Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([NH:23][CH2:22][CH2:21][O:20][CH3:19])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: COCCN
Product: COCCNC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Yield: 50 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(2-fluorobiphenyl-4-yl)propanoic acid and 2-methoxyethanamine. Yield: 50%. 1H NMR (500 MHz, CDCl3): δ 1.54-1.56 (d, 3H), 3.30 (s, 3H), 3.38-3.45 (m, 4H), 3.55 (q, 1H), 5.58 (s br, 1H), 7.11-7.16 (m, 2H), 7.36-7.45 (m, 5H), 7.54 (m, 2H).
Reaction SMILES: Cl.[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([C:8]([NH2:10])=[NH:9])=[CH:4][CH:3]=1.[C:12](OCC)(=[O:19])[CH2:13][C:14](OCC)=[O:15]>>[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:12](=[O:19])[CH2:13][C:14](=[O:15])[N:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(C(=N)N)cc1
Agent: Cl
Product: Cc1ccc(C2=NC(=O)CC(=O)N2)cc1

Procedure:
Similarly, reacting p-toluamidine hydrochloride with diethyl malonate affords 2-(4-tolyl)-4,6-(1H,5H)-pyrimidinedione which is then reacted with phosphoryl chloride to produce 4,6-dichloro-2-(4-tolyl)-pyrimidine, m.p. 84°-85°C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[S:24])[NH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([S:24][CH2:4][CH2:3][O:2][CH3:1])=[N:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCCBr
Reactant: S=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCSc1ncnc2cc(OCc3ccccc3)ccc12
Reaction time: 4 h
Yield: 87.5 %

Procedure:
2-Bromoethyl methyl ether (3.2 ml, 33 mmol) was added dropwise to a solution of 7-benzyloxy-3,4-dihydroquinazolin-4-thione (7.4 g, 28 mmol), (prepared as described for the starting material in Example 8), in DMF (275 ml) containing potassium carbonate (4.6 g, 33 mmol). After stirring for 4 hours, water was added and the precipitate was collected by filtration, washed with water, and dried under vacuum to give 7-benzyloxy4-(2-methoxyethylsulphanyl)quinazoline (8 g, 89%).
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8](=O)[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:20])=O>>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([Cl:20])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1n[nH]c(=O)c2cc(OC)ccc12
Product: CCCCc1nnc(Cl)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-butyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]2[S:37][C:36]([C:38]3([OH:42])[CH2:41][CH2:40][CH2:39]3)=[N:35][CH:34]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:15]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(O)CCC3)=NC=2)=C2C=C(C3C=CC(CN4CCCC4)=CC=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1>>[Cl:1][C:2]1[C:3]([C:33]2[S:37][C:36]([C:38]3([OH:42])[CH2:41][CH2:40][CH2:39]3)=[N:35][CH:34]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(Cc4ccccn4)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2c(-c3ccc(CN4CCCC4)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Product: OC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5cnn(Cc6ccccn6)c5)cc34)s2)CCC1

Procedure:
The title compound was prepared as described in Example 8D, substituting 1-(5-(5-chloro-2-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 84B) 1-(5-(5-chloro-2-(4-(pyrrolidin-1-ylmethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 8C). 1H NMR (300 MHz, DMSO-d6) δ 12.36 (bs, 1H), 8.55 (dd, J=5.0, 1.6 Hz, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.83-7.77 (m, 1H), 7.34 (ddd, J=7.5, 4.8, 0.9 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 6.80 (s, 1H), 6.65 (s, 1H), 5.48 (s, 2H), 2.67-2.55 (m, 2H), 2.44-2.32 (m, 2H), 2.06-1.86 (m, 2H); MS ESI(+) m/z 463.0 [M+H]+.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.O.Cl>C1COCC1.O>[N:12]1([C:9]2[CH:8]=[CH:7][C:6]([C:5]([OH:18])=[O:4])=[CH:11][CH:10]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.9 %

