Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26](=[N:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:26]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:6](/[CH:7]=[CH:8]/[C:3]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[N:11][N:4]=2)=[N:24][N:25]=1
Reactant: NNC(=Nc1ccccc1Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(Cl)cc4Cl)n3-c3ccccc3Cl)o2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 8 (0.2 g, 0.75 mmol) in CH3CN was added POCl3 (0.37 g, 2.4 mmol). The mixture was stirred under reflex for 16 hours, cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in CH3CN, treated with a solution of N-amino-2,4-dichloro-N′-(2-chlorophenyl)benzamidine 4 (0.38 g, 1.2 mmol) in CH3CN and K2CO3 (0.38 g, 1.2 mmol). The mixture was stirred at ambient temperature for 1 hour, refluxed for 2 hours and filtered. The filtrate was concentrated. The residue was subjected to flash column chromatography (FCC) (50-60% EtOAc/hexanes) to afford the title compound 4-(5-((E)-2-(5-(2,4-dichlorophenyl)-4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)vinyl)-1,3,4-oxadiazol-2-yl)-2-methoxypyridine as a white solid. Yield: 0.11 g, 28%.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])CC1.Br[C:18]1C=C(C=CC=1C)C(O)=O.BrC1C=C(C=CC=1C1CC1)C(O)=O.C([Mg]Br)CC>>[C:13]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH3:1])[C:8]([OH:10])=[O:9])(=[O:16])[CH2:14][CH2:15][CH3:18]
Reactant: CCC(=O)c1cc(C(=O)O)ccc1C1CC1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CCC[Mg]Br
Agent: O=C(O)c1ccc(C2CC2)c(Br)c1
Product: CCCC(=O)c1cc(C(=O)O)ccc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 10.6, except 3-bromo-4-methylbenzoic acid was used in place of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3) and propylmagnesium bromide was used in place of ethylmagnesium bromide.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]([OH:8])[CH2:5][C:6]=1[CH3:7].N1C=CC=CC=1.[Cl:15]/[C:16](/[C:26]([F:29])([F:28])[F:27])=[CH:17]\[C@@H:18]1[C@H:20]([C:21](Cl)=[O:22])[C:19]1([CH3:25])[CH3:24]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[Cl:15]/[C:16](/[C:26]([F:27])([F:28])[F:29])=[CH:17]\[C@@H:18]1[C@H:20]([C:21]([O:8][CH:4]2[CH2:5][C:6]([CH3:7])=[C:2]([CH3:1])[CH2:3]2)=[O:22])[C:19]1([CH3:25])[CH3:24]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: CC1=C(C)CC(O)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1=C(C)CC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)C1
Yield: 86.5 %

Procedure:
To a mixture of 3,4-dimethyl-3-cyclopenten-1-ol (175 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (150 mg) and toluene (10 ml), (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (395 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 441 mg of 3,4-dimethyl-3-cyclopenten-1-yl (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 3). Yield 84% nD25 1.4620
Reaction SMILES: [C:1]1([C:7]2[N:11]3[C:12](=[O:16])[NH:13][N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[C:10]=1[CH:15]=[N:14][NH:13][C:12]2=[O:16]
Reactant: O=c1[nH]ncc2cnc(-c3ccccc3)n12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=c1[nH]ncc2c(Br)nc(-c3ccccc3)n12
Temperature: 25 °C

Procedure:
A 3.0 portion of 6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one is stirred with 100 ml. of chloroform. The mixture is heated slightly and a solution of one ml. of bromine in 10 ml. of chloroform is slowly dripped into the reaction mixture. The mixture is refluxed for one hour, cooled to room temperature, and filtered. To the solid is added aqueous Na2CO3 and chloroform and the mixture is shaken in a separatory funnel. The remaining solid and the organic phase are combined and evaporated to a steam bath. Methanol and 2-propanol are added and the mixture is treated twice with charcoal. Cooling gives the desired product as a solid, m.p. 192°-194° C.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=[O:6].CCN(C(C)C)C(C)C.[CH:28]1[CH:33]=[C:32]([CH2:34][O:35][C:36](Cl)=[O:37])[C:31]([Cl:39])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:3][O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:36]([O:35][CH2:34][C:32]3[CH:33]=[CH:28][CH:29]=[CH:30][C:31]=3[Cl:39])=[O:37])[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=[O:6]
Reactant: COC(=O)c1ccc(Cn2cc(N)cn2)o1
Reactant: O=C(Cl)OCc1ccccc1Cl
