Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1.C(N(CC)CC)C>C(#N)C.C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=3)=[O:25])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reactant: NCc1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc(C(=O)NCc2ccccn2)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 200 mg (0.371 mmol) of N-(4-isopropylbenzenesulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide (from Step D) in 2 mL of acetonitrile and 1 mL of dry THF was added 72.2 mg (0.445 mmol) of 1,1'-carbonyldiimidazole. The solution was stirred under N2 at 60° C. for 2 hours. Then 45.9 μL (48.1 mg; 0.445 mmol) of 2-(aminomethyl)pyridine was added, followed by 129 μL (93.7 mg; 0.928 mmol) of triethylamine. The solution was stirred overnight at 60° C. The cooled reaction mixture was quenched by addition of 5% citric acid solution (aqueous) and extracted twice with EtOAc. The combined organic extracts were washed twice with H2O, then with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was flash chromatographed (gradient elution with 1-6% MeOH in CH2Cl2) to give 191 mg (82%) of the title compound as a cream-colored solid, mp 168°-170° C.; homogeneous by TLC in 95:5 CH2Cl2 -MeOH. ESI mass spectrum m/e 630 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.CN(C)C.[CH3:24][C:25]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:26][CH2:27][CH2:28][CH2:29][OH:30].CN(C)CCCN>C(Cl)Cl.C(OCC)(=O)C>[CH3:24][C:25]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:26][CH2:27][CH2:28][CH2:29][O:30][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=CCCCO)CCCC(C)CCCC(C)C
Agent: CN(C)C
Agent: CN(C)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.82 mL (5.9 mmol) of triethylamine, 0.90 g (4.7 mmol) of p-toluenesulfonyl chloride and 38 mg (0.39 mmol) of trimethylamine hydrochloride were added to a solution of 1.0 g (3.9 mmol) of 5,9,13-trimethyltetradec-4-en-1-ol in dry methylene chloride (3 mL) at 0° C., sequentially. After being stirred for 1 hour at room temperature, 0.12 mL (1.0 mmol) of N,N-dimethyl-1,3-propanediamine was added to the reaction mixture. After being stirred for 30 min, the mixture was diluted with ethyl acetate. The solution was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain (5,9,13-trimethyltetradec-4-enyl)tosylate as a crude product.
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.CS(C)=O.[H-].[Na+].[Cl:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1>C1C=CC=CC=1>[ClH:32].[ClH:32].[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[N:2]([CH3:1])[CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)=[CH:35][CH:36]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CN(c1nc2ccccc2[nH]1)C1CCN(CCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CN(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCN(CCc2ccccc2)CC1
Product: Cl
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a stirred and cooled (below 5° C.) mixture of 3.3 parts of N-methyl-N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine, 100 parts of dimethylsulfoxide and 90 parts of benzene are added 0.5 parts of sodium hydride dispersion 50%. After stirring for 30 minutes, 1.5 parts of 1-(chloromethyl)-4-fluorobenzene are added and stirring is continued overnight while the mixture is allowed to reach room temperature. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from 2-propanol, yielding 2.8 parts (54.4%) of 1-[(4-fluorophenyl)methyl]-N-methyl-N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine dihydrochloride; mp. 246.6° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:19][CH3:20])[C:5]([Cl:18])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:21]([Li])CCC.[CH2:26]([OH:37])[C@H:27]1[O:33][C:31](=[O:32])[C@H:30]([OH:34])[C@@H:29]([OH:35])[C@@H:28]1[OH:36].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1.O>[Cl:18][C:5]1[C:4]([O:19][CH3:20])=[CH:3][C:2]([C:31]2([O:32][CH3:21])[C@H:30]([OH:34])[C@@H:29]([OH:35])[C@H:28]([OH:36])[C@@H:27]([CH2:26][OH:37])[O:33]2)=[CH:7][C:6]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1
Reactant: [Li]CCCC
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCOc1ccc(Cc2cc(Br)cc(OC)c2Cl)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc(C3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2Cl)cc1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
To a solution of bromide 74 (5.74 g, 16.14 mmol) in toluene/THF (72 mL/36 mL) at −78° C. under an atmosphere of nitrogen was added dropwise n-butyllithium (2.5 M in hexane, 7.8 mL, 19.36 mmol), and the mixture was stirred for 40 min at the same temperature. Then a solution of TMS-protected gluconolactone 74-1 (9.04 g, 19.36 mmol) in toluene (30 mL) was added dropwise, and the mixture was stirred for 1 hour at the same temperature. To a solution of crude alcohol 74-2 were added CH3SO3H (0.6 N in MeOH, 53.8 mL, 32.28 mmol) at −78° C. The mixture was allowed to slowly warm to −40° C. To a mixture was added aq. saturated NaHCO3 solution (50 mL) to quench the reaction. After dilution with water, the mixture was stirred at room temperature for 30 min and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The (3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)-5-methoxyphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 74-3 (6.6 g) was carried on to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:35])=[C:14]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][C:26]([OH:31])=[CH:27][CH:28]=6)[NH:23][C:22]=5[C:21]([C:32]([NH2:34])=[O:33])=[N:20][CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:36](=[O:39])([O-])[O-].[Cs+].[Cs+].[C:42](OCC)(=O)[CH3:43]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:35])=[C:14]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][C:26]([O:31][CH2:42][CH2:43][CH2:36][OH:39])=[CH:27][CH:28]=6)[NH:23][C:22]=5[C:21]([C:32]([NH2:34])=[O:33])=[N:20][CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(O)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCCCO)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Temperature: 75 °C
Yield: 16.6 %

