Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-])=[C:9]([CH3:14])[CH:8]=1.C([OH:17])C>C(OC(=O)C)(=O)C>[OH:17][CH2:14][C:9]1[CH:8]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:12]=[CH:11][N:10]=1
Reactant: COCCCOc1cc[n+]([O-])c(C)c1
Reactant: CCO
Solvent: CC(=O)OC(C)=O
Product: COCCCOc1ccnc(CO)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
4.05 g (0.02 mol) of 4-methoxypropoxy-2-methylpyridine 1-oxide was dissolved in 50 ml of acetic anhydride to obtain a solution. This solution was stirred at 90° C. for 0.5 hour and cooled, followed by the addition of ethanol. The obtained mixture was concentrated under a reduced pressure, followed by the addition of 150 ml of 1N hydrochloric acid. The obtained mixture was stirred at 100° C. for one hour, cooled, neutralized with sodium hydrogencarbonate and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. Thus, 3.64 g of the title compound was obtained as a crude product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]([CH3:70])[C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH2:65])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)=[O:45]>CN(C=O)C>[CH3:70][N:43]([CH3:42])[C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH:65][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:57][CH:58]=1)=[O:45]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CN(C)C(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)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: CN(C)C(=O)COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid dimethylcarbamoylmethyl ester (49 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (51 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H31N5O5, 494.23. found 494.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[C:26]=2[Cl:27])=[O:21])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1NC(=O)c1scc(CCl)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1NC(=O)c1scc(CN2CCN(C)CC2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (1.0 g, 2.1 mmol) in DMF (40 mL) at 0° C. was added 1-methylpiperazine (1.2 mL, 1.1 g, 11 mmol), and the mixture stirred for 0.5 hours at 0° C., then warmed to ambient temperature. After 7 hours the reaction mixture was poured into water (150 mL) and the resulting solid collected by filtration, washed with water (50 mL) and acetonitrile (10 mL). Purification by flash chromatography on silica gel afforded 0.77 g (64% yield) of N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, as a white foam: NMR (DMSO-d6/TFA) 10.4 (s,1), 9.4 (s, 1), 7.2-8.1 (m, 7), 4.4 (s, 2), 3.8 (s, 3), 3.0-3.8 (br m, 8), 2.8 (s, 3), ppm
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15](Br)[C:16]#[CH:17].Cl>>[O:14]=[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:17][C:16]#[CH:15])[C:11]([OH:13])=[O:12]
Reactant: C#CCBr
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#CCC(C(=O)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 93 %

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml; 20 mmoles) was added to 1.64 g (10 mmoles) of phenylpyruvic acid to form a solution. Then, 1.19 g (10 mmoles) of propargyl bromide was added, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with three 50 ml portions of ether. The ether layers were dried over magnesium sulfate, and the ether was evaporated under reduced pressure to give a pale yellowish white solid. The NMR spectral analysis of this product led to the determination that nearly pure 2-oxo-3-phenyl-5-hexynoic acid (1.88 g; yield 93 %).
Reaction SMILES: C[O-].[Na+].[C:4]1(C)[CH:9]=CC=C[CH:5]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C(Cl)C=C>O>[CH2:9]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])[CH:4]=[CH2:5]
Reactant: Cc1ccccc1
Reactant: O=C1CCCN1
Agent: C[O-]
Agent: [Na+]
Solvent: C=CCCl
Solvent: O
Product: C=CCN1CCCC1=O
Yield: 89.9 %

