Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:8]3[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=3[C:1]#[N:2])=[CH:29][CH:28]=2)=[O:34])=[CH:35][CH:36]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (1.32 g, 5.59 mmol), N-(4-chlorophenethyl)-4-hydroxybenzamide (1.85 g, 671 mmol), and potassium carbonate (0.93 g, 6.70 mmol) in DMSO (10 ml) was stirred at 90° C. for 1 day. The reaction was cooled, diluted with ethyl acetate, and washed with 10% aqueous Na2CO3. The aqueous layer was back extracted with ethyl acetate. The organic washes were combined, washed with 10% Na2CO3 and brine, dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography, eluting with a gradient of 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes gave tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (1.09 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[O:18][CH3:19]>>[NH2:15][C:14]1[CH:13]=[C:12]([O:18][CH3:19])[C:11]([Br:10])=[CH:17][C:16]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1cc(N)ccc1Br
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1Br

Procedure:
(2-amino-5-bromo-4-methoxyphenyl)-(2-chlorophenyl)-methanone (Xd) was prepared by reacting 2-chlorobenzaldehyde with 0.086 moles of 4-bromo-3-methoxy aniline in a manner analogous to Example 1. MH+/Z=340.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:1][C:2]1[C:7]([NH:8][C:18](=[O:19])[CH2:17][Cl:16])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(N)c(C)n1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)CCl)c(C)n1
Reaction time: 1 h

Procedure:
A solution of 2,6-dimethyl-3-aminopyridine (24.9 grams) in ether (200 ml), and pyridine (21 grams) are charged into a glass reaction vessel equipped with mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to a temperature below about 10° C and chloroacetyl chloride (11.3 grams) is slowly added over a period of about 15 minutes. Stirring and cooling is continued for an additional period of about 1 hour to ensure the completion of the reaction. The resulting precipitate is then recovered by filtration, is washed with aqueous potassium carbonate and with water, and is dried to yield the desired product N-(2,6-dimethyl-3-pyridyl)-α-chloroacetamide.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)C(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:5]([C:6](=[O:7])[NH:8][CH3:9])=[CH:4][N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 8.31 g (31.9 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide, 6.53 g (35.0 mmol) 1-tert-butoxycarbonyl piperazine, 16.7 ml (95.6 mmol) N-ethyldiisopropylamine and a catalytic amount of 4-(N,N-dimethylamino)-pyridine was heated at reflux over night. After cooling to room temperature the mixture was dissolved in dichloromethane and washed with two portions of 0.1 N aqueous hydrochloric acid solution. Drying with sodium sulfate and concentration gave 10.7 g of the crude product. Flash column chromatography afforded 6.28 g (48.0%) of the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[N:6][C:7]=1[Cl:8].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:33]=[O:34]>O1CCCC1.O>[Cl:8][C:7]1[C:2]([CH:33]=[O:34])=[CH:3][CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:6]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccc(CNc2ccc(Br)c(Cl)n2)cn1
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(NCc2ccc(C(F)(F)F)nc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To (5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (568, 4.60 g, 0.0125 mol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at −78° C., isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 6.44 mL) was added over 10 minutes. The reaction was stirred at −78° C. for 20 minutes, and then allowed to warm to room temperature for 10 minutes. The reaction was cooled to −78° C., followed by adding tert-butyllithium (1.70 M in hexane, 15.3 mL) over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.23 mL, 0.0158 mol) was added and the reaction was stirred at −78° C. for 40 minutes, then allowed to warm to room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 350%, to 100% ethyl acetate in hexane to give a light yellow solid (569, 2.84 g, 71.7%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].S(=O)(=O)(O)O.O.[CH3:19]O>CCOC(C)=O>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:19])=[O:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Yield: 69 %

