@H]1CSC(=S)N1C(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
At 0° C. to a solution of (S,E)-3-hydroxy-1-((R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-(tritylthio)hept-4-en-1-one (934 mg, 1.66 mmol, prepared according to the procedure in Yurek-George, A. et al, J. Am. Chem. Soc. 2004, 126, 1030) in THF (30 mL) was added a solution of LiOH (196.1 mg, 8.19 mmol) in H2O (10 mL). The reaction mixture was allowed to warm to rt over 1 h, whereupon 1M HCl was added until the pH reached 2. EtOAc (30 mL) was then added and the layers were separated. The aqueous layer was extracted with EtOAc (20 mL) the organic layers were combined, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (eluant 3:7-1:1-1:0 EtOAc/Hexane) gave the 6 as a white solid (600 mg, 1.43 mmol, 86%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.O[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20](F)[C:19]=1[F:32].ClC1SC(COC2C=C([F:47])C(CCC(OCC)=O)=C(F)C=2)=C(C2C=CC(Cl)=CC=2)C=1>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:18]2[C:19]([F:32])=[CH:20][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:22][C:23]=2[F:47])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CCOC(=O)CCc1c(F)cc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)cc1F
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Reactant: CCc1ccc(-c2cc(Cl)sc2CO)cc1
Product: CCc1ccc(-c2cc(Cl)sc2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 197 by coupling of [5-chloro-3-(4-ethylphenyl)thiophen-2-yl]methanol and ethyl 3-(4-hydroxy-2,3-difluorophenyl)propanoate followed by hydrolysis of ethyl 3-(4-((5-chloro-3-(4-chlorophenyl)thiophen-2-yl)methoxy)-2,6-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H-NMR (300 MHz, CD3OD) δ 7.34 (d, J=8.1 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 7.01 (s, 1H), 6.85 (d, J=9.3 Hz, 2H), 5.11 (s, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.59-2.73 (m, 4H), 1.27 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H19C1F2O3S, 435.1 (M−H). found 435.1.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[Cl:12][C:13]1[CH:14]=[CH:15][C:16](=[O:27])[N:17]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)[CH:18]=1.O>C(Cl)Cl>[Br:1][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:17]2[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]2=[O:27])=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccc(Cl)cn1-c1ccc(CO)cc1
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: O=c1ccc(Cl)cn1-c1ccc(CBr)cc1
Temperature: -20 °C
Reaction time: 6 h

Procedure:
To N-bromosuccinimide (0.166 g, 0.929 mmol) in CH2Cl2 (3 mL) at 0° C. was added dimethylsulfide (0.082 mL, 1.11 mmol). The resulting suspension was cooled to -20° C. and a solution of the alcohol from Step 1 (0.146 g, 0.62 mmol) in CH2Cl2 was added dropwise over 2 minutes. The reaction mixture was stirred at 0° C. for 6 hrs and then poured into water and extracted with CH2Cl2. The extracts were dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 1:1 as eluent) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].C1C=CC2N=CN[C:22](=[O:23])[C:20]=2C=1.BrCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:23][CH2:22][CH2:20][N:7]1[C:6](=[O:15])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8]1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=c1[nH]cnc2ccccc12
Agent: O=C([O-])[O-]
Agent: OCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2ncn(CCO)c(=O)c2cc1OC

Procedure:
3-(2-hydroxyethyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared from 6,7-dimethoxy-4(3H)-quinazolinone (3 g, 14.6 mmol). The quinazolinone was combined with 2-bromoethanol (1.14 mL, 16 mmol), an excess of potassium carbonate (10 g) and heated at reflux in 200 mL acetone. The salts were filtered off and the reaction mixture was concentrated. The residue was dissolved in chloroform and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated, 1.39 g (38%); light brown powder; m.p. 130° C., MS: 250.9 (M+H)+
Reaction SMILES: [NH2-:1].[Li+].Cl[SiH:4]1[N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[CH:6][N:5]1[C:13]([CH3:16])([CH3:15])[CH3:14].CCCCCC>COCCOC>[NH2:1][SiH:4]1[N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[CH:6][N:5]1[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: [NH2-]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
In an argon atmosphere, 505 mg (purity: 95%, 20.9 mmol) of lithium amide was suspended in 20 mL of 1,2-dimethoxyethane and after adding 4.65 g (20.0 mmol) of Si(tBuNCHCHNtBu)(H)Cl, the mixture was stirred at room temperature for 2 hours. Subsequently, 20 mL of hexane was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 78° C./3.8×102 Pa) to obtain 2-amino-1,3-di-tert-butyl-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NH2) as a pale yellow liquid (yielded amount: 3.93 g, yield: 92%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].[C:12]([OH:15])(=[O:14])[CH3:13].[CH3:16]N(C=O)C>C[O-].[Na+].CO>[OH:11][C:7]1[CH:6]=[CH:5][C:4]2[C:2](=[O:3])[CH:1]=[C:13]([C:12]([O:15][CH3:16])=[O:14])[O:10][C:9]=2[CH:8]=1
Reactant: CC(=O)O
