Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>>[N+:1]([CH:4]=[C:5]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[NH:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)([O-:3])=[O:2]
Reactant: NCCSCc1nccs1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)-methylthio)ethylamino]ethylene with an excess of 2-[(2-aminoethyl)thiomethyl]thiazole according to the procedure of Example 2(ii) results in the production of 1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)-ethylamino]ethylene.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14]COC)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18]O>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:18])=[O:10])=[C:7]([OH:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: COCOc1cc(C(C)(C)C)ccc1C(=O)O
Product: COC(=O)c1ccc(C(C)(C)C)cc1O
Temperature: 25 °C

Procedure:
A solution of 4-tert-butyl-2-(methoxymethoxy)benzoic acid (61.80 g, 259 mmol) and MeOH (865 mL) was cooled in an ice bath. Gaseous HCl was sparged through the cold fluid for 30 min to saturate it, and the solution was then heated to reflux. A Soxhlet extractor containing 3 Å molecular sieves was used to absorb the water produced in the reaction. After 16 h the heating mantle was removed, and the solution was allowed to cool to ambient temperature. The filtrate was concentrated to a thick semisolid which was taken up in 1:1 water/CH2Cl2 (800 mL). The aqueous layer was extracted once with CH2Cl2 (100 mL), and the combined organic layers were washed with water (250 mL) and 5% (w/w) NaHCO3 (200 mL). The organic layer was dried (MgSO4), filtered and concentrated to 49.54 g (92%) of yellow oil:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].C([Li])CCC.CN(C)[CH:24]=[O:25]>C1COCC1.[Cl-].[NH4+]>[CH2:13]([N:12]([CH2:15][CH3:16])[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:24]=[O:25])[CH:3]=2)[N:8]=[CH:7][CH:6]=1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CCN(CC)c1ccnc2ccc(Br)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of (6-bromo-quinolin-4-yl)-diethylamine (0.510 g, 1.59 mmol) in THF (10 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (0.765 mL, 1.92 mmol, 1.2 equiv.) at −70° C. During the addition, the color of the solution was turned into red and this solution was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (0.246 mL, 3.19 mmol) in THF (1 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to afford 0.205 g (48% yield) of 4-(diethylamino)-quinoline-6-carbaldehyde as a white solid: EI-LRMS m/e calcd for C14H16N2O (M+) 229.1, found 229.1.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[C:13]1=[O:30].[C:31](ON1C(=O)CCC1=O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[C:31]([NH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1.[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[C:13]1=[O:30]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(ON1C(=O)CCC1=O)c1cccnc1
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)c1cccnc1)C(=O)O
Temperature: 25 °C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (200 mg) and 2,5-dioxopyrrolidinyl nicotinate (120 mg) were dissolved in DCM (20 mL). The mixture was stirred on a magnetic stirrer at room temperature. Triethylamine (1 mL) was added in one portion and the mixture was allowed to react overnight. The reaction mixture was then poured into DCM (30 mL), washed with saturated sodium bicarbonate solution three times (30 mL/wash) and brine (30 mL), dried with anhydrous magnesium sulfate, and filtered. The solvent was removed by rotary evaporation in vacuo. The crude product was purified by silica gel column chromatography (eluted with chloroform: acetone=5:2) to yield pure title compound (239 mg). 1HNMR (CDCl3, ppm) δ 9.04 (d, 1H, J=11.2Hz), 8.72 (s, 1H), 8.13 (d, 1H, J=8.0Hz), 7.87-7.90 (m, 2H), 7.76-7.78 (m, 2H), 7.41 (dd, 1H, J=8.0, 11.2Hz), 6.73 (d, 1H, J=9.6Hz), 5.86-5.98 (m, 2H), 5.05-5.08 (m, 1H), 3.00-3.15 (m, 1H), 2.80-2.95 (m, 2H), 2.12-2.28 (m, 1H), 2.10-2.20 (m, 2H), 0.97-1.05 (m, 3H), 0.85-0.88 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)[N:12]=[C:11]([C:22](O)=[O:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)[N:12]=[C:11]([C:22]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: N#Cc1cccc(-n2nc(C(=O)O)cc2-c2ccc(F)c(Cl)c2)c1
Solvent: O=CO
Product: N#Cc1cccc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 108A with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 8 mg (35% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Br:17][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8]
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 82.2 %

