Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.C([N:12]1[C:17]([S:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([C:25]#[N:26])[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=2)=[N:14][CH:13]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C.CCO>C1(C)C=CC=CC=1>[NH2:26][C:25]1[C:16]2[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=3)=[N:14][C:13]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:12][C:17]=2[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CSC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)=NC(c2ccccc2)N1CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc([N+](=O)[O-])c3)c2c1N
Temperature: 0 °C
Reaction time: 48 h

Procedure:
DIPEA (20.0 ml) was added to a stirred solution of ethyl 5-cyano-4(3-nitrophenyl)-2-phenyl-6-(ethoxycarbonylmethylthio)-pyrimidine (example 31(c), 19.7 g) in a mixture of abs. EtOH (100 ml) and toluene p.a. (100 ml). After 48 h at 100° C., the mixture was cooled to 0° C. The resulting precipitate was filtered off, washed with cold EtOH and dried in vacuo at 40° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([NH2:16])[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].[C:27](OCC)(OCC)(OCC)C.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:7]1[N:6]=[C:5]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[N:16]=[CH:27][N:17]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOc2ccccc2)c1C
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc(Oc2ccccc2)c2ncn(CCOc3ccccc3)c2c1C

Procedure:
5,6-Dimethyl-2-phenoxy-N4-(2-phenoxyethyl)pyridine-3,4-diamine (2.41 g), triethyl orthoacetate (1.60 ml), toluene (20 ml), and a catalytic amount of pyridine HCl were combined and heated to reflux for 2 hours. HPLC and MS analysis indicated that the reaction was complete. The reaction mixture was allowed to cool and the resulting solid was filtered and dried. NMR analysis of the dried solid indicated a pure product.
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-])=O)[CH:10]=[C:6]([N+:7]([O-])=O)[CH:5]=1)[N+]([O-])=O.[CH3:17]O>>[CH3:17][N:12]1[CH2:5][CH2:1][CH2:15][C@H:11]1[CH2:10][C:6]#[N:7]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Reactant: CO
Product: CN1CCC[C@H]1CC#N

Procedure:
To a solution of 7.0 g (0.041 mol) of (S)-1-methyl-2-chloromethylpyrrolidine.HCl in 35 ml of 80% aq. ethanol at 0° was added in portions a solution of 3.81 g (0.045 mol) of sodium bicarbonate in 50 ml of water. The mixture was stirred at 0° for 15 min., followed by the addition of a solution of 2.52 g (0.052 mol) of sodium cyanide in 65 ml of 80% aq. ethanol. This mixture was refluxed for 30 min. The resultant solution was cooled, evaporated to a small volume, and extracted with ether (2×25 ml). The combined ethereal layer was dried wtih magnesium sulfate and evaporated to a clear, brown oil. Bulb-to-bulb distillation [oven temp 40°-55° (0.25 torr)] yielded 2.62 g (51%) of the product, a clear, colorless, mobile oil: [α]D20 =-32.5°, c=2.57, methanol; picrate, mp 175° -178°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]1.C(O)C>O1CCCC1.[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Yield: 99.5 %

Procedure:
Ethyl [1-(3,4-dichlorobenzyl)piperidin-4-ylidene]acetate (3.9 g, 11.9 mmol) dissolved in tetrahydrofuran (25 ml) and ethanol (25 ml) was subjected to hydrogenation over platinum oxide (0.1 g) at ambient temperature and atmospheric pressure. The reaction mixture was filtered through a celite pad and concentrated in vacuo to give ethyl [1-(3,4-dichlorobenzyl)piperidin-4-yl]acetate (3.91 g) as a semi-solid.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.C=O.C(N(CC)CC)C.[Cl-].[Li+]>O1CCCC1.C1(C)C=CC=CC=1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 mL of anhydrous tetrahydrofuran, add paraformaldehyde (80 mg, 2.6 mmol), triethyl amine (288 mg, 2.8 mmol) and anhydrous Lithium chloride (186 mg, 4.4 mmol), reflux overnight under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 20 mL of toluene, wash with 5% HCl(aq), saturated Na2CO3 and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OC[C@@H](C)CC)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC[C@H](C)COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 51.5 %

