Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:3]2[N:4]3[C:5]4[CH:18]=[CH:17][CH:16]=[N:15][C:6]=4[NH:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[C:10]3=[N:1][N:2]=2)=[CH:24][CH:23]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Solvent: ClCCl
Product: ClCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)methanol (300 mg, 0.88 mmol) in dichloromethane (10 mL) was added thionyl chloride (excess, 1 mL) and the resulting solution was stirred at room temperature for 1 hour. The volatiles were removed in vacuo and the residue was carefully neutralized with a solution of sodium bicarbonate. The mixture was extracted with dichloromethane (3×25 mL) and the combined organics were dried over sodium sulfate, concentrated in vacuo. The 3-(4-(chloromethyl)phenyl)-9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepine was obtained as a yellow solid (317 mg, quantitative). M.p.=260-262° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.79 (s, 1H), 8.20 (dd, J=4.8, 1.6 Hz, 1H), 7.94 (dd, J=8.0, 1.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.45-7.39 (m, 3H), 7.35-7.31 (m, 1H), 7.16-7.10 (m, 2H), 6.90 (dd, J=7.6, 4.8 Hz, 1H), 4.81 (s, 2H); LCMS [M+H]: 360.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][O:23][C:24](=[O:29])[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:3]=1)([CH3:27])[CH3:26]
Reactant: CC1(C)Cc2cc(C#N)ccc2NC1c1cccc(N)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C#N)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 57.6 %

Procedure:
A mixture of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (0.64 g, 2.3 mmol), 2-bromo-2-methyl-propionic acid methyl ester (1.25 g, 6.9 mmol) and potassium carbonate (1.59 g, 11.5 mmol) in N,N-dimethylformamide (6 mL) was stirred at 25° C. for 5 d. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) to afford 2-[3-(6-cyano-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (500 mg, 43%) as a brown oil: LC/MS m/e calcd for C23H27N3O2 (M+H)+: 378.49, observed: 378.2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].C([NH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25])(=O)C.O>C(O)C>[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)Nc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C=CC(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 94.8 %

Procedure:
To a solution of acetophenone (7.2 g) and 4N-sodium hydroxide solution (14 ml) in ethanol (50 ml) was added 4-acetylamino-3-nitrobenzaldehyde (10.4 g) at ambient temperature under stirring and the resultant mixture was stirred at same condition for 2 hours. To the reaction mixture was added water and precipitate was collected by filtration. The precipitate was suspended in water (300 ml) and the resultant mixture was adjusted to pH 4.0 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with brine and dried to give 3-(4-amino-3-nitrophenyl)-1-phenyl-2-propen-1-one (12.7 g).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH2:18][CH3:19])[C:15]([NH2:17])=[S:16])[CH:8]=2)[N:3]=1.[CH:20]([CH:22](Cl)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O>CN(C)C=O>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:15]3[S:16][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][N:17]=3)[CH2:18][CH3:19])[CH:8]=2)[N:3]=1
Reactant: CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)C(N)=S
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N(CC)Cc2ccc3nc(C)[nH]c(=O)c3c2)s1
Temperature: 100 °C
Yield: 21.8 %

Procedure:
A mixture of the thiourea (4.67 g), ethyl formylchloroacetate (Archiv der Pharmazie, 1953, 286, 494; 2.55 g) and dimethylformamide (25 ml) was stirred and heated to 100° C. for 1 hour. The mixture was cooled, filtered and the filtrate was evaporated. The residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic solution was dried over sodium sulphate, filtered and evaporated. The residue was purified by trituration in ethyl acetate to give ethyl 2-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-ethylamino]thiazole-5-carboxylate (1.37 g), m.p. 188°-192° C.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:21]1([CH3:28])[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>CN(C)C=O>[ClH:27].[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:23]2[CH:22]=[C:21]([CH3:28])[CH:26]=[CH:25][CH:24]=2)=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1cccc(Cl)c1
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)c1