Agent: N#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-amino-pyrazol-1-ylmethyl)-furan-2-carboxylic acid methyl ester (2.90 g, 13.10 mmol) in CH2Cl2 (58.0 mL) was treated with DIPEA (3.37 mL, 19.66 mmol) followed by 2-chlorobenzylchloroformate (2.69 mL, 17.04 mmol). The reaction mixture was stirred at rt for 4 h before being quenched with water (100 mL), extracted with CH2Cl2 (3×50 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a solid. TLC: rf (50:50 hept-EA)=0.22. LC-MS-conditions 02: tR=0.94 min; [M+H]+=390.37. 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 3H), 5.29 (s, 2H), 5.31 (s, 2H), 6.39 (d, J=2.5 Hz, 1H), 6.75 (s, 1H), 7.12 (d, J=3.0 Hz, 1H), 7.23-7.31 (m, 2H), 7.38-7.42 (m, 1H), 7.43-7.46 (m, 2H), 7.75 (s, 1H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[NH2:22].O>C1COCC1>[Cl:20][C:18]1[C:17]([Cl:21])=[CH:16][C:15]2[NH:22][C:1](=[O:2])[NH:13][C:14]=2[CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.49 g (33.9 mmol) of 1,1′-carbonyldiimidazole were added in portions to a stirred solution of 5.00 g (28.2 mmol) of 1,2-diamino-4,5-dichlorobenzene in THF (100 ml) at room temperature. The reaction solution was then stirred at room temperature overnight. The reaction mixture was mixed with water (60 ml) and cooled in an ice bath. The precipitate which separated out was filtered, washed with water and dried in vacuo.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32](O)=[O:33])[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH2:30])=[C:22]([CH3:31])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:68]1[CH2:73][CH2:72][CH:71]([N:74]2[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]2)[CH2:70][CH2:69]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[C:23]([NH2:30])=[C:22]([CH3:31])[CH:21]=3)[C:32](=[O:33])[N:77]3[CH2:76][CH2:75][N:74]([CH:71]4[CH2:72][CH2:73][O:68][CH2:69][CH2:70]4)[CH2:79][CH2:78]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C(F)(F)F)c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 100 mg (0.19 mmol) (R)-2-(4-amino-3-methyl-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 67 mg (0.21 mmol) TBTU and 50 μL (0.36 mmol) triethylamine in 1 mL DMF was stirred for 10 min at RT. Then 40 mg (0.24 mmol) 1-(tetrahydropyran-4-yl)-piperazine were added and the reaction mixture was stirred for a further 20 h at RT. The reaction solution was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[CH:13]=[CH:14][O:15][C:11]=3[C:10](O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.O.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:10]1[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nnc(-c2ccccc2)c2ccoc12
Solvent: O
Solvent: c1ccncc1
Product: Clc1nnc(-c2ccccc2)c2ccoc12

Procedure:
A slurry of 4-phenylfuro[3,2-d]pyridazin-7-ol (0.327 g, 1.5 mmol) and pyridine (0.38 ml, 4.6 mmol) in 5 mL POCl3 was heated with a water-cooled reflux condenser with drying tube to 130° C. for 3 h. The brown solution was cooled and the reaction judged complete by LCMS. The reaction was poured onto ice with stirring. The solution was neutralized with 6 N NaOH and ice to control temperature. The resulting mixture was extracted into DCM (3×). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The solid was adsorbed onto 2 g silica gel from DCM/MeOH and dried. The material was purified by silica gel chromatography, eluting with 0-20% EtOAc/DCM to give 7-chloro-4-phenylfuro[3,2-d]pyridazine as an off-white solid. MS m/z=231 [M+H]+. Calc'd for C12H7ClN2O: 230.7.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:13]=[CH:12][C:11]([NH:14]C(=O)OC(C)(C)C)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCOCC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(CN2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
To a solution of tert-butyl 6-(morpholinomethyl)pyridin-3-ylcarbamate (115; 1.20 g, 4.1 mmol) in dichloromethane (20 mL) was added TFA (6.0 mL). The resulting reaction mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. Enough saturated aqueous Na2CO3 was added to the residue to adjust the pH=9. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 6-(morpholinomethyl)pyridin-3-amine 116 (450 mg, 56%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH:25]([C:27]([CH3:29])=[O:28])=[CH2:26]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:26][CH2:25][C:27](=[O:28])[CH3:29])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: C=CC(C)=O
Solvent: CCO
Product: CC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 62.3 %

Procedure:
3.31 g (0.01 mol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid and 3.9 g of methyl vinyl ketone are heated under reflux in 50 ml of ethanol for 2 hours. The solid is filtered off with suction and washed with methanol to give 2.5 g (62.3% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(3-oxobutyl)-1-piperazinyl]-3-quinolinecarboxylic acid of decomposition point 185°-187° C.