Procedure:
To a 5 liter volume flask of glass equipped with a stirrer, a fractional distillation column, a thermometer and a dropping funnel, there were added 270.1 g (5.0 mol) of sodium methoxide and 2 liters of toluene. After 425.6 g (5.0 mol) of 2-pyrrolidone was dropwise added to the flask through the dropping funnel at room temperature, the resulting methanol was completely removed by the fractional distillation column. 6.9 g (25 mmol) of (Butyl-)4NCl was added as a phase transfer catalyst and 382.7 g (5.0 mol) of allyl chloride was dropwise added to the reaction mixture at a temperature ranging from 60° to 70° C. through the dropping funnel to react them. After the completion of the reaction, water was added to dissolve salts formed during the reaction and then the organic phase was removed. Then the organic phase was distilled to separate the fractions having a boiling point ranging from 75° to 76° C./4 mmHg. Thus, 562.5 g of 1-allyl-2-oxopyrrolidine was obtained in a yield of 89.9%.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[C:17](=O)([O-])O.[Na+].S(OC)(OC)(=O)=O>CN(C)C=O>[OH:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: COc1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc2cc(OC)ccc2cc1O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
6.55 g of 3-hydroxy-7-methoxy-naphthalene-2-carboxylic acid were dissolved in 20 ml of dimethylformamide, treated with 5.5 g of sodium hydrogen carbonate and 4.0 ml of dimethyl sulfate and stirred at 90° C. under argon for 10 minutes. Subsequently, the reaction mixture was poured on to ice-water and extracted with ether. The combined ether phases were washed with water, dried over magnesium sulfate and concentrated. The thus-obtained residue was recrystallized from ethyl acetate/hexane. Methyl 3-hydroxy-7-methoxy-naphthalene-2-carboxylate with m.p. 138° C. was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])OCC2C=CC=CC=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:25][O:26][C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH2:32][CH2:33][CH:34]2[NH2:37])=[CH:29][CH:28]=1.[CH2:38]([N:41]([CH2:55][CH2:56][CH3:57])[C:42]([C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([CH2:53]C)[CH:52]=1)C(O)=O)=[O:43])[CH2:39][CH3:40]>>[F:8][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:24])[C:46]1[CH:50]=[C:51]([CH3:53])[CH:52]=[C:44]([C:42]([N:41]([CH2:38][CH2:39][CH3:40])[CH2:55][CH2:56][CH3:57])=[O:43])[CH:45]=1)[C@H:11]([OH:12])[CH2:13][NH:37][CH:34]1[C:35]2[C:30](=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:36]=2)[CH2:31][CH2:32][CH2:33]1
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Reactant: COc1ccc2c(c1)C(N)CCC2
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2CCCc3ccc(OC)cc32)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V), 7-methoxy-1,2,3,4-tetrahydro-1-naphthalenylamine (VI) and “5-Me-PHTH” (IX), the title compound is obtained, MH+=622.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38]C)=[C:34]([Br:40])[CH:33]=2)=[CH:28][CH:27]=1)[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH3:24])[CH:16]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[CH2:5]([N:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([Br:40])[CH:33]=2)=[CH:28][CH:27]=1)[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH3:24])[CH:16]=1)=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(-c2ccc(CN(Cc3ccccc3)C(=O)c3cn(C)c4ccccc34)cc2)cc1Br
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cn1cc(C(=O)N(Cc2ccccc2)Cc2ccc(-c3ccc(O)c(Br)c3)cc2)c2ccccc21
Reaction time: 3 h
Yield: 78.8 %

Procedure:
Boron tribromide (22.0 mL of a 1 M solution in methylene chloride; 22.0 mmol) was added under nitrogen dropwise over 30 minutes to a solution of N-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide (4.3 g, 7.97 mmol), prepared in the previous step, in 150 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring continued for 3 h. At ice bath temperature water (100 mL) was added dropwise. The aqueous layer was separated and extracted two times with methylene chloride. The extracts were combined, extracted with saturated NaCl, dried (MgSO4) and the solvent removed under reduced pressure to give N-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide (3.3 g, 76%) as a white solid, MS (ESI) m/z 525 [M+H]+. Elemental Analysis for C30H25BrN2O2: Calc'd: C, 68.58; H, 4.80; N, 5.33; Found: C, 67.54; H, 4.92; N, 5.17.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:19])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1COCCN1
Reactant: O=C(O)CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: O=C(CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)N1CCOCC1
Yield: 94.3 %

