Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH2:22]([O:29][CH2:30][C:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([C:31]2([CH2:30][O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:33][CH2:32]2)(=[O:36])=[O:35])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)C1(COCc2ccccc2)CC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(COCc3ccccc3)CC2)c2n(c1=O)CCS2
Yield: 682 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.2 g, 0.048 mmol) in pyridine (2 mL) was reacted with 1-benzyloxymethyl-cyclopropanesulfonyl chloride (137 mg, 0.52 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 0.21 g of the product (70% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[CH3:29][C:30]1([CH3:36])[O:34][C:33](=[O:35])[NH:32][CH2:31]1.N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(O)=O.[Na+]>O1CCOCC1.[Cu]I>[CH3:29][C:30]1([CH3:36])[O:34][C:33](=[O:35])[N:32]([C:6]2[CH:5]=[CH:4][C:3]([N:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:21]=[CH:20][CH:19]=4)=[N:10]3)=[C:2]([F:1])[CH:7]=2)[CH2:31]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: CC1(C)CNC(=O)O1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CC(C)(C)OC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 110 °C
Yield: 66.2 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.500 mmol), 5,5-dimethyl-1,3-oxazolidin-2-one (69.1 mg, 0.600 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.100 mmol), CuI (9.5 mg, 0.050 mmol), and K3PO4 (212 mg, 1.00 mmol) in 1,4-dioxane (2.0 mL) was stirred at 110° C. under Ar atmosphere. The reaction mixture was poured into 5% NaHCO3 aqueous solution (20 mL) and extracted with AcOEt (20 mL×3). The combined organic phase was washed with brine (40 mL), dried with MgSO4, and evaporated. The residue was purified by basic silica gel column chromatography (MeOH/AcOEt=0%-10%) to give the title compound (157.4 mg, 66% yield): 1H NMR (300 MHz, DMSO-d6): δ ppm 1.49 (6H, s), 3.78 (3H, s), 3.89 (2H, s), 6.97 (1H, d, J=1.9 Hz), 7.05 (1H, t, J=9.0 Hz), 7.31 (1H, d, J=8.7 Hz), 7.31 (1H, t, J=1.7 Hz), 7.33 (1H, s), 7.37-7.48 (3H, m), 7.68 (1H, dd, J=13.4, 2.5 Hz), 7.79 (1H, d, J=1.9 Hz), 8.46 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 476 [M+H]+. Anal. Calcd for C25H22FN5O4: C, 63.15; H, 4.66; N, 14.73. Found: C, 63.09; H, 4.70; N, 14.85.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([NH2:32])[CH:19]=[N:20][C:21]=1[O:22][CH:23]([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2].O.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:32][C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH:19]=[N:20][C:21]=1[O:22][CH:23]([C:24]([F:25])([F:26])[F:27])[C:28]([F:31])([F:30])[F:29]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: Nc1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(Nc2cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c2)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 48.2 %

Procedure:
To a degassed suspension of tert-butyl 4-bromobenzoate (Preparation 257, 250 mg, 0.97 mmol), 5-chloro-6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)pyridin-3-amine (Preparation 256, 430 mg, 1.46 mmol) and potassium carbonate (403 mg, 2.92 mmol) in a mixture of terbutanol (10 ml)/water (0.2 ml) was added Pd(OAc)2 (1 mol %) and BrettPhos (3 mol %). The mixture was heated at 110° C. for 18 hours. After 18 hours, further portions of Pd(OAc)2 (1 mol %) and BrettPhos (3 mol %) were added and the reaction was heated for 24 hours at 110° C. The reaction was cooled to room temperature, ethyl acetate (50 mL) and water (15 mL) were added, the phases were separated and the combined organics evaporated. The crude product was purified by silica gel column chromatography, eluting with DCM in Heptane (10% to 80%), to give the title compound as an oil (0.22 g, 48%).
Reaction SMILES: [CH2:1]1[CH:8]2[NH:9][CH:3]([CH2:4][C:5]([CH2:7]2)=O)[CH2:2]1.Cl.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CC(O)C.CO>[NH:9]1[CH:8]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:17][C:5]=3[CH2:4][CH:3]1[CH2:2][CH2:1]2
Reactant: O=C1CC2CCC(C1)N2
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: c1ccc2c3c([nH]c2c1)CC1CCC3N1
Reaction time: 24 h
Yield: 68.4 %

