Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:15]1[S:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[CH:16]=1)[CH2:12][CH2:13][CH3:14]>>[CH2:11]([C:15]1[S:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]=1[S:6]([Cl:10])(=[O:8])=[O:7])[CH2:12][CH2:13][CH3:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCc1cc2ccccc2s1
Solvent: CN(C)C=O
Product: CCCCc1sc2ccccc2c1S(=O)(=O)Cl

Procedure:
2-n-Butylbenzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (6.6 mmoles, 0.51 ml), sulfuryl chloride (5.6 mmoles, 0.45 ml) and 2-n-butylbenzo[b]thiophene (3.3 mmoles, 0.63 g). Flash chromatography (2% ethyl acetate/hexanes) provided 0.68 g (71%) of an orange solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](=[O:21])[CH3:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:22].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](=[O:21])[CH2:20][Br:22])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
The ketone from step 1 (0.310 g, 1.02 mmol) was dissolved in THF (3 ml), and phenyltrimethylammonium tribromide (PTT) (0.386 g, 1.02 mmol) was added as a solid leaving an orange solution which began to deposit a white solid immediately. Stirring for 1.5 hours leaves a colorless mixture to which water (5 ml) was added. THF was then evaporated and the resulting aqueous mixture was extracted with ethyl acetate. Drying over Na2SO4 and evaporation leaves a white crystalline solid (85% desired mono-brominated material by LC-MS, 5% starting material, 10% dibrominated) suitable for the next step. LC-MS (ES+): 381, 379 m/e.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]2([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].N1(S(N)(=O)=O)CCC1.[CH:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]2([C:18]([F:21])([F:19])[F:20])[CH2:15][CH2:16][CH2:17]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:36][S:33]([CH:30]1[CH2:32][CH2:31]1)(=[O:35])=[O:34])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCC2)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: NS(=O)(=O)N1CCC1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCC2)cc1F

Procedure:
Following the procedure as described in Example 218 step 5 and making variations as required to replace trans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoic acid and to replace azetidine-1-sulfonamide with cyclopropanesulfonamide, the title compound was obtained as colorless solid (0.04 g, 47%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.39 (d, J=12.4 Hz, 1H), 4.41 (s, 2H), 3.12-3.03 (m, 1H), 2.37-2.27 (m, 2H), 2.18-2.09 (m, 3H), 2.01-1.92 (m, 1H), 1.15-1.11 (m, 4H); MS (ES+) m/z 430.0, 432.0 (M+1); MS (ES−) m/z 428.1, 430.1 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(C=O)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(CN2CCOCC2)c1
Reaction time: 8 h

Procedure:
3-[5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-3-methyl-isoxazol-4-yl]-benzaldehyde (25 mg, 0.05 mmol) and morpholine (0.3 ml) were mixed with DCE (0.5 ml) in an microwave tube. Sodium triacetoxyborohydride (15 mg, 1.4 equiv) was added, the tube sealed, and nitrogen atmosphere introduced. After 1 hr more sodium triacetoxyborohydride (15 mg) was added and the reaction left stirring overnight. TLC analysis showed that the reaction had not gone to completion so a drop of acetic acid was added and the reaction again left stirring overnight after which the reaction was quenched with 1M NaHCO3 solution (7 ml) and extracted into EtOAc (5 ml). This was dried over MgSO4 and the solvent removed in vaccuo to provide 13 mg of the crude product as an off white powder which was taken over to the deprotection step.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9]2[O:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([C:21]([OH:23])=[O:22])[C:14]=3[C:8]=2[CH2:7]1)=O)C.[OH-].[K+]>CO.O>[CH3:20][O:19][C:18]1[C:13]2[O:12][C:9]3[CH2:10][CH2:11][NH:6][CH2:7][C:8]=3[C:14]=2[C:15]([C:21]([OH:23])=[O:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)N1CCc2oc3c(OC)ccc(C(=O)O)c3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)c2c3c(oc12)CCNC3

Procedure:
2-ethoxycarbonyl-6-methoxy-1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine-9-carboxylic acid (from step 9 of example 9) (1.8 g, 6.10 mmol) was dissolved in methanol (10 ml). To this KOH (6.8 g, 122.03 mmol) dissolved in 10 ml water was added and reaction mixture was refluxed overnight. Reaction mixture was concentrated and residue was diluted with water (25 ml) and neutralized with (15 ml) saturated ammonium chloride solution. The precipitate obtained was filtered and dried under vacuum. Yield=1.6 g (pale yellow solid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:17])[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1CCOCC1>C1(C)C=CC=CC=1>[NH2:17][C:10]1[C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])=[CH:7][CH:6]=2)[N:9]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(-c2cn3ccnc3c(N)n2)cc1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: Nc1nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)cn2ccnc12