Procedure:
Using a procedure similar to that described above in Example 58A, 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 8 g. of sodium methoxide in 200 ml. of N,N-dimethylformamide under an atmosphere of nitrogen and then 8 g. of m-toluyl chloride was added to produce 3-hydroxy-4-(m-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride. This salt was converted to the free base which was treated with acetic acid to yield 11.5 g. of the acetate salt, m.p. 170°-175° C. By treating a slurry of this salt in 100 ml of N,N-dimethylformamide with 40 g. of methanesulfonic acid there was obtained 10.6 g. of the corresponding methanesulfonate salt, m.p. >250° C. (uncorr.). This methanesulfonate (10 g.) was catalytically hydrogenated, using a procedure similar to that described above in Example 30B, to yield 5.4 g. of 3-hydroxy-4-(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 165°-168° C. (uncorr.).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:26][C:27]([F:44])([F:43])[C@@H:28]([O:30][C:31](=O)[O:32]C1C=CC([N+]([O-])=O)=CC=1)[CH3:29]>>[F:26][C:27]([F:44])([F:43])[C@@H:28]([O:30][C:31]([N:23]1[CH2:24][CH2:25][CH:20]([C@@H:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:32])[CH3:29]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: C[C@H](OC(=O)N1CCC([C@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 1. LC (method 1): tR=0.86 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=O.[CH3:14][CH:15]1[NH:20][CH2:19][CH2:18][NH:17][C:16]1=[O:21].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:20]2[CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH:15]2[CH3:14])=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC1NCCNC1=O
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1C(=O)NCCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 69.7 %

Procedure:
A solution of 3,4-dichlorocinnamic acid (190 mg, 0.88 mmol), 3-methylpiperazin-2-one (100 mg, 0.88 mmol), 4-methylmorpholine (443 mg, 4.38 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (500 mg, 1.31 mmol) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 3 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; CH2Cl2/MeOH 95:5) produced the title compound (192 mg, 70%). White solid, MS (ISP)=313.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[Na].[CH3:10][NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>CO>[CH3:10][N:11]1[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:2][C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12]1
Reactant: N#Cc1ccncc1
Reactant: CNNC(=O)c1cccnc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2cccnc2)nc1-c1ccncc1
Reaction time: 0.5 h

Procedure:
To 4-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.). The solution is allowed to stand 0.5 hours at ambient temperature and is then added to a solution of 1-methyl-2-nicotinoyl-hydrazine (3 g.) in methanol (30 ml.). The reaction mixture is heated 5 hours at reflux and is concentrated to an oil which solidifies. After chromatography on silica gel and recrystallization from acetonitrile 0.8 g. of 1-methyl-3-(3-pyridyl)-5-(4-pyridyl)-1,2,4-triazole melting 132°-133°C is obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=O)=[CH:10][CH:9]=1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][NH:7][S:2]4(=[O:1])=[O:19])=[CH:18][CH:17]=3)=[O:14])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc(N2CCCNS2(=O)=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCNS4(=O)=O)cc3)CC2)c(C)c1
Yield: 44.1 %

Procedure:
Using ethyl 4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-2-yl)benzoate (300 mg) described in Preparation Example 47 and 1-(3,5-dimethylpyridin-2-yl)piperazine (202 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (200 mg) was obtained.
Reaction SMILES: [C:1]([N:3]=[C:4](OC)[CH2:5][CH2:6][CH3:7])#[N:2].Cl.[CH3:11][O:12][C:13](=[O:16])[CH2:14][NH2:15].C(N(CC)CC)C>CO>[C:1]([N:3]=[C:4]([NH:15][CH2:14][C:13]([O:12][CH3:11])=[O:16])[CH2:5][CH2:6][CH3:7])#[N:2]
Reactant: CCCC(=NC#N)OC
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCC(=NC#N)NCC(=O)OC
Temperature: -5 °C
Reaction time: 17 h