Procedure:
LiOH (92 mg, 0.22 mmol) was added to a stirred solution of 4-morpholin-4-yl-benzoic acid methyl ester (162 mg, 0.73 mmol) in THF:H2O (1:1, 4 mL), and the resulting mixture was stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added and acidified it with 10% aqueous HCl, filtered the solid precipitated to afford 130 mg (86% yield) of 4-morpholin-4-yl-benzoic acid. 1H NMR (DMSO-d6): δ 12.4 (s, 1H), 7.8 (d, 2H), 7.0 (d, 2H), 3.76 (t, 4H), 3.28 (t, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](=[O:18])N(OC)C)[N:10]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:29][Mg+].[Br-]>C1COCC1>[C:13]([C:11]1[N:10]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[N:9]=[C:8]([N:3]2[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]2[CH3:1])[CH:12]=1)(=[O:18])[CH3:29]
Reactant: CON(C)C(=O)c1cc(-n2c(C)ccc2C)nn1CCNC(=O)OC(C)(C)C
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cc(-n2c(C)ccc2C)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 287d (7.82 g, 1.0 eq., 20.0 mmol) and THF (100 mL) under N2 protection. A solution of MeMgBr (3.0 M in ether) (17 mL, 2.5 eq., 50.0 mmol) was added at −78° C. The mixture was stirred at room temperature for 3 h and quenched with saturated NH4Cl solution. It was then concentrated under reduced pressure and the residue was extracted with ethyl acetate (3×50 mL). The combined organic layer was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 287e as colorless oil (5.40 g, 78%). MS-ESI: [M+H]+ 347.0. 1H NMR (500 MHz, CDCl3) δ 6.57 (s, 1H), 5.91 (s, 2H), 4.93 (bs, 1H), 4.71 (t, J=5.5 Hz, 2H), 3.62 (t, J=5.5 Hz, 2H), 2.57 (s, 3H), 2.16 (s, 6H), 1.28 (s, 9H).
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[S:11][N:10]=[N:9][C:8]=1[C:12]([O:14]C)=O)([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].C(Cl)Cl.C[Al](C)C>CCCCCC>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:12]([C:8]2[N:9]=[N:10][S:11][C:7]=2[CH2:6][O:5][Si:4]([CH:16]([CH3:17])[CH3:18])([CH:19]([CH3:20])[CH3:21])[CH:1]([CH3:2])[CH3:3])=[O:14])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: COC(=O)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: Nc1ccc(F)c(Cl)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)[Si](OCc1snnc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a cooled solution (0° C.) of methyl 5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carboxylate (2.2 g, 0.0066 mol) and 3-chloro-4-fluoroaniline (1.5 g, 0.010 mol) in DCM (20 mL, 0.4 mol) was added 2.0 M of trimethylaluminum in hexane (12 mL) under nitrogen and stirred for 15 minutes. The volatiles were removed in vacuo and the crude was purified by flash chromatography to give the desired product (2.3 g, 78%). MF=C19H27ClFN3O2SSi; LCMS calculated for C19H28ClFN3O2SSi (M+H)+: m/z=444.1.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10](Br)[CH3:11].[Mg].B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>CCOCC.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2([NH2:7])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CCBr
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccc(I)cc2)CC1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
7.09 ml (24.01 mmol) of Ti(OiPr)4 are added to a solution of 4-iodobenzonitrile (5.0 g, 21.83 mmol) in 140 ml of anhydrous Et2O and the reaction mixture is cooled to −65° C. To the resulting solution there are then added, dropwise, 16 ml (48.00 mmol) of a 3M solution of magnesium ethyl bromide in Et2O, and the reaction mixture is returned to ambient temperature. Stirring is continued for 1 hour at ambient temperature and 5.53 ml (43.66 mmol) of BF3.OEt2 are added. Stirring is continued for 1 hour 15 minutes at ambient temperature and 65 ml of 1N HCl are added. A two-phase suspension is obtained; 300 ml of Et2O and then 200 ml of 1N NaOH solution are added. The suspension is filtered and the filtrate is extracted twice with Et2O. The organic phases are collected, washed (water, saturated NaCl solution), dried over MgSO4 and concentrated by half. The residual solution is extracted with 1N HCl and the expected amine is precipitated as a result of making alkaline with concentrated NaOH solution.
Reaction SMILES: O[C:2]1[C:3](O)=[CH:4][C:5]2[CH2:6][C@H:7]3[C:31](=[O:32])[N:30]([CH3:33])[CH2:29][C:28](=[O:34])[N:8]3[C@H:9]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14](C(OC(C)(C)C)=O)[CH:13]=3)[C:10]=2[CH:11]=1.[C:36]([O-])([O-:38])=[O:37].[Cs+].[Cs+].CN(C=O)C.BrCCl>CCOC(C)=O>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C@H:9]2[N:8]3[C@H:7]([C:31](=[O:32])[N:30]([CH3:33])[CH2:29][C:28]3=[O:34])[CH2:6][C:5]3[CH:4]=[C:3]4[O:37][CH2:36][O:38][C:2]4=[CH:11][C:10]2=3)=[CH:13]1
Reactant: O=C([O-])[O-]
Reactant: CN1CC(=O)N2[C@H](c3cn(C(=O)OC(C)(C)C)c4ccccc34)c3cc(O)c(O)cc3C[C@H]2C1=O
Agent: ClCBr
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CC(=O)N2[C@H](c3c[nH]c4ccccc34)c3cc4c(cc3C[C@H]2C1=O)OCO4
Temperature: 150 °C
Yield: 30.7 %

