Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:14](Br)=[C:13]([N+:16]([O-:18])=[O:17])[C:12]([Br:19])=[N:11]1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:14]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([N+:16]([O-:18])=[O:17])[C:12]([Br:19])=[N:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: NCc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Yield: 67.2 %

Procedure:
A mixture of [2-(3,5-dibromo-4-nitropyrazol-1-yl)ethyl]carbamic acid tert-butyl ester (3.5 g; 8.45 mmol), EtOH (100 ml) and benzylamine (12.9 g, 117 mmol) was heated at reflux for 1.5 h. The reaction medium was concentrated as much as possible under reduced pressure. The residue was taken up in DCM (100 ml) and the organic phase was washed with water (5×50 ml) until all excess benzylamine had been removed and was then dried over Na2SO4. The organic solvent was evaporated under reduced pressure to give the [2-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)ethyl]carbamic acid tert-butyl ester (2.5 g, 67%) in the form of a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18](O)=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([C:18]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:19])[CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)O)cc2OCCO)c1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)N3CCOCC3)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoic acid with morpholine there was obtained 4-tert-butyl-N-[3-(2-hydroxy-ethoxy)-2-(3-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-phenyl]-benzenesulphonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH:16]4[CH2:18][CH:13]3[CH2:14][NH:15]4)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH:16]4[CH2:18][CH:13]3[CH2:14][N:15]4[C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:28])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Clc1ccc2c(N3CC4CC3CN4)ccnc2c1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc(F)cc1)N1CC2CC1CN2c1ccnc2cc(Cl)ccc12

Procedure:
7-Chloro-4-(2,5-diazanorborn-2-yl)quinoline (110 mg, 0.42 mmol) and 4-fluorophenyl isocyanate (67 μL, 0.59 mmol) are reacted according to method C yielding the title product as a colorless solid after column chromatography with CH2Cl2-MeOH.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O>O>[C:22]1(=[O:31])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: NCCCCCC(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Combine 6-aminohexanoic acid (6-aminocaproic acid) (8.0 g, 60 mmol) and water (100 mL). Add sodium carbonate (6.84 g, 64 mmol) and N-carbethoxyphthalimide (14.0 g, 64 mmol). After 1.5 hours, extract the reaction mixture with ethyl acetate (100 mL). Cool the aqueous layer in an ice bath and acidify using concentrated hydrochloric acid to give a solid. Collect the solid by filtration, rinse with water, and dry to give 6-phthalimidohexanoic acid (12.7 g, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([CH2:24][CH2:25][C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[C:22]([CH3:35])[NH:21][C:20]=1[CH:36]=O>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:36][C:20]2[NH:21][C:22]([CH3:35])=[C:23]([CH2:24][CH2:25][C:26]([N:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)=[O:27])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (72.1 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-{3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-ylmethylene}-1,3-dihydro-indol-2-one as a yellow solid (47.4 mg, 38%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:31]([O:33]C)=[O:32])=[C:26]2[C:30]=1[O:29][CH2:28][CH2:27]2.Cl>C(O)C.O>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:31]([OH:33])=[O:32])=[C:26]5[C:30]=4[O:29][CH2:28][CH2:27]5)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(N)c2c1CCO2
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
(7S)-2-Chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one 41f (300 mg, 1.70 mmol) and methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate 1g (543 mg, 1.80 mmol) were dissolved in 34 mL of the mixture solvent of ethanol and water (V/V=1:2.4) followed by the addition of 0.4 mL of concentrated hydrochloric acid and heated to reflux for 16 hours. The reaction solution was cooled down to room temperature, put into the refrigerator for 1 hour and filtered. The filter cake was washed with water (50 mL) and dissolved in 20 mL of the mixture solvent of water and 1 M lithium hydroxide (V/V=1:1), extracted with ethyl acetate (50 mL×2), the aqueous phase was added dropwise with 1 M hydrochloric acid to adjust pH to 2 resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-[[(7S)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 41g (0.45 g, yield: 62.0%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>C(O)C>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(F)c(F)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (3.5 g) is dissolved in ethanol (25 ml) and thereto cyclopropylamine (0.84 ml) is added dropwise under ice-cooling. After stirring at room temperature for 30 minutes, the mixture is concentrated and the residue is purified with column chromatography (silica-gel, dichloromethane: n-hexane =1 : 1) to give ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-cyclopropylaminoacrylate (2.7 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([O:25]CC)=[O:24])=[CH:10]2)[C:6]([F:28])=[CH:5][C:4]=1[Cl:29]>C(O)(=O)C>[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]2)[C:6]([F:28])=[CH:5][C:4]=1[Cl:29]
Reactant: CCOC(=O)c1cn(-c2nc(N)c(Cl)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1Cl
Yield: 93.3 %

