Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:31][CH2:32][CH3:33])[C:29]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH2:24][OH:25])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].[Cl:34]C1C(OCC)=CC(C=O)=CC=1OCC.C(OC(=O)C1C=C(OCC)C(Cl)=C(OCC)C=1)C.[H-].C([Al+]CC(C)C)C(C)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.O=[Mn]=O.C(O)(=O)C>[Cl:34][C:29]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH2:24][OH:25])[CH:17]=3)[CH2:10][CH2:9]2)=[CH:27][C:28]=1[O:31][CH2:32][CH3:33]
Reactant: CCOc1cc(C=O)cc(OCC)c1Cl
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1F
Agent: O=[Mn]=O
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxymethyl-5-methoxy-N-piperidin-4-yl-benzamide (example 217) was reacted with 4-chloro-3,5-diethoxy-benzaldehyde [prepared from 4-chloro-3,5-diethoxy-benzoic acid ethyl ester (example 219a) by reduction with di-isobutylaluminium hydride followed by oxidation with MnO2 in analogy to the procedures described in example 1a)], sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless oil. MS: 477.0 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18](O)=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=2)=[O:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (250 mg) and benzylamine. Colorless crystals (210 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[O:14])=[CH:10]2)=[CH:5][CH:4]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[CH:13]([C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([CH2:2][O:1][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:12]2)=[CH:7][CH:8]=1)=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1ccc2ccc(CO)cc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc2ccc(C=O)cc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of the product of step 6 (430 mg, 2.31 mmol) in CH2Cl2 (5 mL) was added MsCl (318 mg, 2.7 mmol) and Et3N (559 mg, 5.5 mmol). The mixture was stirred at 0° C. for 2 h. Aqueous NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (anhyd. MgSO4) and concentrated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:51])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][C@H:16]([N:20]([CH2:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)[C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)[C:15]3[CH:42]=[C:43]([CH3:50])[C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:14]2=3)[CH:7]=1.Cl>CO>[F:36][C:34]([F:35])([F:37])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:31]=1)[CH2:27][N:20]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:16]1[CH2:17][CH2:18][CH2:19][N:13]([CH2:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:5]([OH:51])=[O:4])[C:14]2[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[C:43]([CH3:50])=[CH:42][C:15]1=2
Reactant: COC(=O)c1cccc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1cccc(C(=O)O)c1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C
Yield: 97.6 %

Procedure:
Add 5 N sodium hydroxide solution (0.5 mL) to a solution of (S)-3-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-benzoic acid methyl ester (70 mg, 0.100 mmol) in methanol (1 mL) and heat at 60° C. for 4 h. After the reaction cools to room temperature, acidify to pH 4 with 2 N hydrochloric acid solution and extract the aqueous mixture with ethyl acetate (3×10 mL). Wash the organic layer with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to provide the title compound as a white solid (67 mg, >99%): mp 83-86° C.; 1H NMR (CDCl3, 300 MHz) δ 1.51-1.71 (m, 2H), 2.00-2.12 (m, 2H), 2.29 (s, 3H), 2.78-2.85 (m, 1H), 3.02-3.09 (m, 1H), 4.17 (s, 3H), 4.31-4.43 (m, 2H), 4.86-5.16 (m, 2H), 5.51-5.60 (m, 1H), 6.98 (s, 1H), 7.25 (s, 1H), 7.43-7.49 (m, 1H), 7.60-7.82 (m, 4H), 7.99-8.03 (m, 1H), 8.15 (s, 1H); ESI MS m/z 687 [C31H27F9N6O2+H]+; HPLC 97.6%, tR 17.0 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:16](O)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].CC[N:30](C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:30][C:16](=[O:17])[CH:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(C(=O)O)c2ccccc2F)C1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(C(N)=O)c2ccccc2F)C1

