Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][C:17]([C:27]#[N:28])([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:37]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][C:17]([C:27](=[O:37])[NH2:28])([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: N#CC1(Nc2ccccc2)CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)C1(Nc2ccccc2)CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To 16.5 g of 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-cyano-4-anilinopiperidine is added gradually a solution of 180 g of concentrated sulfuric acid and 20 ml of water under cooling. After the addition is complete, the resulting mixture is stirred at 70° C for 1 hour and then cooled. The reaction mixture is poured into water, and the precipitated powder is collected by filtration. Then water is added to the powder, the aqueous mixture is made alkaline with potassium carbonate, and the alkaline solution is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The precipitated crystals are collected by filration and recrystallized from a mixture of chloroform and acetone to give 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-carbamoyl-4-anilinopiperidine as white crystals, melting at 224°-227° C.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]1[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.C(Cl)Cl>O>[CH2:18]([CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][C:11]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:33]2[CH:32]=[CH:31][S:30][C:29]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH3:19]
Reactant: CCCCCCCCC(O)(CC(CC)CCCC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCC1(CC(CC)CCCC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (0.37 mL) was added dropwise to 7-([2,2′-bithiophen]-3-yl)-5-ethylpentadecan-7-ol (IId) (0.25 g, 0.60 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Id) (0.040 g, 17%). 1H-NMR (CDCl3): δ=7.12 (d, J=4.8 Hz, 2H), 6.93 (d, J=4.8 Hz, 2H), 1.90 (t, 2H), 1.82 (m, 2H), 1.28-1.12 (m, 5H), 1.00-0.74 (m, 16H), 0.62 (t, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C@@H:9]([OH:23])[CH2:10][C:11]1[C:16]([C:17](=[O:22])[NH:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=[CH:13][N:12]=1)(C)(C)C>CCCCC>[NH2:7][C@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C@@H:9]([OH:23])[CH2:10][C:11]1[N:12]=[CH:13][CH:14]=[CH:15][C:16]=1[C:17]([NH:18][CH:19]([CH3:20])[CH3:21])=[O:22]
Reactant: CC(C)NC(=O)c1cccnc1C[C@H](O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Solvent: CCCCC
Product: CC(C)NC(=O)c1cccnc1C[C@H](O)[C@H](N)Cc1ccccc1F

Procedure:
Using general deprotection procedure 5 with [(1R,2S)-1-(2-Fluoro-benzyl)-2-hydroxy-3-(3-isopropylcarbamoyl-pyridin-2-yl)-propyl]-carbamic acid tert-butyl ester (0.16 g, 0.34 mmol) followed by trituration with pentane gives the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])=[CH2:5].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl>CN(C)C=O>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([C:4]([CH3:3])=[CH2:5])[C:7]1=[O:15]
Reactant: ClCCCCCCl
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCCCCl)c2ccccc21
Reaction time: 2 h

Procedure:
To a stirred suspension of 3.2 parts of a sodium hydride dispersion 70% in 9 parts of N,N-dimethylformamide is added dropwise, during a 2 hours-period, a mixture of 17.4 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, 70.5 parts of 1,5-dichloropentane and 45 parts of N,N-dimethylformamide at 25°-30° C. Upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is filtered over hyflo and the filtrate is evaporated. The residue is taken up in 90 parts of methylbenzene and the whole is stirred with activated charcoal. The latter is filtered off. The filtrate is washed with water, dried, filtered and evaporated in an oil-bath at 120° C. (water-jet), yielding 1-(5-chloropentyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH2:13][O:12][C:11]3[CH:16]=[C:17]([S:20]([N:23](CC4C=CC(OC)=CC=4)[C:24]4[S:25][CH:26]=[CH:27][N:28]=4)(=[O:22])=[O:21])[CH:18]=[CH:19][C:10]2=3)=[C:5]([O:38][CH3:39])[CH:4]=1)#[N:2].[Al].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH2:13][O:12][C:11]3[CH:16]=[C:17]([S:20]([NH:23][C:24]4[S:25][CH:26]=[CH:27][N:28]=4)(=[O:21])=[O:22])[CH:18]=[CH:19][C:10]2=3)=[C:5]([O:38][CH3:39])[CH:4]=1)#[N:2]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(=O)N3c2ccc(C#N)cc2OC)cc1
Agent: [Al]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C#N)ccc1N1C(=O)COc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Yield: 22 %

