Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[C:8]([CH3:13])[C:6]=2[N:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(CO)sc2c(N3CCOCC3)nc(Cl)nc12
Reaction time: 2 h

Procedure:
To a suspension of 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (400 mg, 1.34 mmol) in methanol at 0° C. was added sodium borohydride. After stirring for 2 hours, the mixture was quenched with 50:50 H2O:NaHCO3 (sat. aq). The methanol was removed under reduced pressure to give a suspension which was filtered and washed with H2O followed by ether to give (2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36](F)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]2=[O:50])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36]([N:11]4[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]4)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:30]2=[O:50])=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCC(NC(=O)OC(C)(C)C)C4)cc32)cc1
Yield: 86.7 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.28 g, 1.5 mmol), triethylamine (0.2 mL, 1.5 mmol), and 1-(4-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example C-1, 0.2 g, 0.5 mmol) provided 0.25 g of the title compound as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@H:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)[C@@H]1COCCN1
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 86.3 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.55 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.48 g, 86%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:23])[CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5([OH:23])[CH2:22][CH2:21][CH2:20]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCC4)n3)c2n1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2nc(N)nc3c2nnn3Cc2cccc(C3(O)CCC3)n2)c1
Yield: 16 %

Procedure:
Prepared from 7-chloro-3-{6-[1-hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 3-methoxyphenylboronic acid by the method described in Example 7 to give the title compound (0.04 g, 16%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.Cl>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CCC(COc2ccc(N)cc2)CC1
Yield: 81.7 %

Procedure:
A solution of 1-methyl-4-(4-nitrophenoxymethyl)piperidine (24) (1.0 g, 4.0 mmol), MeOH (20 mL), and concentrated HCl (1 mL) was hydrogenated over Pd/C (10%, 100 mg) at 58 psi H2 for 1 h at room temperature. Then, the solid was removed by filtration through Celite, which was washed thoroughly with MeOH (200 mL), and the filtrate was concentrated in vacuo. The residue was dissolved in water (50 mL) and the resulting solution was adjusted to pH 10 with a saturated aqueous solution of NaHCO3 and 2 M NaOH. The mixture was extracted with CH2Cl2 (3×100 mL), dried (MgSO4), and the solvent was removed in vacuo. Purification by column chromatography (CH2Cl2/MeOH, 10:1, 2% NEt3) gave 25 (0.72 g, 82%) as a reddish brown solid. 1H NMR (300 MHz, CDCl3): δ=1.31-1.48 (m, 2 H, 3′-Hax, 5′-Hax), 1.66-1.89 (m, 3 H, 3′-Heq, 4′-H, 5′-Heq), 1.96 (dt, J=11.9, 2.3 Hz, 2 H, 2′-Hax, 6′-Hax), 2.28 (s, 3 H, NMe), 2.84-2.93 (m, 2 H, 2′-Heq, 6′-Heq), 3.41 (sbr, 2 H, NH2), 3.73 (d, J=6.4 Hz, 2 H, OCH2), 6.60-6.67 (m, 2 H, 3-H, 5-H), 6.70-6.76 (m, 2 H, 2-H, 6-H) ppm. —13C NMR (75.5 MHz, CDCl3): δ=29.1 (C-3′, C-5′), 35.3 (C-4′), 46.4 (NMe), 55.4 (C-2′, C-6′), 73.2 (OCH2), 115.4 (C-3, C-5), 116.3 (C-2, C-6), 139.8 (C-1), 152.2 (C-4) ppm. −MS (70 eV, EI): m/z (%)=220 (3) [M]+, 112 (100) [C7H14N]+. —C13H20N2O (220.31): calcd. C, 70.87; H, 9.15; found C, 70.50; H, 8.94.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([S:22][CH2:23][CH2:24][N:25]4[CH2:34][CH2:33][C:32]5[C:27](=[CH:28][C:29]([O:37][CH3:38])=[C:30]([O:35][CH3:36])[CH:31]=5)[CH2:26]4)=[CH:18][CH:17]=3)[N:15]=2)=[C:5]([N+:39]([O-])=O)[CH:4]=1.Cl.[H][H]>[Fe].CO>[CH3:36][O:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:37][CH3:38])[CH2:26][N:25]([CH2:24][CH2:23][S:22][C:19]1[CH:20]=[CH:21][C:16]([N:14]3[N:13]=[N:12][C:11]([C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[NH2:39])=[N:15]3)=[CH:17][CH:18]=1)[CH2:34][CH2:33]2
Reactant: COc1cc2c(cc1OC)CN(CCSc1ccc(-n3nnc(-c4cc(OC)c(OC)cc4[N+](=O)[O-])n3)cc1)CC2
Reactant: [H][H]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(N)c(-c2nnn(-c3ccc(SCCN4CCc5cc(OC)c(OC)cc5C4)cc3)n2)cc1OC
Yield: 79.1 %

