Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11](=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=3)=[CH:15][C:14]=2[F:38])=[CH:6][C:5]=1[C:40]([F:43])([F:42])[F:41])(=[O:3])[CH3:2].[CH3:44][Mg]Br.O>C1COCC1>[CH2:26]([O:25][C:23]1[CH:24]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][C:11]([NH:10][C:7]3[CH:8]=[N:9][C:4]([C:1]([OH:3])([CH3:44])[CH3:2])=[C:5]([C:40]([F:41])([F:43])[F:42])[CH:6]=3)=[O:39])=[C:14]([F:38])[CH:15]=2)[CH:20]=[N:21][C:22]=1[O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[CH3:27]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(C(C)=O)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(C(C)(C)O)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a mixture of N-(6-acetyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (100 mg, 0.167 mmol) in THF (10 mL) was added methylmagnesium bromide (0.167 mL, 0.502 mmol). The mixture was stirred at 0° C. for 2 h under a N2 atmosphere. Then the mixture was added to H2O and extracted with EA. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (DCM/MeOH=15:1, Rf=0.6) to yield a yellow solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (70 mg, 0.086 mmol, 51.1% yield): 1H NMR (400 MHz, CD3OD) δ 8.87 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.44-7.40 (m, 3H), 7.29 (d, J=2.4 Hz, 1H), 6.88 (s, 2H) 6.78 (d, J=2.4 Hz, 1H), 5.35 (s, 2H), 4.17-4.11 (m, 2H), 3.83 (s, 2H), 3.77 (s, 3H), 1.59 (s, 6H), 1.41 (t, J=7.1 Hz, 3H); ES-LCMS m/z 494.2 (M-PMB+H).
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:16])=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:34][CH3:35])(=[O:33])=[O:32])[C:21]([Cl:36])=[CH:20][N:19]=1.Cl.O1CCOCC1.[Na]>O>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:34][CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:16][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[CH2:15][CH:13]3[CH2:14][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]2)=[N:19][CH:20]=1
Reactant: CC(C)N1CC2CC(C1)c1cc(N)ccc12
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(C(C)C)C2)ncc1Cl
Temperature: 120 °C
Yield: 20.7 %

Procedure:
10-Isopropy-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (30 mg, 0.14 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (45 mg, 0.14 mmol) and 4N HCl in dioxane (28 μl, 0.15 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 8 g Isco basic alumina column using 0-2% methanol in methylene chloride as the eluent to yield 2-[5-Chloro-2-(10-isopropyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide (14.85 mg, 20%) as a beige foam. 1H-NMR (CDCl3) δ 9.08 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 8.13 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.30 (s, 1H), 7.21 (m, 2H), 7.08 (d, J=7.8 Hz), 6.93 (s, 1H), 4.52 (d, J=2 Hz, 1H), 3.08 (br s, 1H), (3.02 br s, 1H), 2.71 (m, 2H), 2.63 (d, J=5.3 Hz, 3H), 2.56 (m, 3H), 2.30-2.20 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 0.87 (q, J=1.8, 6.6 Hz, 6H); LC/MS (ESI+): 513 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([O:22][CH3:23])[CH2:20][C@@:19]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br.O>CO>[Br:26][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:25])[C@H:8]([C@H:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:24])[C@H:4]([CH2:3][C@H:2]([OH:1])[C@@H:21]([O:22][CH3:23])[CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Reactant: BrBr
Solvent: CO
Solvent: O
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C[C@@H]1O

Procedure:
A stirred solution of 3α-hydroxy-2β-methoxy-5α-pregnan-20-one (4.0 g.) in dry methanol (300 ml.) was treated at 0° with a solution of bromine (0.65 ml.) in methanol (15 ml.) at such a rate that the yellow colour disappeared before further addition. The mixture was then poured into water and the precipitated solid was collected by filtration, washed with water and dried in vacuo to give title compound (4.0 g) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[C:5]2[N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16].I[CH2:21][CH2:22][CH3:23]>>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[C:5]2[N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:22][CH3:23]
Reactant: CCCI
Reactant: CN(C1=CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Product: CCCOc1ccc2c(c1)C(N(C)S(C)(=O)=O)=CC(C)(C)O2

Procedure:
Similar to Example 8b, 0.5 g of N-(6-hydroxy-2,2-dimethyl-2H-chromen-4-yl)-N-methyl-methanesulfonamide was alkylated with 1 -iodopropane, giving 0.36 g of N-(6-propoxy-2,2-dimethyl-2H-chromen-4-yl)-N-methyl-methanesulfonamide; m.p. 93-95° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])C=1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[C:8](=[O:12])[O:9][C:10]3[C:5]([C:6]=2[CH3:21])=[CH:4][CH:3]=[C:2]([O:1][C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])[CH:11]=3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1
Reactant: C[n+]1ccn(C(=O)N2CCOCC2)c1
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N4CCOCC4)cc3oc2=O)cc1
Yield: 60.7 %