Procedure:
A solution (0.5 M) of 5-methyl-4-nitrothiophene-2-carboxylic acid in methanol was treated with sulfuric acid (3.5 eq.). The reaction mixture was heated to reflux for 48 h. After cooling down, solvent was evaporated giving a residue that was dissolved in AcOEt and water was added. The organic phase was separated and the aqueous layer was extracted with AcOEt. The combined organic phase was washed sequentially with aqueous NaHCO3 (saturated solution) and brine, then dried and concentrated giving the title compound (69%) as solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:30][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(C)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.13 g) and a 37% aqueous solution of formaldehyde (0.04 ml) suspended in 1,2-dichloroethane (5 ml) was added under ice cooling sodium triacetoxyborohydride (0.11 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was then neutralized with a 1 N aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-methylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 61) (0.11 g) as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]([OH:17])[CH2:15][Br:16])=[CH:12][CH:11]=[C:10]([O:18][CH3:19])[C:8]=2[N:9]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14](=[O:17])[CH2:15][Br:16])=[CH:12][CH:11]=[C:10]([O:18][CH3:19])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C(O)CBr)c2s1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2c(OC)ccc(C(=O)CBr)c2s1
Yield: 73 %

Procedure:
1.6 g of rac-[7-(2-bromo-1-hydroxy-ethyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester (0.0044 Mol) were dissolved in CHCl3 (100 ml) and treated with 3.8 g of MnO2 (0.044 Mol) for 3 hrs. at 70° C. The hot reaction mixture was filtered and subsequently concentrated. The crude product was crystallized from Et2O to yield the title compound as a beige solid (73%); F.p.: 250-260° C. (dec.).
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(OCC)(=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:9]2[C:10](=[O:12])[O:11][C:6](=[O:5])[NH:8]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1N[C@@H](Cc2ccc(F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2(S)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (1.5 g, 5.29 mmol) in ethyl acetate (100 mL) under an argon atmosphere was added triphosgene (628 mg, 2.12 mmol). To the solution was added triethylamine (0.8 mL 5.76 mmol,) over 1 min, and the reaction stirred for 72 h at rt. The reaction mixture was filtered, and the filtrate concentrated in vacuo to yield an oily residue. The crude material was crystallised from cold dichloromethane and petroleum ether to give the title compound. δH (CD3OD): 7.20 (2H, m), 7.10 (2H, m), 5.86 (1H, s, (NH)), 4.58 (1H, s), 3.33-3.23 (2H, m), 3.11-3.00 (1H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](Cl)=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH3:30])=[C:25]([CH:28]=1)[CH2:26][NH2:27]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([NH:27][CH2:26][C:25]1[CH:28]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=1[O:29][CH3:30])=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(OCc3ccccc3)cccc2n1
Reactant: COc1ccc(F)cc1CN
Product: COc1ccc(F)cc1CNc1ccc2c(OCc3ccccc3)cccc2n1

Procedure:
5-Benzyloxy-2-chloroquinoline (155 mg, 0.56 mmol) and 5-Fluoro-2-methoxybenzylamine (CAS 1978-39-8) (268 mg, 1.68 mmol) were stirred in a sealed tube at 90° C. for 16 hours. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->50:50 gradient). (5-Benzyloxy-quinolin-2-yl)-(5-fluoro-2-methoxy-benzyl)-amine was obtained as a colorless oil (40 mg, 18%),
Reaction SMILES: [NH2:1][CH:2]1[C:8]([CH3:10])([CH3:9])[S:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:17])[C:3]1=[O:30].[F:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>C(Cl)Cl>[F:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:40])[NH:1][CH:2]2[C:8]([CH3:9])([CH3:10])[S:7][C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[N:4]([CH2:15][C:16]([N:18]([CH:27]([CH3:28])[CH3:29])[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[O:17])[C:3]2=[O:30])[CH:35]=[CH:36][CH:37]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N)C(C)(C)Sc3ccccc32)C(C)C)cc1
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)Nc3cccc(F)c3)C(C)(C)Sc3ccccc32)C(C)C)cc1