Procedure:
To a solution (10 ml) of ethyl 1-(3-cyano-4-((S)-2-methylbutoxy)phenyl)-pyrazole-4-carboxylate (1.7 g) in ethanol was added 1 N aqueous sodium hydroxide solution (6.3 ml) with stirring, and the mixture was heated at 80° C. for 30 minutes. After the completion of the reaction, the reaction mixture was pouted into water and neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solvent of ethyl alcohol and water to give 0.8 g of 1-(3-cyano-4-((S)-2-methylbutoxy) phenyl)pyrazole-4-carboxylic acid, melting point 184-186° C. [α] D25 +10.49° (c=0.5,MeOH)
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([Br:19])[CH:13]=1>C(N(CC)CC)C>[Br:19][C:14]1[CH:15]=[CH:16][C:17]([O:18][C:2]2[N:6]([CH3:7])[C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[CH:12][CH:13]=1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: Oc1ccc(Br)cc1
Solvent: CCN(CC)CC
Product: Cn1c(Oc2ccc(Br)cc2)nc2ccccc21
Temperature: 120 °C
Reaction time: 6 h
Yield: 24.4 %

Procedure:
Triethylamine (18 mL) was added to a mixture of 2-chloro-1-methyl-1H-benzimidazole (7.2 g) and p-bromophenol (22.5 g) at room temperature. The mixture was stirred at 120° C. for 6 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with 1 N NaOH aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 10%-15% EtOAc in hexane) to give 2-(4-bromophenoxy)-1-methyl-1H-benzimidazole (3.2 g) as colorless crystals.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>N1C=CC=CC=1>[S:7]([N:15]1[CH2:16][CH2:17][CH:13]([O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14]1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OC1CCNC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Para-toluenesulphonyl chloride (68.8 g) was added, in portions, to a solution of 3-(R,S)-hydroxypyrrolidine (15 g) in dry pyridine (200 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. The solution was concentrated in vacuo to approximately half the original volume then partitioned between dichloromethane (500 ml) and water (300 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were washed with 2M hydrochloric acid (100 ml) and 10% aqueous sodium hydroxide (100 ml) then dried (MgSO4) and concentrated in vacuo to give an oil which was crystallised from dichloromethane/ether to give the title compound as a microcrystalline powder, yield 28.3 g, m.p. 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C@@H:12]([OH:25])[CH2:13][O:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:26][N:27]([CH2:39][CH2:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=2)[CH2:43][CH2:42]1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C@@H:12]([OH:25])[CH2:13][O:14][C:50]2[CH:49]=[CH:48][C:47]([N:44]3[CH2:45][CH2:46][CH:41]([CH2:40][CH2:39][N:27]([CH3:26])[C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=4)[CH2:42][CH2:43]3)=[CH:52][CH:51]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CCn2cc([N+](=O)[O-])nc2Cl)cc1
Reactant: CN(CCC1CCN(c2ccc(O)cc2)CC1)c1ccc(OC(F)(F)F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(CCC1CCN(c2ccc(OC[C@H](O)CCn3cc([N+](=O)[O-])nc3Cl)cc2)CC1)c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 75.4 %

Procedure:
Toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (988 mg) and 4-(4-{2-[N-methyl-N-(4-trifluoromethoxyphenyl)amino]ethyl}piperidin-1-yl)phenol (1.0 g) were suspended in ethanol (30 ml). Tripotassium phosphate (1.08 g) and sodium iodide (418 mg) were added to the suspension, and the mixture was stirred at 80° C. under a nitrogen atmosphere for 4.5 hours. After being cooled to room temperature, ethyl acetate (20 ml) was added to the reaction mixture, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→methylene chloride:methanol=97:3) to afford the title compound as a reddish brown oil (1.17 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:21]1(=[O:23])=[O:22].C(N(CC)CC)C>CN(C)C=O>[O:22]=[S:21]1(=[O:23])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30](=[O:31])[N:20]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1
Reactant: COc1cccc2c1OC(CN)CC2
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1OC(CNCCCCN1C(=O)c3ccccc3S1(=O)=O)CC2
Yield: 21.5 %