Procedure:
2-((R)-3-(tert-Butoxycarbonylamino)piperidin-1-yl)-2-(2-fluorophenyl)acetic acid (174 mg, 0.494 mmol), ammonium chloride (79 mg, 1.481 mmol), DIPEA (0.431 mL, 2.469 mmol), EDC (142 mg, 0.741 mmol) and HOBT (113 mg, 0.741 mmol) were stirred in DMF (5 mL) at room temperature for 3 days. Saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by MPLC (12-100% EtOAc-hexanes) gave tert-butyl (3R)-1-(2-amino-1-(2-fluorophenyl)-2-oxoethyl)piperidin-3-ylcarbamate as a mixture of diastereoisomers.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]([CH3:14])[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[CH3:15][CH:16]([CH2:20][S:21][CH3:22])[C:17](Cl)=[O:18]>ClC(Cl)C>[CH3:15][CH:16]([CH2:20][S:21][CH3:22])[C:17]([N:2]([CH3:1])[C:3]1[N:4]([CH3:14])[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)=[O:18]
Reactant: CNc1cc(-c2cccnc2)nn1C
Reactant: CSCC(C)C(=O)Cl
Solvent: CC(Cl)Cl
Product: CSCC(C)C(=O)N(C)c1cc(-c2cccnc2)nn1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-amine (150 mg, 0.8 mmol) under N2 in ice-cold dichloroethane (DCE; 2 mL) was added dropwise via pipette a solution of 2-methyl-3-methylsulfanyl-propionylchloride (146 mg, 0.9 mmol) in DCE (1.5 mL). After stirring for 10 minutes (min), a solution of 4-N,N-dimethylaminopyridine (DMAP; 107 mg, 0.9 mmol) in DCE (2 mL) was added dropwise. The ice bath was removed after 30 min, and the mixture was stirred at room temperature for 90 min and then at reflux for 14 h. The mixture was concentrated under reduced pressure and was purified by silica gel chromatography eluting with a gradient of EtOAc in hexane. The product, 2,N-dimethyl-N-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-3-methylsulfanyl-propionamide, was isolated as a yellow semi-solid (44 mg, 24%): 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.58 (s, 1H), 8.08 (br d, J=7.0 Hz, 1H), 7.35 (br dd, J=7.3, 4.8 Hz, 1H), 6.58 (br s, 0.5H), 6.49 (br s, 0.5H), 3.89-3.79 (m, 3H), 3.25 (s, 3H), 2.96-2.80 (m, 1H), 2.42-2.40 (m, 1H), 2.02-1.99 (m, 3H), 2.62 (m, 1H), 1.15 (d, J=6.0 Hz, 3H); MS (m/z) 305.0 [M+1].
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28](/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:31][C:30]1[C:25](=[O:24])[NH:26][N:27]=[C:28]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:43][CH:42]=2)[CH:29]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Product: O=c1[nH]nc(CCc2ccc(C(F)(F)F)cc2)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from (E)-3,4-bis(benzyloxy)-6-(4-(trifluoromethyl)styryl)pyridazine (Intermediate 44) except that the product was recrystallised from a mixture of heptane and ethyl acetate.
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: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
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: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:7]=[CH:6][C:5]=12.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][CH:23]=3)=[O:15])[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: O=C(O)c1cccnc1Oc1ccc2nsnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)cc1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
2-(Benzo[2,1,3]thiadiazol-5-yloxy)-nicotinic acid (30.8 mg, 0.11 mmol), 2-(4-aminomethyl-phenyl)-propan-2-ol (18.6 mg, 0.11 mmol), 1-hydroxybenzotriazole hydrate (16.8 mg, 0.12 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (25.9 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature over night. The solution was poured into water (30 ml) and extracted with ethyl acetate. The combined organic layers were washed successively with 1N NaOH, water, and brine, then dried over sodium sulfate and concentrated in vacuo. The resulting amber oil was purified by flash column chromatography (1:1 ethyl acetate/hexane) to afford a white foam (29 mg, 0.07 mmol).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.F[C:17]1[C:22]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([S:30][CH3:31])[N:24]=2)=[CH:21][C:20]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:35][CH2:34]2)=[CH:19][N:18]=1.[NH2:43][C:44]1[CH:45]=[N:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=1>[NH4+].[Cl-].O.C(OCC)(=O)C>[CH3:51][O:50][C:47]1[N:46]=[CH:45][C:44]([NH:43][C:17]2[C:22]([C:23]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([S:30][CH3:31])[N:24]=3)=[CH:21][C:20]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([S:39]([CH3:42])(=[O:40])=[O:41])[CH2:35][CH2:34]3)=[CH:19][N:18]=2)=[CH:49][CH:48]=1
Reactant: CSc1nc(C)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2F)n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(SC)n2)cn1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
LiHMDS, 1.0 M in THF (0.754 mL, 0.754 mmol) was added dropwise to a stirred solution of 2-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (0.311 g, 0.754 mmol) (Example 34, Step 5) and 3-amino-6-methoxypyridine (0.094 g, 0.754 mmol) in tetrahydrofuran (10 mL, 0.754 mmol) at −10° C. and the mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with NH4Cl(aq) and water (10 mL each) and diluted with ethyl acetate (20 mL). The separated aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (ISCO Combiflash system, Teledyne ISCO, Lincoln, Nebr., DCM to 5% MeOH in DCM) to give N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (237 mg, 0.459 mmol, 60.8% yield) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.CC1C=CC2CCN3C(CC(=O)CC3)C=2C=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:33][S:34]([NH:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=32)[CH2:4][CH2:3]1)(=[O:36])=[O:35]
Reactant: Cc1ccc2c(c1)C1CC(N)CCN1CC2
Reactant: CS(=O)(=O)Cl
Agent: Cc1ccc2c(c1)C1CC(=O)CCN1CC2
Product: Cc1ccc2c(c1)C1CC(NS(C)(=O)=O)CCN1CC2

