Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:7]CC)=O)C.[CH3:11][N:12]([C:14]([NH2:16])=[S:15])[NH2:13].C[O-].[Na+].CO>C(Cl)Cl>[CH3:11][N:12]1[C:14](=[S:15])[NH:16][C:4](=[O:3])[C:5](=[O:7])[NH:13]1
Reactant: CN(N)C(N)=S
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1[nH]c(=O)c(=O)[nH]c1=S
Temperature: 60 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
Under anhydrous condition, 35 g of diethyloxalate is added, dropwise, to a vigorously stirred solution of 21 g of 2-methyl-3-thiosemicarbazide, 32.4 g of fresh sodium methoxide, and 750 ml of methyl alcohol. The resulting suspension is heated at 60° C. for 4 hours, stirred overnight at room teperature, and heated at 70° C. for 15 hours. The white suspension is cooled to room temperature, 200 ml of ice water is added andthe reaction concentrated in vacuo. The residue is cooled to 0° C. and made acidic with 2N hydrochloric acid. The reaction mixture is concentrated, ethyl alcohol is added and the suspension is heated to boiling. The white precipitate is collected, washed with hexane and dried to give 11 g of the crude product. Eight grams of the crude product is heated in methylene chloride and filtered while hot. The collected solid is resuspended in methyl alcohol and a solution of 4N potassium-2-ethyl hexanoate is added. The mixture is cooled to 0° C. and the precipitate collected. The solid is dissolvd in water, filtered, and 2N hydrochloric acid is added to the clear 0° C. solution. The resulting precipitate is collected and dried to give 4.1 g of the pure product. 13C NMR(CDCl3):δ 44,145, 150.115, 152.559, 169.786.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>CO>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(Br)s1
Solvent: CO
Product: CC(=O)Nc1ncc(Br)s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
5-Bromothiazol-2-amine (6.0 g, 23 mmol) and acetic anhydride (50 g, 490 mmol) were charged into a 250 mL round bottom flask. The suspension in the flask was heated to 100° C. After stirring for 3 hours, the reaction mixture was cooled and filtered to yield the crude product. The crude product was charged into a round bottom flask, 50 mL MeOH was added, and the mixture was heated to reflux. The mixture was cooled, and the product N-(5-bromothiazol-2-yl)acetamide (4.5 g, 93%) was obtained by filtration. The collected product was then washed with hexane. The product was used directly in the next step without further purification. LCMS (API-ES) m/z (%): 221.0 (100%, M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][N:4]=1.CCN(C(C)C)C(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.Cl.Cl.[F:40][C:41]1[C:42]([C@H:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[NH2:48])=[N:43][CH:44]=[CH:45][CH:46]=1>C1(C)C=CC=CC=1>[F:40][C:41]1[C:42]([C@H:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=2)[NH:48][C:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[O:11])=[N:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1ncc(C(=O)O)cn1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxypyrimidine-5-carboxylic acid (80 mg, 0.519 mmol), DIPEA (0.25 mL, 1.435 mmol) in toluene (3 mL) was added DPPA (0.19 mL, 0.882 mmol). The reaction was stirred at 80° C. for 2 hours. (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine dihydrochloride (167 mg, 0.487 mmol) was then added as a solid in one portion. After 24 hours, the reaction was concentrated in vacuo and the residue was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 80% EtOAc in hexane, to provide the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 9.02 (d, J=4.7 Hz, 1H), 8.97 (d, J=8.6 Hz, 1H), 8.30 (d, J=7.8 Hz, 1H), 7.63-7.77 (m, 3H), 7.54 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.01 (s, 1H), 6.66 (d, J=8.6 Hz, 1H), 3.93 (s, 3H) MS (ESI pos. ion) m/z: 407.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[Cl:19]N1C(=O)CCC1=O.CN(C)C=O>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2cccc(N)c2n1COC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(N)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of ethyl 7-amino-1-(methoxymethyl)-1H-indole-2-carboxylate (3.18 g), N-chlorosuccinimide (1.74 g) and N,N-dimethylformamide (20 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.91 g, yield 25%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[CH:38]=O>>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[CH2:38][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=1
Reactant: O=Cc1cc2ccccc2o1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cc5ccccc5o4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and benzofuran-2 carbaldehyde. MS (ESI) m/z 509.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([O:3][CH3:4])=[O:2].[C:13](C1C=CC=CC=1C=O)(O)=O.ICC.C([O-])([O-])=O.[K+].[K+]>>[C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([O:3][CH2:4][CH3:13])=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: COC(=O)c1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Product: CCOC(=O)c1ccccc1C=O

