Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.O.[CH:26](/B(O)O)=[CH:27]/[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[C:2](/[CH:26]=[CH:27]\[CH3:28])[CH:7]=1)=[O:9]
Reactant: C/C=C\B(O)O
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C\c1cc(C(=O)OC)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
tert-Butyl 4-(2-iodo-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (127 mg, 0.285 mmol) was dissolved in N,N-dimethylformamide:water=3:1 (2.8 mL). At room temperature, (Z)-propenylboronic acid (59 mg, 0.684 mmol), tetrakistriphenylphosphine palladium (16 mg, 0.0143 mmol) and sodium carbonate (121 mg, 1.14 mmol) were added sequentially, and the mixture was stirred at 80° C. for 1 hour, under microwave irradiation. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (96 mg (yield 94%)) was obtained as a yellow crystal.
Reaction SMILES: CC([N:5]([C@@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH2:30][CH3:31])[CH:23]=2)=[N:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][C@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH2:30][CH3:31])[CH:23]=2)=[N:19][CH:20]=1)=[O:13]
Reactant: CCOc1cc(Oc2ncc(NC(=O)[C@@H](CC)N(C(=O)[O-])C(C)(C)C)cn2)ccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(Oc2ncc(NC(=O)[C@H](N)CC)cn2)ccc1C
Temperature: 0 °C
Yield: 105.6 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-1-{[(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)amino]carbonyl}propyl)carbamate (Intermediate 93, 80 mg) in dichloromethane (1 mL) cooled to 0° C., TFA (573 μl, 7.43 mmol) was added dropwise. The mixture reaction was stirred at 0° C. for 1.5. The solvent and the TFA were evaporated. The mixture was diluted with dichloromethane and an aqueous saturated solution of NaHCO3. The organic layer was separated, dried over sodium sulphate, filtered end evaporated to afford the title compound (65 mg) which was directly used in the next step.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCCCBr
Reactant: Nc1ccccc1Cc1ccccc1
Product: O=C(CCCCCBr)Nc1ccccc1Cc1ccccc1

Procedure:
2-benzylaniline and 6-bromohexanoyl chloride were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CO.C(N(CC)CC)C.[Pd]>[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Oc1cccc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c(C)ncnc1Oc1cccc(-c2ccccc2)c1

Procedure:
Methyl α-[6-methyl-2-chloro-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate is dissolved in methanol/triethylamine (50 ml/10 ml) and hydrogenated over Pd on charcoal (0.2 g). The reaction mixture is evaporated. Addition of potassium carbonate, ether extraction and chromatography on silica gel gives pure methyl α-[6-methyl-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([N:47]=[C:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:43](O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].P([N:78]=[N+:79]=[N-:80])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>C1COCC1>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C@H:44]([N:47]=[C:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@H:43]([N:78]=[N+:79]=[N-:80])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N=C(c2ccccc2)c2ccccc2)C(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](N=C(c2ccccc2)c2ccccc2)[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
In a flame-dried flask triphenylphosphine (3.86 g; 14.7 mmol; 2 eq.) was dissolved in anhydrous THF (15 ml) and cooled to 0 C. DIAD (2.97 g; 14.7 mmol; 2 eq.) was slowly added dropwise. Upon addition a white precipitate formed. A THF solution containing tert-butyl-4-[(diphenylmethylene)amino]-3-hydroxypiperidine-1-carboxylate (Intermediate 268, 2.8 g; 7.36 mmol) was added (amount of THF added was such that the final concentration of alcohol was ca. 0.5-1M). The resultant reaction slurry was stirred at 0 C for 30 minutes. (PhO)2PON3 (4.05 g; 14.7 mmol; 2 eq.) was then added and the reaction was allowed to warm to RT and stirred for 12 hrs. Monitored by LC/MS. The reaction was concentrated and purified by flash column chromatography (0-30% EtOAc/hexanes with 0.1% triethylamine). Isolation gave 2.13 g of the title compound in 71% yield. LC/MS (ES+)[(M+H)+]: 406 for C23H27N5O2.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12]1COCC1>>[CH2:12]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: C1CCOC1
Reactant: O=C1CCCc2ccccc21
Product: C=C1CCc2ccccc2C1=O

