Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].C([Li])CCC.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[CH:25]=O>C1COCC1.CCCCCC.O.C([O-])([O-])=O.[Na+].[Na+]>[CH3:7][C:6](=[CH:25][C:24]1[CH:23]=[C:22]([F:21])[C:29]([F:30])=[C:28]([F:31])[CH:27]=1)[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)C(C)=Cc1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4.3 ml of triethyl 2-phosphonopropionate are dissolved in 30 ml of anhydrous THF and 12.5 ml of a 1.6 N solution of n-butyllithium in hexane are added dropwise at 0° C. The mixture is stirred at RT for 15 minutes and a solution of 3.2 g of 3,4,5-trifluorobenzaldehyde in 8 ml of anhydrous THF is then added dropwise. It is stirred at RT for one hour and allowed to stand at RT for 16 hours. The reaction mixture is diluted with 300 ml of water, 30 ml of a saturated aqueous Na2CO3 solution are added and it is extracted 3 times using 100 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:8 yields 3.8 g if colorless crystals; m.p. 54° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:5](=[O:7])[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOC(C)=O.C(Cl)Cl>C(O)C.[Pd]>[CH3:1][CH:2]1[O:6][C:5](=[O:7])[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C1OC(=O)C=C1c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1OC(=O)C=C1c1ccccc1
Reaction time: 24 h
Yield: 90 %

Procedure:
A solution of 5-methylene-4-phenyl-2(5H)furanone (2.63 mmol) in ethanol (50 mL) containing Pd—C (25 mgs; 5%) was hydrogenated under an atmosphere of hydrogen at room temperature for 24 hr. The catalyst was filtered off using a pad of Celite and the solvent evaporated in vacuo, leaving a colourless semi-solid, which upon flash chromatography using (EtOAc, CH2Cl2; 1:5) as the eluent gave 5-methyl-4-phenyl-2(5H)furanone 27 as a semi-solid in 90% yield. 1H NMR: δ(CDCl3) 3.33 (d, J 4 Hz, 3H, C5-Me), 5.56 (q, J 4 Hz, 1H, C5-H), 6.26 (s, 1H, C3-H) and 7.47 (s, 5H, Ar H's). 13C NMR: 19.71, 65.85, 66.39, 113.67, 127.11, 129.14, 129.87, 131.20 168.79, 172.54.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([C:24]#[N:25])=[CH:4][N:3]=1.Cl.[CH3:27][N:28]1[CH:32]=[CH:31][C:30](N)=[N:29]1.CC[N:36](C(C)C)C(C)C>C(O)CCC>[C:24]([C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:36][C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[N:3][CH:4]=1)#[N:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3C#N)CC2C1
Agent: Cl
Solvent: CCCCO
Product: Cn1cc(Nc2ncc(C#N)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl 5-((2-chloro-5-cyanopyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (377.2 mg, 1.037 mmol) and 1-methylpyrazol-3-amine hydrochloride (277.5 mg, 2.077 mmol) in butan-1-ol (15 mL) was added DIPEA (335.5 mg, 2.596 mmol). The mixture was stirred at 150° C. overnight, then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title product as a yellow solid (425 mg, 96.56%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:56][C:57]([O:60][C:61]([NH:63][C:64]([N:73]1[CH2:78][CH2:77][CH:76]([C:79](O)=[O:80])[CH2:75][CH2:74]1)=[N:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[O:62])([CH3:59])[CH3:58].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:72][C:69]([O:68][C:66]([NH:65][C:64]([N:73]1[CH2:78][CH2:77][CH:76]([C:79]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:80])[CH2:75][CH2:74]1)=[N:63][C:61]([O:60][C:57]([CH3:56])([CH3:58])[CH3:59])=[O:62])=[O:67])([CH3:70])[CH3:71]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To a solution of the compound prepared in Example 6 (0.2 g, 0.7 mmol) in N,N-dimethylformamide (2 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.10 g, 0.26 mmol) at 0° C. After stirring for 20 minutes, the compound prepared in Example 7 (0.12 g, 0.26 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.8 mmol) were added and the reaction stirred at room temperature for 2 h. The reaction was quenched by adding ice cold water and the resulting precipitate was collected by filtration, dried and the crude product purified by flash chromatography to afford the title compound (0.11 g, 61%) as a white solid.
Reaction SMILES: OC1C=C(C=CC=1[NH2:11])C(O)=O.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:21])[NH2:11]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccc(C(=O)O)cc1O
Product: NC(=O)Nc1ccccc1Br