Procedure:
(FIG. 1) Procedure: A mixture of 1.00 eq. of 6-(4-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamine, 1.50 eq. of phenylisocyanate, and 2.00 eq. of N-methylmorpholine, in toluene is mixed at room temperature for 2 hr. The mixture is partitioned between 1 N NaOH and ethyl acetate and extracted three times. The organic extracts are combined and dried over MgSO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (50% ethyl acetate/hexanes) to yield 8.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]1=[O:19]>>[CH2:9]([O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:16]2[CH2:17][CH2:18][NH:13][C:14](=[O:19])[CH2:15]2)[CH:7]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: O=C1CNCCN1
Reactant: CC(C)COc1cc(Cl)ncn1
Product: CC(C)COc1cc(N2CCNC(=O)C2)ncn1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of intermediate C using 4-chloro-6-isobutoxypyrimidine and piperazin-2-one.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C([Sn](=O)CCCC)CCC.C([C@@]1(O)[C@H](OCCCC)[C@@H](C(=[SnH2])O)O[C@H]1N1C=CC(=O)NC1=O)CCC.I[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>>[CH2:55]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCCCCCCCCI
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CCCCO[C@@H]1[C@@H](C(O)=[SnH2])O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]1(O)CCCC
Agent: CCCC[Sn](=O)CCCC
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
As per the procedure of Example 49, uridine (22.5 g) was treated with dibutyl tin oxide (22.5 g, 1 eq). The resulting 2',3'-O-dibutylstannyleneuridine was treated with iodononane (11 ml, 1.3 eq.) at 130°-140° C. as per Example 50 to give the 2' and 3' isomers (11.2 g) as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].C[C:23]([N:25](C)C)=O>O>[C:23]([C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8])#[N:25]
Reactant: Nc1c(I)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(=O)N(C)C
Solvent: O
Product: N#Cc1cc(-c2ccccc2C(F)(F)F)cc([N+](=O)[O-])c1N
Temperature: 140 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
The title compound was prepared by an adaptation of the method described by Youngblood, W. J. (J. Org. Chem. 2006, 71, 3345-3356). 3-Iodo-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (230 mg, 0.564 mmol, as prepared in the previous step) and Cu(I)CN (1.5 eq., 7.57 mg, 0.845 mmol) were placed in an 8 mL vial equipped with a magnetic stir bar. Dry DMA (2.5 mL) was added via syringe, and the vial was tightly capped and placed in a heating block. The reaction was stirred at 140° C. for 14 h, cooled to RT, and poured into water. The precipitate was isolated by filtration and washed with water (10 mL). The precipitate was dissolved in EtOAc (25 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC on a 2000 μm SiO2 plate developed with EtOAc/hexanes, 1:9 v/v, yielding 86 mg (50%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.37 (d, J=1.8 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.62 (t, J=7.3 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 6.84 (br. s., 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].[Cl-].[Li+].[Cu]C#N.C(Br)C=C>C1COCC1>[CH2:12]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])[CH:10]=[CH2:11]
Reactant: CC(C)[Mg]Cl
Reactant: Cc1cc(Br)ccc1I
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1ccc(Br)cc1C
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a solution of 4-bromo-1-iodo-2-methylbenzene (8.41 mL, 58.9 mmol) in THF (200 mL) in a 1.0 L flask under Ar at −20° C., was added isopropylmagnesium chloride (2M, THF) (52.5 mL, 105 mmol) though a dropping funnel. The reaction was stirred for 20 min at −20° C. A solution of lithium chloride (6.00 g, 141 mmol) and copper(I) cyanide (6.33 g, 70.7 mmol) in THF (140 mL) (stirred 15 min at rt to dissolve the LiCl) was cannulated to the above solution. The pale green solution was stirred for 10 min at −10° C., then allyl bromide (15.30 mL, 177 mmol) was added. The mixture was stirred at −10° C. for 30 min. The reaction was quenched with 0.5 N HCl and the solvent was evaporated. The residue was redissolved in diethyl ether/ethylacetate and organic phase was washed with 1N HCl, H2O, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was purified by flash chromatography (0% to 15% EtOAc in hexanes). The desired fractions were combined and concentrated to give 16A (12.10 g, 97% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.15-7.25 (m, 2H) 6.92 (d, J=8.24 Hz, 1H) 5.83 (dddd, J=16.97, 10.37, 6.18, 6.05 Hz, 1H) 5.00 (d, J=9.89 Hz, 1H) 4.85-4.94 (m, 1H) 3.23 (d, J=6.60 Hz, 2H) 2.18 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:20][C:21]3[CH:27]=[C:26]([C:28]([O-:30])=O)[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[NH:20][C:21]3[CH:27]=[C:26]([C:28]([NH:1][C:2]4[CH:10]=[CH:9][C:5]5[NH:6][C:7]([C:16]6[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[CH:14][CH:15]=6)=[N:8][C:4]=5[CH:3]=4)=[O:30])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:17][CH:18]=1)#[N:12]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: N#Cc1ccc(-c2nc3ccc(C(=O)[O-])cc3[nH]2)cc1
Product: N#Cc1ccc(-c2nc3cc(NC(=O)c4ccc5nc(-c6ccc(C#N)cc6)[nH]c5c4)ccc3[nH]2)cc1