Procedure:
To 2 ml of the mixed solution of 4N hydrochloric acid and acetic acid (1:1) was added 430 mg of ethyl 1-(6-amino-5-chloro-3-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux for 6 hours with stirring and allowed to cool. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 375 mg of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30](O)=[O:31]>>[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:31]
Reactant: Cc1ccc2ccccc2c1C(=O)O
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: Cc1ccc2ccccc2c1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-methyl-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for C25H22N4OS, 426.54; m/z found, 427.2 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](B2OC(C)(C)C(C)(C)O2)=[C:14]([NH:16]C(=O)OC(C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.[NH:33]1[C:41]2[C:36](=[CH:37][C:38]([C:42]#[C:43][C:44]3[CH:45]=[C:46](Cl)[C:47]([C:50]#[N:51])=[N:48][CH:49]=3)=[CH:39][CH:40]=2)[CH:35]=[CH:34]1>>[NH:33]1[C:41]2[C:36](=[CH:37][C:38]([CH2:42][CH2:43][C:44]3[CH:49]=[N:48][C:47]4[C:50]([NH2:51])=[N:16][C:14]5[CH:15]=[C:10]([CH2:9][OH:8])[CH:11]=[CH:12][C:13]=5[C:46]=4[CH:45]=3)=[CH:39][CH:40]=2)[CH:35]=[CH:34]1
Reactant: N#Cc1ncc(C#Cc2ccc3[nH]ccc3c2)cc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Product: Nc1nc2cc(CO)ccc2c2cc(CCc3ccc4[nH]ccc4c3)cnc12

Procedure:
(2-(2-(1H-indol-5-yl)ethyl)-5-aminobenzo[f][1,7]naphthyridin-8-yl)methanol was prepared from tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 99/step 1) and 5-((1H-indol-5-yl)ethynyl)-3-chloropicolinonitrile (from Example 44/step 3) following the procedures described for Example 44/Step 4 and Example 99/step 3 (deprotection of TBS). 1H NMR (acetone-d6): δ 10.19 (t, 1H), 8.83 (d, 1H), 8.71 (d, 1H), 8.35 (d, 1H), 7.60 (d, 1H), 7.46 (d, 1H), 7.36-7.27 (m, 3H), 7.04 (dd, 1H), 6.57 (br s, 2H), 6.38 (dt, 1H), 4.77 (d, 2H), 4.36 (t, 1H), 3.29 (t, 2H), 3.19 (t, 2H). LRMS [M+H]=369.2.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH2:6])[NH2:5])#[N:2].[OH:7][CH:8]([CH3:12])[C:9](=O)[CH3:10].Cl>>[NH:3]([C:1]1[O:7][C:8]([CH3:12])=[C:9]([CH3:10])[N:2]=1)[C:4]([NH2:6])=[NH:5]
Reactant: N#CN=C(N)N
Reactant: CC(=O)C(C)O
Agent: Cl
Product: Cc1nc(NC(=N)N)oc1C

Procedure:
reacting any dicyanodiamide obtained in step (b) with 3-hydroxy-2-butanone in a non-aqueous, alcoholic hydrochloric acid medium to form 2-guanidino-4,5-dimethyloxazole;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[CH2:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:15])=[CH:7]2
Reactant: C1COCCN1
Reactant: C=Cc1nc([C@H](C)Nc2ncnc3c2ncn3Cc2ccc(OC)cc2)cc2cccc(Cl)c12
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(CCN5CCOCC5)n4)ncnc32)cc1
Temperature: 25 °C

Procedure:
Compound 2 was then converted to compound 4 in two steps: To a stirred mixture of (S)—N-(1-(8-chloro-1-vinylisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 2 (200 mg, 0.42 mmol, 1 eq) in EtOH (50 mL) at RT, morpholine (183 mg, 2.1 mmol, 5 eq) and triethylamine (213 mg, 2.1 mmol, 5 eq) were added sequentially. The resulting mixture was stirred at reflux for 4 h. The mixture was allowed to cool to RT and then concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 3. The PMB group was then subsequently deprotected using Method L to provide compound 4. ESI-MS m/z: 438.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:22]([O:24]CC)=[O:23])=[CH:6][N:7]2[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].C(O)(=O)C.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[C:11]([F:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)c(Cl)c2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)c(Cl)c2c1=O
Temperature: 0 °C
Yield: 91.5 %

