Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:23])=[CH:4][C:5]([F:22])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)[CH:7]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1.C(Cl)Cl>O>[Br:23][C:3]1[C:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:7][C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:5]([F:22])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Br
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Br
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 8-(5-amino-4-bromo-2-fluorophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (5.0 g), methanesulfonyl chloride (1.21 g), pyridine (2.02 g) and methylene chloride (30 ml) was stirred for 5 days at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The extract layer was washed with water and dried on anhydrous magnesium sulfate followed by distilling off the solvent under reduced pressure. The residual solid was washed with ether to give the compound of interest (4.8 g) as a white solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:39]([NH2:41])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].F[P-](F)(F)(F)(F)F.[N:69]1(OC(N(C)C)=[N+](C)C)[C:73]2N=[CH:75][CH:76]=[CH:77][C:72]=2N=[N:70]1.C([N:89]([CH2:93]C)C(C)C)(C)C.[F:95][C:96]([F:101])([F:100])[C:97]([OH:99])=[O:98]>CN(C=O)C.ClCCl>[F:95][C:96]([F:101])([F:100])[C:97]([OH:99])=[O:98].[NH2:89][CH2:93][CH2:75][CH2:76][CH2:77][CH2:72][C:73]([NH:69][NH:70][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:39]([NH2:41])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:98]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
146 mg (50 μmol) of (N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 5 ml of DMF and then admixed with 30.6 mg (80 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 19 μl of N,N-diisopropylethylamine and with 22.4 mg (60 μmol) of tert-butyl 6-hydrazino-6-oxohexyl carbamate. The reaction mixture was stirred at RT for 1.5 h. This was followed by concentration under high vacuum and purification of the remaining residue by means of preparative HPLC. Thus, 43 mg (68% of theory) of the protected intermediate were obtained, which were then taken up in 10 ml of dichloromethane and deprotected with 1 ml of trifluoroacetic acid. The reaction mixture was concentrated and the residue was stirred with dichloromethane, and the solvent was removed again under reduced pressure. Thus, 45 mg (68% of theory over 2 stages) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH2:26][CH3:27])[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3>>[CH2:26]([N:17]1[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:11])=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:27]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)c3cc(Cl)ccc3O)ccc21
Yield: 64.6 %

Procedure:
Using 5-chlorosalicylic acid and 3-amino-9-ethylcarbazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:14][OH:15])=[CH:9][C:8]=1[O:16][CH3:17])(=[O:5])=[O:4].ClN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]([C:38]([F:41])([F:40])[F:39])=[CH2:37])[CH:32]=[C:33]([Cl:35])[CH:34]=1.C(N(CC)CC)C>CN(C)C=O>[F:19][C:2]([F:18])([F:1])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:37][C:36]([C:31]3[CH:32]=[C:33]([Cl:35])[CH:34]=[C:29]([Cl:28])[CH:30]=3)([C:38]([F:39])([F:41])[F:40])[O:15][N:14]=2)=[CH:9][C:8]=1[O:16][CH3:17])(=[O:4])=[O:5]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: COc1cc(C=NO)ccc1OS(=O)(=O)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
In a solution of 2.0 g of 4-hydroxyiminomethyl-2-methoxyphenyl trifluoromethane sulfonate in 30 ml of N,N-dimethylformamide, 0.9 g of N-chlorosuccinic acid imide was added, and stirred at 40 to 50° C. for 30 minutes. Then, the reaction mixture was left and cooled to room temperature, 1.5 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 3 and 0.7 g of triethylamine were added, and stirred at room temperature for 90 minutes. After the completion of the reaction, the reaction mixture was poured in 100 ml of ice water, extracted with ethyl acetate (50 ml×2), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:7), and 1.4 g of the aimed product was obtained as colorless resinous substance.