Procedure:
Compound 295 was prepared according to the procedure similar to that described in Scheme V from 2-(4-cyano)phenyl)-5-aminobenzimidazole and 2-(4-cyanophenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C29H17N7O: 480.15; found: 479.89.
Reaction SMILES: COC1C=CC(C2CCCC3C=C(OC)C=CC=3C=2)=C(N)C=1.Cl.[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N1(CCOC2C=C[C:56]([CH2:57][NH:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[C:67]3[CH2:73][CH2:72][CH2:71][C:70]4[CH:74]=[C:75]([O:78][CH3:79])[CH:76]=[CH:77][C:69]=4[CH:68]=3)=CC=2)CCCCCC1>>[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([CH2:38][N:58]([CH2:57][CH3:56])[C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[C:67]3[CH2:73][CH2:72][CH2:71][C:70]4[CH:74]=[C:75]([O:78][CH3:79])[CH:76]=[CH:77][C:69]=4[CH:68]=3)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc2c(c1)CCCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)=C2
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc(C2=Cc3ccc(OC)cc3CCC2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1=Cc2ccc(OC)cc2CCC1

Procedure:
Synthesized from 5-methoxy-2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][5-methoxy-2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenyl]amine (458 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[5-methoxy-2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenyl]amine (324 mg). This compound (322 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (280 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:33][CH:32]=1>>[C:1]1([C:7]2[N:8]=[C:9]([N:12]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][C:31]4[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:33][CH:32]=4)=[CH:26][CH:27]=3)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCc1ccc(CN(CCc2ccccn2)c2nc(-c3ccccc3)cs2)cc1
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccn3)c3nc(-c4ccccc4)cs3)cc2)cc1
Yield: 57 %

Procedure:
The title compound was synthesized in the same manner as in Example 8 from (4-{[(4-phenyl-1,3-thiazol-2-yl)(2-pyridin-2-ylethyl)amino]methyl}phenyl)methanol and methyl 3-(4-hydroxyphenyl)propanoate by Mitsunobu reaction (yield 57%). Yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[C:14]([CH:17]=1)[C:15]#[N:16]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc(Br)cc1C#N

Procedure:
After 2,2-dimethyl-1-propanol and sodium hydride were stirred at 0° C. in DMF, 5-bromo-2-fluorobenzonitrile was added thereto, followed by reaction at room temperature to obtain 5-bromo-2-(2,2-dimethylpropoxy)benzonitrile. NMRC: 3.67 (2H, s), 6.83 (1H, d), 7.64 (1H, d).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C([O-])(=O)C.[Na+].[I:15]Cl>C(O)(=O)C>[CH2:1]([C:3]1[CH:9]=[C:8]([I:15])[CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2]
Reactant: ClI
Reactant: CCc1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc(I)ccc1N
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-ethylaniline (1.88 g, available from Aldrich) and sodium acetate (1.27 g) in acetic acid (20 ml) was added iodine monochloride (1 ml, available from Aldrich). The mixture was stirred at 20° C. for 90 min and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (25 ml) and saturated aqueous sodium carbonate solution (25 ml). The organic layer was dried using a hydrophobic frit and the solvent was removed in vacuo. Purification by C18 SPE eluting with 20% acetonitrile in water gave the title compound as a purple solid (0.402 g).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:32])[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)(C)(C)C>ClCCl>[F:30][C:28]([F:29])([F:31])[C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([O:15][CH2:14][C:13]([OH:32])=[O:12])[CH2:17][CH2:18]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)COC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 100 %