Procedure:
Dissolved 4-(4-cyano-2-methoxyphenyl)-N-(4-methoxybenzyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (133 mg, 0.236 mmol) in 500 μl of DCM in a 10 mL rbf (wrapped with aluminum foil to exclude light) and added trifloroacetic acid (500 μl, 5.91 mmol). The solution was maintained at rt for 30 min until reaction was complete by LCMS. The reaction mixture was concentrated via rotary evaporation then purified using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 μm column with a gradient 5-95% acetonitrile and water with 0.1% NHOH to give 4-(4-cyano-2-methoxyphenyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (23 mg, 0.052 mmol, 22% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.78 (s, 3 H) 4.89 (s, 2 H) 6.39 (d, J=8.48 Hz, 1 H) 6.80 (d, J=4.47 Hz, 1 H) 7.23 (d, J=4.47 Hz, 1 H) 7.28-7.35 (m, 1 H) 7.35-7.49 (m, 1 H) 7.53-7.66 (m, 2 H) 7.80 (s, 1 H). m/z ESI 441.0 (M−H)−.
Reaction SMILES: [CH:1](=[C:8]([CH2:12][C:13](=[O:26])[NH:14][CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.Cl.Cl.[CH3:47][O:48][C:49](=[O:58])[C@H:50]([CH2:52][C:53]1[N:57]=[CH:56][NH:55][CH:54]=1)[NH2:51].CN1CCOCC1>C(#N)C.CN(C)C=O.N1C=CC=CC=1>[CH3:47][O:48][C:49](=[O:58])[C@H:50]([CH2:52][C:53]1[N:57]=[CH:56][NH:55][CH:54]=1)[NH:51][C:9](=[O:10])[C:8](=[CH:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][C:13](=[O:26])[NH:14][CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(CC(=Cc1ccccc1)C(=O)O)NCc1cccc2ccccc12
Agent: Cl
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(=Cc1ccccc1)CC(=O)NCc1cccc2ccccc12
Temperature: 40 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A solution of 330 mg of 2-benzylidene-3-(1-naphthylmethylcarbamoyl)propionic acid, 260 mg of N,N'-disuccinimidylcarbonate and 1 ml of pyridine in 20 ml of dry acetonitrile was stirred for 3 hour at room temperature. The solution was added to a solution of 300 mg of L-histidine methyl ester dihydrochloride and 150 mg of N-methylmorpholine in 20 ml of dry N,N-dimethylformamide, and the mixture was stirred for 16 hours at 40° C. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The precipitates were collected by filtration to obtain 350 mg of N-[2-benzylidene-3-(1-naphthylmethylcarbamoyl)propionyl]-L-histidine methyl ester as a white powder.
Reaction SMILES: C(C1C2CCC(OC3C=C(N)C=CC=3)=CC=2NN=1)=CC1C=CC=CC=1.CC1SC(C([N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:43][C:44]4[CH:45]=[C:46]([NH:50][C:51]([C:53]5[S:54][C:55]([CH3:58])=[CH:56][N:57]=5)=[O:52])[CH:47]=[CH:48][CH:49]=4)[CH:41]=3)[C:36]([CH:59]=[CH:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[N:35]2)=O)=NC=1.CC1SC(C(O)=O)=NC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CN(C=O)C>[CH:59]([C:36]1[C:37]2[C:42](=[CH:41][C:40]([O:43][C:44]3[CH:45]=[C:46]([NH:50][C:51]([C:53]4[S:54][C:55]([CH3:58])=[CH:56][N:57]=4)=[O:52])[CH:47]=[CH:48][CH:49]=3)=[CH:39][CH:38]=2)[NH:34][N:35]=1)=[CH:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: Cc1cnc(C(=O)Nc2cccc(Oc3ccc4c(C=Cc5ccccc5)nn(C(=O)c5ncc(C)s5)c4c3)c2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1cnc(C(=O)O)s1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cnc(C(=O)Nc2cccc(Oc3ccc4c(C=Cc5ccccc5)n[nH]c4c3)c2)s1