Procedure:
5.3 g (0.027 mol) 2-aminomethyl-8-methoxychroman from example 93g, 9.5 g (0.03 mol) N-(4-bromobutyl)saccharin, 3.05 g (0.03 mol) triethylamine and 80 ml dimethylformamide were heated to 50° C. for 4h. Work-up as described in example 93h furnished 16.6 g crude product, which was filtered through 175 g silica with toluene/ethyl acetate. This gave 3.4 g dialkylation product and 7.1 g monoalkylation product. Rechromatography of the monoalkylation product on 230 g silica with toluene/methanol (10:1) gave 2.5 g pure 2-(N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl}-8-methoxy-chroman.
Reaction SMILES: COC([C:5]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O.COC(C(S(C)(=O)=O)(CC#C[C@@H](OC(=O)C)CCCCC)CCCCCCC(OC)=O)=O>>[CH3:32][S:29]([CH:5]([CH2:16][C:17]#[C:18][C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:30])=[O:31]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: CCCCC[C@@H](C#CCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Product: CCCCC[C@@H](C#CCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O

Procedure:
The synthesis of this compound is carried out by the method of Example 3, Step D, except that methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxyheptadecanoate is replaced by an equivalent quantity of methyl 8-methoxycarbonyl-8-methylsulfonyl-12(S)-acetoxy-10-heptadecynoate.
Reaction SMILES: C([S:8][C:9]([CH3:20])([CH3:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])C1C=CC=CC=1.N.[Na]>CCOCC>[CH3:20][C:9]([SH:8])([CH3:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)SCc1ccccc1
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CC(C)(S)CNC(=O)OC(C)(C)C
Yield: 94.5 %

Procedure:
3.49 g (11.8 mmol) of tert-butyl [2-(benzylthio)-2-methylpropyl]carbamate dissolved in 10 ml of ether are placed in a flask which is fitted with an ammonia condenser and a gas inlet. The solution is cooled to -78°, thereafter about 35 ml of ammonia are condensed in. Sodium (about 1 g) in small pieces is added to this solution until the blue colour of the solution persists. The mixture is allowed to warm slowly, the excess sodium is destroyed by the addition of ammonium chloride (about 3.5 g) and the ammonia is blown off using nitrogen. The residue is partitioned between 50 ml of water and 250 ml of ether. The organic phase is separated, dried over sodium sulphate and evaporated. There are obtained 2.29 g of tert-butyl [2-methyl-2-mercaptopropyl]carbamate as a colourless solid; MS: 149 (M-C4H8)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][N:6]([C:16](=[O:18])[CH3:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(CNc1ccccn1)OCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(CN(C(C)=O)c1ccccn1)OCC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 2-pyridylaminoacetaldehyde diethyl acetal (8.0 g.) in a mixture of acetic anhydride (30 ml.) and pyridine (30 ml.) was stirred for 4 hours at 80° C and allowed to stand for 12 hours at ambient temperature. The reaction mixture was post-treated according to a similar manner to that of Example 5 (a) (2) to give oil of N-acetyl-N-(2-pyridyl)aminoacetaldehyde diethyl acetal (6 g.).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][NH2:26]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:26][NH:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NNc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Product: Clc1ccc(NNc2nc(Cl)nc3c2ncn3C2CCCC2)c(Cl)c1

Procedure:
2-Chloro-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,4-dichlorophenylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]#[N:40])=[C:33]([Br:41])[CH:32]=2)=[CH:27][CH:26]=1)[C:9]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[CH2:20][CH2:21][CH2:22][CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:42]=[N+:43]=[N-:44].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[CH2:1]([N:8]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[NH:44][N:43]=[N:42][N:40]=3)=[C:33]([Br:41])[CH:32]=2)=[CH:29][CH:30]=1)[C:9]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[CH2:20][CH2:21][CH2:22][CH3:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc(-c2ccc(OCc3nnn[nH]3)c(Br)c2)cc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 43.7 %

