Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[C:17](Cl)(=[O:26])[C:18]1[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccccc1OC
Reaction time: 8 h
Yield: 30.4 %

Procedure:
A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286 mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parr bottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hour. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. A 235-ml portion of the filtrate was used in this reaction. Under nitrogen atmosphere, o-anisoyl chloride (9.72 g, 0.057 mole) and triethylamine (6.33 g, 0.063 mole) were added dropwise simultaneously to the above-stirred filtrate at room temperature. The reaction mixture was allowed to stir overnight. The reaction mixture was filtered, and the filtrate was treated with Florisil® (30 g), and evaporated to a solid. The solid was recrystallized from hot tetrahydrofuran (minimum). The solid was filtered off, washed with cold tetrahydrofuran, and dried under high vacuum at room temperature to give 5.7 g of title compound, mp 111°-12° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([OH:8])=[N:6][CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11].N#N.CCOCC>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Oc1ncc(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccc(-c2cc3cc(Br)cnc3o2)cc1
Temperature: 90 °C
Yield: 65.5 %

Procedure:
5-bromo-3-iodopyridin-2-ol (6.7 g, 22 mmol) (Heterocycles. 57, 1, pp 55), 1-ethynyl-4-fluorobenzene (4.03 g, 33.5 mmol), copper(I) iodide (0.255 g, 1.34 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.784 g, 1.12 mmol) were combined and evacuated/backfilled with N2 (3×) then diluted with triethylamine (223 mL) and heated to 90° C. for 2 hours. The solvent was evaporated and the reaction was dissolved in EtOAc. The organic phase was washed with water (50 mL), brine, dried over Na2SO4, filtered, and concentrated. Trituration with Et2O afforded the expected product 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (4.2 g, 14.4 mmol, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35-8.42 (2H, m), 8.03 (2H, dd, J=8.78, 5.27 Hz), 7.46 (1H, s), 7.39 (2H, t, J=8.91 Hz). LC-MS retention time: 2.36 min; m/z (MH+): 292, 294. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[CH:29]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:30]([O:32][CH3:33])=[O:31])=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:42][CH3:43]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[C:29]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)([CH2:42][CH3:43])[C:30]([O:32][CH3:33])=[O:31])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
LiHMDS (20 mL, 0.020 mol) was added dropwise to a stirred solution of methyl 2-(4-(tert-butoxycarbonylamino)-6-fluoro-1H-indol-1-yl)-2-(4-chlorophenyl)acetate (4.32 g, 0.010 mol) in THF (80 mL) and HMPA (20 mL) at −78° C. The resulting mixture was stirred for another 1 h at −78° C. Iodoethane (2.3 g, 0.015 mol) was added to the above solution. The reaction mixture was warmed to −20° C. and stirred for 20 min. The mixture was quenched with sat. ammonium chloride and extracted with EA, washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE:EA=8:1) to afford the title compound. LC/MS m/z=405.1 [M-tBu+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12]
Reactant: O=C(O)CCc1ccccc1Br
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Yield: 59.2 %

Procedure:
A solution of (3-(2-bromophenyl)propionic acid (257 mg, 1.12 mmoles) and benzoic acid N′-isopropyl-hydrazide (200 mg, 1.12 mmoles) in DMF (6 mL) was treated with triethylamine (0.47 mL, 3.36 mmol), HOBT (182 mg, 1.34 mmoles) and EDCI (2.58 g, 1.34 mmol) at room temperature for 72 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a solid (258 mg, 59%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[S:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:29]=2[N:28]=[CH:27]1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:35]([C:33]1[CH:32]=[CH:31][C:30]3[S:26][CH:27]=[N:28][C:29]=3[CH:34]=1)=[O:36])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(O)c1ccc2scnc2c1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc3scnc3c2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
3-{[(Benzothiazole-5-carbonyl)-amino]-methyl}-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate I and benzothiazole-5-carboxylic acid. MS calcd. for C26H19ClN3O4S [(M+H)+] 504.1, obsd. 503.9.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(N)c(CO)c1
Reactant: C1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N)c(CN2CCCCC2)c1

Procedure:
N-(2-Amino-5-methoxy-benzyl)-piperidine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and piperidine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=O)[CH2:10][CH2:9]1.B.CSC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][NH2:16])[CH2:12][CH2:13]1
Reactant: NC(=O)C1CCN(c2ccccc2Cl)CC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: NCC1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2-chlorophenyl)piperidine-4-carboxamide (0.25 g, prepared in a similar manner to that described above) was dissolved in tetrahydrofuran (25 ml) and borane-dimethyl sulphide complex (1M in dimethyl sulphide; 0.4 ml) was added. The resulting solution was heated under reflux for 2 hours. The solvent was removed in vacuo, hydrochloric acid (1M; 50 ml) was added, and the mixture stirred at ambient temperature for 1 hour. The solution was basified by the addition of aqueous sodium hydroxide solution (5M) and the product extracted into ether. The extracts were washed with water then dried over magnesium sulphate and the solvent removed in vacuo to give 1-[1-(2-chlorophenyl)piperid-4-yl]methylamine as an oil (0.19 g). The reaction was repeated on a 4.4× scale to give further 1-[1-(2-chlorophenyl)piperid-4-yl]methylamine (1.0 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:31]2[C:32]([C:37](O)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:37]([C:32]3[C:31]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:38])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: COc1cccc(-c2ccccc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: COc1cccc(-c2ccccc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 3′-methoxy-biphenyl-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11]([OH:15])[C:12]#[C:13][CH3:14].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH2:11]([O:15][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1)[C:12]#[C:13][CH3:14]
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CC#CCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cnc(C(=O)O)cn1
Temperature: 65 °C
Yield: 11.4 %