Procedure:
A mixture of 4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-hydroxy-9H-pyrido[3,4-b]indole-1-carboxamide (32 mg, 0.066 mmol) and cesium carbonate (25.9 mg, 0.080 mmol) in DMF (3 mL) was heated at 75° C. for 4 hr. The mixture was diluted with ethyl acetate (60 mL), washed with water (2×20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum and the residue was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (6.2 mg, 0.011 mmol, 16.6% yield) as a yellow solid. LCMS (M+H)+=541.28. 1H NMR (500 MHz, DMSO-d6) δ: 11.70 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.87 (s, 1H), 7.80-7.78 (m, 3H), 7.72 (m, 1H), 7.59 (m, 1H), 7.50 (m, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 6.74 (dd, J1=8.9 Hz, J2=2.4 Hz, 1H), 5.09 (d, J=17.5 Hz, 1H), 5.00 (d, J=17.5 Hz, 1H), 4.17 (m, 2H), 3.65 (m, 2H), 1.97 (m, 2H), 1.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=[C:12]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:20]=[CH:21][C:11]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:53][O:54][CH2:55][C@@H:56]([OH:58])[CH3:57].CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:58][C@@H:56]([CH3:57])[CH2:55][O:54][NH:53][C:16]([C:15]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[CH:21]=[N:20][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:12]2=[N:13][CH:14]=1)=[O:18]
Reactant: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)cnc32)cc1
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)NOC[C@H](C)O)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (728 mg, 1.4 mmol), HOBt (228 mg, 1.7 mmol) and EDCI (323 mg, 1.7 mmol) in DMF (15 mL) was added a solution of (S)-1-aminooxypropan-2-ol hydrochloride (200 mg, 1.5 mmol), and DIPEA (596 μL, 3.5 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 3 hours then diluted with water (30 mL) and the aqueous layer extracted with dichloromethane (3×20 mL). The combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a cream solid (500 mg, 60%). LCMS (Method B): RT=3.23 min, [M+H]+=592.
Reaction SMILES: [C-:1]#[N:2].[K+].[NH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[O:10]1[C:14]2([CH2:19][CH2:18][CH:17]([CH:20]=O)[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1.C(OCC)(=O)C>C(O)C.O>[N:4]1([CH:20]([CH:17]2[CH2:16][CH2:15][C:14]3([O:10][CH2:11][CH2:12][O:13]3)[CH2:19][CH2:18]2)[C:1]#[N:2])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C1CCNCC1
Reactant: [C-]#N
Reactant: O=CC1CCC2(CC1)OCCO2
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(C1CCC2(CC1)OCCO2)N1CCCCC1
Reaction time: 72 h