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (2.0 g) in trifluroacetic acid (8 ml) was added concentrated sulfuric acid (2.5 ml) followed by N-bromosuccinimide (3.4 g). After stirring for 24 hours the reaction mixture was then diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to give 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (2.48 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4].[CH3:31][NH:32][CH3:33]>O1CCOCC1.C(O)C>[CH3:31][N:32]([CH3:33])[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4]
Reactant: CNC
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CNC(=O)CCl)c3)cc12)c1ccccc1
Solvent: C1COCCO1
Solvent: CCO
Product: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CNC(=O)CN(C)C)c3)cc12)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 210 mg (0.5 mmol) 2-chloro-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide in 3 ml dry dioxane is treated with 268 μl (1.5 mmol) of a 5.6 N dimethylamine solution in ethanol (Fluka, Buchs, Switzerland) and then heated to 100° C. for 6 h. The clear yellow solution is cooled and the solvent evaporated. The residue is purified by flash chromatography using a mixture of dichloromethane/methanol with gradually increasing concentrations of methanol starting with 100:2.5 and ending with 100:5 and then switching to dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 and ending with 100:10:0.5. The title compound is obtained as a colorless foam; Rf(dichloromethane/methanol/conc. ammonia 90:10:1)=0.41; MS-ES+: (M+H)+=429.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.ClC(Cl)C.[CH3:14][C@H:15]1[CH2:20][O:19][CH2:18][CH2:17][NH:16]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:16]2[CH2:17][CH2:18][O:19][CH2:20][C@@H:15]2[CH3:14])[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1COCCN1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C[C@H]1COCCN1Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Reductive Amination Method B: 6-Bromopyridine-2-carbaldehyde (1.3 g, 7.0 mmol) was added to a 200 ml, round bottom under argon. Dichloroethane (28.0 ml) was added followed by (3S)-3-methylmorpholine (HCl salt) (1 g, 7.3 mmol) and triethylamine (1.0 ml, 7.3 mmol). The mixture was stirred for 0.5 hours at room temperature followed by the addition of sodium triacetoxyborohydride (2.07 g, 9.8 mmol) and the resulting slurry was maintained at room temperature overnight. The reaction was quenched by the careful addition of saturated aqueous sodium bicarbonate and was extracted once with DCM and once with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oily residue was purified via flash chromatography (silica, 0-10% methanol/ethyl acetate) to afford the title compound as a colorless oil.
Reaction SMILES: CO[C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O>[NH:16]([C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)cc1Nc1ccccc1

Procedure:
3-Methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.0 g) and aniline (10 mL) were heated to reflux for 5 hours and diluted with water. Hydrochloric acid (2N) was added and the mixture extracted with ethyl acetate. The organic extracts were washed (acid, brine), dried and evaporated to give a solid which was purified by chromatography, with ethyl acetate:toluene (1:4) as the eluent. Recrystallization from ethyl acetate gave the title compound (0.405 g); mp 227°-228° C.: NMR: 6.28 (s,1); MS(EI): m/z=264(M). Analysis for C16H12N2O2.0.1 H2O : Calculated: C, 72.22; H, 4.62; N, 10.53; Found: C, 72.32; H, 4.68; N, 10.65.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc(N)cc1
Yield: 94.1 %