Procedure:
To a solution of 1-tetralone (164.5 g) in about 400 ml THF was added, in four separate portions, TAMA (243 g) and trioxymethylene (99 g) over 31/2 hours, and the mixture refluxed for 20 hours. The mixture was cooled and portioned between Et2O and water, the layers separated and the aqueous layer extracted twice with Et2O. The combined Et2O layers are exhaustively washed with water, NaHCO3 and then with brine, dried (MgSO4) and concentrated in vacuo to yield an oil which is flash chromatographed on silica gel using CH2Cl2 in several runs of 10-20 g per run. Fractions containing the fast moving material are combined, concentrated in vacuo to obtain the desired 2-methylene-1-tetralone.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=2)[C:8](I)=[N:7]1.[C:28]([Cu])#[N:29]>CN(C=O)C>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=2)[C:8]([C:28]#[N:29])=[N:7]1
Reactant: N#C[Cu]
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=O)cc12
Temperature: 170 °C

Procedure:
A mixture of 1-[2,4-bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-carbaldehyde (2 mmol) and CuCN (5 mmol) in DMF (5 mL) was heated under microwave irradiation at 170° C. for 30 min. The mixture was partitioned between EtOAc and water. The EtOAc extracts were combined, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes 1:4 v/v) to afford 1-[2,4-bis(trifluoromethyl)benzyl]-3-cyano-1H-indazol-5-carbaldehyde as a white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13](=[O:20])[C:12]2=[CH:21][CH:22]=[CH:23][N:11]12>C1COCC1>[Br:1][C:23]1[N:11]2[N:10]([CH3:9])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13](=[O:20])[C:12]2=[CH:21][CH:22]=1
Reactant: Cn1c2ccccc2c(=O)c2cccn21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1c2ccccc2c(=O)c2ccc(Br)n21
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
A solution of N-bromosuccinimide (3.5 g) in 50 mL of THF was added dropwise to a solution of 5-methylpyrrolo[1,2-b]cinnolin -10(5H)-one (3.8 g) in 70 mL of dry THF at 0° C. After 16 hours of stirring at room temperature, the solution was concentrated and the residue taken up in 200 mL of CHCl3. This solution was washed with H2O, dried over MgSO4, filtered and concentrated. The residue was purified by HPLC (silica, dichloromethane) to give 3.8 g of yellow crystals. This material was recrystallized from ether to give 3.6 g of pale yellow crystals, mp 103°-105° C.
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[C:22]3[C:27]([CH:28]=[CH:29][C:19]=2[N:18]=1)=[CH:26][C:25]1[C:30]2[C:35]([CH2:36][O:37][C:24]=1[CH:23]=3)=[CH:34][C:33]([C:38]1[NH:42][C:41]([C@@H:43]3[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]3[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[N:40][CH:39]=1)=[CH:32][CH:31]=2)=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)C.[Pd]>[CH3:50][O:49][CH2:48][C@@H:46]1[CH2:45][N:44]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[C@H:43]([C:41]2[NH:42][C:38]([C:33]3[CH:34]=[C:35]4[CH2:36][O:37][C:24]5[CH:23]=[C:22]6[C:27]([CH:28]=[CH:29][C:19]7[N:18]=[C:17]([C@@H:12]8[CH2:13][CH2:14][C@H:15]([CH3:16])[NH:11]8)[NH:21][C:20]=76)=[CH:26][C:25]=5[C:30]4=[CH:31][CH:32]=3)=[CH:39][N:40]=2)[CH2:47]1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)OCc7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
A mixture of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[(benzyloxy)carbonyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (830 mg, 1.08 mmol) and 100 mg 10% Pd/C in 20 mL ethanol was hydrogenated at 1 atm overnight. Additional 10% Pd/C (300 mg) and a portion of solid NaHCO3 was added and hydrogenation continued for 4 hours. Filtration through celite and concentration of the filtrate under reduced pressure gave the product as a dark brown solid, 722 mg. Purification by reverse phase HPLC gave 100 mg purified product.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:18]([OH:20])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1)[NH2:22].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:18]([NH:22][NH:21][C:23]2[N:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[CH:25][N:24]=2)=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN(CC1(C(=O)O)CCCC1)OCc1ccccc1
Reactant: NNc1nccc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
To a mixture of 1-[(Benzyloxy-formyl-amino)-methyl]-cyclopentanecarboxylic acid (0.10 g, 0.36 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.10 g, 0.43 mmol), NMM (0.11 g, 1.08 mmol) and HOAt (0.059 g, 0.43 mmol) in DMF (2 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.085 g, 0.43 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.085 g, 57%). MH+438.
Reaction SMILES: [CH2:1]=O.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4[N:30]=[C:29]([CH:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)[O:28][N:27]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]>C(O)=O>[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4[N:30]=[C:29]([CH:31]5[CH2:36][CH2:35][N:34]([CH3:1])[CH2:33][CH2:32]5)[O:28][N:27]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1noc(C2CCNCC2)n1
Reactant: C=O
Solvent: O=CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1noc(C2CCN(C)CC2)n1
Temperature: 95 °C
Yield: 69.3 %