Procedure:
2-Amino-1,3,4,6,7,11b-hexahydro-10-methyl-2H-benzo[a]quinolizine [prepared from 1,3,4,6,7,11b-hexahydro-10-methyl-2H-benzo[a]quinolizin-2-one (Neth.Appln. No. 6,508,468) by reduction of the oxime] is reacted with methane sulphonyl chloride by a process analogous to that of Example 7(a) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=O.[OH-].[Na+]>O>[F:9][C:10]1[CH:11]=[C:12]([C:13]2[NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccncc1N
Reactant: O=C(O)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(-c2nc3cnccc3[nH]2)c1
Temperature: 200 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
A mixture of 3,4-diaminopyridine (1.09 g., 1 mmoles), 3-fluorobenzoic acid (1.40 g., 10 mmoles), and polyphosphoric acid (PPA, 40 g.) was heated to about 200° C. with stirring for 3.5 hours. The solution was then slowly added to water. The solution was then neutralized by the addition of 50% aqueous sodium hydroxide and the resulting precipitate was collected by filtration. Crystallization from isopropanol/water gave 1.72 g. (81% yield) of 2-(3-fluorophenyl)imidazo[4,5-c]pyridine (base), m.p. about 290°-291° C.
Reaction SMILES: C12CC(CC1)CC2NC1SC(C)C(=O)N=1.BrC1C=CC(C#N)=CC=1.[CH3:25][C:26]1([C:45]2[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=2)[S:30][C:29]([NH:31][C@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36]C=2C(F)(F)F)[CH3:33])=[N:28][C:27]1=[O:44]>>[CH:34]12[CH2:36][CH:37]([CH2:38][CH2:39]1)[CH2:33][CH:32]2[NH:31][C:29]1[S:30][C:26]([C:45]2[CH:46]=[CH:47][C:48]([C:49]#[N:50])=[CH:51][CH:52]=2)([CH3:25])[C:27](=[O:44])[N:28]=1
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Agent: CC1SC(NC2CC3CCC2C3)=NC1=O
Agent: N#Cc1ccc(Br)cc1
Product: CC1(c2ccc(C#N)cc2)SC(NC2CC3CCC2C3)=NC1=O

Procedure:
The title compound was prepared from the reaction of 2-(bicyclo[2.2.1 ]heptan-2-ylamino)-5-methylthiazol-4(5H)-one with 4-bromobenzonitrile using the procedure described for 2a. MS (ESI, pos. ion) m/z: 326 (M+1).
Reaction SMILES: C(NC(=O)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)C.[F:37]C1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1N>>[F:37][C:11]1[CH:10]=[C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][N:19]([CH3:20])[CH2:18][C:16]=3[N:17]=2)[CH:8]=[CH:7][C:6]=1[NH2:5]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Product: C[C@H]1COCCN1c1nc(-c2ccc(N)c(F)c2)nc2c1CN(C)C2
Yield: 98 %