Procedure:
To a slurry of 5-chloro-pyrazine-2-carboxylic acid (0.79 g, 5.00 mmol) in DMF (35 mL) were added 2-butyn-1-ol (3.74 mL, 50.0 mmol) and potassium tert-butoxide (2.24 g, 20.0 mmol). The resulting mixture was heated at 65° C. overnight. The reaction mixture was neutralized with 2 M HCl and then concentrated in vacuo. A part (400 mg) of the crude material was partitioned between 0.5 M NaOH and a 1:1 mixture of heptane and EtOAc. The aqueous phase was made slightly acidic (pH-3-4) by addition of 1 M HCl. To the obtained suspension was added NaCl(s) and the mixture was extracted twice with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated to give 0.11 g of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (t, 3H), 5.06 (q, 2H), 8.42 (d, 1H), 8.82 (d, 1H), 13.38 (br. s., 1H); MS (ES+) m/z 193 [M+H]+.
Reaction SMILES: [C:1]([S:11]C1C=CC(Cl)=CC=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-:19].[Al+3].[Cl-].[Cl-]>>[Cl:19][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[O:10][C:1](=[S:11])[CH:2]=[CH:3]2
Reactant: [Cl-]
Reactant: O=C(C=Cc1ccccc1)Sc1ccc(Cl)cc1
Agent: [Al+3]
Product: S=c1ccc2cc(Cl)ccc2o1
Temperature: 125 °C
Yield: 14.4 %

Procedure:
A powdered mixture of S-(4-chlorophenyl) thiocinnamate (19.4 g) and aluminum chloride (52 g) was stirred and heated at 125° C. for 3 hours. The hot reaction mixture was poured carefully over ice/water, then was extracted with ethyl acetate (3×300 mL), washed with brine (200 mL), dried (MgSO4) and was concentrated. The residue was triturated with hexane/ethyl acetate to afford 2.0 g (14%) of the desired product as pale yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[F:23])=[O:11].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:23][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1)=[O:11]
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 463 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.40-6.50 (m, 9H), 4.95-2.70 (m, 5H), 2.05-0.65 (m, 8H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:10]12[CH2:17][CH2:16][CH2:15][C:14]1([CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12][CH2:11]2.N1C=CC=CC=1>O>[N:10]12[CH2:17][CH2:16][CH2:15][C:14]1([CH2:18][CH2:19][NH:20][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:13][CH2:12][CH2:11]2
Reactant: N#Cc1ccccc1F
Reactant: NCCC12CCCN1CCC2
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccccc1NCCC12CCCN1CCC2
Yield: 95.8 %

Procedure:
2-Fluorobenzonitrile (1.00 g, 8.26 mmol) and 2-(1-azabicyclo[3.3.0]octan-5-yl)ethylamine (3.15 g, 20.4 mmol) were added into anhydrous pyridine (10.0 ml) to react the mixture in a sealed tube for 10.5 hours at 180° C. After addition of water subsequent to concentration in vacuo, the reaction mixture was extracted by ethyl acetate, dried over anhydrous sodium sulfate, concentrated in vacuo, and refined by column chromatography to afford the desired compound (2.02 g, 95.8%), as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[OH-].[Na+].Cl>O.CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
Methyl 4-hydroxy-3-nitrophenylacetate (21.1 g, 0.1 mol) was suspended in a mixture of water (55 ml) and methanol (105 ml). The suspension was stirred at room temperature while a solution of sodium hydroxide (8.8 g, 0.22 mol) in water (50 ml) was added dropwise over 20 minutes, maintaining the reaction temperature between 20 and 25° C. by water bath cooling. The resultant dark red solution was stirred at room temperature for 15 minutes, diluted with water and acidified to pH1-2 by addition of 2M hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine (200 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 4-hydroxy-3-nitrophenylacetic acid (19.6 g) as a yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:19]=1.[N+:26]([O-])([OH:28])=[O:27]>>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([N+:26]([O-:28])=[O:27])=[CH:9][C:8]=1[C:14]1[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:19]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(Cl)cc2Cl)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To 1.7 ml of concentrated sulfuric acid was added 0.26 g of 3-(2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-332) at 5° C. Furthermore, 85 til of 61% nitric acid was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was added to ice water, followed by extraction with chloroform. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.29 g (yield, 95%) of 3-(2,4dichloro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-333; m.p., 114.3° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13](Cl)[C:12]([Cl:20])=[N:11]2>CCO>[Cl:20][C:12]1[C:13]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:14][C:15]2[C:10](=[CH:9][C:8]([F:7])=[C:17]([F:18])[CH:16]=2)[N:11]=1
Reactant: Fc1cc2nc(Cl)c(Cl)nc2cc1F
Reactant: C1CNCCN1
Solvent: CCO
Product: Fc1cc2nc(Cl)c(N3CCNCC3)nc2cc1F
Temperature: 75 °C