Procedure:
The title compound (120 mg, 61% yield, crystals) was prepared from 7-hydroxy-3-(4-methoxy-phenyl)-4-methyl-chromen-2-one (141 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
Reaction SMILES: Br[CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.[Na].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([S:25][CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: CC(=O)c1ccc(OCC=C(C)CBr)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCC=C(C)CSCc2ccccc2)cc1
Reaction time: 20 h

Procedure:
14.15 g (0.05 mol) of 4'-(4-bromo-3-methyl-2-butenyloxy)-acetophenone are added at 10°-15° during the course of 1 hour to 7.3 g (0.05 mol) of sodium salt of benzylmercaptan which is dissolved in 120 cc of dimethylformamide. The mixture is stirred at 20°-25° for 20 hours, is subsequently filtered and the filtrate is evaporated at reduced pressure. The residue is dissolved in ether, is extracted with saturated salt solution and the ether solution is evaporated. The remaining yellowish oil is chromatographed on silica gel with hexane/ethyl acetate 2 : 1. After recrystallization from ether/hexane the 4'-(4-benzylthio-3-methyl-2-butenyloxy)-acetophenone is obtained as colourless crystals. M.P. 75°-76.5°.
Reaction SMILES: [H][H].[Si:3]([O:10][CH2:11][C@@H:12]([CH3:44])[C@H:13]([NH:24]C1(C2C=CC=CC=2)C2C=CC=CC=2C2C1=CC=CC=2)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>CCOC(C)=O.C(Cl)Cl.[Pd]>[NH2:24][C@@H:13]([C@H:12]([CH3:44])[CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4])[C:14]([OH:16])=[O:15]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A balloon of hydrogen was attached to a mixture of (2S,3S)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (836 mg, 1.447 mmol) and 10% Pd/C (213 mg) in EtOAc (16 mL) and the mixture was stirred at room temperature for ˜21 hr, where the balloon was recharged with H2 as necessary. The reaction mixture was diluted with CH2Cl2 and filtered through a pad of diatomaceous earth (CELITE®-545), and the pad was washed with EtOAc (200 mL), EtOAc/MeOH (1:1 mixture, 200 mL) and MeOH (750 mL). The combined organic phase was concentrated, and a silica gel mesh was prepared from the resulting crude material and submitted to a flash chromatography (8:2:1 mixture of EtOAc/1-PrOH/H2O) to afford (2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid as a white fluffy solid (325 mg). (2S,3R)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was similarly elaborated to (2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid. (2S,3S)-amino acid isomer: 1H NMR (Methanol-d4, δ=3.29 ppm, 400 MHz), 3.76 (dd, J=10.5, 5.2, 1H), 3.73 (d, J=3.0, 1H), 3.67 (dd, J=10.5, 7.0, 1H), 2.37 (m, 1H), 0.97 (d, J=7.0, 3H), 0.92 (s, 9H), 0.10 (s, 6H). LC/MS: Anal. Calcd. for [M+H]+ C11H26NO3Si: 248.17; found 248.44. (2S,3R)-amino acid isomer: 1H NMR (Methanol-d4, δ=3.29 ppm, 400 MHz), 3.76-3.75 (m, 2H), 3.60 (d, J=4.1, 1H), 2.16 (m, 1H), 1.06 (d, J=7.3, 3H), 0.91 (s, 9H), 0.09 (s, 6H). Anal. Calcd. for [M+H]+ C11H26NO3Si: 248.17; found 248.44.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([O:16][CH3:17])=[N:10][C:11]([CH3:15])=[CH:12][C:13]=2[CH3:14])[C:5]([F:18])=[CH:4][C:3]=1[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:30]([NH2:32])=[O:31].[Cl-].[NH4+].O>CN1C(=O)CCC1>[F:18][C:5]1[C:6]([C:8]2[C:9]([O:16][CH3:17])=[N:10][C:11]([CH3:15])=[CH:12][C:13]=2[CH3:14])=[CH:7][C:2]2[NH:32][C:30](=[O:31])[C:20]3[CH:21]=[N:22][N:23]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:19]=3[C:3]=2[CH:4]=1
Reactant: COc1nc(C)cc(C)c1-c1cc(F)c(-c2c(C(N)=O)cnn2C2CCOCC2)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1nc(C)cc(C)c1-c1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
KTB (41 mg) was added to a solution of 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide (81 mg) in NMP (0.4 mL), and the mixture was heated to 90° C. After one hour, KTB (20 mg) was further added, followed by stirring for 30 minutes. The reaction mixture was cooled to room temperature, followed by adding a saturated aqueous ammonium chloride solution (2 mL) and water (1 mL). The generated solid was filtered off, washed with water (2 mL) and dried under reduced pressure at 60° C. to give the title compound (57 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[CH:17]OCC)[C:6](=[O:16])[C:7]1[C:8]([Cl:15])=[N:9][C:10]([Cl:14])=[C:11]([F:13])[CH:12]=1)[CH3:2].[CH2:22]([CH2:24][NH2:25])[OH:23]>CCOCC>[Cl:15][C:8]1[N:9]=[C:10]([Cl:14])[C:11]([F:13])=[CH:12][C:7]=1[C:6](/[C:5](=[CH:17]/[NH:25][CH2:24][CH2:22][OH:23])/[C:4]([O:3][CH2:1][CH3:2])=[O:21])=[O:16]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)nc1Cl
Reactant: NCCO
Solvent: CCOCC
Product: CCOC(=O)/C(=C\NCCO)C(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2,6-dichloro-α-(ethoxymethylene)-5-fluoro-β-oxo-3-pyridinepropanoic acid ethyl ester (1.00 g; prepared according to EP 132845) was treated with ethanolamine (0.18 mL). After a few minutes, the reaction mixture became sticky and was diluted with Hept/ether (1:1; 10 mL). After further stirring at rt for 1.5 h, the solvents were evaporated under reduced pressure and the crude yellow oil was directly used in the next step.
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][CH:8]=[CH2:9])[C:5](=[O:10])[CH:4]=[CH:3]1.C(=O)([O-])[OH:13].[Na+]>>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:13])[C:2]=1[CH3:11])[CH:8]=[CH2:9]
Reactant: O=C([O-])O
Reactant: C=CCC1C(=O)C=CC1(C)O
Agent: [Na+]
Product: C=CCC1=C(C)C(O)CC1=O
Yield: 75 %

