Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][CH:7]([CH2:13][C:14]1[S:18][CH:17]=[N:16][CH:15]=1)[C:8](OCC)=[O:9])(=[O:5])[CH3:4]>C(O)C>[OH:9][CH2:8][CH:7]([NH:6][C:3](=[O:5])[CH3:4])[CH2:13][C:14]1[S:18][CH:17]=[N:16][CH:15]=1
Reactant: CCOC(=O)C(Cc1cncs1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NC(CO)Cc1cncs1
Temperature: 20 °C
Reaction time: 18 h
Yield: 63.5 %

Procedure:
0.4 g of sodium borohydride is added to a solution of 1.2 g of ethyl (2RS)-2-acetylamino-3-(5-thiazolyl)propanoate in 20 cm3 of ethanol, followed by stirring under an inert atmosphere at a temperature in the region of 20° C. After 18 hours, a further 0.1 g of sodium borohydride is added and the mixture is then stirred for 24 hours at a temperature in the region of 20° C. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is taken up in 10 cm3 of water and extracted with 3 times 30 cm3 of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is chromatographed under an argon pressure of 60 kPa on a column of silica gel (particle size 40-63μ; diameter 3.5 cm; height 31 cm), eluting with 100 cm3 of dichloromethane, 600 cm3 of a dichloromethane/methanol mixture (98/2 by volume), 500 cm3 of a dichloromethane/methanol mixture (96/4 by volume) and 1 dm3 of a dichloromethane/methanol mixture (90/10 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 0.63 g of N-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)-ethyl]acetamide is obtained in the form of a yellow oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.80 (s: 3H); 2.85 (dd, J=15 and 9 Hz: 1H); 3.16 (dd, J=15 and 5 Hz: 1H); from 3.25 to 3.45 (mt: 2H); 3.87 (mt: 1H); 4.85 (mt: 1H); 7.65 (S: 1H); 7.79 (d, J=8.5 Hz: 1H); 8.91 (s: 1H)].
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:13]1([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:14]=1>O1CCCC1>[C:1]([NH:5][S:23]([C:13]1[CH:14]=[C:15]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A solution of 1.46 grams (20 mmole) of t-butylamine and 2.02 grams (20 mmole) of triethylamine in tetrahydrofuran was added dropwise to a solution of 5.5 grams (20 mmole) of 1,3-benzenedisulfonyl chloride in tetrahydrofuran. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo. The residue was purified on silica gel eluting with methylene chloride to give 3.86 grams of the titled compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][OH:20]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:6]([CH2:18][CH2:19][OH:20])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: OCCBr
Reactant: Cc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1CCO
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-1H-benzimidazole (3.50 g, 25.95 mmol) in DMF (70.0 mL), Cs2CO3 (12.08 g, 36.33 mmol) and 2-bromoethanol (2.5 mL, 34.15 mmol) was added. After stirring at 150° C. for 1 h, the reaction mixture was allowed to reach rt and was diluted with EtOAc. The org. layer was separated and the aq. layer was extracted with EtOAc (5×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 2-(2-methyl-1H-benzoimidazol-1-yl)ethanol which was used in the next step without further purification. LC-MS conditions B: tR=0.25 min, [M+H]+=177.17.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](Br)[CH:22]=[CH2:23].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:18])[C:15]([O:17][CH2:23][CH:22]=[CH2:21])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: C=CCBr
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Cl)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (24 mg, 0.078 mmol) in dichloromethane (2 mL) was treated with allyl bromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 23 mg of a white solid. MS calculated for C16H17ClF3NO2+H: 348, observed: 348.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=O)=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[N:21]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCCCCNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCCCN1CCCC1)OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a pressure vessel was added 4-(benzyloxycarbonylamino)butyl methanesulfonate (330 mg, 1.10 mmol) and pyrrolidine (234 mg, 3.3 mmol) in THF. The reaction was heated to 100° C., stirred overnight, cooled to 20-25° C., and concentrated. The crude concentrate was purified by Biotage column chromatography to give benzyl 4-(pyrrolidin-1-yl)butylcarbamate (200 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:13])=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=1)#N.[Cl:14][C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.[CH:24]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH:30]2[NH:13][C:6]3[CH:5]=[CH:4][C:3]([C:1]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:14])=[CH:8][C:7]=3[S:9](=[O:11])(=[O:10])[NH:12]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)c1ccccc1Cl
