Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[N:4]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[OH-].[K+].Cl.O>CO>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1
Reactant: COC(=O)c1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
To a suspension of methyl 3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridine-6-carboxylate (6.0 g, 12.04 mmol) in MeOH (60 mL), 1N KOH (42.1 mL, 42.1 mmol) was added. The reaction mixture was heated to 50° C. for 1 h. After cooling down to room temperature, 1N HCl was added to pH=4. The product 8a was collected by filtration and washed with H2O (5.3 g, 10.95 mmol, 91%). MS ESI calc'd. for C26H19BrN3O2 [M+H]+ 484, found 484.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[H][H]>CC(O)=O.[Pd]>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH2:4][NH:3][C:2]2=[O:1]
Reactant: [H][H]
Reactant: Oc1cccc2c(O)nccc12
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1NCCc2c(O)cccc21
Yield: 86.4 %

Procedure:
A mixture of 10.0 g (62.0 mmol) of 1,5-dihydroxyisoquinoline in 500 ml of HOAc and 2 g of 20% Pd-C was hydrogenated at room temperature until the required amount of hydrogen was absorbed. The solution was filtered and concentrated. The resulting solid was recrystallized from water (200 ml) to give 8.74 g (86%) of product; mp 195°-198°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.[CH:18](=[O:21])[CH2:19][CH3:20]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([CH:18]([CH2:19][CH3:20])[OH:21])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Reactant: CCC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 4 h

Procedure:
A solution of 7.0 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 50 ml of dry tetrahydrofuran is cooled to -30°, using a dry ice-carbon tetrachloride bath and to the mixture is added dropwise, 35 ml of 2.2M n-butyllithium in hexane while the temperature is maintained below -20°. Following the addition, the bath is replaced with an ice-water bath and the reaction is stirred for 4 hrs at a temperature of 0°-5°. To the mixture is added dropwise solution of 3 ml of freshly distilled proprionaldehyde in 5 ml of tetrahydrofuran. The bath is removed. The reaction mixture is stirred for 20 mins and poured onto cold 10% hydrochloric acid. The mixture is extracted 3 times with ethyl ether. The combined ether extracts are washed, dried and the solvent is removed to give a solid. Recrystallization from ethyl ether and hexane gives 5.9 g of 6,7-dichloro-5-hydroxy-α-ethylbenzo[b]thiophene-2-methanol, mp 145°-145.5°.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH3:17])[CH:6]=[N:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[O:38]1[CH2:37][CH2:36][N:35]([CH2:34][CH2:33][NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:2]3[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]4[C:8](=[O:16])[N:7]([CH3:17])[CH:6]=[N:5][C:4]=4[CH:3]=3)=[CH:27][C:28]=2[S:41]([CH3:44])(=[O:42])=[O:43])[CH2:40][CH2:39]1
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)c(S(C)(=O)=O)c2)OC1(C)C
Reactant: CC(C)Nc1nc(Cl)cc2ncn(C)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)Nc1nc(-c2ccc(NCCN3CCOCC3)c(S(C)(=O)=O)c2)cc2ncn(C)c(=O)c12
Temperature: 140 °C