Procedure:
The title compound was prepared from 3-(4-(adamantan-1-yl)phenoxy)propanoic acid (0.2 g, 0.66 mmol) and morpholine (0.058 g, 0.66 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)phenoxy)-1-morpholinopropan-1-one as a white solid (0.23 g, 93.4% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:22][O:23][NH:24][CH3:25].C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:24]([O:23][CH3:22])[CH3:25])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccnc(Br)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To 2-bromoisonicotinic acid, (25.2 g, 124 mmol), HOBt (20.2 g, 149 mmol) and O,N-dimethyl-hydroxylamine hydrochloride (14.6 g, 149 mmol) in DMF (150 mL) at 0° C., was added diisopropylethyalamine (26.0 mL, 149 mmol). EDC (28.6 g, 149 mmol) was then added and the mixture stirred at room temperature for 1 hour. The mixture was then poured into ice cold water (500 mL) and the resulting solution extracted with EtOAc (3×150 mL). The combined organic fraction was were washed with water (2×200 mL), 0.5 M HCl (200 mL), sat. NaHCO3 solution, brine (200 mL) and then dried (MgSO4). The solvent was evaporated in vacuo to give 2-bromo-N-methoxy-N-methyl-isonicotinamide (23 g, 75%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27]>N1C=CC=CC=1.C(Cl)Cl>[C:26]([NH:30][C:31]([N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([CH2:18][NH:17][C:15]2[C:14]([F:25])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:8][CH:9]=3)[N:16]=2)[CH2:20]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N=C=O
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC[C@@H]1CCCNC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)pyrimidin-4-amine, 12a, (0.013 g, 0.036 mmol) in mixture of pyridine/CH2Cl2 (1 mL of 1:1 mixture was added tert-butyl isocyanate (0.005 mL, 0.046 mmol). The reaction mixture was stirred at 40° C. for 12 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 20.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Br:39])=[C:35]([O:40][CH3:41])[CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][N:27]([C:25](=[O:26])[CH2:24][N:4]3[C:3]([C:13]([F:14])([F:16])[F:15])=[C:2]([Cl:1])[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5]3)[CH2:28][CH2:29]2)=[CH:34][C:35]=1[O:40][CH3:41]
Reactant: FC(F)(F)c1n[nH]c(-c2ccccc2)c1Cl
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ccccc4)c(Cl)c3C(F)(F)F)CC2)ccc1Br

Procedure:
Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.42–7.52 (m, 4H), 7.36–7.38 (d, 1H), 6.42–6.46 (d, 1H), 6.34–6.38 (dd, 1H), 4.72 (s, 2H), 3.88 (s, 3H), 3.74–3.78 (m, 2H), 3.54–3.58 (m, 2H), 3.12–3.18 (m, 4H). 13C NMR (400 MHz, CDCl3): 164, 156.2, 152, 132.6, 130.2, 130, 128.8, 110, 102.2, 56, 52, 50, 44.8, 42.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH:15]3[O:19]CCO3)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:20].[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=[O:19])[C:9]=3[CH2:8][CH2:7][C:6]2=[O:20])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1CCCBr
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc2c1CCC(=O)N2CCCN1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
1-(3-Bromopropyl)-5-(1,3-dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (790 mg, 2.32 mmol), 4-benzylpiperidine (0.49 ml, 2.79 mmol) and potassium carbonate (142 mg, 1.03 mmol) were added to acetonitrile (15 ml), followed by heating under reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered to remove the insoluble matter. The solid was washed with acetonitrile, and the filtrate and washing were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→ethyl acetate:methanol=50:1). The purified product was concentrated under reduced pressure, and the residue was dissolved in acetone (15 ml). p-Toluenesulfonic acid monohydrate (368 mg) was added, and the resulting mixture was heated under reflux for 2 hours. An aqueous solution of potassium carbonate was added to the reaction mixture, followed by concentration under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain 672 mg (yield: quantitative) of 1-[3-(4-benzylpiperidin-1-yl)propyl]-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH:19]([F:21])[F:20])=[O:5])C.[OH-].[Li+].C(O)(=O)C>O1CCCC1.O>[F:21][CH:19]([F:20])[C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[S:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc(C(F)F)c(C(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
3.0 g 4-Difluoromethyl-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester were dissolved in 90 ml tetrahydrofuran. A solution of 2.29 g lithium hydroxide dissolved in 30 ml water was added and the reaction mixture stirred at room temperature overnight. Concentrated acetic acid were added until a pH of ˜6 was attained, then the tetrahydrofuran was removed in vacuo. The residual aqueous phase was extracted three time with portions of 100 ml ethyl acetate. The combined organic layers were dried over MgSO4. Then the solvent was removed in vacuo to obtain 2.73 g 4-difluoromethyl-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid as pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:17][C:16]=2[CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:11][CH:10]=1.Cl[CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:46][CH3:47])=[C:40]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:41]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>C(=O)([O-])[O-].[Na+].[Na+]>[ClH:8].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:46][CH3:47])=[C:40]([S:42]([NH2:45])(=[O:43])=[O:44])[CH:41]=4)[CH2:22][CH2:21]3)=[N:17][C:16]=2[CH2:26][O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:11][CH:10]=1
Reactant: COc1ccc(CCCl)cc1S(N)(=O)=O
Reactant: FC(F)(F)COCc1nc(C2CCNCC2)oc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2CCC(c3nc(COCC(F)(F)F)c(-c4ccc(Cl)cc4)o3)CC2)cc1S(N)(=O)=O
Product: Cl
Temperature: 100 °C