Procedure:
0.665 g (1.4 mmol) (5) and 0.6853 g (2.1 mmol) Cs2CO3 was suspended in 3.3 ml freshly distilled DMF. 0.140 ml (2.1 mmol) BrCH2Cl was added and the mixture was heated at 150° C. for 1.5 h. The heat source was removed and the mixture was allowed to cool to r.t. after which the mixture was filtered and separated with 100 ml EtOAc and 100 ml H2O. The water phase was extracted with 2×100 ml EtOAc. The pooled organic phases were washed with 150 ml brine, dried over Na2SO4, filtered and evaporated. Flash chromatography (Pet. ether:EtOAc, 1:4) gave 0.167 g (0.43 mmol, 31%) (6).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C@@H:40]([OH:42])[CH3:41])[CH:38]=2)O1>>[F:21][C:20]([F:23])([F:22])[CH2:19][N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:34]5[CH:35]=[N:36][N:37]([CH2:39][C@@H:40]([OH:42])[CH3:41])[CH:38]=5)[CH:25]=[CH:24][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: C[C@H](O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: C[C@H](O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with (S)-1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 381. MS (ESI+) 477.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:21]=[N:22][C:23]([O:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)=[C:24]([C:26]([CH3:28])=[CH2:27])[CH:25]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:21]=[N:22][C:23]([O:29][C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:25]=3)(=[O:18])=[O:19])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: C=C(C)c1cc(S(=O)(=O)N(C)[C@@H]2CCCc3c2cnn3CC(=O)OCC)cnc1Oc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(C(C)C)c1
Yield: 53.2 %

Procedure:
A solution of ((R)-4-{[6-(4-chloro-phenoxy)-5-isopropenyl-pyridine-3-sulfonyl]-methyl-amino}-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (42 mg, 0.077 mmol) in methanol was hydrogenated over 10% palladium on carbon (6 mg) under atmospheric pressure for 2.5 hours at room temperature. The reaction mixture was filtered through a glass funnel and the filtrate was purified by preparative HPLC to afford ((R)-4-{[6-(4-chloro-phenoxy)-5-isopropyl-pyridine-3-sulfonyl]-methyl-amino}-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (22.4 mg, 53%) as a white solid. MS cald. for C26H31ClN4O5S 546, obsd. (ESI+) [(M+H)+] 547.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[C:20]([N:26]=[C:27]=[S:28])=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:27](=[S:28])[NH:26][C:20]1[C:19]([Cl:18])=[CH:24][C:23]([Cl:25])=[CH:22][N:21]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ncc(Cl)cc2Cl)c1NCCCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.2 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (3.13 g, 12.1 mmol) and 3,5-dichloro-2-isothiocyanatopyridine (3.23 g, 15.7 mmol) in tetrahydrofuran (40 mL) was stirred at room temperature for 3 days. The mixture was concentrated in vacuo, and the residue was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (3.43 g, 7.40 mmol, 61%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C(Cl)(Cl)Cl>[Cl:12][C:7]1[CH2:9][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:5])[CH:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)C=C(Cl)C1
Reaction time: 18 h

Procedure:
A mixture of dimedone (50.0 g), phosphorus pentachloride (34.25 g) and dry chloroform (400 ml) was heated at the reflux temperature for a period of 2.5 hours, after which it was kept at the ambient temperature for 18 hours. After removal of the chloroform by evaporation under reduced pressure, the residue was mixed with water and ice and extracted with diethyl ether (3 × 100 ml). The combined ethereal extracts were washed with dilute potassium hydroxide and with water. The combined washings were extracted with fresh ether and these extracts combined with the washed ethereal extracts, and the whole dried over anhydrous magnesium sulphate. The ethereal extract was concentrated by evaporation under reduced pressure, and the residual oil purified by distillation to yield 3-chloro-5,5-dimethylcyclohex-2-enone, b.p. 94° C./15 mm Hg. The infra-red spectrum (liquid film) showed main absorption bands at 3000, 1700, 1620, 1360, 1310, 1160, 1010, 910 and 850 cm-1.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11](O)[CH:10]=[CH:9][N:8]=2)[CH:2]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:3]2[CH:2]=[C:1]([CH3:14])[CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2nccc(O)n2)c1
Product: Cc1cccc(-c2nccc(Cl)n2)c1
Temperature: 0 °C

