Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:32][CH:31]([OH:33])[CH2:30][NH:29][CH2:28][CH2:27]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[N:20]=[C:21]([N:26]6[CH2:32][CH:31]([OH:33])[CH2:30][NH:29][CH2:28][CH2:27]6)[CH:22]=[CH:23][CH:24]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: OC1CNCCNC1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5CC5)c4)cc32)n1
Product: OC1CNCCN(c2cccc(-n3ncc4cnc(-c5cncc(C6CC6)c5)cc43)n2)C1
Yield: 17 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 6-(5-cyclopropylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepan-6-ol, 115 was obtained as an off-white solid (25.1 mg, 17%). 1H NMR (400 MHz, DMSO) δ 9.31-9.27 (s, 1H), 9.07-9.00 (dd, J=16.3, 6.5 Hz, 2H), 8.65-8.59 (d, J=5.6 Hz, 1H), 8.48-8.44 (t, J=2.8 Hz, 1H), 8.09-8.03 (t, J=2.0 Hz, 1H), 7.73-7.67 (t, J=8.1 Hz, 1H), 7.20-7.14 (d, J=7.7 Hz, 1H), 6.73-6.68 (d, J=8.5 Hz, 1H), 4.82-4.73 (s, 1H), 4.03-3.87 (m, 3H), 3.74-3.57 (m, 2H), 3.02-2.93 (t, J=5.4 Hz, 2H), 2.87-2.75 (dd, J=13.8, 3.8 Hz, 1H), 2.70-2.60 (dd, J=13.8, 5.9 Hz, 1H), 2.15-2.03 (m, 1H), 1.10-1.02 (m, 2H), 0.92-0.82 (m, 2H); MS (ESI) m/z: 428.2 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:27]([O-:29])=[O:28])[CH2:13][CH2:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:41](O)[CH2:42][OH:43].C1C=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:27]([O-:29])=[O:28])[CH2:13][CH2:14][C:15]2([O:43][CH2:42][CH2:41][O:26]2)[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OCCO
Reactant: COc1ccc(CCC(=O)CCC(Cc2ccc(OC)c(OC)c2)[N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(CCC2(CCC(Cc3ccc(OC)c(OC)c3)[N+](=O)[O-])OCCO2)cc1
Temperature: 25 °C

Procedure:
Into a 1 l. r.b. flask equipped with a Dean-Stark trap was placed 22 g. (0.055 mole) of 1-(3,4-dimethoxyphenyl)-7-(4-methoxyphenyl)-2-nitro-5-heptanone, 2 g. of p-toluenesulfonic acid, 25 ml. of ethylene glycol, and 500 ml. of benzene, the mixture was refluxed until no more water was separated, and then cooled to room temperature. The dark solution was poured into cold dil. NaHCO3 solution and extracted with ethyl acetate. The organic layer was backwashed with water and dried over anhydrous MgSO4. Upon removing solvent by distillation a gray solid was obtained from trituration with ether. Recrystallization from 80% ethanol yielded 25 g. of product as a white solid; m.p. 98°-100° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1F>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([S:26](=[O:28])(=[O:27])[NH2:29])[CH:22]=[CH:23][C:24]=1[O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(COc2ccc(S(N)(=O)=O)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (0.478 g) in anhydrous N,N-dimethylformamide (5 mL) was added sodium hydride (0.280 g). The mixture was stirred at room temperature for 30 minutes, followed by addition of 3-chloro-4-fluorobenzenesulfonamide (0.419 g). The mixture was stirred at 40° C. overnight. The reaction was quenched with water (10 mL), and the mixture was adjusted to pH 7 and extracted with ethyl acetate. The crude product was purified on a silica gel column eluting with 60% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: C(O[C@H]1CC[C@H]2[C@H]3[C@H]([C@@H](F)C[C@]12C)[C@]1(C)C(=CC(=O)CC1)CC3)(=O)C.ClN1C(=O)CCC1=O.[C:34]([O:37][C@H:38]1[CH2:43][CH2:42][C@H:41]2[C@H:44]3[C@H:54]([C@@H:55]([F:57])[CH2:56][C@:39]12[CH3:40])[C@:52]1([CH3:53])[C:47](=[CH:48][C:49](=[O:58])[CH2:50][CH2:51]1)[C@H:46]([Cl:59])[CH2:45]3)(=[O:36])[CH3:35].Cl>C(Cl)Cl.C(O)(=O)C.C(Cl)(Cl)Cl.O.CC(C)=O>[C:34]([O:37][C@H:38]1[CH2:43][CH2:42][C@H:41]2[C@H:44]3[C@H:54]([C@@H:55]([F:57])[CH2:56][C@:39]12[CH3:40])[C@:52]1([CH3:53])[C:47](=[CH:48][C:49](=[O:58])[CH2:50][CH2:51]1)[C@@H:46]([Cl:59])[CH2:45]3)(=[O:36])[CH3:35]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C[C@@H](Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@]12C