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=CC1CCCCC1
Product: O=S1(=O)NC(C2CCCCC2)Nc2ccc(-c3ccccc3Cl)cc21

Procedure:
5-Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H (using 2-chlorophenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). M.p. 233–236° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[P:24]1(=[O:29])[O:28][CH2:27][CH2:26][O:25]1>C(OCC)C>[O:29]=[P:24]1([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][CH:9]=2)[O:28][CH2:27][CH2:26][O:25]1
Reactant: O=P1(Cl)OCCO1
Reactant: C=Cc1ccc(COCCCCO)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=Cc1ccc(COCCCCOP2(=O)OCCO2)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
4-Hydroxy-1(4′-vinylbenzyloxy)butane (5) (10.03 g; 48.69 mmol) and dried triethylamine (4.92 g, 48.69 mmol) were dissolved in dry diethyl ether (150 ml) and the resulting solution placed in a rigorously dried flask. The solution was cooled to -−30° and 2-chloro-2-oxo-1,3,2-dioxaphospholane (6.94 g; 48.69 mmol) added dropwise over 30 minutes, the temperature being held at −30°. The reaction mixture was then stirred for a further 2 hours, during which time the temperature was allowed to rise to 10°. The mixture was filtered and the precipitate washed with dry ether. The filtrate was evaporated (20°/21 mm) to give a cloudy oil. The residue was shaken with 50 ml of dry ether and refiltered. Evaporation of the filtrate gave the product as a viscous yellow oil (13.73 g; 90.4%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[SH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:27][N:18]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:21])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[NH:10][C:9]([C:7]1[S:8][CH:4]([CH2:3][CH2:2][S:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:5][N:6]=1)=[CH:17]2
Reactant: CN(c1cccc2cc(C3=NCC(CCCl)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CSCCC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of N-{2-[5-(2-chloroethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (100 mg) in N,N-dimethylformamide (3 mL) were added potassium carbonate (65 mg) and ethyl mercaptoacetate (50 μL), and the mixture was stirred overnight at 50° C. Potassium carbonate (20 mg) was added to the reaction mixture, and the mixture was stirred at 50° C. for 3 hr, and cooled to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (60 mg, yield 50%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 524 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][C:12]([CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:37][CH:38]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(CCCc1ccccc1)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Sodium hydride (55% suspension in oil, 0.48 g) was added to a solution of diethyl 2-(3-phenylpropyl)malonate (2.78 g) in a mixture of N,N-dimethylacetamide (10 ml) and toluene (20 ml). The mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture 4-benzyloxybenzyl chloride (2.45 g) was added and the mixture was stirred at ambient temperature for 30 minutes and then at 60° C. for 30 minutes. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=9/1 as the eluant to afford the desired compound (3.91 g) as a syrup.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][C:10](=O)[CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].Cl.[Br:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)N)=[CH:17][CH:16]=1.C(O)(=O)C.C(Cl)(=O)C>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[C:22]3[C:23](=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:9]([CH2:8][C@@H:2]([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[C:10]2[CH3:11])=[CH:17][CH:16]=1
Reactant: COC(=O)C[C@H](C)CCC(C)=O