Procedure:
Using the same procedure as for the preparation of 2-carbomethoxybenzaldehyde (Compound 43), but instead using 5.0 g (33 mmol) of 2-carboxybenzaldehyde, 23.4 g (150 mmol) of iodoethane and 13.8 g (100 mmol) of K2CO3 gave the title compound as a clear colorless oil.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C@H:6]([CH3:18])[CH2:5][CH2:4]1)#[CH:2].Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C(N(CC)CC)C>CCOC(C)=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]#[C:1][C@@H:3]2[CH2:4][CH2:5][C@@H:6]([CH3:18])[N:7]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[CH2:8]2)=[N:21][CH:22]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C#C[C@@H]1CC[C@@H](C)N(Cc2ccc(OC)cc2)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C[C@H](C#Cc3ccc(F)cn3)CC[C@H]2C)cc1
Temperature: 90 °C

Procedure:
A solution of (2R,55)-5-ethynyl-1-(4-methoxybenzyl)-2-methylpiperidine (284 mg, 1.17 mmol), 2-bromo-5-fluoropyridine (226 mg, 1.28 mmol), copper (I) iodide (67 mg, 0.35 mmol), and triethylamine (2.12 mL, 15.2 mmol) was purged subsurface with nitrogen. Palladium tetrakis (135 mg, 0.117 mmol) was added and the reaction was capped and heated at 90° C. overnight. The reaction was diluted with EtOAc and washed with water and then brine. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-85% EtOAc in hexanes to provide 5-fluoro-2-{[(3S,6R)-1-(4-methoxybenzyl)-6-methylpiperidin-3-yl]ethynyl}pyridine as a yellow oil, which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 339.2 for M+H+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][OH:21].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Solvent: O
Product: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 63.9 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 45 mmol) K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2O and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140°-142° C. ANALYSIS: Calculated for C13H19FN2O2: 64.73%C 6.88%H 10.06%N Found:. 64.79%C 6.97%H 10.03%N
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18](/[CH:21]=[CH:22]/[CH2:23]O)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:10]([C@H:15]1[CH2:16][CH2:17][C@H:18](/[CH:21]=[CH:22]/[CH2:23][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:19][CH2:20]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(C=O)cc2)CC1

Procedure:
2.9 g of 4-hydroxybenzaldehyde, 5.0 g of (E)-3-(trans-4-pentylcyclohexyl)allyl alcohol, 4.1 g of diethyl azodicarboxylate, 6.2 g of triphenylphosphine and 100 ml of tetrahydrofuran were reacted in an analogous manner to Example 1 to give 4.5 g of 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]benzaldehyde (m.p. 54-55° C.).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N:6]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[C:23](=[O:25])[CH3:24].[H-].[Na+]>CN(C=O)C>[Cl:19][C:18]1[C:13]([S:1][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=3[N:6]=2)=[C:14]([C:23](=[O:25])[CH3:24])[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=1
Reactant: Cc1ccc2sc(S)nc2c1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Sc1nc2cc(C)ccc2s1
Yield: 97.3 %