Procedure:
Methyl N-cyanobutyrimidate (240 g, 1.90 mol) from Example 2 was dissolved in absolute methanol (1.5 L) and glycine methyl ester HCl (250 g, 1.99 mol) added to the reaction mixture. The suspension was cooled to -5° C. and triethylamine (211 g, 2.09 mol) added over a period of 15 minutes. The resulting solution was stirred at 20° C. for 17 hours, then concentrated under reduced pressure to an oily-solid residue (690 g). The residue was taken up in ethyl acetate and the insoluble salts removed by filtration. The filtrate was washed with water followed by 10% aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. This product (370 g) was used in the next step without further purification.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[S:18]1[C:22]([C:23](O)=[O:24])=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2.C(=O)([O-])O.[Na+]>O>[S:18]1[C:22]([C:23]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:15])[F:16])=[O:24])=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1cc2ccccc2s1)=C(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.40 g (1.8 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.33 g (1.9 mmol) of benzo[b]thiophene-2-carboxylicacid, followed by the addition of 0.46 g (5.5 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 2 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:7) to obtain 0.48 g (yield: 93%) of 4,4-difluoro-3-methyl-3-butenyl benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:18])[C:4]([N:6]1[CH2:13][C:12](OC)([O:14]C)[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].Cl>CCOCC>[SH:1][CH2:2][CH:3]([CH3:18])[C:4]([N:6]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(C)CS)C1
Agent: Cl
Solvent: CCOCC
Product: CC(CS)C(=O)N1CC(=O)C[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
The (S)-1-(3-mercapto-2-methyl-1-oxopropyl)-4,4-dimethoxy-L-proline (0.4 g., 0.0014 mole) is added to 8 ml. of stirred N HCl through which argon had previously been passed for ten minutes. After a solution is obtained, the flask is stoppered under argon and kept overnight at room temperature. The following steps are also carried out under an atmosphere of argon to the extent possible. To the stirred solution there is added 20 ml. of methylene chloride and after saturating with sodium chloride the layers are separated. The aqueous phase is extracted with additional methylene chloride (3×15 ml.), the organic layers are combined, dried (MgSO4), and the solvents evaporated to give a foamy residue. Following trituration with ether (evaporation repeated), 0.26 g. of (S)-1-(3-mercapto-2-methyl-1-oxopropyl)-4-oxo-L-proline are obtained as an amorphous solid (hygroscopic).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH:15]=2)[CH2:10]1)=O)(C)(C)C.[ClH:27].O1CCOCC1>C(O)(=O)C>[ClH:27].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[CH:15]=2)[CH2:10]1
Reactant: Cc1ccc(/C=C/c2ccc3c(c2)CC(NC(=O)OC(C)(C)C)C3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1ccc(/C=C/c2ccc3c(c2)CC(N)C3)cc1

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-[(E)-2-(4-methylphenyl)ethenyl]indan (20 mg, 0.060 mmol) synthesized in Preparation Example 2, 4N hydrochloric acid-dioxane (2.0 ml) and acetic acid (6.0 ml), a similar procedure to Example 24 was carried out to obtain 2-amino-5-[(E)-2-(4-methylphenyl)ethenyl]indan hydrochloride (16 mg, 0.06 mmol) having the following physical properties:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:23][NH:22][CH2:21]3)=[N:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[BH3-][C:33]#N.[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:21][N:22]([CH3:33])[CH2:23]3)=[N:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CNC3)o2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC(c2nnc(C(=C3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3)o2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-(azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.029 g, 0.074 mmol) in MeOH (5 mL) was added formaldehyde (0.322 mL, 57% solution in H2O) dropwise at rt. A solution of NaCNBH3 (0.026 g, 0.415 mmol) in MeOH (0.3 mL) was then added and the solution was stirred at rt for 15 min. The resulting mixture was poured into H2O and extracted with EtOAc (×3), and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC (NH4OAc) to afford the title compound (0.012 g, 17%) as a colorless solid:
Reaction SMILES: [NH2:1][C:2]1[CH2:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:4][N:3]=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.Cl>C(O)(C)C>[ClH:15].[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2=NN=C(N)C2)cc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2cc(Nc3ncnc4cc(OCC5CCN(C)CC5)c(OC)cc34)n[nH]2)cc1
Temperature: 5 °C
Yield: 76.5 %