Procedure:
4-[5-(4-chloro-phenyl)-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2yl]-piperidine trifluoroacetate (1.1 g, 2.05 mmol), prepared as in Intermediate 12, is taken up in saturated sodium carbonate and extracted with ethyl acetate. The organics are dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up in 1,4-dioxane (70 ml) and stirred. To this solution is added 5-(2-chloro-ethyl)-2-methoxy-benzenesulfonamide (0.77 g, 3.07 mmol), prepared as in Intermediate 13, sodium iodide (0.61 g, 4.10 mmol), and diisopropyl ethyl amine (0.71 ml, 4.10 mmol) and the mixture is heated to 100° C. for 16 h. After cooling to room temperature, the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using a gradient of (1:9) methanol/ethyl acetate to (1:9) methanol/ethyl acetate with 1% ammonium hydroxide as eluant. (Rf =0.13 in (1:9) methanol/ethyl acetate, visualization by UV and iodoplatinate solution) The product is further purified by reverse phase HPLC using acetonitrile/water (15% to 80% gradient over 30 min) as eluant. The fractions collected are washed with saturated sodium carbonate and extracted with ethyl acetate. The organics are dried over magnesium sulfate and the solvent removed under reduced pressure. The residue is taken up in minimal ethyl acetate (5 ml) and 1M hydrochloric acid in ether is added dropwise until a precipitate formed. The solvent is removed under reduced pressure to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[NH2:13][C:14]1[C:23](Cl)=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>O1CCCC1>[NH2:13][C:14]1[C:23]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: COc1ccc(CO)cc1
Reactant: Nc1nc2ccccc2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2nc3ccccc3nc2N)cc1
Yield: 76 %

Procedure:
According to Step 2 of Reference Example 7-1, by use of 4-methoxybenzyl alcohol (625 μL, 5.01 mmol), 60% sodium hydride (in oil) (200 mg, 5.01 mmol), tetrahydrofuran (6.0 mL) and 2-amino-3-chloroquinoxaline (300 mg, 1.67 mmol), the mixture was stirred and reacted at room temperature for 17 hours. Then, slurry purification was performed using diisopropyl ether, to give 2-amino-3-[(4-methoxyphenyl)methoxy]quinoxaline (Compound BB) (357 mg, yield: 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([NH2:8])=[O:7].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)CCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([N:8]=[C:16]=[O:17])=[O:7]
Reactant: COc1cc(C(N)=O)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: COc1cc(C(=O)N=C=O)ccc1[N+](=O)[O-]
Yield: 88.3 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzamide (1.00 g, 5.10 mmol) in EDC (10 mL) was added oxalyl chloride (0.64 g, 6.12 mmol). The reaction mass was refluxed for 24 h. Excess of solvent was removed under vacuum to afford 1.0 g of desired product.