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(=O)c2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2,4-dihydroxyacetophenone (7.1 g, 0.05 mol) and dimethyl oxylate (7.2 g) were dissolved in DMF containing a solution of sodium methoxide in methanol (4.0 g Na, 100 ml MeOH) and the mixture was stirred at room temperature for 48 hours. At this point, acetic acid (180 ml) was added and the mixture was heated to 100° C. for 5 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was thoroughly extracted with more ethyl acetate, and the combined organic extracts were washed with brine. Evaporation of the dried (Na2SO4) solvent in vacuo afforded methyl 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (6a) as a crude yellow solid which was crystallized from from ethyl acetate/hexane to afford 3.5 g of pure product.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.C(N(CC)CC)C>ClCCl>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]2[CH2:12][NH:8][CH2:9][C@H:10]2[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:15]=1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl (3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylate, from preparation 25 (0.93 g, 2.8 mmol) in dichloromethane (9 mL) cooled with an ice-bath was added 1-chloroethyl chloroformate (0.46 mL). The reaction mixture was allowed to warm to room temperature and stirred for 48 hours. The reaction mixture was then cooled to 0° C. and triethylamine (0.43 mL, 3.1 mmol) was added followed by additional 1-chloroethylchloroformate (0.31 mL, 2.8 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours before being diluted with dichloromethane, washed with water (20 mL), 5% aqueous citric acid (20 mL) and then dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the residual oil was refluxed in methanol (20 mL) for 1 hour. The solvent was then removed in vacuo and the residue was triturated with diethyl ether and filtered to give the desired product as a white solid, 0.874 g.
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.ClC(OCC)=[O:10].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([CH:25]1[CH:33]2[C:28](C(O)=O)([CH2:29][C:30]3[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=3[CH:32]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:27][NH:26]1)=[O:24].[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[N-:3]=[C:6]=[O:10].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([CH:25]1[CH:33]2[CH:28]([CH2:29][C:30]3[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=3[CH:32]2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:27][NH:26]1)=[O:24]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: COc1ccccc1CC(=O)C1NCC2(C(=O)O)Cc3ccccc3C(c3ccccc3)C12
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccccc1CC(=O)C1NCC2Cc3ccccc3C(c3ccccc3)C21
Product: [N-]=C=O
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
0.9 g (8.9 mmol) of triethylamine and 1.085 g (10 mmol) of ethyl chloroformate in solution in 40 cm3 of acetone are successively added to a solution of 3.43 g (7.4 mmol) of (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano-2-(2-methoxyphenyl)acetyl-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid in 20 cm3 of acetone and 6 cm3 of water, which solution has been cooled to 0-2° C. and maintained under a nitrogen atmosphere. After stirring for 30 minutes at 0-5° C., a solution of 0.77 g (7.4 mmol) of sodium azide in 15 cm3 of water is added dropwise and stirring is then maintained at 0-5° C. for 1 hour. The reaction mixture is then poured into 200 cm3 of water and the acylazide is extracted with 5 times 40 cm3 of ethyl ether. The combined organic phases are washed with water and then dried over magnesium sulphate. After evaporating the ether under reduced pressure, 50 cm3 of toluene are added. The mixture is then gradually heated to 85-90° C. and then at reflux for 1 hour after gas evolution has ceased. The crystals formed on cooling are filtered off and then washed with petroleum ether. 2.98 g (88%) of (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano-3a-isocyanate-2-(2-methoxyphenyl)acetyl-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole are thus obtained in the form of a white powder, the characteristics of which are as follows: melting point=185° C., mass spectrum (E.I.) M/Z=464 (M+)
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6](O)[CH3:7].[Br:9][C:10]1[NH:11][C:12]([C:17]#[N:18])=[C:13]([C:15]#N)[N:14]=1.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>O>[Br:9][C:10]1[N:14]([CH2:13][C:15]#[C:6][CH3:7])[C:20]([C:19]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]([C:17]#[N:18])[N:11]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1nc(Br)[nH]c1C#N
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC#CCn1c(Br)nc(C#N)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.56 ml of sulfuric acid was added to 170 ml of ethanol containing 16.80 g of 2-bromo-1H-imidazole-4,5-dicarbonitrile [CAS No. 50847-09-1], and the mixture was heated under reflux for 48 hours. The solution was cooled, and then 500 ml of ethyl acetate and 200 ml of water were added thereto. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide, and 14.1 g of potassium carbonate and 8.6 ml of 2-butynyl bromide were added thereto. The mixture was stirred at room temperature for 18 hours. 500 ml of ethyl acetate was added to the solution, and the mixture was washed three times with 300 ml of water, and then with 300 ml of a saturated sodium chloride solution. Then, the solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 4.09 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (9:1).