Procedure:
A 23.91 g portion of 2-(3-tolyl)-4-pyrimidinol was mixed with 400 ml of phosphorous oxychloride in a one liter round bottom flask, under a drying tube and heated on a steam bath overnight. The mixture was allowed to cool and then poured over 2 liters of ice. The resulting solid was collected, washed with 50 ml of ether, dried and recrystallized from 100 ml of ethanol, giving 16.23 g of the desired intermediate, mp 74°-75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][OH:12].[C:13]([NH:20][CH2:21][C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][CH2:10][CH2:11][OH:12])=[C:2]([NH:1][C:22](=[O:23])[CH2:21][NH:20][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:7]=1
Reactant: Nc1cc(Br)ccc1NCCO
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cc(Br)ccc1NCCO
Yield: 107.1 %

Procedure:
2-(2-Amino-4-bromophenylamino)ethanol (700 mg, 3.03 mmol), N-Boc-glycine (639 mg, 3.65 mmol), HATU (1.39 g, 3.66 mmol) and i-Pr2NEt (785 mg, 1.0 mL, 6.09 mmol) were stirred in methylene chloride (20 mL) for 20 min. The mixture was purified by column chromatography eluting with methylene chloride and a 9:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 85% methylene chloride, to provide the title compound (1.26 g, quant) as a yellow oil: ESI MS m/z 388 [M+H]+.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+]>CO.C1COCC1>[N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Methyl 4-(1H-indol-1-ylmethyl)benzoate (9.05 g; 34 mmol) was dissolved in MeOH/THF (1:1), treated with sodium hydroxide (1.36 g, 34 mmol) stirred at room temperature overnight and concentrated under reduced pressure. The resultant concentrate was diluted with 1N sodium hydroxide (50 mL), washed with EtOAc, acidified with concentrated HCl and extracted with EtOAc. The combined extracts were dried over MgSO4 and concentrated to dryness to give the title product in 77% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 250 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:25]([OH:37])[C@H:24]([OH:38])[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49]Br)=[CH:45][CH:44]=1>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:25]([O:37][CH2:49][C:46]3[CH:47]=[CH:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=3)[C@H:24]([O:38][CH2:49][C:46]3[CH:47]=[CH:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=3)[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N(CCOCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(CCOCc4ccccc4)C(=O)OC(C)(C)C)S[C@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OCc2ccc(OC)cc2)cc1
Reaction time: 1.5 h
Yield: 50 %

Procedure:
A solution of 132 (12 g, 21 mmol) in DMF (60 mL) was treated with sodium hydride (2.9 g, 84 mmol, 70% dispersed by mineral oil) for 30 minutes at 0° C., followed by addition of PMBBr (25 g, 126 mmol). After additional 1.5 hours at 15° C., the reaction was quenched with water (200 mL), and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (3×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 5%-20% ethyl acetate in petroleum ether to afford 133 as light yellow oil (8.5 g, 50%). (ES, m/z) [M+H]+ 809.0; 1H NMR (300 MHz, CDCl3) δ 7.21-7.34 (m, 9H), 6.82-6.89 (m, 4H), 6.08 (d, J=6.3 Hz, 1H), 4.52-4.57 (m, 4H), 4.50 (s, 2H), 4.33-4.35 (m, 1H), 4.05-4.06 (m, 1H), 3.84-3.91 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.58-3.66 (m, 2H), 3.31-3.54 (m, 5H), 1.56 (s, 9H), 0.96 (s, 9H), 0.14 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14]([C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34])[CH2:13][CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)=[CH:23][CH:24]=1)[N:14]([C:33]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:34])[CH2:13][CH2:12]2
Reactant: O=C(c1ccccc1)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(c1ccccc1)N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1
Yield: 79.1 %

Procedure:
A mixture of {6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-isoquinolin-2-yl}phenylmethanone (0.043 g, 0.08 mmol), ammonium formate (0.127 g, 2.01 mmol), and 20% Pd(OH)2/C (0.025 g) in MeOH (10 ml) was refluxed under N2 for 1 hr, then filtered through Celite. The filtrate was evaporated in vacuo to a white residue that was dissolved in CH2Cl2 (10 ml) and washed with 1M NaOH (5 ml). The aqueous layer was extracted with CH2Cl2 (3×10 ml) and all of the combined organic solutions were dried over MgSO4 and concentrated in vacuo to give 0.028 g (78% yield) of colorless residue.
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)([Cl:13])=O>ClC1C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: CCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
86.6 g (0.6 mol) of octanoic acid and 890 g of monochlorobenzene are introduced into the reactor and 600 g (6.07 mol) of phosgene are then added over about 30 minutes, while maintaining the temperature of the reaction medium at a maximum of 25° C. The set pressure is adjusted to 10.5 bar relative and the reaction medium is heated. After two hours, the level of residual acid is about 1 mol %, the level of residual anhydride is zero and the level of octanoyl chloride obtained is 99 mol %.