Procedure:
3-(3-Styryl-4,5-dihydro-1H-indazol-6-yloxy)-phenylamine was converted to 5-methyl-thiazole-2-carboxylic acid{3-[1-(5-methyl-thiazole-2-carbonyl)-3-styryl-1H-indazol-6-yloxy]-phenyl}amide by treatment with 5-methyl-thiazole-2-carboxylic acid and HATU (o-(2-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate) in DMF and analogous work-up, DDQ treatment and isolation to Example 4(a), step (iv) (50% yield): 1H NMR(DMSO-d6) δ 10.85 (s, 1H), 8.45 (d, 1H, J=9.8 Hz), 8.24 (m, 3H), 7.99–7.62 (m, 6H), 7.54–7.34 (m, 5H), 6.96 (d, 1H, J=8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:19]=[CH:18][C:17]2[C@@H:16]([OH:20])[C@H:15]([NH:21][CH:22]([CH3:31])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13][C:12]=2[C:11]=1[C:32]([NH2:34])=[O:33])C1C=CC=CC=1>CO.[Pd]>[ClH:1].[OH:9][C:10]1[CH:19]=[CH:18][C:17]2[C@@H:16]([OH:20])[C@H:15]([NH:21][CH:22]([CH3:31])[CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:14][CH2:13][C:12]=2[C:11]=1[C:32]([NH2:34])=[O:33]
Reactant: CC(CCc1ccccc1)N[C@@H]1CCc2c(ccc(OCc3ccccc3)c2C(N)=O)[C@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(CCc1ccccc1)N[C@@H]1CCc2c(ccc(O)c2C(N)=O)[C@H]1O
Yield: 68.9 %

Procedure:
In 50 ml of methanol was dissolved 1 g of trans-2-benzyloxy-5-hydroxy-6-(1-methyl-3-phenylpropylamino)-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride and catalytic reduction was carried out in the presence of 1 g of 10% palladium-on-carbon at atmospheric temperature and pressure. After the absorption of hydrogen was completed, the catalyst was filtered off and the filtrate was distilled under reduced pressure. To the residue was added 50 ml of ethyl ether, whereby 0.56 g of trans-2,5-dihydroxy-6-(1-methyl-3-phenylpropylamino)-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride was obtained as colorless powder.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15].O>C1COCC1>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[Sn](C)(C)c1ccccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 7.5 ml of n-butyllithium (15% strength in hexane, 12 mmol) were added dropwise to a solution of 1.9 g (12.0 mmol) of 2-bromopyridine in 50 ml of absolute THF cooled to −78° C. After stirring at −78° C. for 1 h, 12 ml (12 mmol) of a 1 M solution of trimethyltin chloride in THF were added dropwise and the mixture was stirred at −78° C. for a further hour. The reaction solution was warmed to 0° C. and treated with water. The organic phase was separated off and the aqueous phase was extracted a number of times with diethyl ether. The combined organic phases were dried over sodium sulfate and concentrated. The residue was distilled in vacuo (0.3 bar) in a bulb tube. 1.9 g of the title compound resulted as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N:40]=[C:41]=[O:42])=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[OH:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C>ClCCl>[N:46]1([CH2:45][CH2:44][O:43][C:41](=[O:42])[NH:40][C:3]2[C:2]([F:1])=[CH:12][C:11]([C:13]3[CH:14]=[C:15]4[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]5[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=5)(=[O:32])=[O:31])[C:16]4=[N:17][CH:18]=3)=[CH:10][C:4]=2[C:5](=[O:6])[N:7]([CH3:9])[CH3:8])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N=C=O)c(C(=O)N(C)C)c3)cc12
Reactant: OCCN1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC(=O)OCCN4CCOCC4)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
75 mg (0.13 mmol) of 3-fluoro-2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 1.0 mL dichloromethane and combined with 31 μL (0.26 mmol) of 4-(2-hydroxyethyl)-morpholine (which was dried over molecular sieves) and 22 μL (0.13 mmol) of N,N-diisopropylethylamine. The reaction was stirred for 16 hours at room temperature. 31 μL (0.26 mmol) of 4-(2-hydroxyethyl)morpholine was added and the reaction was continued to stir for 24 hours at room temperature. The reaction was concentrated and purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes. The clean fractions were concentrated. MS: m/z 715.3 (M+H+).
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:24]=[C:23]([C:25](=[O:27])[CH3:26])[CH:22]=[CH:21][C:20]=1O.C[CH2:31][N:32](C(C)C)C(C)C.[O-]S(C(F)(F)F)(=O)=O.[NH4+].[OH-]>C(Cl)Cl.CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.O>[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:24]=[C:23]([C:25](=[O:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[C:31]#[N:32]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: CCN(C(C)C)C(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [C-]#N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C(C)=O)ccc1C#N
Temperature: -10 °C
Reaction time: 16 h