Agent: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@]12C
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@]12C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 1.8 g. of 17β-acetoxy-11β-fluoro-4-androsten-3-one in 60 ml. of acetone and 12 ml. of water is combined with 2.6 g. of N-chlorosuccinimide; the reaction mixture is allowed to stand for 1 day at room temperature. Then, the solution is diluted with methylene chloride, washed successively with sodium thiosulfate solution and water, and dried over sodium sulfate. Chromatography of the crude product on silica gel with acetone/hexane yields 1.1 g. of 17β-acetoxy-6β-chloro-11β-fluoro-4-androsten-3-one. This product is dissolved in 100 ml. of chloroform and combined with 6 ml. of glacial acetic acid saturated with gaseous hydrogen chloride. The solution is allowed to stand at 0° for 2 hours and then introduced into ice/water. The precipitate is vacuum-filtered, washed with water, and dried. After purification by means of preparative layer chromatography (hexane/ethyl acetate 7 : 3), 530 mg. of 17β-acetoxy-6α-chloro-11β-fluoro-4-androsten-3-one is isolated as an oil. UV: ε236 = 15,400 (methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[C:13]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[C:26](Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][O:18][CH3:26])[CH:14]=[C:13]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1cc(CO)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCc1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
20 mg of (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanol (Example 140) was dissolved in methylene chloride, and 59 mg of carbon tetrabromide and 47 mg of triphenylphosphine were added under ice-cooling, and the mixture was stirred for 30 minutes. Subsequently, 90 μl of 9.8M sodium methoxide/methanol solution was added thereto, and the mixture was stirred overnight. The reaction solution was diluted with ethyl acetate and was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled of f under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 7 mg of the objective compound as yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:22]
Reactant: COc1ccccc1CN
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: COc1ccccc1CNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-(2-Methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-methoxybenzylamine using method N. NMR; δH [2H6]—DMSO 8.95,(1H, t), 8.02,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.51,(3H, m), 7.26-7.19,(2H, m), 7.00,(1H, d), 6.91,(1H, t), 4.48,(2H, d), 3.83,(3H, s), 2.56,(3H, s), 2.32,(3H, s). LCMS; retention time 3.41 min, MH+ 414.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Br:25])[CH:18]=1.I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Br:25])[CH:18]=1)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(SC)c(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(SC)c(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A solution of diisopropylamine (4.8 mL, 34.27 mmol) in dry tetrahydrofuran (30 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (13.8 mL, 34.27 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (8.57 g, 31.15 mmol) in dry tetrahydrofuran (30 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). The resulting reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (7.85 g, 37.38 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (300 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (9.20 g, 83%) as a light yellow oil: EI-HRMS m/e calcd for C16H21BrO2S (M+) 356.0446, found 356.0435.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)(C)N