Procedure:
Similarly to Example 22, to 2-(3-amino-2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazepin-5-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, intermediate 34 G (300 mg, 0.70 mmol) in DCM (2 mL) was added m-fluorophenyl isocyanate (0.80 mL, 0.70 mmol) to give the crude titled compound (225 mg, 57%). A sample (75 mg) was purified by RP-HPLC (40-60%, over 30 min) to give the titled product (47 mg). tR =20.9 min (40-60%, over 30 min); 1HNMR (300 MHz, d6-DMSO) d 0.96 (d, J=6.2 Hz, 3H), 1.21 (s, 6H), 3.59 (d, J=16.2 Hz, 1H), 3.76 (s, 3H), 4.26 (d, J=7.8, 1H), 4.55 (d, J=16.2, 1H), 4.80 (m, 1H), 6.74 (m, 1H), 7.19 (m, 3H), 7.20 (m, 2H), 7.32 (m, 1H), 7.49 (m, 1H), 7.60 (m, 2H), 9.03 (s, 1H); MS(FAB) m/z 565.1 (MH+).
Reaction SMILES: Br[C:2]1[Te:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[Te:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8]
Reactant: Brc1ccc[te]1
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccc(-c2ccc[te]2)c(F)c1F

Procedure:
A mixture of 10.0 g (38.7 mmol) of 2-bromotellurophene, 8.0 g (39.6 mmol) of 4-ethoxy-2,3-difluorophenylboronic acid, 3.5 g (3.0 mmol) of tetrakis-(triphenylphosphine)palladium(0) and 100 ml of 2 N sodium carbonate soln. in 200 ml of toluene/ethanol (1:1) is heated under reflux for 1.5 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=3:2). Further purification is carried out by recrystallisation from ethanol; 2-(4-ethoxy-2,3-difluorophenyl)tellurophene is obtained as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH:14]=[O:15].O>CO>[F:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:11])[F:13])[C:5]=1[CH2:14][OH:15]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1nc(C(F)(F)F)c(CO)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of 3.9 g (102.6 mmoles) of sodium borohydride dissolved in 500 ml of methanol was added, with ice-cooling, a solution of 36.8 g (187.6 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 200 ml of methanol. The resulting mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 35.4 g (yield: 95.4%) of (5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH:2]=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].C(N(CC)CC)C>O1CCCC1>[C:18]1([O:17][C:15](=[O:16])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2cccnc2)c1)Oc1ccccc1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of 3-pyridin-3-ylaniline (500 mg, 2.94 mmol) in tetrahydrofuran (6 mL) was added at room temperature to a solution of phenyl chloroformate (450 mg, 2.94 mmol), then triethylamine (288 mg, 2.84 mmol) was added. After 15 min the reaction mixture was concentrated under vacuum, then the residue was partitioned between ethyl acetate and 1 M aq. sodium hydrogencarbonate solution. The organic layer was dried (MgSO4) and evaporated. The residue was taken up in tetrahydrofuran (1 mL), then heptane (10 mL) was added. The slurry was stirred for 30 min, then the precipitate was collected by filtration to afford the title compound (566 mg, 68%). Off-white solid, MS (ISP)=291.1 (M+H)+.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3[O:14][C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.[CH:49]1[CH:50]=[CH:51][C:52]([NH2:63])=[C:53]([C:55]([CH2:57][C@H:58]([NH2:62])[C:59]([OH:61])=[O:60])=[O:56])[CH:54]=1>>[CH:49]1[CH:50]=[C:51]([OH:14])[C:52]([NH2:63])=[C:53]([C:55]([CH2:57][C@H:58]([NH2:62])[C:59]([OH:61])=[O:60])=[O:56])[CH:54]=1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: Nc1ccccc1C(=O)C[C@H](N)C(=O)O
Product: Nc1c(O)cccc1C(=O)C[C@H](N)C(=O)O