Procedure:
Piperazine (0.86 g, 10 mmol) was added to a stirred suspension of 6,7-difluoro-2,3-dichloroquinoxaline*(1.18 g, 5 mmol) in EtOH (50 mL) at room temperature. The mixture was heated at 75° C. for 17 h, allowed to cool and filtered to give the product as a pale yellow solid: yield 0.40 g (28%); mp 294-297° C. (dec). MS m/z 285/287 (M+H)+.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[CH3:5][C:6]1[C:15]2[NH:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.C=O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:14]1[C:15]2[C:6]([CH3:5])=[CH:7][CH:8]=[C:9]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:11][CH2:12][CH2:13]1
Reactant: Cc1ccc(C(=O)O)c2c1NCCC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)O)c2c1N(C)CCC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
24 mmol of sodium cyanoborohydride were added to 5 mmol of 8-methyl-1,2,3,4-tetrahydroquinoline-5-carboxylic acid and 50 mmol of paraformaldehyde in 30 ml of glacial acetic acid, the temperature being kept below 30° C. using an ice bath. The mixture was stirred at room temperature for 15 hours and then poured onto ice and adjusted to pH 4 using aqueous sodium hydroxide solution. The mixture was then extracted with ethyl acetate and the organic phase was washed with water, dried over sodium sulfate and concentrated.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17].[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([CH2:33][C:34]([NH:36][CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:38][CH2:39][CH3:40])=[O:35])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])[CH3:22]>C(Cl)Cl.[Cu]Cl>[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([CH2:33][C:34]([NH:36][CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N:47]2[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]2)[CH2:38][CH2:39][CH3:40])=[O:35])[CH:30]=[CH:29][C:25]=1[C:26]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:27])[CH3:22]
Reactant: CC(C)(C)O
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: Cl[Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1ccc(C(=O)OC(C)(C)C)c(OCC)c1)c1ccccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 1.9 g (9.6 mmols) of N,N'-dicyclohexyl-carbodiimide, 1.06 ml (11.2 mmols) of absolute tert.butanol and 0.020 g (0.20 mmol) of copper(I) chloride was stirred for 60 hours at room temperature. Then, 6.6 ml of methylene chloride were added, and the resulting solution was added dropwise to a solution of 0.44 g (1 mmol) of 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoic acid in 15 ml of methylene chloride. After 60 hours' stirring at 20° C., the precipitate which had formed was filtered off, washed with methylene chloride, and the methylene chloride solution was evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (chloroform/ethyl acetate-9/1).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:22])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]=1[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:22][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([F:23])=[C:25]([CH3:33])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CN1CCC(Oc2ccc(N)cc2-c2c(Cl)cnn2C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(OC3CCN(C)CC3)c(-c3c(Cl)cnn3C)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(I-methyl-piperidin-4-yloxy)-phenylamine (0.040 g, 0.12 mmol), 4-fluoro-3-methylbenzoyl chloride (0.026 g, 0.12 mmol) and triethylamine (0.016 mL, 0.13 mmol)) in methylene chloride (1.5 mL) was stirred at room temperature overnight and concentrated to give a crude product that was subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to give a TFA-salt of Compound 745 as a white solid in 57.0% yield. LCMS m/z (%)=457.4 (+H, 100).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-])=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[H][H]>C(O)C.[Pt]>[CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[NH2:18])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOP(=O)(CNc1ccc(Cl)cc1[N+](=O)[O-])OCC
Agent: [Pt]
Solvent: CCO
Product: CCOP(=O)(CNc1ccc(Cl)cc1N)OCC

Procedure:
A solution of [(4-Chloro-2-nitro-phenylamino)-methyl]-phosphonic acid diethyl ester (45g, 0.139 moles) in ethanol (500 mL) was treated under nitrogen at once with 5% Platinum on carbon (1.125 g) and then hydrogenated at 30° C. until the hydrogen uptake ceased. After purging the reaction vessel with nitrogen the reaction mixture was filtered through solka floc. The filter cake was washed with ethanol (100 mL) and the filtrate was used as such for next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@H:15]([CH3:35])[CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (R)-(−)-2-amino-1-propanol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.52 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 4.16 (q, 1H, J=6.4 Hz), 3.56 (m, 2H), 2.20 (s, 3H), 1.22 (d, 3H, J=6.0 Hz). ESHRMS m/z 464.1186 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).