Procedure:
Triflic anhydride (10 g, 35.4 mmol) was added dropwise to a cold (−40° C.) solution of 5-acetyl-2-hydroxy-benzoic acid methyl ester (6.9 g, 35.4 mmol) and DIPEA (5.3 g, 42.5 mmol) in CH2Cl2 (100 mL). The reaction was warmed to −10° C. and stirred for 16 h. The reaction was warmed to rt, evaporated to dryness in vacuo, and re-dissolved in EtOAc. The organic layer was washed with ½ sat. brine, dried over MgSO4, filtered and evaporated in vacuo. A portion of the crude triflate (5.01 g, 15.3 mmol) was dissolved in DMF (40 mL). Palladium(0)tetrakis(triphenylphosphine) (1.3 g, 1.1 mmol) and zinc cyanide (2.16 g, 18.4 mmol) were added to the flask, and the mixture was heated to 90° C. for 2.5 h. The reaction was cooled to rt and stirred with a 1:1 solution of conc. NH4OH and water (160 mL). The resulting suspension was extracted with ETOAc. The combined organic extracts were washed with ½ sat. brine, dried over MgSO4, filtered and evaporated in vacuo. The title compound was isolated by SiO2 chromatography to yield 439 mg (14%) of a white solid. MS 221.1 (M+NH4)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:15])[N:31]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17](=[O:19])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCCc1ccccc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(CCc1ccccc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with phenethylamine (0.16 mL, 1.3 mmol). Purification using silica gel, eluting with 3:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 112 as a white solid (m.p. 235-240° C.).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[ClH:12]>>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Cl:12]
Reactant: Cl
Reactant: COc1cccc(CO)c1F
Product: COc1cccc(CCl)c1F
Temperature: 25 °C
Reaction time: 21 h
Yield: 76 %

Procedure:
2-Fluoro-3-methoxybenzyl alcohol from Step 2 (12.16 g, 78 mmol) was dissolved in concentrated hydrochloric acid (60 mL) and hydrochloric acid gas was bubbled through the solution for 3 minutes. The flask was capped and the reaction stirred at room temperature (21 hours). The reaction mixture was extracted with ether, dried over MgSO4 and concentrated in vacuo to give 2-fluoro-3-methoxybenzyl chloride (10.36 g, 76%) as a green oil: 1H NMR (acetone-d6) 300 MHz 7.12 (m, 2H) 7.05 (m, 1H) 4.73 (s, 2H) 3.89 (s, 3H); 19F NMR (acetone-d6) 300 MHz -142.07(m).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:29][CH2:30][CH2:31][C:32](ON2C(=O)CCC2=O)=[O:33])C=CC=CC=1.C(N(CC)CC)C.ClCCl>CO>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][C:32](=[O:33])[CH2:31][CH2:30][SH:29])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Reactant: Cc1nc2c(N)nc3ccccc3c2n1NCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)CCS