Procedure:
Method as described for intermediate 5 using 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting material. The crude reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by flash SCX2 chromatography affording the title compound (139 mg, 0.40 mmol, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2=NCCc3ccccc32)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(C2NCCc3ccccc32)cc1F
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(3,4-difluorophenyl)-3,4-dihydroisoquinoline (1.34 g, 5.51 mmol) in 20 mL of MeOH, sodium borohydride (0.4366 g, 11.5 mmol) was added. The mixture was stirred for 1 h. MeOH was evaporated and the residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford a white solid. The crude product was purified by silica gel chromatography (0-5% iso-propanol (with 10% ammonium hydroxide) in CHCl3) to afford the title compound as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.99-7.22 (m, 6H) 6.74 (d, J=7.60 Hz, 1H) 5.08 (s, 1H) 3.18-3.32 (m, 1H) 2.96-3.18 (m, 2H) 2.76-2.90 (m, 1H).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: FC1C=CC(C([N:8]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]2[CH:15]=[C:16](C2C=C(F)C=CC=2C([O-])=O)[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)=CC=1.[OH2:36].[ClH:37]>>[ClH:37].[CH3:13][C:12]1[N:8]=[C:9]([CH2:15][C:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:36])[NH:10][C:11]=1[CH3:14]
Reactant: Cc1nc(C=C(c2ccc(F)cc2)c2cc(F)ccc2C(=O)[O-])n(C(=O)c2ccc(F)cc2)c1C
Reactant: O
Agent: Cl
Product: Cc1nc(CC(=O)c2ccc(F)cc2)[nH]c1C
Yield: 10 %

Procedure:
12.97 g crude compound of Example III are refluxed 1.5 h in 200 ml concentrated hydrochloric acid. The mixture is cooled to rT and 200 mL water are added. The solution is extracted twice with toluene and the aqueous phase is concentrated under vacuum. The residue is stirred with ethanol, filtered, washed once with ethyl acetate and once with petrol ether and dried to yield 0.74 g (10% of th.) 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(4-fluorophenyl)ethanone hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH:28]([CH3:30])[CH3:29])[CH2:9][C:8]([CH3:32])([CH3:31])[C:5]2=[N:6][CH:7]=1.CC(C)([O-])C.[Na+].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:32][C:8]1([CH3:31])[C:5]2=[N:6][CH:7]=[C:2]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:3]=[C:4]2[N:10]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:12]=2[CH:28]([CH3:29])[CH3:30])[CH2:9]1
Reactant: C1COCCN1
Reactant: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure N using 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-isopropyl-2-(pyridin-2-yl)quinoline (30 mg, 0.061 mmol), sodium tert-butoxide (11.73 mg, 0.122 mmol), morpholine (5.85 μL, 0.067 mmol), XPhos (5.82 mg, 0.012 mmol) and Pd2(dba)3 (5.6 mg, 6.11 μmol) in toluene (2.0 mL) and heating at 120° C. in the microwave for 90 min. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-(1-methylethyl)-2-(2-pyridinyl)quinoline was obtained as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=4.9, 2.2 Hz), 7.86-7.93 (1H, m), 7.82 (1H, dd, J=9.8, 2.7 Hz), 7.66 (1H, d, J=7.4 Hz), 7.62 (1H, d, J=2.3 Hz), 7.53 (1H, dd, J=9.4, 5.9 Hz), 7.42 (1H, dd, J=7.4, 3.9 Hz), 7.17-7.25 (1H, m), 5.75 (1H, d, J=2.3 Hz), 3.80-3.93 (2H, m), 3.70-3.78 (4H, m), 3.34-3.48 (1H, m), 2.88-3.04 (4H, m), 1.62 (3H, s), 1.51 (3H, s), 1.29 (3H, d, J=7.0 Hz), 1.23 (3H, d, J=7.0 Hz). Mass Spectrum (ESI) m/e=498 (M+1).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[C:17]1([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:2]([NH:5][C:6]([CH:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(c1ccccc1)c1ccccc1
Reaction time: 0.08 h

Procedure:
Dissolve sodium (2 g) in 400 ml ethanol and add diethyl acetamidomalonate (10.4 g). Stir 5 minutes, add diphenyl bromomethane (12.4 g), and stir 7 hours at room temperature. Acidify the reaction mixture, partition between water and methylene chloride (CH2Cl2), dry the organic layer over magnesium sulfate (MgSO4), filter, and evaporate the solvent to obtain the crude title compound as a pale yellow oil. Rf (silica gel; Et2O)=0.89.