Procedure:
The urea was prepared from 3-hydroxy 4-amino benzoic acid (3.69 g, 24 mmol) and 2-bromophenylisocyanate(24 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(4.0 g, 48%). EI-MS m/z 351(M+H)+.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][C:11]([C:23]1[C:31]2[C:26](=[C:27]([CH2:32][S:33][CH3:34])[CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH3:12])(=O)=O.O.ClCCl>CS(C)=O>[CH3:34][S:33][CH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[NH:25][CH:24]=[C:23]2[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][CH:14]=1)([CH3:12])[CH2:10][CH2:9][C:1]#[N:2]
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(C)(CCOS(C)(=O)=O)c3ccc(C(F)(F)F)cc3)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CSCc1cccc2c(C(C)(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
33 mg (0.50 mmol) of potassium cyanide were added to 118 mg (0.25 mmol) of the compound from Example 113A in 1.5 ml of DMSO. The mixture was stirred at 80° C. for 4 h, water and dichloromethane were added to the reaction solution, and the phases were separated. The organic phase was extracted with dichloromethane, and the combined organic phases were freed of solvent. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 62 mg (62% of theory) of the target compound were obtained.
Reaction SMILES: N[C:2]1C(Cl)=C(C(OCC)=O)C(C)=NC=1NCC.[NH2:18][C:19]1[C:20]([Cl:36])=[C:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:22]([CH3:30])=[N:23][C:24]=1[NH:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:26]([N:25]1[C:24]2=[N:23][C:22]([CH3:30])=[C:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:20]([Cl:36])=[C:19]2[N:18]=[CH:2]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCNc1nc(C)c(C(=O)OCC)c(Cl)c1N
Reactant: CCCCNc1nc(C)c(C(=O)OCC)c(Cl)c1N
Product: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21

Procedure:
By replacing 5-amino-6-ethylamino-4-chloro-2-methylpyridine-3-carboxylic acid, ethyl ester in Example 1 d with 5-amino-6-butylamino-4-chloro-2-methylpyridine-3-carboxylic acid, ethyl ester, 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]-pyridine-6-carboxylic acid, ethyl ester is obtained. Yield 83%, b.p. 190°-200° 10/01.
Reaction SMILES: [Cl:1]C1C2C(=O)N[C@H]3CN(C(OC(C)(C)C)=O)C[C@@H]3C=2C(C)=CC=1.[Cl:24][C:25]1[C:34]2[C:33](=[O:35])[NH:32][C@@H:31]3[CH2:36][N:37](C(OC(C)(C)C)=O)[CH2:38][C@H:30]3[C:29]=2[C:28]([CH3:46])=[CH:27][CH:26]=1>>[ClH:1].[Cl:24][C:25]1[C:34]2[C:33](=[O:35])[NH:32][C@H:31]3[CH2:36][NH:37][CH2:38][C@@H:30]3[C:29]=2[C:28]([CH3:46])=[CH:27][CH:26]=1
Reactant: Cc1ccc(Cl)c2c1[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Reactant: Cc1ccc(Cl)c2c1[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Product: Cc1ccc(Cl)c2c1[C@H]1CNC[C@@H]1NC2=O
Product: Cl

Procedure:
Following the procedure described in Example 45, Part I, (3aR,9bS)-tert-butyl 6-chloro-9-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the second eluting compound from Part B above, was converted into the title compound of Example 54 as a white solid. 1H NMR (DMSO-D6): δ 9.77 (broad s, 1H), 9.63 (broad s, 1H), 8.89 (s, 1H), 7.37 (d, 1H, J=8.2 Hz), 7.32 (d, 1H, J=8.2 Hz), 4.02-3.96 (m, 1H), 3.65-3.60 (m, 1H), 3.47-3.41 (m, 1H), 3.35-3.27 (m, 2H), 3.10-3.02 (m, 1H), 2.26 (s, 3H). LRMS (ESI): 237.2/239.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:20]1([C:24]([C:26]2[CH:31]=[N:30][C:29](Cl)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-]>CC(N(C)C)=O>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(O)cc(O[C@@H]2CCN(C)C2=O)c1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@@H]2CCN(C)C2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 12) (265 mg, 1 mmol), azetidin-1-yl-(5-chloropyrazin-2-yl)methanone (Intermediate 32) (298 mg, 1.5 mmol) and polymer supported-carbonate (860 mg, 2.5 mmol) in DMA (5 mL) was stirred at 100° C. for 2 hours. The mixture was filtered and the DMA was removed under reduced pressure. The residue was purified by flash chromatography on silica eluting with 20-100% ethyl acetate in isohexane then 10% methanol in DCM to afford the product (292 mg, 68%). 1H NMR δ (300 MHz, CDCl3) 2.13-2.27 (m, 1H), 2.31-2.44 (m, 2H), 2.53-2.66 (m, 1H), 2.94 (s, 3H), 3.35-3.58 (m, 2H), 3.90 (s, 3H), 4.26 (t, 2H), 4.68 (t, 2H), 4.93 (t, 1H), 7.14 (s, 1H), 7.46 (s, 1H), 7.60 (s, 1H), 8.31 (s, 1H), 8.84 (s, 1H); m/z 427 (M+H)+
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)(Cl)[Cl:52]>CN(C=O)C>[ClH:52].[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:22])[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: ClC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cl
Product: N#Cc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A suspension of 1-[2-(4-amino-1-piperidinyl)ethyl]-2-oxo-1,2-dihydro-7-quinolinecarbonitrile (300 mg, 1.01 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (167 mg, 1.01 mmol) in chloroform (10 mL), methanol (15 mL) and DMF (20 mL) was stirred at rt for 30 min then NaBH(OAc)3 (642 mg, 3.03 mmol) was added. The reaction was stirred at rt overnight. The solvents were removed and residue dried in vacuo. The residue was subjected to column chromatography on silica gel eluting with 0-20% methanol-DCM to afford the free base of the title compound (247 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.[OH-].[Na+:33].C(O)[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>O>[Na+:33].[Na+:33].[NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[O:18])=[CH:29][CH:30]=3)[C:5]=2[C:4](=[O:31])[N:3]=1
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1