Procedure:
Trifluoroacetic acid (2 mL) is added to a solution of [1-(4-trifluoromethyl-phenyl)-piperidin-4-yloxy]-acetic acid tert-butyl ester (769 mg; 2.14 mmol, prepared in accordance with Example 10) in dichloromethane (2 mL). The reaction mixture is stirred until complete conversion is observed, is then concentrated under reduced pressure and co-evaporated with toluene (10 mL) to yield the desired product (985 mg, 2.14 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1)[NH2:23]
Reactant: NN
Reactant: Cc1ccccc1C(=O)N1CCc2nnc(Cl)cc2C1
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=O)N1CCc2nnc(NN)cc2C1

Procedure:
13.0 g of 3-chloro-5,6,7,8-tetrahydro-6-(o-toluoyl)pyrido[4,3-c]pyridazine and 100 cc of hydrazine hydrate are reacted as described in Example 4. Reaction time 2 hours. The bis[3-hydrazino-5,6,7,8-tetrahydro-6-(o-toluoyl)pyrido[4,3-c]pyridazine]trisfumarate has a M.P. of 98°-100° (decomp., from 95% ethanol).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([NH2:9])[S:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)#[N:11]>>[NH2:9][C:6]1[S:7][C:8]([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1
Reactant: Nc1nc(C2CC2)cs1
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(Oc2sc(N)nc2C2CC2)cc1

Procedure:
The title compound was prepared by analogous procedure to Example 6-1 A using 4-cyclopropyl-thiazol-2-ylamine (WO2005110980) and 4-cyanophenol. m/z 258.1 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=4)=[O:21])[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)n1)C2

Procedure:
In a manner similar to that described in Example 108, a mixture of 6-[2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid and 3-trifluoromethylaniline were converted to the title compound (560 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1.C(OC(C)C)(C)C>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)cn1
Reactant: O=C(Cl)C1CC1
Solvent: CC(C)OC(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C2CC2)cn1
Yield: 71 %

Procedure:
As described for example 179b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg, 0.53 mmol) was converted, using cyclopropanecarbonylchloride instead of acetyl chloride, to the title compound (132 mg, 71%) which was obtained as a white solid after trituration with diisopropylether. MS: m/e=350.0 [M+H]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[O:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=3)[CH:21]=2)[NH:16][N:15]=1.[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36].O>CN(C=O)C>[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:28]([C:26]1[O:27][C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[NH2:13])=[CH:24][CH:25]=1)=[O:30]
Reactant: NCc1cccc(O)c1
Reactant: Nc1n[nH]c2ccc(-c3ccc(C(=O)O)o3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1n[nH]c2ccc(-c3ccc(C(=O)NCc4cccc(O)c4)o3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
144 mg (0.75 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 146 mg (0.60 mmol) of 5-(3-amino-1H-indazol-5-yl)furan-2-carboxylic acid and 73.9 mg (0.60 mmol) of 3-hydroxybenzylamine in 1 ml of DMF, and the mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture, which is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated, and the residue is purified by preparative HPLC, giving N-3-hydroxybenzyl-5-(3-amino-1H-indazol-5-yl)furan-2-carboxamide (“62”) as yellowish solid, ESI 349.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][CH:19]([CH2:24][CH3:25])[CH2:20][C:21](O)=[O:22].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[CH2:20][CH:19]([CH3:18])[CH2:24][CH3:25])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCC(C)CC(=O)O
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CCC(C)CC(=O)Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40 mg, 1.1 eq, 0.18 mmol) was added to a solution 3-methylpentanoic acid (20 μl, 1.0 eq, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 1.1 eq, 0.18 mmol), 1-hydroxybenzotriazole (22 mg, 1.0 eq, 0.17 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 48 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was purified by mass directed preparative HPLC to yield the title compound as a white solid (31 mg, 0.10 mmol, 61%). LCMS: [M+H]+=325, Rt=1.64 min, 100% purity.