Reaction SMILES: Br[C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.[C:40](=[O:42])=[O:41]>O1CCCC1.C1CCCCC1>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:6]1[CH2:7][CH2:8][CH2:9][C:10]2=[C:2]([C:40]([OH:42])=[O:41])[N:3]([CH3:20])[N:4]=[C:5]12
Reactant: O=C=O
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(Cl)c1
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3C(=O)O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (1-1; 1.46 g) and a few crystals of 1,10 phenanthroline were dissolved in 25 mL of dry tetrahydrofuran and chilled to −78° C. under an argon atmosphere. A 2.0 M solution of n-butyllithium in cyclohexane was added dropwise until the dark color of the phenanthroline/organolithium complex persisted. An additional 2.05 mL of the n-butyllithium solution was added. After 10 minutes, carbon dioxide, generated from dry ice, was bubbled through the reaction mixture for 5 minutes. After the reaction mixture had been stirred at −78° C. for 5 minutes, the cooling bath was removed and the mixture was allowed to warm for 5 minutes before being quenched by the addition of water. The mixture was partitioned between ethyl acetate and water, acidified with dilute hydrochloric acid. The ethyl acetate was dried with magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel eluting with an acetone/hexane gradient to provide 1.11 g of 5-1: mp 247.8-248.3° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])=O)C.O.[NH3:20]>C(O)C>[C:4]([CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])(=[O:3])[NH2:20]
Reactant: N
Reactant: CCOC(=O)CN1C(=O)COc2cc(F)ccc21
Solvent: O
Solvent: CCO
Product: NC(=O)CN1C(=O)COc2cc(F)ccc21
Yield: 40 %

Procedure:
A mixture of 4-ethoxycarbonylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (1.27 g), ethanol (20 ml) and 28% ammonia water (10 g) was mixed at room temperature for 2 hours, and refluxed for 3 hours. After the solvent was concentrated, it was mixed with water, and filtered. Resulting product was washed with water and ethanol in that order, and recrystallized from methylisobutyl ketone to give the desired 4-carbamoylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (0.45 g). mp. 216.5°-219° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)CC)C.CCCP(=O)=O.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: NCc1ccccc1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)NCc3ccccc3)c1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
To a mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (54 mg, 0.20 mmol), triethylamine (0.084 mL, 0.60 mmol), and catalytic DMAP in 4.5 mL CH2Cl2 at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.131 mL, 0.22 mmol). After 5 min at rt, benzyl amine (0.023 mL, 0.21 mmol) was added and the reaction stirred at rt for 23 hours. The reaction was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with aqueous NaHCO3 solution, H2O, brine, dried with anhydrous Na2SO4 and evaporated to a solid. The solid was chromatographed eluting with CHCl3/EtOAc plus 5% MeOH and then triturated with acetone/hexane to give the title compound as a light beige solid (20 mg, 28%). 1H NMR (Acetone-d6) δ: 8.39 (br. s., 1H), 8.12 (s, 1H), 7.58 (br. s., 1H), 7.27-7.38 (m, 5H), 7.16-7.26 (m, 2H), 4.59 (d, J=5.6 Hz, 2H), 4.30 (s, 2H), 3.66 (t, J=5.3 Hz, 2H), 2.82 (t, J=5.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Br)cc1C
Reactant: CCC(N)CC
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C(=O)OC
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(4-bromo-2,6-dimethyl-phenoxy)-nicotinic acid methyl ester and 1-ethyl-propyl-amine in DMSO was heated at 120° C. for 16 hr. The mixture was quenched with water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography using hexane to 3% ethyl acetate in hexane as eluent to give the title compound as a white solid. 1H NMR(CDCl3) d 8.1(d,1H), 7.18(s,2H), 6.08(s,1H), 3.87(s,3H), 3.35(m,1H), 2.10(s,3H), 2.08(s,6H), 1.4–1.7(m,4H), 0.96(t,6H) ppm.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]3[NH:16][CH:17]=[CH:18][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].O>CN(C)C=O>[CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]3[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1cnc2[nH]ccc2c1NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C=O)cnc21
Yield: 63.3 %

Procedure:
4-(Cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (273 mg, 1.12 mmol) in N,N-dimethylformamide (3 mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil, 61.2 mg, 1.53 mmol) for 1 hour under cooling with ice. The reaction mixture was stirred with [2-(chloromethoxy)ethyl]trimethylsilane (260 μL, 1.47 mmol) at room temperature for one day, and after addition of water, extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 (v/v)) to give the title compound as a pale yellow oil (265 mg, yield 63%).