Procedure:
5 grams of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid was dissolved in 1 L of distilled water and 11.698 ml of a 2.0 M solution of sodium hydroxide was added to the solution. Mannitol (10 g) was then added to the solution and dissolved. The solution was then filtered through a bacterial filter and dried in a freeze-drier to afford 15.5 g of title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:31]O>>[CH3:31][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:17][CH2:18]2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)O)cc2[N+](=O)[O-])CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])c1

Procedure:
3-Nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (1.0 g, 2.9 mmol) was taken in methanol (100 mL) with sulphuric acid (1.0 mL) and reflux for 16 h. Concentrated and dissolved in ethyl acetate (300 mL) and washed the organic layer with a solution of satd. NaHCO3, dried and concentrated to give 0.37 g of 3-Nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid methyl ester.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2].C(O[C:17](=[O:29])[CH2:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=1)C.N12CCCN=C1CCCCC2.II>C(OCC)(=O)C.CCCCCCC>[CH3:13][S:12][C:6]1[N:7]=[CH:8][C:9]2[CH:10]=[C:18]([C:19]3[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=3)[C:17](=[O:29])[N:3]([CH2:1][CH3:2])[C:4]=2[N:5]=1
Reactant: CCOC(=O)Cc1cc(OC)cc(OC)c1
Reactant: CCNc1nc(SC)ncc1C=O
Agent: II
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Temperature: 80 °C
Yield: 56.6 %

Procedure:
A 5-L round bottomed flask was charged with 516 g (2.62 mol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde, 587 g (2.62 mol) of (3,5-dimethoxy-phenyl)-acetic acid ethyl ester, and 391 mL (2.62 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was heated at 80° C. for one hour. Thin layer chromatography (TLC) (silica, 6:4/heptane:ethyl acetate, developed in an iodine chamber) showed all the 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was consumed. Ethyl alcohol (absolute, 2.75 L) was added to the reaction vessel, and the reaction mixture was cooled to room temperature. The solid that precipitated was collected by filtration, washed once with ethyl alcohol, and dried in a vacuum oven at 45° C. for 12 hours to provide 530 g (57% yield) of 2-methylsulfanyl-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one. Proton NMR (DMSO) is consistent with the structure: 1H NMR (DMSO): δ 8.86 (s, 1H), 8.10 (s, 1H), 6.83 (d, 2H), 6.51 (s, 1H), 4.36 (q, 2H), 3.75 (s, 1H), 2.58 (s, 3H), 1.22 (t, 3H). The combined mother liquor and washes were allowed to stand at room temperature for seven days. At this time a second crop of precipitate was collected, washed once with ethyl alcohol, and dried in a vacuum oven at 45° C. for 12 hours to provide 79 g (8.5% yield) of 2-methylsulfanyl-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one. Proton NMR (DMSO) is consistent with the structure.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].B(F)(F)F.[N+](C1C=CC=CC=1)([O-])=O.[Cl-].Cl[CH2:20][CH:21]([NH+:41]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=1)[CH3:42])[CH2:22][CH2:23][CH2:24][C:25]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1)([C:29]#[N:30])[CH:26]([CH3:28])[CH3:27]>C(Cl)Cl.[N+](C)([O-])=O>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([C:25]([CH:26]([CH3:27])[CH3:28])([C:29]#[N:30])[CH2:24][CH2:23][CH2:22][CH:21]2[CH2:20][C:49]3[C:44](=[CH:45][C:46]([O:52][CH3:53])=[C:47]([O:50][CH3:51])[CH:48]=3)[CH2:43][N:41]2[CH3:42])[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: COc1ccc(C[NH+](C)C(CCl)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1OC
Agent: FB(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3CN2C)C(C)C)cc1OC