Procedure:
A mixture of N1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinoline-1,4-diamine hydrochloride (1.00 g, 3.26 mmol), succinimido 3-(triphenylmethylthio)propanoate (A. Bray et. al. Aust. J. Chem. 1990, 43, 629-634; 2.22 g, 4.89 mmol), triethylamine (0.45 mL, 3.26 mmol), dichloromethane (33 mL), and methanol (15 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform). The purified compound was treated with trifluoroacetic acid (3 mL) and triethylsilane (2 mL) in dichloromethane (30 mL) at room temperature overnight. More trifluoroacetic acid was added and after an additional day the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) to yield 327 mg of N-{3-[(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}-3-mercaptopropanamide. MS (ESI) m/z 359 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:20]3=[CH:21][N:22]([C:24]4[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[N:23]=[C:19]3[C:18]([Br:32])=[CH:17][N:16]=2)[N:11]=[CH:10][N:9]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:32][C:18]1[C:19]2[C:20](=[CH:21][N:22]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:23]=2)[C:15]([NH:14][C:12]2[CH:13]=[C:8]([NH2:7])[N:9]=[CH:10][N:11]=2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Nc2ncc(Br)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(Nc2ncc(Br)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Yield: 28.3 %

Procedure:
A solution of {6-[7-bromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-carbamic acid tert-butyl ester (95 mg, 0.18 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at room temperature for 3 hours. The solvent was removed and the residue partitioned between DCM and NaHCO3 (sat. aq.). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (70-90% ethyl acetate in cyclohexane), to afford the title compound as a white solid (23 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 9.29 (s, 1H), 8.15 (d, J=0.9 Hz, 1H), 8.04 (s, 1H), 7.84 (d, J=1.2 Hz, 1H), 7.82 (s, 1H), 7.73 (dd, J=7.1 and 9.0 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 6.74 (br s, 2H). LCMS (Method B): RT=3.25 min, m/z: 450 [M+H+].
Reaction SMILES: [C:1]([NH:4][C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15])=[S:6])(=[NH:3])[NH2:2].ClN1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)Cl>[NH2:3][C:1]1[N:4]=[C:5]([NH:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])[S:6][N:2]=1
Reactant: Cc1cccc(C)c1NC(=S)NC(=N)N
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cccc(C)c1Nc1nc(N)ns1

Procedure:
A solution of 7.0 g (0.03 mole) 1-amidino-3-(2,6-dimethylphenyl)-thiourea in 150 ml methylene chloride is stirred with 4.2 g (0.03 mole) N-chlorosuccinimide (95%) for 1 hour at 20° C., then for another hour after the addition of 15 ml conc. NaOH. After dilution with water, the methylene chloride phase is separated by filtration and, by column-chromatography with silica gel (MeOH/CHCl3 : 10/90), 4.8 g 3-amino-5-(2,6-dimethylphenylamino)-1,2,4-thiadiazole having a melting point of 180° C. is obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:20])[CH:3]=1.[CH2:21]([CH:23]([NH2:26])[CH2:24][CH3:25])[CH3:22]>CN1CCCC1=O>[CH2:21]([CH:23]([NH:26][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:20])[CH:3]=1)[CH2:24][CH3:25])[CH3:22]
Reactant: Cc1cc(C)c(-c2cnn3c(Cl)cc(C)nc23)c(C)c1
Reactant: CCC(N)CC
Solvent: CN1CCCC1=O
Product: CCC(CC)Nc1cc(C)nc2c(-c3c(C)cc(C)cc3C)cnn12
Temperature: 125 °C
Yield: 87 %

Procedure:
A mixture of 7-chloro-5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (190 mg, 0.63 mmol) and 1-ethylpropylamine (4 ml) in 1 ml of N-methylpyrrolidinone was heated at 125° C. oil bath for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated and purified through silica gel column chromatography using chloroform to 2% methanol in chloroform as eluent to give 195 mg (87%) of the title compound as a green solid. 1H NMR (CDCl3) ä 7.87(s, 1H), 6.97(s, 2H), 6.12(d, 1H), 5.85(s, 1H), 3.52(m, 1H), 2.48(s, 3H), 2.09(s, 3H), 2.16(s, 6H), 1.6-1.9(m, 4H), 1.05(t, 6H)ppm.