Procedure:
The reaction mixture contained: 75 μl of suspended homogenate; 100 μl of substrate solution containing 50 mM K-phosphate buffer pH 7.5, 2 mM MgCl2, 0.4 mM NADPH, 50 μM L-kynurenine (final concentration), and 25 μl of different concentrations of inhibitor solutions. The reaction was stopped by addition of 200 μl of 1 M HClO4 after 60 min incubation. L-3-hydroxykynurenine formed was quantified by HPLC with coulometric detection at a working voltage of +0.2 V. The column was a 10 cm C18 reversed phase (3 μm. The mobile phase consisted of 950 ml distilled water, 20 ml acetonitrile, 9 ml triethylamine, 5.9 ml phosphoric acid, 100 mg sodium EDTA and 1.5 g heptanesulfonic acid. The flow rate was 1 ml/min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.Cl[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH:13][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH:24]=[CH:25][C:26](=[O:30])[O:27][C:28]=4[CH:29]=3)[O:8][C:7]=2[CH:14]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)OC(CNCCCOc1ccc3ccc(=O)oc3c1)CO2
Temperature: 100 °C
Yield: 40.3 %

Procedure:
2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine (3.8 g, 20 mmole), 7-(3-chloropropoxy)coumarin (4.8 g, 20 mmole), diisopropylethylamine (2.6 g, 20 mmole) and sodium iodide (5.0 g, 33 mmole) were combined in 200 ml of DMF and heated at 100° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with 500 ml of dichloromethane. The mixture was washed with 300 ml portions of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 100 g of silica gel using first dichloromethane, then chloroform, and finally 2% methanol in chloroform as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue crystallized from 100 ml of isopropanol with the addition of 5.0 ml of 4N isopropanolic HCl to give 3.2 g of title compound as a white solid, monohydrochloride, m.p. 223°- 225° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[F:8][C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=1.O>CN(C)C(=O)C>[F:8][C:9]1[CH:10]=[C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[C:16]2=[N:21][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:17]2[CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3F)C2=N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A solution of 2-chloroethanesulfonyl chloride (208.2 mg) in N,N-dimethylacetoamide (2 mL) was added dropwise to a suspension of 3-(3-fluorobiphenyl-4-yl)pyridin-2-amine (149.5 mg) in N,N-dimethylacetoamide (2 mL) and additional N,N-dimethylacetoamide (1 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 3 h, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and THF (3 mL), and dried in vacuo at 60° C. to give the title compound (143 mg) as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: O=C1CCc2cc(Cl)c(Cl)cc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cc(Cl)c(Cl)cc2C1=O
Yield: 69 %

Procedure:
A solution of 12.3 g of 5,6-dichloro-1-indanone, 12.6 ml of 3-buten-2-ol and 125 mg of p-toluenesulfonic acid in 125 ml of 2,2-dimethoxy-propane was boiled under reflux for 68 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). In addition to 4.3 g of educt, there were obtained 10.8 g (69%) of (RS)-2-(2-buten-1-yl)-5,6-dichloro-1-indanone as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18]>>[CH3:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:12]=[C:11]([O:10][CH3:9])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=[CH:4][N:5]=1
Reactant: Cc1cc(Cl)ncn1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: COc1cc(-c2cc(C)ncn2)cc(OC)c1OC

Procedure:
4-Chloro-6-methylpyrimidine (913 mg) and 3,4,5-trimethoxyphenylboronic acid (2.73 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[C:11]1[CH:16]=[CH:15]C(F)=[CH:13][C:12]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C@H:16]([CH2:11][CH:12]=[CH2:13])[CH3:15]
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Reactant: Oc1ccc(F)cc1Br
Product: C=CC[C@H](C)Oc1ccc(F)cc1Br
Yield: 88 %

Procedure:
Prepared from 2-bromo-4-fluorophenol in 88% yield following the same procedure as (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.39-7.33 (m, 1H), 7.30 (dd, J=8.0, 3.0 Hz, 1H), 7.01-6.94 (m, 1H), 6.91-6.85 (m, 1H), 5.90 (ddt, J=17.2, 10.2, 7.0 Hz, 1H), 5.20-5.10 (m, 2H), 4.36 (sxt, J=6.1 Hz, 1H), 2.58-2.49 (m, 1H), 2.45-2.36 (m, 1H), 1.34 (d, J=6.0 Hz, 3H).