Reaction SMILES: CC(C)(OC([CH2:7][NH:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([O:25]CC)=[O:24])=[CH:10]1)=O)C.C(O)(=O)C.Cl>O>[F:21][C:15]1[CH:14]=[C:13]2[C:18](=[C:17]([F:19])[C:16]=1[F:20])[N:9]([NH:8][CH3:7])[CH:10]=[C:11]([C:23]([OH:25])=[O:24])[C:12]2=[O:22]
Reactant: CCOC(=O)c1cn(NCC(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
To 2.00 g (5.0 mmol) of 1-[[(1,1-dimethylethoxy)carbonyl]methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester was added 35 ml of acetic acid and 15 ml of 2N hydrochloric acid. The mixture was placed on a steam bath for 2.5 hours, was diluted with 15 ml of water, and was cooled. The solids were filtered to give 1.09 g of 6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3quinolinecarboxylic acid, mp 237°-238° C.
Reaction SMILES: C(O[C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=O)C.[CH2:27]([O:34][CH2:35][CH2:36][NH2:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[C:19]([O:18][C@@H:8]1[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6][C@H:5]2[C@H:10]([N:11]=[C:12]([NH:37][CH2:36][CH2:35][O:34][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:13]2)[C@H:9]1[O:14][C:15](=[O:17])[CH3:16])(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H]2SC(NCCOCc3ccccc3)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (9.8 g, 25 mmol) in dichloromethane (100 mL) was added 128 (4 g, 26 mmol) at 0° C. After stirred for 2 hours, trifluoroacetic acid (15.4 g, 159 mmol) was added. The resulting solution was stirred for 12 hours at room temperature, then quenched with ice-water (200 mL) and neutralized by the addition of NaHCO3 (26 g, 318 mmol). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (2×100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by silica gel column, eluted with 10%-50% ethyl acetate in petroleum ether to afford 129 as a white syrup (9.8 g, 77%). (ES, m/z) [M+H]+ 481.0; 1H NMR (300 MHz, CDCl3) δ 7.31-7.38 (m, 5H), 6.24 (d, J=6.3 Hz, 1H), 5.41-5.43 (m, 1H), 4.94-4.98 (m, 1H), 4.55 (s, 2H), 4.34-4.37 (m, 1H), 4.14-4.16 (m, 3H), 3.83-3.87 (m, 1H), 3.64 (t, J=5.4 Hz, 2H), 3.53 (t, J=5.1 Hz, 2H), 2.12 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: CN(C)C=O.[C:6]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH2:22]Cl)[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[CH3:24])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C(OCC)(=O)C.O>[C:6]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH2:22][NH:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[CH3:24])=[CH:8][CH:7]=1
Reactant: Cc1nc2ccc(CCl)cc2n1Cc1ccc(-c2ccccc2)cc1
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(CNCc3ccccn3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To an N,N-dimethylformamide (3 ml) solution of 1-(biphenyl-4-ylmethyl)-6-chloromethyl-2-methylbenzimidazole (0.597 g) and potassium carbonate (0.350 g), 2-aminomethylpyridine (0.372 g) is added and the solution is stirred for two hours at 60° C. Water and ethyl acetate are added and extraction is performed. An organic layer is washed with water (twice). The solvent is removed under reduced pressure and a residue is obtained. The residue is purified through silica gel column chromatography (eluate: chloroform/methanol=9/1). Recrystallization is performed in a mixture solvent of ethyl acetate and hexane and thus, 1-(biphenyl4-ylmethyl)-2-methyl-6-[(2-pyridylmethyl) aminomethyl]benzimidazole 0.300 g is obtained. 1H-NMR (CDCl3, δ): 2.57 (3H, s), 3.91 (2H, s), 3.93 (2H, s), 5.35 (2H, s), 7.08-7.14 (3H, m), 7.23 (2H, d, J=7.3 Hz), 7.30-7.35 (2H, m) 7.41 (2H, t), 7.50-7.55 (4H, m), 7.57 (1H, dt, J=1.8 and 7.6 Hz), 7.68 (1H, d, J=8.1 Hz), 8.53 (1H, d, J=4.