Procedure:
0.2 g of the compound obtained in Step 3, 0.1 g of Iron and 0.15 ml of concentrated HCl were added to 3 ml of methanol, and stirred under 1 atmospheric hydrogen atmosphere for 18 hours. The reaction mixture was filtrated through a cellite pad, the pad was washed with methanol, the filtrate and wash solution were combined, and distilled under a reduced pressure to obtain a residue that gave 0.15 g of the title compound (yield 79%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:24][O:25][CH2:26][CH2:27]Br>O>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:27][CH2:26][O:25][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:13])[NH:7]2
Reactant: COCCBr
Reactant: O=C1CCc2c(O)ccc(O)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1ccc(O)c2c1NC(=O)CC2
Yield: 52.4 %

Procedure:
21.6 g of 5,8-dihydroxy-3,4-dihydrocarbostyril and 19.9 g of potassium carbonate were added to a mixture comprising 480 ml of acetone and 120 ml of water, and the resulting mixture was stirred while refluxing for 30 minutes. 76 g of 2-methoxyethyl bromide was then added thereto followed by stirring while refluxing for 8 hours. The solvent was evaporated, and water was added to the residue. The mixture was extracted with diethyl ether. The aqueous layer was rendered acidic with hydrochloric acid and then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the chloroform evaporated to obtain 15 g of 5-hydroxy-8-(2-methoxyethoxy)-3,4-dihydrocarbostyril as a black oily substance.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:17][CH2:18][C:19](Cl)=[O:20]>O>[CH:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:19](=[O:20])[CH2:18][Cl:17])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(C)NCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)N(CC1OCCO1)C(=O)CCl

Procedure:
N-Isopropyl-N-(1,3-dioxolan-2-ylmethyl)amine (9.5 grams) benzene (100 ml), water (100 ml) and sodium carbonate (10 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-isopropyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:29])[NH:12][C:13]1[C:14]([CH3:28])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26]O)=[CH:20][CH:19]=1)[CH3:9].[F:30][C:31]([F:43])([F:42])[C:32]1[NH:36][N:35]=[CH:34][C:33]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:40]([O:39][C:37]([C:33]1[CH:34]=[N:35][N:36]([CH2:26][C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:28])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:29])=[CH:19][CH:20]=2)[C:32]=1[C:31]([F:30])([F:42])[F:43])=[O:38])[CH3:41]
Reactant: CCOC(=O)c1cn[nH]c1C(F)(F)F
Reactant: Cc1noc(-c2ccc(C#CCO)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(CC#Cc2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {5-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-3-methyl-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.200 g, 0.49 mmol), ethyl 5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.101 g, 0.49 mmol), and triphenylphosphine (0.127 g, 0.49 mmol) in THF (4 mL) was added diisopropyl azodicarboxylate (0.10 mL, 0.49 mmol), and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:26]=[CH:25][C:19](/[CH:20]=[CH:21]/[C:22]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[CH:18][CH:17]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(Br)cc3)nc2n(CC)c1=O
Yield: 21.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.20 g (11.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.78 g (12.2 mmol) of 4-bromocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 930 mg (yield 22%) of Compound 140 as yellow columns.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: ClCCOCCCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.1 %

Procedure:
To a stirred suspension of 2-(4-chlorophenyl)acetonitrile (3.06 g, 20.3 mmol) at 0° C. in DMSO (200 mL) was added NaH (1.79 g, 60% in mineral oil, 44.6 mmol). The reaction was stirred at 0° C. for 15 min then at room temperature for 30 min, resulting in a dark purple solution. To this solution was added 1-chloro-2-(2-chloroethoxy)ethane (3.18 g, 22.33 mmol) dropwise. The resulting mixture was stirred at room temperature overnight before diluting with 50 mL water and neutralizing to pH˜7.0 with 1.0 M aq. HCl. The reaction was extracted with Et2O (3×200 mL) and the combined organics were washed with brine (200 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (10-30% EtOAc/hexane eluent) to provide 4-(4-chlorophenyl)tetrahydro-2H-pyran-4-carbonitrile as a yellow crystalline solid (4.01 g, 89% yield) (Note: This compound does not ionize well on LC/MS. It does not have intense UV absorption at 220 nM. The TLC Rf is 0.6 in 30% EA/Hexane).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:26](OC)=[O:27])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:8]2[C:17]=1[CH2:16][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:9]2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[OH:27][CH2:26][C:6]1[C:5]([CH2:3][OH:2])=[C:17]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N:8]2[C:7]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)cc2)n2c1Cc1ccccc1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(-c2c(CO)c(CO)c3n2Cc2ccccc2C3)cc1
Reaction time: 2 h