Procedure:
A solution of 30 g of product from Example 81 in 150 ml of ethyl alcohol and 20 ml of ethyl acetate is treated with 2 g of 10% palladium/carbon in a Parr Hydrogenator for 18 hours. The reaction solution is filtered and concentrated in vacuo. The residue is recrystallized from hexane to give 25.7 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:17]([CH2:18][CH2:19][OH:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.CN(C)C=O.[H-].[Na+].Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:17]([CH2:18][CH2:19][O:20][C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: Clc1ncccn1
Reactant: CN1CCC(Nc2nc3cccnc3n2CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Nc2nc3cccnc3n2CCOc2ncccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a stirred mixture of 4.13 parts of 2-[(1-methyl-4-piperidinyl)amino]-3H-imidazo[4,5-b]pyridine-3-ethanol and 90 parts of N,N-dimethylformamide were added 0.75 parts of a sodium hydride dispersion 50%. After stirring for 30 minutes at room temperature, 1.7 parts of 2-chloropyrimidine were added. The whole was stirred for 1 hour at room temperature and the reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.7 parts (32.0%) of N-(1-methyl-4-piperdinyl)-3-[2-(2-pyrimidinyloxy)ethyl]-3H-imidazo[4,5-b]-pyridin-2-amine; mp. 158.1° C. (compound 168).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14].ClCC(NN)=O>C1(C(C2C=CC=CC=2)CCN2CCCNCC2)C=CC=CC=1.CO.C(Cl)Cl>[C:1]([NH:9][NH:10][C:13](=[O:14])[CH2:12][Cl:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: NNC(=O)CCl
Agent: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(CCl)NNC(=O)c1ccccc1
Yield: 54.5 %

Procedure:
1-Benzoyl-2-(chloroacetyl)hydrazine (850 mg, 54%) was prepared from benzhydrazide (1.00 g, 7.34 mmol) and chloroacetyl chloride (0.58 mL, 7.34 mmol, 1 equiv) using general procedure. Compound No. 78 (300 mg, 51%) was prepared from 1-(3,3-diphenyipropyl)homopiperazine (100 mg, 0.34 mmol) and 1-benzoyl-2-(chloroacetylhydrazine (80 mg, 0.38 mmol) employing general alkylation procedure. TLC Rf=0.44 (10% CH3OH—CH2Cl2), RPLC tR=5.85 min (>85%), 220 nm (Method B): ESI/MS m/e 471.3 (M++H, C29H34N4O2).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2cnccc2C(=O)O)cc1
Temperature: -78 °C
Yield: 12.7 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and p-anisidine (44 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative RP chromatography to give 11 mg (45 μmol, 13% yield) of pure desired product. LC-MS (method V): rt=1.82 min; m/z [M+H]+ 245.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][OH:24])[O:17]2)=[C:9]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1)=[O:6].[N:40]1([C:45](N)=[O:46])[CH:44]=[CH:43][N:42]=[CH:41]1>C1(C)C=CC=CC=1.C(O)(C)C>[OH:21][C@@H:20]1[C@H:19]([OH:22])[C@@H:18]([CH2:23][OH:24])[O:17][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:45]([NH:40][CH2:44][CH2:43][N:42]1[CH2:20][CH2:19][CH2:18][CH2:23][CH2:41]1)=[O:46])=[O:6])=[N:8][C:9]=2[NH:25][CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: NC(=O)n1ccnc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=C(NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)NCCN1CCCCC1
Yield: 145.4 %

Procedure:
N-(2-Aminoethyl)-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxamide (Preparation 17) (90 mg, 0.17 mmol) and N-[2-1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 18) (40 mg, 0.18 mmol) were dissolved in a mixture of toluene (4 ml) and isopropanol (1 ml) and the solution heated under reflux for four hours. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). Product containing fractions were evaporated and the resulting solid triturated with diethyl ether, filtered and dried to afford the title compound as a white powder (85 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19](F)=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1>CS(C)=O.C(OCC)(=O)C>[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:8][CH2:7][CH2:6][CH2:5][NH:4][CH3:3])=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:29])([F:30])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1
Reactant: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Reactant: CNCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNCCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2N[C@@H](C)C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To sodium hydride (60% in mineral oil, 2.3 g, 57.6 mmol) in 20 mL of dimethylsulfoxide at room temperature is added a solution of 3-(methylamino)propan-1-ol (5.14 g, 57.6 mmol) in 10 mL of dimethylsulfoxide. The solution is stirred at room temperature for 1 h, and 5-chloro-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine (5.7 g, 14.4 mmol) is added. The mixture is heated at 60° C. for 3 h, and cooled to room temperature. The reaction mixture is diluted with ethyl acetate, and washed with water and saturated sodium chloride. The organic layer is dried over magnesium sulfate, and concentrated to a residue. The residue is triturated with small amount of acetone, then hexanes, and chromatographed over silica gel, eluting with a gradient of 100% ethyl acetate to 100% methyl alcohol. Concentration provides 5-chloro-6{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a white solid (2.7 g). MS: m/z 465.1 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C:4]([C:6]1[C:7]([C:22](OC)=[O:23])=[CH:8][N:9]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=O.O.[NH2:28][NH2:29].O>C(O)C>[CH3:1][CH:2]([CH3:26])[CH2:3][C:4]1[C:6]2[C:7](=[CH:8][N:9]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[C:22](=[O:23])[NH:28][N:29]=1
Reactant: COC(=O)c1cn(Cc2cccc3ccccc23)cc1C(=O)CC(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)Cc1n[nH]c(=O)c2cn(Cc3cccc4ccccc34)cc12