Procedure:
Aqueous formaldehyde (37%, 894 ml, 12.0 mmol) was added to a solution of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-4-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine (1 g, 2.0 mmol) in formic acid (2 ml). The mixture was heated at 95° C. for two hours. The volatiles were removed under vacuum, the residue was dissolved in CH3OH and the pH of the solution was adjusted to 9 by addition of Biorad AG® 1-X8 hydroxide form resin. The solution was filtered, concentrated in vacuo and the residue was crystallized from MeOH/H2O to give N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine (714 mg; 69% yield). 1H NMR (400 MHz; DMSO-d6): 1.69-1.82 (m, 2H), 1.97-2.05 (m, 4H), 2.16 (s, 3H), 2.71-2.78 (m, 2H), 2.98-3.10 (m, 1H), 3.96 (s, 3H), 5.44 (s, 2H), 7.39 (s, 1H), 7.62 (d, 1H), 7.83 (s, 1H), 7.87 (dd, 1H), 8.22 (d, 1H), 8.53 (s, 1H), 9.63 (s, 1H); MS (EI) for C24H24Cl2N6O3: 515.07 (MH+)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([CH3:19])=[N:14]3)=[N:7][NH:6][C:5]1=[S:20].Br[CH2:22][CH2:23][CH2:24][Cl:25]>>[Cl:25][CH2:24][CH2:23][CH2:22][S:20][C:5]1[N:4]([CH3:3])[C:8]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([CH3:19])=[N:14]3)=[N:7][N:6]=1
Reactant: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Temperature: 0 °C