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:33]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (161 mg, 363 μmol) produced in Example D25(iii) in pyridine (4 mL) was added acetyl chloride (65 μL, 908 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (129 mg, 73%) as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:9][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ncc(N)cc1I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 5-iodo-6-methylpyridin-3-amine (125 mg, 0.534 mmol) in methylene chloride (1 mL) was added triethylamine (0.087 mL, 0.627 mmol) and cooled at 0° C. Into the reaction was added 3-(trifluoromethyl)benzoyl chloride (0.0812 mL, 0.538 mmol) dropwise and stirred at 0° C. for 45 minutes and at 25° C. for 16 hours. The reaction was extracted with EtOAc and the organic extracts were washed with water saturated Na2CO3, saturated NaCl, dried (MgSO4) and stripped in vacuo. The product was used in the next reaction without purification.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-cyano-2-fluoro benzoic acid (650 mg, 3.9 mmol) in CH2Cl2 (20 mL) were added 2 drops of DMF and oxalyl chloride (0.7 mL, 7.8 mmol). The mixture was stirred at rt overnight and became a clear solution. The volatile was evaporated to dryness to give 4-cyano-2-fluoro-bezoyl chloride. To a solution of compound 6 (900 mg, 2.62 mmol) in THF (10 mL) was added a THF solution of 4-cyano-2-fluoro-bezoyl chloride. The mixture was stirred for 1 h, and concentrated. The residue was dissolved in EtOAc, washed with sat NaHCO3 and water. The organic layer was dried and evaporated to give compound 7 (1.2 g, 94% yield). MS found for C25H20ClFN4O2Si as (M+H)+: 491.1.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH2:15][CH3:16])[C:7]([OH:9])=[O:8].Cl.[C:18](=N)(OC)[CH3:19]>C(OCC)C>[CH3:18][C:19]1[N:13]([CH2:14][CH2:15][CH3:16])[C:12]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=2[N:3]=1
Reactant: CCCNc1ccc(C(=O)O)cc1N
Reactant: COC(C)=N
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCCn1c(C)nc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 116.5 %

Procedure:
To a methanol (17 mL) solution of 3-amino-4-n-propylaminobenzoic acid (see Working Example 82-2) (1.68 g, 8.65 mmol) was added methyl acetimidate hydrochloride (1.14 g, 10.4 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, diethyl ether was added, and this was allowed to stand at room temperature for 10 minutes. The crystals obtained were filtered, and after being washed with diethyl ether, they were dried to yield the title compound (2.20 g, quant.).
Reaction SMILES: ClC1C=CC(CN2CCC(NC3C=C(NC(=O)C)C=CC=3)CC2)=CC=1OCC.Cl.Cl.[Cl:31][C:32]1[N:33]=[C:34]([NH:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2.[CH2:49]([O:51][C:52]1[CH:57]=[C:56]([CH:58]=O)[CH:55]=[C:54]([O:60][CH2:61][CH3:62])[C:53]=1[C:63]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=1)[CH3:50]>>[Cl:31][C:32]1[N:33]=[C:34]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:58][C:56]3[CH:55]=[C:54]([O:60][CH2:61][CH3:62])[C:53]([C:63]4[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=4)=[C:52]([O:51][CH2:49][CH3:50])[CH:57]=3)[CH2:45][CH2:44]2)[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Reactant: Clc1cc2ccccc2c(NC2CCNCC2)n1
Agent: CCOc1cc(CN2CCC(Nc3cccc(NC(C)=O)c3)CC2)ccc1Cl
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3nc(Cl)cc4ccccc34)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinonitrile (example 38/step 3) from (3-chloro-isoquinolin-1-yl)-piperidin-4-yl-amine dihydrochloride (intermediate B13) and 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (intermediate E22) in a yield of 8.9 mg (11%). MS (ISP): 534.5 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C-:19]#[N:20].[Na+]>CC(C)=O.C(O)C.O>[C:19]([CH2:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:20]
Reactant: [C-]#N
Reactant: Fc1ccc(-c2coc3c(CCl)cccc23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: N#CCc1cccc2c(-c3ccc(F)cc3)coc12

Procedure:
To a solution of 7-chloromethyl-3-(4-fluorophenyl)benzofuran (130.3 g., 0.50 mole) in acetone (750 ml.) and ethanol (500 ml.) is added a solution of sodium cyanide (39.5 g., 0.50 mole) in water 150 ml.). The mixture is heated to its reflux for 5 hours. The mixture is then evaporated in vacuo to concentrate it. The residue is dissolved in dichloromethane, then washed thoroughly with water, dried and concentrated by evaporation in vacuo. The oily residue is recrystallized twice from cyclohexane, then deposited on 70 g. of a magnesium silicate material used for elution chromatography and chromatographed on 400 g. of the silicate type column. Elution with hexane, benzene-hexane (1:4), (1:1) and (3:2), followed by benzene gives the desired product, 7-cyanomethyl-3-(4-fluorophenyl)benzofuran, in the benzene fractions.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:26])[C:14]=2[C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18]([OH:20])=[O:19])[N:10]=1.C(N([CH2:37][CH3:38])CC)C.[CH2:39]([O:41]C(Cl)=O)C>C(Cl)Cl>[C:39]([O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([C:14]2[C:13](=[O:26])[CH:12]=[CH:11][N:9]3[C:8]=2[CH:7]=[CH:6][C:5]([O:4][C:3]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:2]=2[F:1])=[N:10]3)[CH:16]=1)(=[O:41])[CH2:37][CH3:38]
Reactant: COc1ccc(C(=O)O)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OC(=O)c1ccc(OC)c(-c2c(=O)ccn3nc(Oc4ccc(F)cc4F)ccc23)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-[2-(2,4-difluorophenoxy)-6-oxo-6H-pyrido[1,2-b]pyridazin-5-yl]-4-methoxybenzoic acid (Intermediate 1, 424 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added triethyl amine (202 mg, 2.0 mmol) and ethylchloroformate (162 mg, 1.8 mmol) at 0° C. The mixture was warmed to ambient temperature and stirred for 10 min. The reaction was complete by LCMS analysis and concentrated in vacuo to yield 3-[2-(2,4-difluorophenoxy)-6-oxo-6H-pyrido[1,2-b]pyridazin-5-yl]-4-methoxybenzoic propanoic anhydride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].C([O-])([O-])=O.[K+].[K+].[Cl:24][C:25]1[CH:42]=[CH:41][C:28]([CH2:29][CH2:30][NH:31][C:32](=[O:40])[C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1>CN1CCCC1=O>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][NH:31][C:32]([C:33]2[CH:38]=[CH:37][C:36]([O:39][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:35][CH:34]=2)=[O:40])=[CH:41][CH:42]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Temperature: 110 °C
Reaction time: 6 h
Yield: 48.5 %

Procedure:
Methyl 6-cyano-7-fluorochroman-4-carboxylate (50 mg, 0.21 mmol) was diluted with 1-methyl-2-pyrrolidinone (2 mL) followed by the addition of K2CO3 (147 mg, 1.1 mmol) and N-(4-chlorophenethyl)-4-hydroxybenzamide (59 mg, 0.21 mmol). The reaction was bubbled with argon for 10 minutes and then heated to 110° C. and stirred for 6 hours. After the reaction was allowed to cool, it was loaded directly onto a Biotage 25 column and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (50 mg, 48% yield). MS (ESI)=490.9 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][CH:28]=4)=[CH:20][CH:19]=3)=[CH:16][C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10].[CH3:33][NH2:34].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[ClH:1].[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:13]([C:5]3[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([CH:4]=3)[CH2:2][NH:34][CH3:33])[N:14]=[C:15]([C:29]([F:31])([F:32])[F:30])[CH:16]=2)=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)cc2)cc1CCl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNCc1cc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)cc2)ccc1S(C)(=O)=O
Product: Cl
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 1-[3-chloromethyl-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole from step1 (70 mg, 0.15 mmol) in THF (3.0 mL), methylamine (5.0 ml, 10 mmol, 2.0 M in THF) and K2CO3 (200 mg, 1.5 mmol) was added at room temperature and stirred for 1 hour. The mixture was concentrated and ethyl acetate (30 mL) was added, dried over MgSO4, and concentarted in vacuo. The solid was dissolved in 10% methanolic HCl (10 mL), and volatiles were removed by evaporation. The residual solid was recrystallized from ethanol to give the title compound (45 mg, 59%).