Procedure:
In 200 ml of a 5% aqueous sodium hydrogencarbonate solution, was dissolved 29 g of 4-hydroxy-4-methyl-5-allyl-2-cyclopentenone. The solution was heated with stirring under reflux for one hour. After having been allowed to cool, the reaction mixture was extracted three times with chloroform. The extract solution was dried over anhydrous magnesium sulfate and freed from the chloroform by distillation. The residue was distilled in vacuo to obtain 21.7 g (75% yield) of 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone boiling at 155° C./1 mmHg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][CH2:10][C@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1>N1C=CC=CC=1>[CH2:1]([N:8]1[C@H:9]([CH3:15])[CH2:10][N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:28])[F:27])[CH:18]=2)[C@@H:12]([CH3:14])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccccc1
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1Cc1ccccc1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A 15 ml portion of pyridine solution containing 0.63 g of (2R,5S)-1-benzyl-2,5-dimethylpiperazine was mixed with 0.7 g of 4-fluoro-2-trifluoromethylbenzonitrile and stirred at 90° C. for 2 days. The reaction mixture was concentrated and the residue was purified by a silica gel column chromatography to obtain the title compound from n-hexane-ethyl acetate (9:2, v/v) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Cl)(=[O:30])=[O:29]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:30])=[O:29]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NCCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCCCCO
Yield: 95.6 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and N-(4-hydroxybutyl)-6-chlorohexanesulfonamide (543.6 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(4-hydroxybutyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (1001.2 mg) as a pale yellow oil (95.6%).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:11][CH2:10][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:8]#[N:9])[CH2:6][CH2:5]1.[ClH:18].S(Cl)([Cl:21])=O>C(Cl)Cl>[ClH:21].[Cl:18][CH2:2][CH2:3][N:4]1[CH2:11][CH2:10][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:8]#[N:9])[CH2:6][CH2:5]1
Reactant: N#CC1(c2ccccc2)CCN(CCO)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: N#CC1(c2ccccc2)CCN(CCCl)CC1