Procedure:
Method A, A solution of nortropinone hydrochloride (10.0 g, 61.9 mmol) and phenylhydrazine (7.7 g, 71.2 mmol) in 175 mL of 2-propanol was refluxed for 30 minutes, then it was allowed to cool to room temperature, saturated with hydrogen chloride, and heated under reflux for an additional 10 hours. The resulting solution was concentrated under reduced pressure to give a dark residue which was dissolved in methanol. Amberlite IRA-400 resin (pre-washed with methanol) was added until the pH exceeded 10. The mixture was filtered and the filter cake was washed with hot methanol to complete removal of the product from the resin. After the filtrate was treated with decolorizing carbon, it was filtered through a pad a diatomaceous earth and concentrated in vacuo. The residue was suspended in 50 mL of methylene chloride and the mixture was held at -5° C. for 24 hours. Filtration afforded 8.4 g (69%) of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole which was converted into a hydrogen fumarate in ethanol, mp 208°-209° C. (dec); NMR (DMSO-d6) d 1.63 (1H, m), 1.90 (1H, m), 2.15-2.19 (2H, m), 2.68 (1H, d, J=16, 4 Hz), 3.31 (1H, dd, J=16.6, 4 7.28 (1H, d, J=8 Hz), 7.46 (1H, d, J=8 Hz), 11.10 (1H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[C:15]1[O:16][C:17]([CH:32]([CH3:34])[CH3:33])=[C:18]([CH2:20][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH3:31])[CH:25]=2)=[O:23])[N:19]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[C:15]1[O:16][C:17]([CH:32]([CH3:34])[CH3:33])=[C:18]([CH2:20][CH2:21][CH:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH3:31])[CH:25]=2)[OH:23])[N:19]=1
Reactant: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)ccc1O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(C(O)CCc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)ccc1O
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of lithium aluminum hydride (92 mg, 2.42 mmol) in dry THF (20 mL), 3-[2-(2,4-dichlorophenyl)-5-isopropyloxazol-4-yl]-1-(4-hydroxy-3-methylphenyl)propan-1-one (1.01 g, 2.41 mmol) was gradually added while cooling with ice. The mixture was stirred for 1 hour, and further stirred at room temperature. The reaction mixture was again cooled with ice. To the mixture, a saturated aqueous sodium sulfate solution was dropwise added. After insoluble materials were filtered out, the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate, washed with water (15 mL) containing a small amount of a 1M aqueous solution of hydrochloric acid, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the desired compound (997 mg) as ocher yellow crystal (yield 98%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][C:34]=5[CH3:35])=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][C:34]=5[CH3:35])=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1ccncc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccncc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO)C4)CC2)cc1
Yield: 77.5 %

Procedure:
A solution of the compound (380 mg, 0.73 mmol) obtained in Example 19-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (230 mg, 78%) as a colorless solid.
Reaction SMILES: C=CCCC(O)=O.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:15]([NH2:19])[C:16](=[CH2:18])[CH3:17]>>[C:8]1(=[N:19][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCCCC1
Reactant: C=C(C)CN
Agent: C=CCCC(=O)O
Product: CC(C)=CN=C1CCCCC1