Procedure:
A solution of 3-amino-5-(4-methoxyphenyl)-4H-pyrazole (74 mg, 0.39 mmol), (Synthesis, 1984, 3, 276), in isopropanol (3.5 ml) was added to 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (110 mg, 0.34 mmol) followed by 5M hydrogen chloride in isopropanol (78 μl, 0.39 mmol) and the mixture was heated at reflux for 1.5 hours. After cooling to 5° C., the precipitate was collected by filtration washed with isopropanol, followed by ether and dried under vacuum at 60° C. to give 4-(5-(4-methoxyphenyl)pyrazol-3-ylamino)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline hydrochloride (133 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[C:18][Si](C)(C)C)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2
Reactant: C[C@@H](C1CC1)N1Cc2cc(C#C[Si](C)(C)C)cc(Cl)c2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#Cc1cc(Cl)c2c(c1)CN([C@@H](C)C1CC1)C2=O
Temperature: 25 °C
Yield: 64.9 %

Procedure:
7-chloro-2-((S)-1-cyclopropylethyl)-5-(2-(trimethylsilyl)ethynyl)isoindolin-1-one (40.88 g, 123.17 mmol) was dissolved in 250 mL of ethanol and stirred at room temperature. To the reaction mixture was added a solution of potassium hydroxide (0.10 g, 1.85 mmol) in 20 mL of water. The reaction immediately turned black and was allowed to continue stirring for 90 minutes at room temperature. The volatiles were removed under reduced pressure and the product purified by flash chromatography on silica gel eluting with a gradient of 0 to 40% ethyl acetate in hexane. This afforded the desired product as a light tan solid (20.75 g, 69.7%). 1H NMR (300 MHz, CDCl3) δ ppm 0.34-0.50 (m, 3H) 0.58-0.69 (m, 1H) 0.93-1.07 (m, 1H) 1.34 (d, 3H) 3.22 (s, 1H) 3.76 (dq, 1H) 4.31-4.54 (m, 2H) 7.45 (s, 1H) 7.51 (s, 1H). MS ESI m/z=260 (M+H). HPLC Method B: 0.80 min.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Br[CH2:6][CH2:7][O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1.C(N(CC)CC)C>CO>[CH3:2][N:3]([CH3:4])[CH2:6][CH2:7][O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1
Reactant: CNC
Reactant: BrCCOc1cc(-c2ccccc2)on1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)CCOc1cc(-c2ccccc2)on1
Yield: 62.9 %

Procedure:
After dimethylamine hydrochloride (815 mg) was dissolved in methanol (50 ml), 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg) and triethylamine (2.8 ml) were added thereto, followed by reflux of the resulting mixture for 8 hours. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ether (20 ml), and the solution was washed with a diluted aqueous NaCl solution (20 ml), followed by drying of the organic layer over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (146 mg, 63%) as colorless crystals.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].CN(C1C=CC=CN=1)C>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([NH:14][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[C:12]#[CH:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C#CCN
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C#CCNS(=O)(=O)c1ccccc1
Reaction time: 15 h

Procedure:
Benzene sulfonyl chloride (1.16 mL, 9.1 mmol) was added to stirred solution of propargylamine (0.62 mL, 9.1 mmol) and dimethylaminopyridine (22 mg, 0.18 mmol) in pyridine (5 mL) at room temperature. The resulting solution was aged at ambient temperature for approximately 15 h. The reaction mixture was diluted with ethyl acetate and washed successively with 1N HCl and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to furnish the title compound (i-2), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:11]([C:9]2[CH:10]=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cc(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cc(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
66 mg (0.33 mol) of 5-fluoro-1H-indol-7-carboxylic acid, 86 mg (0.30 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine and 63 mg (0.33 mmol) of EDC.HCl were dissolved in 3 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 7:3) to yield 98 mg (73%) product as a light yellow viscous oil. MS (ISP) 447.2 (M+H)+.