Procedure:
A solution is prepared from 5.9 parts of the nitrile obtained in the preceding paragraph and 134 parts of methylene chloride. This solution is saturated with hydrogen chloride gas at below 10° C. and 5.1 parts of thionyl chloride is added. The mixture is refluxed for 1 hour and then cooled and volatile material is removed under reduced pressure. The residue is dissolved in 88 parts of benzene, and the solution evaporated under reduced pressure. The residue is then crystallized from a mixture of ethanol and ether to give 1-(2-chloroethyl)-4-phenylisonipecotonitrile hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[NH:8][C:5]2=[CH:6][N:7]=1.[NH3:15].O>CCO>[CH:11]1([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([NH2:15])[CH:3]=[C:4]3[CH:10]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N
Reactant: Clc1cc2cc(C3CCC3)[nH]c2cn1
Solvent: CCO
Solvent: O
Product: Nc1cc2cc(C3CCC3)[nH]c2cn1
Temperature: 180 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To the solution of 5-chloro-2-cyclobutyl-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.97 mmol) in EtOH (10 mL) and NH3.H2O (30 mL) was added CuSO4.5H2O (30 mg, 0.12 mmol). The reaction mixture was stirred under 3 MPa at 180° C. for 16 h. The mixture was extracted with ethyl acetate (3×30 mL). The extract was dried, concentrated in vacuo and purified by chromatography on silica gel (5-10% MeOH in ethyl acetate as eluant) to afford the pure 2-cyclobutyl-1H-pyrrolo[2,3-c]pyridin-5-amine (40 mg, 22% yield). 1H NMR (300 MHz, MeOH) δ: 8.02 (s, 1H), 6.72 (s, 1H), 6.11 (s 1H), 3.72-3.60 (m, 1H), 2.47-1.90 (m, 6H). MS (ESI): m/z [M+H+] 188.1.
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([CH2:26][CH2:27][CH2:28][CH3:29])[C:10]1=[O:30])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH2:26]([N:11]1[C:12]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]([F:25])=[CH:16][C:13]=2[C:14](=[O:15])[N:9]([OH:8])[C:10]1=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)nc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)nc21
Yield: 106.6 %

Procedure:
Twenty percent Pd/C (70 mg) was added to a solution of 3-benzyloxy-1-butyl-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example O-4, 0.13 g, 0.32 mmol) in 25 mL of THF, and this was shaken under 50 PSI of hydrogen for 17.5 hours. The mixture was filtered and concentrated to give 0.11 g of the title compound as a solid, mp 153-155° C.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1)[CH:2]=[CH2:3]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3O)nc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: C=CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 9.8 %

Procedure:
Allyl bromide (0.02 g, 0.00023 mol) was added to a stirred suspension of 5-[2-hydroxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.103 g, 0.00023 mol) and potassium carbonate (0.032 g, 0.00023 mol) in 2-butanone (10 ml) and the mixture heated under reflux for 8 hours. After cooling, the reaction mixture was evaporated under vacuum and the residue suspended in water (20 ml). The aqueous suspension was extracted with ethyl acetate (3×20 ml), the combined extracts dried (Na2SO4) and, after filtration, evaporated under vacuum to give an oil. Column chromatography on silica gel (2 g) using a methanol in dichloromethane elution gradient (0-3%), followed by evaporation under vacuum of appropriate fractions, gave a semi-solid which was dissolved in acetone; evaporation under vacuum of the solution gave the title compound (0.011 g, 10%), m.p. 151-153° C., Rf 0.5 (silica; dichloromethane, methanol; 95:5), m/e 87 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH2:25](O)[CH2:26][CH2:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:25][CH2:26][CH2:27][CH3:28])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: CCCCO
Product: CCCCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 77 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 1-butanol (7.4 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 77% yield (18.5 mg). 1H NMR (500 MHz, CDCl3) δ ppm 0.95 (t, J=7.39 Hz, 3 H) 1.37-1.46 (m, 2 H) 1.65-1.72 (m, 2 H) 2.44 (s, 3 H) 4.27 (t, J=6.65 Hz, 2H) 6.88 (s, 1 H) 7.36 (dd, J=8.06, 7.67 Hz, 1 H) 7.42 (ddd, J=8.06, 2.32, 1.22 Hz, 1 H) 7.45 (dd, J=8.67, 1.95 Hz, 1 H) 7.71 (dd, J=8.67, 0.52 Hz, 1 H) 7.70-7.71 (m, 1 H) 7.71 (dd, J=1.95, 0.52 Hz, 1 H) 7.84 (ddd, J=7.67, 1.50, 1.21 Hz, 1 H). MS (ESI+) m/z 438 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][C:14]1=[O:26].[Br:27][C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:27][C:28]1[CH:29]=[N:30][C:31]([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:16]3[CH:17]=[CH:18][N:13]([C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])[C:14](=[O:26])[CH:15]=3)[CH2:21][CH2:22]2)=[N:32][CH:33]=1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCNCC3)cc2=O)c(F)c1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ncc(Br)cn4)CC3)cc2=O)c(F)c1
Temperature: 160 °C
Yield: 53.9 %

Procedure:
A mixture of 1-(2-fluoro-4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-one hydrochloride (100 mg, 0.248 mmol, prepared according to the procedures described in Example 9), 5-bromo-2-chloropyrimidine (144 mg, 0.745 mmol) and cesium carbonate (324 mg, 0.993 mmol) in DMF (3 mL) was placed in a microwave and heated at 160° C. for 20 min. The reaction mixture was diluted with EtOAc (30 mL) and washed with water 3 times. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a crude yellow solid. The residue was purified by flash chromatography (SiO2, 0-100% EtOAc/Hexanes) to give a white solid (70 mg, 53.9%). MS (ESI) 523 (M+H).