Procedure:
The procedure described in Example (1a) is repeated, except that 302.5 g (2 mols) of N-cyclohexylidene-(2-methypropenylamine) and 250 g (4.62 mols) of 1,3-butadiene are used. Distillation yields 382 g (1.48 mols) of 3,3-dimethyl-12,12-pentamethylene-1-aza-1,5,9-cyclododecatriene; boiling point 96° C./4 Pa; nD20 =1.5116. The N-cyclohexylidene-(2-methylpropenylamine) was prepared from cyclohexanone and methallylamine, with subsequent isomerisation of the reaction product with potassium tert.-butylate; boiling point 96° C./1,700 Pa; nD20 =1.5160.
Reaction SMILES: C[Al](C)C.[N:5]([Si](C)(C)C)=[N+:6]=[N-:7].[Si:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:29]3[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:28]=3[N:27]=2)=[CH:22][CH:21]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:30]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[C:29]3[CH:37]=[CH:38][C:39]([C:41]4[NH:7][N:6]=[N:5][N:42]=4)=[CH:40][C:28]=3[N:27]=2)=[CH:24][CH:25]=1)([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C#N)ccc3n2C2CCCCC2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(-c4nnn[nH]4)ccc3n2C2CCCCC2)cc1
Temperature: 95 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Trimethylaluminum (20 mL of a 2.0 M solution in toluene, 0.040 mol) was added to a dry flask. Azidotrimethylsilane (5.3 mL, 0.040 mol) and compound 20 were added. The solution was stirred for 18 h at an oil bath temperature of 95° C. The solution was cooled and poured into a mixture of ethyl acetate and ice. The mixture was carefully acidified with dilute hydrochloric acid (caution-done in hood, hydrazoic acid liberated) to precipitate compound 21. The compound was crystallized from ethyl acetate—hexanes to afford 21 as a pinkish solid (4.13 g, 87%).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:10][OH:11])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:23][CH3:24])(=[O:22])[C:19]([CH3:21])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:21][C:19]1([C:18]([O:23][CH3:24])=[O:22])[O:9][CH2:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:10][O:11]1
Reactant: COC(=O)C(C)=O
Reactant: OCC(CO)(c1ccccc1)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COC(=O)C1(C)OCC(c2ccccc2)(c2ccccc2)CO1
Yield: 22.4 %

Procedure:
A mixture of 22.8 g (0.1 M) of 2,2-diphenyl-1,3-propanediol and 100 g (0.98 M) of methyl pyruvate is brought to 70° C. in a 500 ml round-bottomed flask under a nitrogen atmosphere. 22.4 g (0.156 M) of P2O5 are added portionwise. An exothermic reaction takes place and the temperature rises to 98° C. The mixture is allowed to return to room temperature and is poured slowly into ice-cold water. This mixture is extracted with methylene chloride and the extracts are washed with sodium hydroxide and water. The extracts are concentrated and the residue is chromatographed by flash chromatography (70 CH2Cl2/50 cyclohexane eluent). The product is then recrystallized from 40 ml of diisopropyl ether. 7 g of a product of m.p. 116° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]3[N:18]=[C:19]([S:22][C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[S:20][CH:21]=3)=[C:10]([C:33]([OH:35])=O)[CH:9]=2)=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[C:27]([O:26][C:24](=[O:25])[C:23]([S:22][C:19]1[S:20][CH:21]=[C:17]([CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][C:10]=2[C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:35])[N:18]=1)([CH3:31])[CH3:32])([CH3:28])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2C(=O)O)cs1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2C(=O)N2CCOCC2)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.4 %

Procedure:
4′-Fluoro-4-(2-{2-[(2-tert-butyl-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)biphenyl-3-carboxylic acid (170 mg) obtained in Example 93-1 and morpholine (43 mg) were dissolved in dichloromethane (2 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (94 mg) and 1-hydroxybenztriazole (HOBt) monohydrate (75 mg) were successively added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (180 mg) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[C:9]([F:17])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH2:14])=[C:9]([F:17])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2cc(N)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
A suspension of 2-tert-butyl-6-fluoro-5-nitro-1H-indole (1.5 g, 6.36 mmol) and Ni (0.5 g) in MeOH (20 mL) was stirred under H2 atmosphere (1 atm) at the room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to dryness. The residue was recrystallized in ether to give 2-tert-butyl-6-fluoro-1H-indol-5-amine (520 mg, 38%). 1H-NMR (300 MHz, DMSO-d6) δ 10.46 (brs, 1H), 6.90 (d, J=8.7 Hz, 1H), 6.75 (d, J=9.0 Hz, 1H), 5.86 (s, 1H), 4.37 (brs, 2H), 1.29 (s, 9H); MS (ESI) ink 206.6.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:7][CH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:6])[CH2:4][OH:5].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C(Cl)Cl>[CH3:20][S:21]([O:5][CH2:4][C:3]([CH2:2][Br:1])([CH2:7][CH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)[CH3:6])(=[O:23])=[O:22]
Reactant: CC(CO)(CBr)CC1C=CC=C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(CBr)(COS(C)(=O)=O)CC1C=CC=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
In a 200 ml Schlenk tube fitted with a septum, 6.97 g of crude product 3 and 4.35 ml (45 mmol) of triethylamine were dissolved in 100 ml of methylene chloride. At 0° C., 2.37 ml (31 mmol) of methanesulfonyl chloride were injected over a period of 2 minutes. After half the methanesulfonyl chloride had been added, a colorless precipitate formed. The suspension was held at this temperature for another half hour and was then stirred for 2 hours at room temperature. The reaction solution was subsequently hydrolyzed with 20 ml of water. The phases were separated and the aqueous phase was extracted three times with 20 ml of methylene chloride. The combined organic phases were washed with sodium chloride solution until neutral and dried over sodium sulfate. Removal of the solvent in an oil pump vacuum gave a slightly brownish oil which was dissolved in methylene chloride and absorbed on kieselguhr. This was followed by flash chromatography on a silical gel column (4*25 cm; PE/THF in a ratio of 8:2; RF =0.42). Evaporation of the product fractions in an oil pump vacuum gave 5.9 g (66%) of 4 as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH:39]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:31]3[N:30]([CH3:29])[C:38]4[C:33]([CH:32]=3)=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cn1c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc2ccccc21