Procedure:
7-Chloro-5-(isopropylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (60 mg, 0.24 mmol), crude 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(methylsulfonyl)-N-(2-morpholinoethyl)benzenamine (240 mg, ˜0.28 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol) and Na2CO3 (102 mg, 0.96 mol) in a mixed solvent of acetonitrile (4 mL) and H2O (4 mL) were added to a 20 mL microwave tube and sealed. The tube was then heated in a Microwave Reactor at 140° C. for 10 minutes. The solvent was removed and the crude product purified by silica column using 7% MeOH in DCM to give the final product as a pale solid. ESI-MS m/z 501.2 (MH+); 1H NMR (DMSO-d6) δ 8.71 (d, J=7.2 Hz, 1H), 8.46 (d, J=2.4 HZ, 1H), 8.40 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 7.04 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.77 (t, J=4.8 Hz, 1H), 3.59 (m, 4H), 3.42 (s, 3H), 3.33 (m, 4H), 3.20 (s, 3H), 2.62 (m, 2H), 2.44 (s, 3H), 1.29 (d, J=6.4 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:22][CH3:23])=[C:9]([CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)[N:10]=2)[N:7]=1.[CH2:24]([O:26]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:25].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:22]([C:8]1[N:6]2[N:7]=[C:2]([C:24](=[O:26])[CH3:25])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:23]
Reactant: CCc1c(Cn2ccnc2-c2nccs2)nc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1c(Cn2ccnc2-c2nccs2)nc2ccc(C(C)=O)nn12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-3-ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-imidazo[1,2-b]pyridazine (100 mg, 0.26 mmol), 1-ethoxyvinyltributylstannane (142 mg, 0.39 mmol) and PdCl2(Ph3P)2 (10 mg) in anhydrous toluene (5 mL) is heated at 110° C. in a sealed tube for 5 hours. On cooling, water (2 mL), and concentrated HCl (2 mL) are added and the mixture is stirred at room temperature for 2 hours. The mixture is neutralized with sodium carbonate solution and extracted with methylene chloride (3×15 mL). The combined organic layers are dried (Na2SO4) and the solvent removed. The residue is purified by PTLC (5% methanol in methylene chloride) to give 1-[3-ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)imidazo[1,2-b]pyridazin-6-yl]ethanone as a solid. 1H NMR (CDCl3): 7.95, d (1H); 7.86, d (1H0; 7.70, d (1H); 7.36, d (1H); 7.25, d (1H); 7.11, d (1H); 6.18, s (2H); 3.10, q (2H); 2.75, s (3H); 1.18, t (3H).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:32](Cl)(=[O:34])[CH3:33]>>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][C:32](=[O:34])[CH3:33])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 72 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide (100 mg, 0.25 mmol) was reacted with acetyl chloride to yield 82 mg (72%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[C:31]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[C:34]([C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:33][CH:32]=[C:31]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(C(C)(C)C)ccc(C(C)(C)C)c5s4)cc3CC[C@@H]12
Yield: 17.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4,7-di(t-butyl)benzothiazole (130 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 33 mg (17%) of the title compound as an amorphous foam. FDMS: m/e=506.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7]#[C:8][CH:9]=[O:10])=[CH:3][CH:2]=1.[CH2:12]([Mg]Br)[CH:13]=[CH2:14]>C1COCC1>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([C:7]#[C:8][CH:9]([OH:10])[CH2:14][CH:13]=[CH2:12])=[CH:5][CH:6]=1
Reactant: C=CC[Mg]Br
Reactant: Cc1ccc(C#CC=O)cc1
Solvent: C1CCOC1
Product: C=CCC(O)C#Cc1ccc(C)cc1
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 3-p-tolylprop-2-yn-1-al (4.69 g; 32.5 mmol; 1 eq) in THF (40 mL) was added to a solution of allylmagnesium bromide (49 mL; 1M in Et20, 1.5 eq) at 0° C. over 25 minutes. Stirring was continued for an additional 2 h, and the reaction was carefully quenched with water (50 mL) at 0° C. MTBE (100 mL) was added, the layers were stirred, and then allowed to separate. The aqueous phase was re-extracted with MTBE (50 mL) and the combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated using a rotary evaporator, and purification of the residue by flash chromatography (4:1→2:1 heptane/EtOAc) afforded the desired homoallylic alcohol (4.9 g; 26.3 mmol; 81%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.34 ((s, 3 H)) 2.56 (t, 2 H) 4.64 (t, 1H) 5.19-5.26 (m, 2H) 5.88-5.99 (m, 1H) 7.10 (d, 2H) 7.31 (d, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.[CH2:24](C1(C(OCC)=O)CCC(O)CC1)[CH:25]=C>>[CH2:21]([O:20][C:18]([C:15]1([CH2:23][CH:24]=[CH2:25])[CH2:16][CH2:17][CH:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C1(C)CCC(N2C(=O)c3ccccc3C2=O)CC1
Reactant: C=CCC1(C(=O)OCC)CCC(O)CC1
Product: C=CCC1(C(=O)OCC)CCC(N2C(=O)c3ccccc3C2=O)CC1