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Product: CC(C)(C)Nc1cc(Cl)nc(N)n1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
10 g of 2-amino-4,6-dichloropyrimidine are suspended in 100 ml of ethanol. 44.50 g of tert-butylamine are added. The reaction mixture is refluxed for 48 hours. It is evaporated to dryness. The residue is taken up in 50 ml of water. The mixture is stirred for 1 hour and the precipitate is then filtered off on sintered glass. It is recrystallized from 60 ml of a 50/50 ethanol-water mixture. 9.25 g of 2-amino-4-tert-butylamino-6-chloro-pyrimidine are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:62])[NH:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[N:36]=[C:37]([C@@H:40]6[CH2:44][C@H:43]([CH3:45])[CH2:42][N:41]6[C:46](=[O:56])[C@@H:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])[NH:38][CH:39]=5)=[CH:31][CH:30]=4)=[C:24]([O:57][C:58]([F:61])([F:60])[F:59])[CH:23]=3)[CH2:16][CH2:15]2)[C@@H:10]([CH3:63])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:55][O:54][C:52](=[O:53])[NH:51][C@H:47]([C:46]([N:41]1[CH2:42][C@@H:43]([CH3:45])[CH2:44][C@H:40]1[C:37]1[NH:38][CH:39]=[C:35]([C:32]2[CH:31]=[CH:30][C:29]([C:25]3[CH:26]=[C:27]([Cl:28])[C:22]([NH:21][C:20]([N:17]4[CH2:18][CH2:19][CH:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]5[CH3:63])[CH2:15][CH2:16]4)=[O:62])=[CH:23][C:24]=3[O:57][C:58]([F:61])([F:60])[F:59])=[CH:34][CH:33]=2)[N:36]=1)=[O:56])[CH:48]([CH3:49])[CH3:50]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)N4CCC(N5CCN(C(=O)OC(C)(C)C)C[C@@H]5C)CC4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)N4CCC(N5CCNC[C@@H]5C)CC4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C

Procedure:
A solution of (S)-4-[1-(5-Chloro-4′-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-piperidin-4-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester 2 TFA (6.35 mg, 0.006 mmol; Preparation 24) in 4.0 M HCl in 1,4-dioxane (0.1 mL) was stirred at RT for 30 min and concentrated under vacuum to provide the title intermediate. (m/z): [M+H]+ calcd for C39H50ClF3N8O5 803.35 found 803.8.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1.[NH4+].[Cl-]>O1CCCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C1COC1
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)COC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.6 mol/L in hexanes, 1.33 mL) was added to a solution of 1,4-dibromobenzene (0.50 g) in tetrahydrofuran (5 mL) cooled to −78° C. The solution was stirred at this temperature for 30 min prior to the dropwise addition of 3-oxetanone (0.15 g) dissolved in tetrahydrofuran (2 mL). The solution was warmed in the cooling bath to room temperature overnight. Aqueous NH4Cl solution was then added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was evaporated. The residue was purified by HPLC on reversed phase (acetonitrile/water) to give the title compound. Yield: 0.19 g (39% of theory); Mass spectrum (ESI−): m/z=273/275 (Br) [M+HCOO]−.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2([C:25]#[N:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:57]([C:65]1[CH:66]=[C:67]([C:71](O)=[O:72])[CH:68]=[N:69][CH:70]=1)[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2([C:25]#[N:26])[CH2:24][CH2:23][N:22]([C:71]([C:67]3[CH:68]=[N:69][CH:70]=[C:65]([CH2:57][CH2:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[CH:66]=3)=[O:72])[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(c2cccc(CNC(=O)OCc3ccccc3)c2)CCNCC1
Reactant: O=C(O)c1cncc(CCc2ccccc2)c1
Agent: CCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: N#CC1(c2cccc(CNC(=O)OCc3ccccc3)c2)CCN(C(=O)c2cncc(CCc3ccccc3)c2)CC1
Reaction time: 2 h
Yield: 108.5 %