Procedure:
The ammonium compound of formula 29 is then cyclized to form a compound of formula 1 (step 7). This reaction is performed using 1-1.5 moles of a Lewis acid, such as AlCl3, FeCl3, BF3, and the like, in a suitable aprotic solvent, preferably a halogenated hydrocarbon solvent, nitromethane, or nitrobenzene, particularly CH2Cl2, at a temperature of about -10° to about 80° C., for a period of about 10 minutes to about five hours, preferably about two hours. For example, N-[1-chloro-6-(3,4-dimethoxyphenyl)-6-cyano-6-(prop-2-yl)hex-2-yl]-N-(3,4-dimethoxybenzyl)-N-methylammonium chloride (29) is suspended in CH2Cl2 at 0° C. and stirred with 1.5 moles of AlCl3 for 2 hours to produce 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (1).
Reaction SMILES: [N+]([O-])(O)=[O:2].[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2OC)[O:9][C:8](=[O:18])[CH:7]=1>C(Cl)(Cl)Cl>[OH2:2].[OH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:2])=[CH:13][CH:14]=2)[O:9][C:8](=[O:18])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccc2oc(=O)cc(O)c12
Solvent: ClC(Cl)Cl
Product: O
Product: O=c1cc(O)c2ccc(O)cc2o1

Procedure:
Fuming nitric acid (10 ml) was added to a stirred solution of 4-hydroxy-5-methoxycoumarin (m.p. 154.5°-156°; 1.63g) in chloroform (100 ml) at room temperature over 1 hour. After a further hour, the solvent was removed in vacuo and 6N hydrochloric acid (35 ml) added to the residue. Filtration gave the product, m.p. 175°-177.5°(d), (C10H7NO6 requires C, 50.64; H, 2.97; N, 5.91. Found: C, 50.54; H, 2.97; N, 5.63).
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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH2:42]([N:44]([CH2:48][CH3:49])[CH2:45][CH2:46][NH2:47])[CH3:43]>C(Cl)(Cl)Cl.O>[CH2:42]([N:44]([CH2:48][CH3:49])[CH2:45][CH2:46][NH:47][C:34]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[O:40])[CH3:43]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCN(CC)CCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in chloroform (5 ml), and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (77 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diethyl-1,2-ethanediamine (30 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (10 mg, yield 13%).
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)[F:32].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([F:32])[C:19](=[O:23])[N:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(=O)n(-c2ccccc2)c(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1F
Reaction time: 72 h
Yield: 19 %

Procedure:
A suspension of 2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (9.91 mg, 0.0245 mmol and selectfluor (10.0 mg, 0.0282 mmol) in acetonitrile (0.1 mL) was sonicated for 3 hrs at 40° C. then allowed to stand for 3 days. It was quenched with water (3 ml) and extracted with ethyl acetate (3×1 mL). The combined organic solution was transferred to a preparative TLC plate (SiO2, 0.25 mm×20 cm×20 cm) and eluted with ethyl acetate to give the crude title product (4 mg, 19% yield). LC-MS (m/z) 423.2 (MH+); tR=1.44.
Reaction SMILES: [O:1]1[CH2:4][C:3]([CH2:7][NH2:8])([CH2:5][NH2:6])[CH2:2]1.C(N(CC)CC)C.[Cl:16][C:17]1[N:26]=[C:25](Cl)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:28])[CH:23]=2)[N:18]=1>ClCCl.O>[NH2:6][CH2:5][C:3]1([CH2:7][NH:8][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:28])[CH:23]=3)[N:18]=[C:17]([Cl:16])[N:26]=2)[CH2:4][O:1][CH2:2]1
Reactant: NCC1(CN)COC1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2nc(Cl)nc(NCC3(CN)COC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a mixture of oxetane-3,3-diyldimethanamine (1.16 g, 10.0 mmol) and triethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was added dropwise of a solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.36 mmol) in dichloromethane (5 mL). After being stirred at room temperature overnight, the resulting mixture was diluted with water (50 mL), and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 300 mg of the desired product as a white solid.