Procedure:
Methyl 4-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrrole-3-carboxylate (0.35 g) prepared as described in Example 1c) above and hydrazine hydrate (0.2 ml) were stirred in ethanol (10 ml) for 2 days. The reaction mixture was poured into water to give a solid which was collected and recrystallised from ethyl acetate-cyclohexane to afford the sub-title pyrrole (0.22 g).
Reaction SMILES: [Br:1][CH2:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[Br:1][CH2:2][CH:3]([CH3:7])[CH2:4][CH2:5][O:6][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: C1=COCCC1
Reactant: CC(CBr)CCO
Solvent: ClCCl
Product: CC(CBr)CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
16.7 g of 4-bromo-3-methylbutanol was dissolved in 200 ml of anhydrous methylene chloride, and with ice cooling, 10.0 g of dihydropyran was added dropwise. After the addition, the mixture was stirred at room temperature for 2 hours, and then the solvent was distilled off. The residue was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent to give 16.2 g of 2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran. The NMR spectrum of this product was as follows:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH3:11][O:12][Na]>CO>[CH3:11][O:12][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: O=Cc1cccc(CBr)c1
Reactant: CO[Na]
Solvent: CO
Product: COCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
3-(bromomethyl)benzaldehyde (1.00 g, 5.02 mmol) was dissolved in MeOH (100 mL) and treated with 0.5M solution of MeONa (5 equiv.) in MeOH. The mixture was stirred overnight at RT and MeOH was evaporated under reduced pressure. The residue was acidified to pH ˜6 with 1M aqueous HCl solution. DCM (100 mL) was added and the mixture was vigorously stirred overnight. The organic layer was separated, dried over Na2SO4 and the solvent was removed under reduce pressure to furnish the desired material as yellowish oil (560 mg, 3.75 mmol, 74%). 1H NMR (DMSO, 400 MHz): δ3.33 (s, 3H), 4.51 (s, 1H), 7.62 (m, 2H), 7.85 (m, 2H), 10.02 (s, 1H). MS 151 (MH1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]#[N:30])=[N:4][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]([CH3:20])[CH3:19])[C:9]2=[O:28])[C:6]=1[CH3:7].[CH2:31](N)[CH2:32][NH2:33]>CC(O)=O.CCO>[Cl:1][C:2]1[C:3]([C:29]2[NH:33][CH2:32][CH2:31][N:30]=2)=[N:4][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[C:17]=3[CH:18]([CH3:20])[CH3:19])[C:9]2=[O:28])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C#N)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C(C)C)C1=O
Reactant: NCCN
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(Cl)c(C2=NCCN2)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C(C)C)C1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 87 %

Procedure:
A mixture of 4-chloro-1-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]-5-methylpyrazole-3-carbonitrile (0.042 g, 0.10 mmol) in ethane-1,2-diamine (1.5 mL), HOAc (0.23 mL) and EtOH (1.25 mL) was stirred at 100° C. for 2.5 hrs. The mixture was then cooled to room temperature, quenched with sat. aq. NaHCO3 (50 mL), and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-[4-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-5-methylpyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.041 g, 87%).