Procedure:
KCN (0.17 mol) and piperidine (14.45 g, 0.17 mol) were added to a solution of 1,4-dioxa-spiro[4.5]decane-8-carboxaldehyde (0.141 mol) in a mixture of ethanol (141 ml) and water (70 ml), and stirring was carried out for 72 h at 25° C. After addition of ethyl acetate (700 ml), the organic phase was separated off and washed in succession with water (4×150 ml) and aqueous FeSO4 solution (4×150 ml). The organic phase was separated off and dried over Na2SO4 and then filtered off. The solvent was removed in vacuo, and the product was used in the next stage without being purified further.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[F:28])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]4[NH:37][N:36]=[N:35][N:25]=4)=[CH:22][C:21]=3[F:28])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1cc(-c2nnn[nH]2)ccc1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile (example 37.2) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as off-white solid. MS: m/e=521.3 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(C1CCN(C(OCC2C=CC=CC=2)=O)CC1)=O.Cl.[NH2:40][CH2:41][C:42]1[C:47]([Cl:48])=[N:46][CH:45]=[CH:44][N:43]=1>>[Cl:48][C:47]1[C:42]([CH2:41][NH:40][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[N:43][CH:44]=[CH:45][N:46]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCc1nccnc1Cl
Agent: Cl
Agent: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(NCc1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 83.4 %

Procedure:
Using the procedures described in example 16 step 16a 1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid (2.5 g) was transformed into 2.75 g of crude benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate and the latter compound was coupled with 2-aminomethyl-3-chloropyrazine hydrochloride (content 77%; 2.28 g) to give benzyl 4-((3-chloropyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (3.08 g) after purification by column chromatography (silica gel, dichloromethane/methanol gradient 100/0 to 90/10).
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=O)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[CH3:23][O:24][C:25]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:26]=1[NH2:27].C(N(CC)CC)C>O1CCCC1.ClCCl>[CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:19]([NH:27][C:26]2[C:28]([O:34][CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:25]=2[O:24][CH3:23])=[O:21])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc(CC(=O)O)on1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc(CC(=O)Nc2c(OC)cc(OC)cc2OC)on1
Reaction time: 2 h

Procedure:
To a stirred, room temperature solution of 3-dodecyl-5-isoxazole acetic acid (0.64 g, 0.0022 mol) in dry tetrahydrofuran (20 mL) under nitrogen was added in one portion, 1,1-carbonyldiimidazole (0.38 g, 0.0024 mol), and the mixture was stirred for 2 hours. To this solution was added 2,4,6-trimethoxyaniline hydrochloride (0.48 g, 0.0022 mol) and triethylamine (0.33 mL, 0.0024 mol) in THF (30 mL). The mixture was stirred for 2 days and allowed to cool. The solution was rotoevaporated and the residue dissolved in dichloromethane. The solid was filtered through silica gel (77 g, 70-230 mesh) using petroleum ether-acetone (4:1, 35×75 mL) and the filtrate rotoevaporated to an oil. The oil was dried in vacuo. The oil crystallized to give a pale yellow waxy solid; yield 0.96 g (96%); mp 107°-109° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.ClC(OCC)=O.C(N(C(C)C)CC)(C)C.C(Cl)Cl>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([C:18]3[CH:19]=[N:20][C:15]([N:12]4[CH2:11][CH2:10][N:9]([CH3:8])[CH2:14][CH2:13]4)=[CH:16][CH:17]=3)[S:22][C:23]=2[CH:29]=1)=[O:4]
Reactant: CN1CCN(c2ccc(-c3nc4ccc(N)cc4s3)cn2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(-c3nc4ccc(NC(=O)C(F)(F)F)cc4s3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazol-6-amine trifluoroacetate (0.12 g, 0.27 mmol), ethyl chloroformate (36 μL, 0.38 mmol) and diisopropylethylamine (0.238 mL, 1.44 mmol) in DCM/THF (1:1, 7 mL) was stirred at r.t. overnight. Additional DCM was added before washing the sol. with sat. sodium hydrogencarbonate and then brine. The sol. was then dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by prep. HPLC, to give intermediate 2,2,2-trifluoro-N-{2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazol-6-yl}acetamide (43 mg). MS m/z (M+H) 422, (M−H) 420. To this intermediate (43 mg) in THF (5 mL) was added lithium aluminium hydride (12 mg, 0.3 mmol). The r.m. was refluxed for 1.5 h then allowed to come to r.t. Two drops of sat. Na2SO4, followed by ethyl acetate was added and the mixture was stirred for a few minutes. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by prep. HPLC to yield the title compound (25 mg) as a pale yellow solid. 1H NMR (MeOH-D4) δ 8.59 (d, 1H) 7.97 (dd, 1H) 7.60 (d, 1H) 7.11 (d, 1H) 6.75-6.87 (m, 2H) 3.80 (q, 2H) 3.55-3.70 (m, 4H) 2.50-2.61 (m, 4H) 2.33 (s, 3H); MS m/z (M+H) 408, (M−H) 406.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([NH2:19])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.C([O-])(O)=O.[Na+].Cl[CH2:28][CH:29]=O.O>CCO>[F:21][C:2]([F:1])([F:20])[C:3]1[C:4]2[N:5]([CH:28]=[CH:29][N:19]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3nccn3c2)cc1
Yield: 69 %