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 1-methylindole-2-carboxaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 522.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][OH:36])[CH2:22][CH2:21]4)=[N:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3cnc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: OCCBr
Product: CN(C)C(=O)c1cc2cnc(Nc3cnc(N4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 54.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 0.114 mmol) and 2-bromo ethanol (25 mg, 0.20 mmol) to give 7-cyclopentyl-2-[4-(2-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 54%). MS (ESI) m/z 480.6 (M+H)+
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([O:17][CH2:18][CH3:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1>[Pd].O1CCCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([O:17][CH2:18][CH3:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=1
Reactant: CCOC(=Cc1ccc(OCCCl)cc1)C(=O)OC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCCl)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 100 ml of tetrahydrofuran add the compound obtained in Step A (0.0175 mol) and then palladium-on-carbon (0.2 g). Stir at ambient temperature under hydrogen for 1 day. Filter off the palladium-on-carbon and then evaporate the filtrate. The oily product is purified on a column of silica gel using the eluant mixture: petroleum ether/dichloromethane (1/1). The title compound is obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][OH:15])[N:12]=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:20][C:19]([F:21])([F:22])[C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:18]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][O:15][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)[N:12]=1
Reactant: C1=COCCC1
Reactant: OCCn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(CNc2nnn(CCOC3CCCCO3)n2)cc(C(F)(F)F)c1

Procedure:
A mixture of 2-(5-{N-[3,5-bis(trifluoromethyl)benzyl]amino}tetrazol-2-yl)ethanol (0.68 g, 1.9 mmol), 3,4-dihydro-2H-pyran (DHP, 0.35 g, 4.2 mmol) and a catalytic amount of pyridinium p-toluene sulfonate (PPTS, 0.050 g, 0.20 mmol) in CH2Cl2 (10 mL) is stirred at room temperature for 10 hours. The resulting mixture is quenched by addition of sat. NaHCO3 aq. and extracted with EtOAc. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give N-[3,5-bis(trifluoromethyl)benzyl]-N-{2-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-tetrazol-5-yl}amine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[C:13]([O:22]C)[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.B(Br)(Br)[Br:26].BrBr>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[C:13]([OH:22])[CH:12]=2)=[O:9])=[C:6]([Br:26])[N:5]=[CH:4][N:3]=1
Reactant: BrB(Br)Br
Reactant: COc1cc(NC(=O)c2c(N)ncnc2Cl)ccc1-c1cnco1
Agent: BrBr
Solvent: ClCCl
Product: Nc1ncnc(Br)c1C(=O)Nc1ccc(-c2cnco2)c(O)c1
Yield: 33.6 %

Procedure:
4-Amino-6-chloro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)pyrimidine-5-carboxamide (788 mg, 1.74 mmol) was treated with boron tribromide (1 M in dichloromethane, 11.8 ml, 11.8 mmol) with dichloromethane (10 ml) as a solvent according to the method described in Example 23. In this reaction conditions the chlorine atom was transformed into bromine. The solid residue (220 mg, 33% yield) was used in the next synthetic step without further purification. Purity 99%.