Procedure:
The title compound was prepared using the method of example 258, starting with 5-methyl-benzothiazole-2-thiol (245) (1.90 g, 10.5 mmol), 1-(2,3-dichloro-5-nitro-phenyl)-ethanone (248) (2.45 g, 10.5 mmol) and NaH (Aldrich, 60% suspension, 420 mg, 10.5 mmol) in DMF (20 mL). Compound 264 (3.87 g, 98%) was obtained as a yellow solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].Cl.[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18]Cl)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:15])[CH3:14]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
A suspension of 2.94 g of isatin, 4.20 g of 2-diisopropylaminoethyl chloride hydrochloride, and 3.17 g of anhydrous potassium carbonate in 50 ml of toluene was stirred for 4 hours at 90° C. After cooling, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 4.93 g of 1-(2-diisopropylaminoethyl)isatin. The chemical properties of this product are identical with those of the product obtained by Reference Example 1.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:18])=[CH:12]3)=[O:7])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN(C)C=O>[CH3:18][C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]1[CH:19]=[CH:20][C:2]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[C:3]([C:21]([F:24])([F:23])[F:22])[CH:4]=1)=[CH:17][CH:16]=2
Reactant: C1CNCCN1
Reactant: Cc1cc2cc(NC(=O)c3ccc(F)c(C(F)(F)F)c3)ccc2[nH]1
Solvent: CN(C)C=O
Product: Cc1cc2cc(NC(=O)c3ccc(N4CCNCC4)c(C(F)(F)F)c3)ccc2[nH]1
Temperature: 125 °C

Procedure:
Synthesis: 4-Fluoro-3-trifluoromethyl benzoyl chloride (0.42 mL, 2.77 mmol) was added to a solution of 2-methyl-1H-indol-5-ylamine (472 mg, 3.23 mmol) and triethylamine (0.42 mL, 3.01 mmol) in anhydrous dichloromethane at room temperature. The reaction mixture was stirred at room temperature for two hours then diluted with a 1:1 mixture of ethyl acetate and water (80 mL). The organic layer was washed sequentially with 0.5N HCl, saturated NaHCO3, water, saturated NaCl and dried over anhydrous sodium sulfate. The desired 4-fluoro-N-(2-methyl-1H-indol-5-yl)-3-trifluoromethyl-benzamide was obtained as a purple solid in nearly quantitative yield. This material was taken onto the next step without further purification. 4-Fluoro-N-(2-methyl-1H-indol-5-yl)-3-trifluoromethyl-benzamide (1.02 g, 3.03 mmol) and piperazine (1.83 g, 21.21 mmol) was dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was heated in a sealed glass tube at 125° C. for two and a half hours. The crude mixture was then cooled to room temperature, concentrated and the residue chromatographed with 10% MeOH/CH2Cl2+2% triethylamine to afford N-(2-Methyl-1H-indol-5-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide, the title compound (86% yield). 1H NMR (400 MHz , CD3OD) δ 8.26 (d, J=2.3 Hz, 1H), 8.18 (dd, J=8.6, 2.3 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H, 7.55 (d, J=8.6 Hz, 1H), 7.28-7.17 (m, 2H), 2.99 (s, 8H), 2.41 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][NH:13][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>COCCOC>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:13]3[C:7]4[N:6]=[CH:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[C:8]=4[CH:11]=[CH:12]3)=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CC(C)n1cnc2[nH]ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)n1cnc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Yield: 88.8 %