Procedure:
The title compound was prepared by a method analogous to the method used to prepare Intermediate 72 using ethyl 1-allyl-4-hydroxycyclohexanecarboxylate (Intermediate 99) as the starting material.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]1([O:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[CH2:27][CH2:26][CH2:25]1>>[CH:27]1([CH2:24][O:28][C:29]2[CH:34]=[C:33]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:32]=[N:31][CH:30]=2)[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2cncc(OC3CCC3)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OCC5CC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-cyclobutoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 60.1.1) to give the title compound as a white solid. (HPLC: tR 2.39 min (Method A); M+H=441 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99-8.98 (m, 1H), 8.32-8.27 (m, 2H), 8.15 (s, 1H), 8.13-8.09 (m, 1H), 8.02-7.97 (m, 1H), 7.59-7.57 (m, 1H), 7.37-7.35 (m, 1H), 4.02-3.92 (m, 2H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H), 1.32-1.23 (m, 1H), 0.65-0.59 (m, 2H), 0.41-0.36 (m, 2H))
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Br)[CH:18]=1>>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:10][C:9]2[C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Br:1])[CH:18]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCOc1cc(C=O)cc(Br)c1O
Product: CCOc1cc(C=O)cc(Br)c1OCc1cccc(C(=O)OC)c1

Procedure:
Alkylation of 3-bromo-5-ethoxy-4-hydroxy benzaldehyde (2 g) with 3-bromomethyl-benzoic acid methyl ester (2.06 g) was performed according to the method described in example 1a. The residue was chromatographed on silica gel in heptane/ethyl acetate=7/3 (v/v) as eluent. Yield: 2.42 g. MS-ESI: [M+H]+=393/395
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([SH:26])=[N:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-])=O)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].Cl>C(O)C>[NH2:17][C:10]1[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:8][C:7]([SH:26])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(S)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(S)nc(-c2ccccc2)c(N)c1C(=O)OCC
Temperature: 60 °C
Yield: 76.1 %

Procedure:
A mixture of 0.30 g of 3,4-diethoxycarbonyl-2-mercapto-5-nitro-6-phenylpyridine, 0.41 g of reduced iron and 7 ml of ethanol was heated to 60° C., followed by addition of 1.7 ml of conc. hydrochloric acid. The mixture was heated under reflux for 30 minutes. After the reaction mixture was concentrated, the concentrate was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The concentrate was subjected to silica gel column chromatography with chloroform as the eluent, to give 0.21 g of the title compound as a yellowish orange viscous oily substance.
Reaction SMILES: [Br-:1].[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.[Cl:34][C:35]1[CH:36]=[C:37]([C:42]2([C:46](=[O:54])[CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:45][CH2:44][CH2:43]2)[CH:38]=[CH:39][C:40]=1[Cl:41]>O1CCCC1>[Br:1][CH:47]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:46]([C:42]1([C:37]2[CH:38]=[CH:39][C:40]([Cl:41])=[C:35]([Cl:34])[CH:36]=2)[CH2:45][CH2:44][CH2:43]1)=[O:54]
Reactant: O=C(Cc1ccccc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(C(Br)c1ccccc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 153.9 %