Procedure:
To a mixture of 3-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine (12.77 g, 42 mmol) and NaHCO3 (5.96 g, 71 mmol) in EtOH (300 mL) was added chloracetaldehyde solution 55% in water (22 mL, 188 mmol), then refluxed overnight. The reaction mixture was concentrated and purified by column chromatography (CH2Cl2/Et2O 1:1) to give the product as a white crystalline solid (9.6 g, 69%). MS (ISP) 331.1 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[N:8]([CH2:21][CH2:22][CH3:23])[C:7]=2[CH:24]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[N:8]([CH2:21][CH2:22][CH3:23])[C:7]=2[CH:24]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCc1nc2ccc(CN)cc2n1CCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.1 %

Procedure:
An anhydrous methanol solution (4.0 ml) containing the compound (0.244 g) obtained in Example 46-6 and 2-imidazole carboxaldehyde (85.0 mg) was added with trimethyl orthoformate (0.242 ml). The whole was stirred at room temperature for 14 hours and then added with sodium borohydride (0.140 g). After the solution was stirred for 2 hours, the solvent was distilled off. The resultant was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous magnesium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (0.167 g) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:23]#[N:24].[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[N:17]1([CH2:16][CH2:15][N:14]2[C:8]3[C:9](=[CH:10][C:11]4[C:2]([NH:36][C:35]5[CH:34]=[CH:33][C:32]([O:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[CH:38][CH:37]=5)=[C:3]([C:23]#[N:24])[CH:4]=[N:5][C:6]=4[CH:7]=3)[N:12]=[CH:13]2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1cnc2cc3c(cc2c1Cl)ncn3CCN1CCOCC1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc(Oc2ccccc2)cc1)ncn3CCN1CCOCC1
Temperature: 132.5 °C
Yield: 69 %

Procedure:
Following the procedure of Example 7, a mixture of 82.2 mg (0.24 mmol) of 8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonitrile, 53.3 mg (0.29 mmol) of 4-phenoxyaniline and 33.5 mg (0.29 mmol) of pyridine hydrochloride in 3.5 mL of 2-ethoxyethanol is heated at 130-135° C. for 1 hour to yield 81.2 mg (69%) of the product as a yellow solid, mp>260° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(N(CC)CC)C.[CH:21]1([S:24]([Cl:27])(=[O:26])=[O:25])[CH2:23][CH2:22]1>C(Cl)Cl>[ClH:27].[CH:21]1([S:24]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)(=[O:26])=[O:25])[CH2:23][CH2:22]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Product: O=S(=O)(C1CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To N—BOC-piperazine (1.3 g) in dry DCM (10 ml) was added triethylamine (1.2 mL) and cyclopropanesulphonyl chloride (1.04 g) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with DCM, washed with water, dried (MgSO4) and reduced in vacuo. The residue was dissolved in methanol (10 mL) and 4M HCL in dioxane was added (20 mL). After stirring overnight the solvent was reduced in vacuo to yield 1-cyclopropanesulfonyl-piperazine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.C[Si]([C:13]#[N:14])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:13]([C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]=1)#[N:14]
Reactant: Cc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 42.1 %

Procedure:
4-Methylpyridine N-oxide (2.0 g, 18.3 mmol) was dissolved in nitroethane (25 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) and N,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 5 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, washed with diisopropyl ether and dried to give the titled compound (0.91 g, 42%).