Procedure:
A mixture of N-benzyl-N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-2-butyl-1-benzofuran-3-carboxamide (800 mg, 1.3 mmol), prepared in the previous step, sodium azide (320 mg, 4.9 mmol) and ammonium chloride (264 mg, 4.9 mmol) in 40 mL of DMF was stirred under nitrogen at 100° C. for 3.5 h. By TLC some starting material remained. An additional 320 mg (4.9 mmol) of sodium azide and 264 mg (4.9 mmol) of ammonium chloride were added and the reaction was stirred at 100° C. for 4 h. The reaction was diluted with water, made basic by the addition of 1 N NaOH and partitioned with ethyl acetate. The organic layer was separated and the aqueous layer extracted multiple times with ethyl acetate. By TLC the product was in the ethyl acetate layer. The ethyl acetate solution was concentrated. The residue was dissolved in methylene chloride and acidified with 1 N HCl. The organic layer was separated, extracted three times with water, dried (MgSO4) and the solvent removed under reduced pressure to give the title compound (370 mg, 43%) as a white solid, MS (ESI) m/z 650 [M+H]+. Elemental Analysis for C35H32BrN5O3.0.34 H2O: Calc'd: C, 64.01; H, 5.02; N, 10.66; Found: C, 62.18; H, 5.32; N:9.50
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]4[CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][C:27]=4[N:28]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37].CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]4[CH2:23][NH:24][CH2:25][CH2:26][C:27]=4[N:28]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)N3CCC(N4CCc5ccc(F)cc54)CC3)sc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1nc2c(s1)CNCC2)N1CCC(N2CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (501 mg, 1.0 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 45 min and then Et2O (40 mL) was added. The resulting mixture was stirred vigorously for 20 min and the solid was filtered. The solid was washed with Et2O (2 mL×3) and dried to yield 4-(6-fluoroindolin-1-yl)-N-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperidine-1-carboxamide as a TFA salt.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([S:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[C:28]([F:27])([F:39])[F:40])(=[O:37])=[O:36])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1C(F)(F)F)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 27B (50 mg, 0.192 mmol) and triethylamine (29.2 mg, 0.288 mmol) in dichloromethane (1 mL) was added 2-(trifluoromethyl)benzene-1-sulfonyl chloride (47 mg, 1.92 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was purified by chromatography on silica gel (ethyl acetate/hexane=4:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.84 (m, 2H), 2.09 (m, 1H), 2.22 (m, 2H), 2.33 (m, 1H), 2.52 (m, 1H), 2.78 (m, 1H), 2.99 (m, 1H), 3.64 (m, 2H), 3.82 (m, 1H), 5.25 (m, 1H), 7.92 (m, 2H), 8.15 (m, 4H); MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13]C)=[O:11])=[C:6](OCC)[CH:5]=1)([O-])=O.[Mg].[C:21](OCC)(=[O:23])[CH3:22]>CO>[CH2:21]([O:23][CH:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])[CH3:22]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1OCC
Agent: [Mg]
Solvent: CO
Product: CCOC(Cc1ccc(N)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Ethyl 4-nitro2-ethoxycinnamate (10 g, 1 eq, 37.7 mmol) obtained in step (i) of preparation 1, was treated with activated magnesium turnings (18 g, 20 eq, 754 mmol) in dry methanol (400 ml). The reaction mixture was refluxed for 2-3 h, and allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and quenched with cold aqueous ammonium chloride. The organic layer was washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound as liquid (6 g, yield 72%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([OH:14])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH2:22][CH3:23])=[CH:4][N:3]=1
Reactant: CCI
Reactant: COc1ccc2c(Cl)ncc(O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2ccc(OC)cc12
Reaction time: 18 h
Yield: 26.4 %

Procedure:
To a solution of 1-chloro-6-methoxyisoquinolin-4-ol (0.05 g, 0.239 mmol) in acetonitrile (5 ml) was added potassium carbonate (0.099 g, 0.716 mmol) followed by iodoethane (0.039 ml, 0.477 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.015 g, 25.1%) as solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.14-8.12 (d, J=8 Hz, 1H), 7.90 (s, 1H), 7.46-7.42 (m, 2H), 4.34-4.27 (q, J=8 Hz, 2H), 3.95 (s, 3H), 1.48 (t, J=10 Hz, 3H).