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: COC(=O)C[C@H](C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of ketone from Step 3 (92 mg, 0.3 mmol), N-(4-bromobenzyl)-N-(4-methoxyphenyl))hydrazine (52 mg, 0.3 mmol) from Example 1, Step 5, acetic acid (36 mg, 0.6 mmol) and toluene (3 mL) was stirred at room temperature for 1.5 h. The solvent was evaporated and replaced by ethanol (3 mL). Then acetyl chloride (110 mg, 5 eq) was added and the mixture was heated at 60° C. for 45 min. After evaporation of the ethanol, the mixture was chromatographed on silica gel, eluting with a 1:3 mixture of EtOAc and hexane, to afford the product as an oil which solidified (80 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]([O:16]C1CCCCO1)[CH3:15].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]([OH:16])[CH3:15]
Reactant: CC(COc1c([N+](=O)[O-])ccc(F)c1F)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(O)COc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.35 g of 2,3-difluoro-6-nitro-{[2-(tetrahydropyran-2-yl)oxypropyl]oxy}benzene (I, Xa=Xb=F, Rc=THP), 60 ml of anhydrous ethanol and 640 mg of pyridinium tosylate was stirred at room temperature overnight and then heated under refluxing for 1 hour. The solvent was removed under reduced pressure. To the residue were added ethyl acetate and 1 N hydrochloric acid. The mixture was shaken, and the organic layer was separated. The organic layer was washed successively with a saturated sodium bicarbonate aqueous solution and water, then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield the oily titled compound. This product was used in the following reaction without purification.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:15][C:16]1[C:17]([N:27]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[C:8]1[N:13]=[C:12](Cl)[N:11]=[CH:10][N:9]=1.C(N(C(C)C)CC)(C)C.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:15][C:16]1[C:17]([N:27]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[C:8]1[N:13]=[C:12]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[N:11]=[CH:10][N:9]=1
Reactant: Cc1cccc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncnc(Cl)n3)c(N(CC3CC3)CC3CC3)nc12
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncnc(N4CCOCC4)n3)c(N(CC3CC3)CC3CC3)nc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
A mixture of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(4-chloro-[1,3,5]triazin-2-yl)-amino]methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine (Example 117) (60 mg, 0.09 mmol), diisopropyl ethylamine (13 μL, 0.1 mmol) was taken in DMF (10 mL). The flask was cooled to 0° C. and the contents were stirred for 5 min. To this, morpholine (12 μL, 0.13 mmol) was added and the stirring was continued for 30 min at 0° C. and then warming up to room temperature. Contents of the flask were taken in 100 mL EtOAc and washed with water (100 mL×3). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography; (silica gel 230-400 mesh). Elution with 2% EtOAc in hexane afforded 58 mg of colorless mass (yield: 78%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:4][OH:5].[CH3:12][O:13][CH:14]([OH:19])[C:15](OC)=O.C(O)(=O)C>CO.[Pd]>[CH:6]1([CH:3]([CH2:4][OH:5])[CH2:2][NH:1][CH2:15][C:14]([O:13][CH3:12])=[O:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(O)OC
Reactant: NCC(CO)C1CCCCC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CNCC(CO)C1CCCCC1
Yield: 53.4 %

Procedure:
A solution of 3-amino-2-cyclohexyl-1-propanol (1 g, 6.37 mmole) and methyl glyoxylate methylhemiacetal (790 mg, 6.56 mmole; see Tetrahedron, 881, 1977) in methanol (9 ml) was stirred at room temperature under argon for 24 hours. The resulting solution was transferred to a Parr bottle, treated with additional methanol (22 ml), acetic acid (3.6 ml), and 10% Pd on carbon (857 mg) and hydrogenated at 50 psi overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo. Acetic acid was removed by evaporation from toluene. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was extracted with additional HCl and the combined aqueous extracts were washed with ethyl acetate. The pH of the product rich aqueous solution was raised to 10.2, and sodium chloride was added to saturation. Extraction with ethyl acetate followed by drying (sodium sulfate), filtration and concentration in vacuo produced 780 mg (53%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]([CH3:15])[C:10]([O:12]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH2:24][Mg+].[Br-]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([C:10]1([OH:12])[CH2:24][CH2:23]1)[CH3:15])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC[Mg+]