Procedure:
Sodium hydride (2.65 g, 60% in oil) was added portionwise to stirred absolute ethanole at 0° C., under a nitrogen atmosphere. Then 4-methyl-5-(2-methyl-5-quinolinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (21.8 g) (intermediate 7) was added portionwise and the reaction mixture was allowed to reach room temperature. Then 1-bromo-3-chloropropane (12.6 ml) was added over 10 min and the reaction mixture was brought to 80° C. and left to react an additional hour after which time the reaction mixture was allowed to reach room temperature and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel with 90% ethyl acetate-acetone to give the title compound (14.18 g) as a white solid.
Reaction SMILES: [N:1]1([C:7]([NH:9][C@@H:10]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](O)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]([C@H:42]([CH2:47][OH:48])[CH2:43][CH2:44][CH2:45][NH2:46])[CH2:38][CH:39]([CH3:41])[CH3:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:42]([CH2:47][OH:48])[CH2:43][CH2:44][CH2:45][NH:46][C:11]([C@@H:10]([NH:9][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=C(O)[C@@H](NC(=O)N1CCOCC1)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CN([C@H](CO)CCCN)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](NC(=O)N1CCOCC1)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from general procedure A using (2S)-2-[(morpholine-4-carbonyl)-amino]-3,3-diphenyl-propionic acid and amine intermediate VII. The final product was obtained in 36% yield. Rf=0.15 EtOAc 100%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[O:13])=[CH:6][CH:5]=1.I[CH3:30]>O1CCCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH:11]([CH3:30])[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C(C)[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 23 mg, 0.54 mmol) was added to a solution of (R)-3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-1-(2-methylpyridin-4-yl)propan-1-one (example 282, step 1; 208 mg, 0.49 mmol) in tetrahydrofuran (7 mL), then after 90 min the reaction mixture was cooled to 0° C. and treated with iodomethane (73 mg, 0.54 mmol). The ice bath was removed, then after 2 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate 1:1) produced the title compound (149 mg, 70%). Light yellow oil, MS (ESI+): m/z=442.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[Li]CCCC.CN([CH:19]=[O:20])C.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH:19]=[O:20])[S:7][C:6]=2[CH:10]=1
Reactant: Clc1ccc2ccsc2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-chlorobenzo[b]thiophene (1.0 g, 5.93 mmol) in THF (60 mL) at −78° C. is added a 1.6 M solution of n-BuLi in THF (3.9 mL, 6.23 mmol). After 10 minutes, 0.5 mL of DMF is added. The solution is stirred for 0.5 hours, then allowed to warm to ambient temperature. The solution is poured into a solution of saturated NH4Cl. The solution is diluted with ether and the layers are separated. The organic layer is washed with H2O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The title compound is obtained as a white solid. MS (EI): m/z 196 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5](C#N)[C:6](=[O:12])[NH:7]2.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2
Reactant: Cc1nccc2[nH]c(=O)c(C#N)cc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1nccc2[nH]c(=O)ccc12

Procedure:
5-Methyl-1,6-naphthyridin-2(1H)-one also was prepared directly from the corresponding 3-cyano compound, as follows: A 650 g portion of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile was added with stirring at room temperature to a solution of 2100 ml 18 M sulfuric acid in 350 ml of water. The reaction mixture was stirred mechanically and refluxed (internal temperature at 215°-220° C.) for 24 hours. The dark solution was allowed to come to ambient temperature and poured on ice. The solution was stirred and basified with 6 l of concentrated ammonium hydroxide to pH 10.5, the internal temperature being maintained at 20°-30° C. during this addition. The dark beige solid was collected by filtration, washed with a minimum of cold water and dried in an oven chamber at 65° overnight. The crude product was recrystallized twice from water with decolorizing charcoal treatment to produce 330 g of 5-methyl-1,6-naphthyridin-2(1H)-one, m.p. 245°-246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4-Chlorophenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][S-:12].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][CH3:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: C[S-]
Reactant: COc1cc(F)ccc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(SC)ccc1Br
Temperature: 85 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
To a stirred solution of 1-bromo-4-fluoro-2-methoxybenzene (4.0 g) in DMF (40 mL) was added sodium methanethiolate (2.76 g). The mixture was stirred at room temperature for 30 minutes and at 85° C. for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 280 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12]
Reactant: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Br)c(C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-3-methyl-2-nitrophenol (2.200 g, 9.48 mmol) in acetone (35 mL) was added potassium carbonate (3.276 g, 23.70 mmol) and methyl iodide (1.47 mL, 23.70 mmol) and the mixture was heated to reflux for 4 h. The reaction was cooled to rt, filtered and the filtrate was evaporated under reduced pressure to afford the crude product. Purification of the crude product by column chromatography over silica gel eluting with EtOAc/hexane afforded pure 1-bromo-4-methoxy-2-methyl-3-nitrobenzene as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ=2.33 (s, 2H), 3.87 (s, 3H), 6.78 (d, J=8.84 Hz, 1H) and 7.58 (d, J=8.84 Hz, 1H); MS (ES+): m/z 247.26 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)c(Cl)ccc2c1Cl
Reactant: CCCCN
Product: CCCCNc1c(C(=O)OCC)cnc2c(OC)c(Cl)ccc12

Procedure:
4,7-Dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.84 mmol) was treated with butylamine following general procedure B to afford 7-chloro-4-butylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (210 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (125 mg) following general procedure E. The above ethylamide (0.37 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 8-chloro-3-ethyl-1-butyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (75 mg). LCMS: m/z 380 [M+1]+.