Procedure:
41.6 g of ethyl 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate are heated under reflux with 250 ml of acetic acid, 200 ml of water and 28.5 ml of concentrated sulphuric acid for 3 hours. After cooling, the mixture is poured into 2 liter of ice-water and the precipitate is filtered off with suction, washed with water and dried. 35.5 g of 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting point: 244°-246° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C@@H:13]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:14]([NH:16][C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)=[O:15]>>[CH2:22]([N:19]1[CH2:20][CH2:21][C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10]([NH:9][C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[O:11])[C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C=Nc1cc(F)ccc1F
Reactant: CC(C)(C)[C@H](N)C(=O)N[C@@H]1CCN(Cc2ccccc2)C1
Product: CC(C)(C)[C@H](NC(=O)Nc1cc(F)ccc1F)C(=O)N[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
Compound 3d was prepared from 2,5-difluorophenyl isocyanate and compound 2a using the method described in Example 9. MS (EI)=444 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[BH3-]C#N.[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([N:24]2[CH:33]3[CH:28]([CH2:29][CH2:30][CH2:31][CH:32]3[N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[NH:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([N:24]2[CH:33]3[CH:28]([CH2:29][CH2:30][CH2:31][CH:32]3[N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:27]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:26][CH2:25]2)=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=Cc1ccccn1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccn2)C2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine-2-carbaldehyde (268 mg, 2.5 mmol) was dissolved in MeOH (5 ml) and NaBH3CN (157 mg, 2.5 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (98 mg, 0.25 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred at room temperature overnight. After addition of saturated Na2CO3 solution (15 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off. The aqueous phase of the filtrate was extracted five times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified four times by flash chromatography (in each case Ø 2 cm, l=15 cm, V=5 ml; 1. CH2Cl2/MeOH/NH3 9.5:0.5:0.1, 2. CH2Cl2/MeOH/NH3 9.5:0.5:0.1, 3. CH2Cl2/MeOH/NH3 9.75:0.25:0.15, 4. CH2Cl2/MeOH/NH3 9.5:0.5:0.15). The crude product was then purified by preparative HPLC (as described under Example 14 in MeOH/H2O/Et2NH 80:20:0.1). MeOH was evaporated off from the product fraction, the aqueous phase was extracted by shaking three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated. A yellowish resin was isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>C(Cl)Cl>[CH:27]([O:26][C:24]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)=[O:25])([CH3:29])[CH3:28]
Reactant: NCCCCSc1cccc2nccn12
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)NCCCCSc1cccc2nccn12
Yield: 41.9 %

Procedure:
To a solution of 5-[4-(amino)butylthio]imidazo[1,2-a]pyridine (370 mg, 1.67 mmoles) and triethylamine (0.35 ml, 2.51 mmoles) in metylene chloride (20 ml) was added isopropyl chloroformate (0.25 g, 2.04 mmoles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was washed in turn with an aqueous sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 215 mg of the desired product (41.8%, light tan oily product).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10]Cl)=[C:4]([F:13])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:13])[CH:3]=1)[C:8](=[O:12])[CH2:9][CH2:10]2
Reactant: O=C(CCCl)c1ccc(Br)cc1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: O=C1CCc2cc(Br)cc(F)c21
Temperature: 180 °C
Yield: 21.2 %

Procedure:
1-(4-Bromo-2-fluoro-phenyl)-3-chloro-propan-1-one (27.45 g, 103 mmol) was added to a slurry of aluminum chloride (164 g, 1.23 mol) and sodium chloride (43.19 g, 0.739 mol) at 130° C. The mixture was stirred with a mechanical stirrer and heated to 180° C. for 6 hours. The whole mixture was quenched with ice and concentrated hydrochloric solution (122 ml, 1.24 mol). The resulting mixture was extracted with dichloromethane. The organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and filtered. After concentrating under reduced pressure, purification by silica gel chromatography afforded 5-Bromo-7-fluoro-indan-1-one (5 g, 21.8 mmol).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([Br:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCCCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 12-tridecen-1-ol (2.11 g, 10.7 mmol) and carbon tetrabromide (4.37 g, 13.1 mmol) in dichloromethane (15 ml) at 0° C. was added triphenyl phosphine (3.45 g, 13.1 mmol) in portions over 5 min. After stirring for 1.5 h at 25° C. the solvent was evaporated and the residue extracted with hexane (3×30 ml), filtering off any solids. The solvent was evaporated to afford 12-tridecenyl bromide as a clear oil which was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.C(N(CC)CC)C.Cl[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>ClCCl>[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][N:2]1[CH2:33][CH2:34][CH2:35][C:36]1=[O:37])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCCCl
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(=O)n(C)c(CCN3CCCC3=O)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (125 mg, 0.362 mmol) in 15 mL of dichloromethane was added triethylamine (0.202 mL, 1.45 mmol), followed by 4-chlorobutanoyl chloride (0.045 mL, 0.40 mmol). After 45 minutes, the mixture was concentrated in vacuo. Tetrahydrofuran was added (15 mL), and the solution was cooled to 0° C. Sodium hydride was added (58 mg, 60% dispersion in mineral oil, 1.45 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 16 hours, then at 50° C. for 2 hours. The solution was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product. Proton NMR for the product was consistent with the titled compound. ESI+MS: 377.27 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)Cl.F[B-](F)(F)F.[O:27]=[N+:28]=[O:29]>C(OCC)(=O)C>[F:1][C:2]1[C:3]([C:9]2[C:13]([N+:28]([O-:29])=[O:27])=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=[N+]=O
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1OC(F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ncc(Cl)cc2F)c([N+](=O)[O-])c1OC(F)F
Reaction time: 8 h
Yield: 93.6 %

Procedure:
4.0 g of 3-(3-fluoro-5chloro-2-pyridyl)-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example HIS) are initially introduced into 30 ml of methylene chloride. 3.83 g of nitronium tetrafluoroborate are added, while stirring and cooling in an ice-bath, and the mixture is subsequently stirred overnight at 22° C. The following day, it is poured onto water, and ethyl acetate is added. After extraction by shaking and separation of the phases, the organic phase is washed with dilute bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo. 4.35 g of the desired title compound are obtained as a brown solid of melting point 108-109° C.