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: C[C@H](N(Cc1ccccc1)Cc1ccccc1)C1(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 26 (8.80 g, 29.5 mmol) and titanium tetraisopropoxide (1.28 g, 5.90 mmol) in dry THF (100 mL) was added EtMgBr (30 mL, 90 mmol, 3.0 N in THF) at 0° C. After stirring at RT overnight, the mixture was cooled to 0° C. and quenched with NH4Cl solution. The solid was filtered off and filtrate was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (20:1) to afford 7.5 g (90%) of 7.5 g (90%) of (S)-1-(1-(dibenzylamino)ethyl)cyclopropanol (28). LCMS (ESI) m/z: 282.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C(Cl)[Cl:30]>>[ClH:30].[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH2:6][CH2:7][NH:8][C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Reactant: ClCCl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)cc2c1CCN2
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 2000 ml flask were added of methyl 6-bromo-1H-indole-4-carboxylate 54.1.A (20.0 g, 78.7 mmole), 500 ml of DCM, 100 ml of TFA and triethylsilane (19 ml, 236 mmole). The reaction was stirred at room temperature for 16 hours at which time the reaction was partitioned between 1500 ml of DCM and 500 ml of saturated sodiumbicarbonate and the solvent was removed. The crude solid was resuspended in a 1 to 1 mixture 300 ml of EtAc/hexane and then HCl added (24 ml of 4N in Dioxane, 94.4 mmole), at which time the product crashed out. The solid was collected and dried to give of methyl 6-bromoindoline-4-carboxylate HCl 54.1.B as an off white solid (19.1 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:28][CH:29]=4)=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[F:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>CO.C(Cl)(Cl)Cl>[F:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:17]=[N:16][C:15]4[C:14]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[N:13][C:12]([C:24]5[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[N:28][CH:29]=5)=[N:11][C:10]=4[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)(=[O:53])=[O:52])=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(N)c4)cc3n2)cn1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NS(=O)(=O)c5ccc(F)cc5)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
To a 25 mL flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (Example 7, Step 2) (0.1 g, 0.0002 mol) and pyridine (4 mL) were added. To the same flask, 4-fluorobenzenesulfonyl chloride (0.038 g, 0.0002 mol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with 10% methanol in chloroform and washed with water. The organic layer was washed with brine, dried over sodium sulfate and was evaporated to provide the crude product. The crude product was purified by flash column chromatography (3% methanol in chloroform) to obtain the title compound (0.06 g, 45%). 1H NMR (300 MHz, DMSO-d6): δ 10.57 (s, 1H), 10.42 (s, 1H), 9.48 (s, 1H), 8.98 (d, J=2.1 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 7.91 (dd, J′=5.1 Hz, J″=3.9 Hz, 2H), 7.65 (d, J=7.8 Hz, 1H), 7.56 (s, 1H), 7.45 (dd, J′=8.7 Hz, J″=1.5 Hz, 3H), 7.23 (d, J=7.8 Hz, 1H), 4.57 (br s, 4H), 3.83 (br s, 4H), 1.49 (s, 9H). LC-MS (ESI): Calculated mass: 658.2; Observed mass [M+H]+: 658.9 (RT=1.69 min).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH:11]=[CH:12][CH:13]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[F:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B (K2CO3) using 1-(3-fluorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33]>O1CCCC1.ClCCl.CO>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1

Procedure:
The procedure described in Example 1 (step 1.4.) is used. Starting with 0.66 g (1.51 mmol) of 2-(ethyloxy)-2-oxo-ethyl 4-{6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl}-1-piperazinecarboxylate, obtained in step 10.2., and 3 ml (6.02 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 96/4 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 0.50 g of product is obtained in the form of a white solid.