Procedure:
A solution of the 3-(4-methoxyphenyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline-1,2-dicarboxylic acid dimethyl ester (3.91 g, 10 mmol) in anhydrous dichloromethane (20 mL) was added dropwise to a stirred suspension of LiAlH4 (0.87 g, 23 mmol) in anhydrous diethyl ether (30 mL) at 10-15° C. The reaction mixture was further stirred for 2 hours after the addition was completed. The mixture was cooled in an ice bath and the excess hydride was destroyed by the sequential addition of water (1.2 mL), 15% aqueous NaOH (1.2 mL), and water (3.6 mL) at 0° C. The inorganic salt was removed by filtration, was washed with hot THF (300 mL), and the combined filtrate and washings was evaporated under reduced pressure to dryness. The solid residue was recrystallized from dichloromethane/ether to give [2-hydroxymethyl-3-(4-methoxyphenyl)-5,10-dihydropyrrolo[1,2-b]-isoquinolin-1-yl]methanol (DA-1106), 2.29 g (68.4%); mp 174-176° C.; 1H NMR (DMSO-d6) δ 3.82 (3H, s, OMe), 4.05 (2H, s, CH2), 4.26 (2H, d, J=5.0 Hz, CH2), 4.45-4.54 (4H, m, CH2 and exchangeable, 2×OH), 4.93 (2H, s, CH2), 7.05 (2H, d, J=8.4 Hz, ArH), 7.17-7.21 (1H, m, ArH), 7.25-7.28 (2H, m, ArH), 7.38 (2H, d, J=8.4 Hz, ArH), 7.37-7.39 (1H, m, ArH); m/z 451.9 (M+H)+ Anal. Calcld. for C21H21NO3 0.2H2O: C, 74.40; H, 6.36; N, 4.13. Found: C, 74.41; H, 6.30; N, 4.13.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1.C1CCN2C(=NCCC2)CC1>C(O)(C)C>[CH3:17][C:18]1[N:19]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH:20]=[CH:21][N:22]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: Cc1nccn1CCCOc1ccc2c(c1)CCC(=O)N2

Procedure:
2.0 Grams (7.0 mM) of 6-(3-bromopropoxy)-3,4-dihydrocarbostyril, 2.2 g (7.7 mM) of 2-methylimidazol and 1.3 ml (8.4 mM) of DBU were dissolved in 80 ml of isopropanol, and the resulting solution was refluxed by heating for 20 hours. The reaction mixture was concentrated, and to the resulting residue was added water, then extracted with chloroform. The chloroform extract was washed with water, dried with anhydrous sodium sulfate, then concentrated. The resulting residue was purified by means of a silica gel column chromatography (eluent: dichloromethane: methanol=20:1), and recrystallized from ethanol-n-hexane to yield 1.0 g of 6- [3-(2-methyl-1-imidazolyl)propoxy]-3,4-dihydrocarbostyril. White powdery substance. Melting point: 141.5°-142.5° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>>[OH:23][CH2:22][CH2:24][NH:25][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Reactant: NCCO
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccccc23)cn1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (12 mg, 0.040 mmol) and ethanolamine (28 μl) by a procedure similar to example 10 and was isolated as off white solid (8 mg, 66%). 1H NMR (CDCl3): 8.03 (brd, J=3.0 Hz, 1H), 7.47-7.35 (m, 3H), 6.91 (brd, J=8.7 Hz, 1H), 6.78-6.73 (m, 2H), 5.56 (brs, 1H), 3.94 (s, 3H), 3.93-3.90 (m, 2H), 3.70-3.56 (m, 2H), 3.48 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[NH:13][N:12]=[CH:11][C:10]=2[NH:14][C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[N:22][C:21]=23)=[O:16])[CH:8]=1)#[N:2].[CH3:28][C:29]1([O:32][CH2:31]1)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:10]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:11][N:12]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[N:13]=2)[CH:8]=1)#[N:2]
Reactant: COc1ccc(C#N)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C#N)cc1-c1nn(CC(C)(C)O)cc1NC(=O)c1cnn2cccnc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 11.3 %