Procedure:
Under argon gas, 3-isopropyl-7H-pyrrolo[2,3-d]-pyrimidin-4-one (89 mg) was dissolved in anhydrous DME (2 ml) and, under ice-cooling and stirring, 60% sodium hydride-oil (22 mg) was added. The mixture was stirred for 30 minutes, after which a solution of 4-(4-chlorobenzoyl)benzyl bromide (201 mg) in anhydrous DME (1 ml) was added. Then, the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel, 12 g; hexane: ethyl acetate =4:1-3:2) to provide the title compound as colorless powder (181 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[Br:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:34](=[O:35])[CH2:33][Br:32])[C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)CBr
Reactant: c1ccc(Oc2ccccc2NCc2cccc3c2OCO3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)N(Cc1cccc2c1OCO2)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of N-(benzo[1,3]dioxol-4-ylmethyl)-N-(2-phenyloxy-phenyl)amine (0.18 g, 0.58 mmol) dissolved in DCM (4 mL) was added triethylamine (0.24 g, 2.32 mmol, 0.32 mL). The reaction was cooled to 0° C. and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) was added. The mixture was stirred at room temperature for 2 h. LC-MS indicated starting material and product (1:1). Further triethylamine (0.24 g, 2.32 mmol, 0.32 mL) and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) were added and stirred at room temperature for 2 h. The solvents were removed in vacuo, the residue quenched with water (10 mL), extracted with DCM (2×20 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with DCM (A) and MeOH (B) (1% B, 80 g, 2 CV, 60 mL/min). The impure product was further purified by silica gel chromatography eluting with DCM (A) and EtOAc (B) (1-5% B, 80 g, 4.5 CV, 60 mL/min) to afford 120 mg (47%) of N-(benzo[1,3]dioxol-4-ylmethyl)-2-Bromo-N-(2-phenyloxy-phenyl)acetamide as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br>CC(O)=O.CCOC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Br:14])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2,4-dinitroaniline (2,2 g, 12 mmol) in 40 ml of AcOH was added 1.0 ml of Br2 dropwise and reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, yielding a dark residue which was diluted with EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo to provide 2.9 g (11 mmol, 92%) of 2,4-dinitro-6-bromo-aniline which was characterized by NMR and used in a following reaction without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:13][NH2:14].C(O)C>CCOCC>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:13][NH:14][C:4](=[O:6])[CH2:3][C:1]#[N:2]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: CCOCC
Product: N#CCC(=O)NCc1ccc(Cl)c(Cl)c1
Reaction time: 42 h

Procedure:
A solution of 113.3 g. (1.002 moles) of ethyl cyanoacetate and 176.4 g. (1.002 moles) of 3,4-dichlorobenzylamine in 400 ml. of absolute ethanol is heated at reflux with stirring for 42 hours which upon cooling the entire solution solidifies. The latter is broken-up, slurried in ether, isolated by filtration and dried in vacuo to give 179.8 g. of product as a white solid, m.p. 144°-5° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][CH3:21])=[O:19])[CH:13]=3)[CH:8]=[C:7]([Cl:22])[C:5]=2[N:6]=1.Br[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Cl:22][C:7]1[C:5]2[N:6]=[C:2]([NH:1][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[S:3][C:4]=2[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][CH3:21])=[O:19])[CH:13]=2)[CH:8]=1
Reactant: BrCC1CCCCC1
Reactant: CNC(=O)c1cc(Oc2cc(Cl)c3nc(N)sc3c2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2cc(Cl)c3nc(NCC4CCCCC4)sc3c2)ccn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To the solution of 4-(2-amino-4-chlorobenzo[d]thiazol-6-yloxy)-N-methylpicolinamide (30 mg, 0.089 mmol, 1.0 eq) in 2 mL of NMP was added bromomethyl cyclohexane (18 μL, 0.134 mmol, 1.5 eq) and potassium carbonate (36 mg, 0.267 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 80° C. for 2 hours and thereafter purified via reverse phase HPLC. LC/MS (m/z) [431.0] (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1.C(O)(=O)C>CCCCCC>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1ccc(-n2cccc2)cc1
Temperature: -100 °C
Yield: 40.6 %

Procedure:
The title compound was prepared in analogy to the procedure described in European Patent Application 480204. 4-Methylaniline (30 g, 280 mmol), 2,5-dimethoxytetrahydrofuran (22 g, 166 mmol) and acetic acid (200 mL) were combined under a nitrogen atmosphere and heated at -100° C. for 90 minutes. The solvent was removed under reduced pressure and the residue obtained suspended in hexane and filtered. The filtrate was passed through a pad of silica gel and concentrated in vacuo. The residue obtained was crystallized from methanol to afford 10.6 g (45%) of the title compound. MS (DCI/NH3) m/e 158 (M+H)+.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:12]>>[NH2:12][C@H:2]([C:1]([OH:11])=[O:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: N
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Phenylalanine can be produced by adding cinnamic acid and an ammonia generator to the culture medium during cultivation. Alternatively, phenylalanine may be produced by dissolving or suspending the microbial cells (live or treated cells) in an aqueous medium containing cinnamic acid and an ammonia generator and allowing the solution or suspension to stand (with stirring when desired) while maintaining the temperature at a suitable level between 10° and 70° C.