Procedure:
To a solution of 0.15 g (0.33 mmole) of 4-(3-benzyloxycarbonylaminomethyl-phenyl)-piperidine-4-carbonitrile in 20 ml of acetonitrile was added 0.038 g (0.33 mmole) of N-ethylmopholine followed by 0.11 g (0.33 mmole) of TBTU. To this solution was added 0.075 g (0,33 mmole) of 5-phenethylpyridine-3-carboxylic acid in portions over 10 minutes. The mixture was stirred for 2 hours. The solution was concentrated and the residue was purified by flash chromatography using 95:5 dichloromethane:methanol to provide 0.2 g of product: 1H-NMR (300 MHz, CDCl3)δ (TMS) 1.79-2.20 (m, 4H), 2.70-2.82 (m, 4H), 2.90-3.07 (m, 2H), 3.15-3.70 (m, 2H), 4.35-4.40(d, 2H), 5.07-5.25 (d, 2H), 7.10-7.50 (m, 15H), 8.42-8.58 (m, 2H); MS (ESI) m/e 559 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1ccnc(F)c1
Product: COc1ccc(CNc2cc(C#N)ccn2)cc1
Temperature: 130 °C

Procedure:
Compound 18 was prepared as outlined in Scheme 4. Accordingly, potassium t-butoxide (6.1 g) was added slowly to a stirred solution of tert-butylnitrite (5.5 mL) and 2-fluoro-4-methylpyridine (compound 1001, 4.0 g) in 75 mL of THF at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the crude product extracted with ethyl acetate (4×50 mL). The resulting solid was washed with hexanes to yield (2-fluoropyridin-4-yl)methan-N-hydroxyimine (compound 1002; 4.0 g; ESMS: M+H+=141). Thionyl chloride (2.6 mL) was added slowly to a stirred solution of compound 1002 (4.0 g in 40 mL of THF) at 0° C. After stirring for 1 hour at room temperature, the volatiles were removed in vacuo. The residue was taken up in ethyl acetate (50 mL) and the organics were washed with water and brine. The organics were concentrated in vacuo to give 2-fluoropyridine-4-carbonitrile (compound 1003) as a white solid (3.0 g; ESMS: M+H+=123). Compound 1003 (1.0 g) and 4-methoxybenzylamine were combined and heated at 130° C. for 1 hour. The crude product was partitioned between water and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate and the combined organics dried over Na2SO4, concentrated, and recrystallized from ethyl acetate/hexanes to provide 2-(4-methoxybenzylamino)pyridine-4-carbonitrile (compound 1004; 1.7 g; ESMS: M+H+=238) as pale yellow solid. Compound 1004 (1.6 g) was dissolved in 50 mL of anhydrous ether and 9 mL of 3M methyl magnesium bromide in ether was added. The reaction mixture was stirred at room temperature for 16 hours and poured over ice (c. 50 g), which was subsequently acidified with 6M HCl, followed by basicification with 1M ammonium hydroxide. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organics were concentrated in vacuo and purified by silica gel chromatography to provide 1-(2-(4-methoxybenzylamino)pyridin-4-yl)ethanone (Compound 1005; 1.2 g; ESMS: M+H+=257) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C([BH3-])#N.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Br)c2c1CNCC2
Temperature: 25 °C

Procedure:
Alternatively, a solution of 5-bromo-8-nitroisoquinoline (1.0 g) in glacial acetic acid (30 mL) was cooled to 0° C. and, before freezing, was treated with sodium cyanoborohydride (1.10 g). The reaction mixture was warmed slowly to room temperature under nitrogen. The reaction mixture was diluted with water and basified. Organic layer extracts were chromatographed on silica gel as before.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14]C2C(C3C=CC=CC=3)=C(OCCN)N=C(SC)N=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(C)(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[C:8]1([S:11]([NH2:14])(=[O:13])=[O:12])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccccc2)c(OCCN)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: NS(=O)(=O)c1ccccc1

Procedure:
According to Example 4a) 100 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamide was reacted with 123 mg toluene-4-sulfonylchloride to give 120 mg 4-tert.-butyl-N-[6-(2-(p-methylphenylsulfonyl)-amino)-ethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamide. LC-MS: tR=6.16 min. [M−1]−=625.49.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[C:13]([F:24])=[CH:12][N:11]=1>>[F:24][C:13]1[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)=[N:15][C:10]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1ccc(Nc2nc(Cl)ncc2F)nc1
Product: Cc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)nc1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-5-fluoro-N4-(5-methylpyridin-2-yl)-4-pyrimidineamine gave 5-fluoro-N2-(3-hydroxyphenyl)-N4-(5-methylpyridin-2-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 11.39 (bs, 1H), 10.59 (bs, 1H), 8.58 (s, 1H0, 8.41 (d, 1H, J=3 Hz), 8.12 (d, 1H, J=8.7 Hz), 7.82 (d, 1H, J=8.7 Hz), 7.29 (s, 1H), 7.16 (d, 1H, J=9 Hz), 7.05 (t, 1H, J=8.4 Hz), 6.38 (dd, 1H, 1.2 and 6.9 Hz); LCMS: purity: 99%; MS (m/e): 312 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]C)=[O:12])=[C:4]2[CH2:3]1.[OH-].[Li+].O>C(O)(=O)C>[O:1]=[C:2]1[CH:3]=[CH:4][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:6]2[NH:7]1
Reactant: COC(=O)c1cnn2c1CC(=O)N=C2
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnn2ccc(=O)[nH]c12
Yield: 93.5 %

Procedure:
A solution of methyl 5-oxo-4,5-dihydropyrazolo[1,5-c]pyrimidine-3-carboxylate (0.75 g 3.89 mM, 1.0 equiv), lithium hydroxide (0.466 g, 19.4 mM, 5.0 equiv) and 20 mL of water was stirred at ambient temperature for 3 hours. HPLC indicated complete reaction. Acetic acid (5 mL) was added and the precipitated solid was collected by vacuum filtration to give 0.65 g (93%) 5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ: 12.5 (br s, 1H,), 11.3 (br s, 1H), 8.57 (d, 1H), 8.08 (d, 1H), 6.15 (d, 1H).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([CH3:16])[CH2:12]2)C1C=CC=CC=1.C(O)C>[Pd].O>[CH3:16][N:11]1[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: CN1CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CN1CC2CCC(C1)N2
Reaction time: 20 h

Procedure:
A solution of 8.2 g (0.038 mole) 8-benzyl-3-methyl-3,8-diazabicyclo[3.2.1]octane in 80 ml absolute ethanol containing 0.11 mole dry hydrogen chloride was hydrogenated in the presence of 1.5 g 10% palladium on charcoal at ambient temperature and pressure for 20 hours. The precipitated hydrochloride salt of the desired product was dissolved by addition of a little water, and, after filtration, the solvent was removed carefully in vacuo. The crystalline residue (6.9 g) was triturated with ethanol-diethyl ether containing dry hydrogen chloride to insure complete formation of the somewhat unstable dihydrochloride salt. Filtration gave 6.0 g (79%) of pure product, melting point 272°-280° C (dec.) with sublimation above 200° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.S(OC)(O[CH3:15])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-3-pyridinecarboxylic acid, methyl ester (11) is prepared as follows: a suspension of 22.06 g (140 mmol) of 2-chloro-3-pyridinecarboxylic acid (10), 14.6 mL (154 mmol) of dimethyl sulfate, 29 g (210 mmol) of anhydrous powdered potassium carbonate, and 140 mL of acetone is stirred at room temperature overnight. The mixture is filtered, the salts are washed with acetone, and the filtrate is concentrated to an oil that is diluted with dichloromethane. The organic phase is washed with saturated aqueous sodium dicarbonate, dried, then filtered through a pad of silica gel (230-400 mesh). The filtrate is concentrated to give an oil that is distilled at 90°-91° C./0.17 mm to leave 19.9 g of the pure product as a colorless oil.