Procedure:
To a solution of N-(5-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.557 mmol) in 20 mL DMF was added isobutylene oxide (0.20 mL, 2.2 mmol) and cesium carbonate (363 mg, 1.11 mmol). The reaction mixture was stirred at 80° C. for 6 hours, then diluted with ethyl acetate and filtered, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 27.2 mg (11%) of desired product. LCMS (ESI) m+H=431.9. 1H NMR (CDCl3, 400 MHz): 69.68 (s, 1H), 8.78 (dd, J=2.0, 6.8 Hz, 1H), 8.71 (s, 1H), 8.56 (q, J=1.6 Hz, 1H), 8.37 (s, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.72 (dd, J=2.0, 8.4 Hz, 1H), 7.1 (d, J=8.8 Hz, 1H), 7.01 (dd, J=4.4, 7.2 Hz, 1H), 4.11 (s, 2H), 3.91 (s, 3H), 1.23 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C@@H:18]1[CH2:20][O:19]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:22][NH2:23]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[C@@H:18]([OH:19])[CH2:20][NH:23][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H]1CO1
Product: CNC[C@H](O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-(2,5-difluoro-phenyl)-ethyl]carbamic acid tert-butylester (0.17 g, 0.57 mmol) and methylamine (7 mL, 2M solution in methanol, 14 mmol; used as solvent) gives the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]1(=O)[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1>>[N:1]1([C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCCC(=O)C1
Reactant: c1ccc2c(c1)CCN2
Product: O=C1C=C(N2CCc3ccccc32)CCC1
Yield: 75.7 %

Procedure:
A mixture of indoline (5.39 g) and cyclohexane-1,3-dione (5.07 g) was heated at ca. 150° for 7 h. After cooling, the mixture was purified by FCC eluting with ethyl acetate: methanol (10:1) to give a solid (7.30 g) which was recrystallised from ethyl acetate: ether (ca. 4:1) to give the title compound (5.08 g), m.p. 85°-86°.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:15]=[C:14]([N:16]([CH3:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]=[C:12]([NH2:24])[N:11]=3)[N:6]=2)[CH2:2]1.FC(F)(F)[CH2:27][CH:28]=[O:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:24][C:12]1[N:13]=[C:14]([N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]=[C:10]([C:7]2[N:6]=[C:5]([CH:3]3[CH2:2][N:1]([C:28](=[O:29])[CH3:27])[CH2:4]3)[O:9][N:8]=2)[N:11]=1
Reactant: O=CCC(F)(F)F
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CNC3)n2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)N1CC(c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.2 %

Procedure:
6-[5-(Azetidin-3-yl)-1,2,4-oxadiazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-triazine-2,4-diamine (Intermediate 149, 85 mg, 0.26 mmol), 3,3,3-trifluoropropanal (32 μL, 0.28 mmol) and acetic acid (45 μL, 0.78 mmol) were combined in DCE (5 mL) and stirred for 3 h at room temperature. Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added and the mixture was heated to 70 C for 5 h. The reaction mixture was cooled at room temperature, concentrated under vacuum and purified by preparative HPLC, Method C, to afford the title compound as a white solid (25 mg, 26%).
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:9]=1[OH:21])#[N:7].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([C:31]12[CH2:38][CH2:37][C:34]([CH2:39]Br)([CH2:35][CH2:36]1)[CH2:33][CH2:32]2)[CH2:29][CH3:30]>O>[C:6]([C:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:9]=1[O:21][CH2:39][C:34]12[CH2:35][CH2:36][C:31]([CH2:28][CH2:29][CH3:30])([CH2:38][CH2:37]1)[CH2:32][CH2:33]2)#[N:7]
Reactant: CCCC12CCC(CBr)(CC1)CC2
Reactant: CCCCCc1ccc(O)c(C#N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCc1ccc(OCC23CCC(CCC)(CC2)CC3)c(C#N)c1C#N
Temperature: 80 °C
Reaction time: 48 h

Procedure:
50 ml of dimethylformamide were added to 0.04 mole of 2,3-dicyano-4-pentylphenol, 0.2 mole of potassium carbonate and 0.04 mole of 4-propyl-1-bicyclo(2,2,2)-octylmethyl bromide. The mixture was stirred at 80° C. for 48 hours. The mixture was then cooled to room temperature and poured into 200 ml of water and the organic phase was extracted. The organic extract was washed with water and dried over magnesium sulfate. After the solvent had been evaporated off, the crude product was recrystallized several times. The pure product has a high melting point of 133.1° C. and a negative DCA.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C@H:16]([C:13]([OH:12])([CH3:15])[CH3:14])[C@@H:17]2[CH3:21])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(F)cc1Cl
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1cc(Cl)c(C#N)cc1F

Procedure:
Using 2-chloro-4,5-difluorobenzonitrile (240 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (390 mg) and lithium carbonate (152 mg), the title compound was obtained as a colorless solid (yield: 200 mg) by an operation similar to that in Example 3.