Procedure:
Phenyltrimethylammonium tribromide (4.02 g) was added in portions at −10° C. to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenylethanone (3.41 g) in tetrahydrofuran (100 ml). The mixture was stirred at ambient temperature for 4 hours, then it was filtered, and the solvent removed in vacuo. The residue was purified via flash chromatography over silica using a 3:97 mixture of ethyl acetate and petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined, and the solvents removed in vacuo to give 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenylethanone as a colourless oil (3.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].ClS([N:14]=[C:15]=O)(=O)=O.CN(C)C=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:15]#[N:14])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)c[nH]1
Temperature: -20 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
4-Cyano-1H-pyrrole-2-carboxylic acid methyl ester was prepared as described in Can. J. Chem., 59, 2673-76 (1981). 1H-Pyrrole-2-carboxylic acid methyl ester (2.00 g, 16.00 mmol) was dissolved in acetonitrile (5 mL) and the solution was cooled to −20° C. Chlorosulfonylisocyanate (3.40 g, 24.00 mmol) was dissolved in acetonitrile (5 mL) and added dropwise via syringe over a period of 5 min to the above solution. The solution was allowed to warm to 25° C. and was stirred for 20 h. The solution was cooled back to 0° C., N,N-dimethylformamide (2 mL) was added and the solution was heated to 50° C. for 15 min. The reaction mixture was poured into ice and was extracted with chloroform, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 40% ethyl acetate in hexanes) afforded the desired product, 4-cyano-1H-pyrrole-2-carboxylic acid methyl ester (1.09 g, 7.265 mmol, 45.4% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 3.91 (3H, s), 7.12 (1H, t, J=2.0 Hz), 7.40-7.41 (1H, m), 9.60 (1H, bs). FT-IR (ATR) νmax (neat): 2228, 1691 cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][S:25]([CH2:28][C:29](O)=[O:30])(=[O:27])=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:24][S:25]([CH2:28][C:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1)=[O:30])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 62.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), (methylsulfonyl)acetic acid (67 mg, 0.485 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99 mg, 0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol), triethylamine (0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL), and by a reaction in the same manner as in Example 187, the title compound (87 mg, 63%) was obtained as pale-yellow crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:18][N:17]=1.Cl>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:18][N:17]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nnc(N)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Yield: 73 %

Procedure:
To a solution of p-acetamidobenzenesulfonyl chloride (1.98 g, 8.47 mmol) in pyridine (20 mL) was added ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (1.2 g, 7.06 mmol). The reaction mixture was stirred at room temperature for 4.5 h, than 2 M HCl (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×60 mL). The organic extracts were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 201-202° C., in 73% yield (1.91 g, 5.15 mmol); 1H NMR (300 MHz, DMSO-d6) δ 1.29 (t, 3H, J=6.9 Hz), 2.08 (s, 3H), 4.37 (q, 2H, J=7.8 Hz), 7.74 (m, 4H), 10.32 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 13.9, 14.0, 24.1, 62.9, 118.6, 127.1, 134.9, 143.2, 147.2, 157.5, 167.6, 169.0; MS (LCQ, ESI+) Calcd for C13H15N4O5S2 371.0. found 371.0 (M+H)+. HRMS (ESI+, m/z) Calcd for C13H15N4O5S2 371.0484. found 371.0472 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNC1
Yield: 99.9 %

Procedure:
(1-Benzyl-3-phenylpyrrolidin-3-yl)carbamic acid tert-butyl ester (Hagen S. E., Domagala J. M., Heifetz C. L., Sanchez J. P., Solomon M., J. Med. Chem., 1990; 33(2):849-854) (2.79 g, 7.9 mmol) in 100 mL of methanol is treated with 1.0 g of 20% Pd/C and shaken for 17 hours under 50 psi of hydrogen. The solution is filtered and concentrated to afford 2.07 g of the title compound as a foam; MS EI+: m/z 263 (MH+).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH2:27])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH:27][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([OH:1])[N:7]=3)=[O:10])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: O=C(O)c1cccc(O)n1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1cccc(O)n1
Yield: 21.8 %

Procedure:
Using the general method of Example 97 6-hydroxypicolinic acid (0.24 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.15 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-hydroxy-2-pyridinecarboxamide as a white powder, m.p. 258-260° C. Analysis: Calculated for C21H23N7O2+1/2 CH3CN: %C, 62.03; %H, 5.80; %N, 24.66; Found: %C, 61.87; %H, 5.70; %N, 24.60.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]4[NH:34][C:33]5[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=5[N:31]=4)[CH:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C>C(O)(C)C>[NH:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[C:25]1[CH:24]=[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[O:15])[CH2:17][CH2:18]2)[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)CC2)C1
Solvent: CC(C)O
Solvent: CC(=O)Cl
Product: O=C(C1CCCNC1)N1CCCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Temperature: 40 °C
Yield: 111.2 %

Procedure:
3-{4-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-[1,4]diazepane-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester (0.21 g, 0.39 mmol) was dissolved in isopropanol (4 mL) and acetyl chloride (0.17 mL, 2.4 mmol) was added. Reaction was heated at 40° C. for 16 h then cooled to room temperature and concentrated under reduced pressure and dried at 60° C. to afford 0.19 g of the title compound as dichlorhydrate salt. (94%).