Reaction SMILES: C[O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])=[CH:5][CH:4]=1.C(Cl)Cl.B(I)(I)I>C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]([C:11]23[CH2:12][CH:13]4[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]4)[CH2:20]2)[CH2:18]3)=[O:10])=[CH:21][CH:22]=1
Reactant: COc1ccc(CNC(=O)C23CC4CC(CC(C4)C2)C3)cc1
Agent: IB(I)I
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1ccc(O)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 3.0 g. of N-(4-methoxybenzyl)-1-adamantanecarboxamide in 25 ml. of methylene chloride and cool the solution to about -78° C. Add 2.6 g. of boron triiodide and allow the reaction mixture to warm up to about 0° C. with vigorous stirring. Stir the reaction mixture at about 0° C. overnight, then follow the procedure described in Example 6B and crystallize the residue obtained thereby from ethyl acetate to obtain the product of this Example, m.p. 196°-198° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[Cl:12][CH2:13][C:14](Cl)=[O:15].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:14](=[O:15])[CH2:13][Cl:12])[CH2:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCCN2
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CCl)N1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-bromo-1,2,3,4-tetrahydroquinoline (2.09 g, 9.85 mmol) in 55 mL toluene was treated with 2-chloroacetyl chloride (0.863 mL, 10.84 mmol) dropwise over 10 minutes. The resulting suspension was stirred at room temperature for 1.5 hour then heated at 95° C. for 30 minutes. After cooling to room temperature, the yellow solution was diluted with 20 mL ethyl acetate and treated with 25 mL of a saturated aqueous sodium bicarbonate solution. The mixture was poured into a separatory funnel and extracted. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using 30% ethyl acetate:70% hexanes as eluant. A white solid was obtained after drying under reduced pressure (Yield: 2.4 g, 84%). 1H-NMR (CDCl3) δ 7.35-7.33 (m, 3H), 4.19 (s, 2H), 3.80 (t, J=6.3 Hz, 2H), 2.74 (t, J=6.6 Hz, 2H), 2.04-1.98 (m, 2H).
Reaction SMILES: [CH:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>C(C(C)=O)C>[CH:21]1([C@@:7]([OH:8])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][N:38]5[C:46](=[O:47])[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[C:39]5=[O:48])=[CH:34][CH:35]=4)[CH2:17][CH2:16]3)[N:10]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OC(c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
Cyclohexyl-phenyl-(1-piperidin-4-ylmethyl-1H-[1,2,4]triazol-3-yl)-methanol (Preparation 4, 0.40 g, 1.13 mmol) and 2-{2-[4-(2-Bromo-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione (Preparation 11, 0.404 g, 1.13 mmol) and diisopropylethylamine (0.59 ml, 3.38 mmol) were dissolved in methyl ethyl ketone (8 mL). After stirring at 90° C. for 24 hours the reaction was allowed to cool slowly to room temperature. Crystallisation occured and the resulting solid was collected by filtration and dried in vacuo to yield the title compound as a cream coloured solid, in 74% yield, 0.532 g.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:33][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: NC(c1ccc(F)cc1)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccc(F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-fluoro-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine (example 4.5).