Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][C:19]1[CH:63]=[CH:62][C:22]([O:23][CH2:24][C@@H:25]([OH:61])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:60]=[CH:59][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[CH:48]=[CH:47][C:46]([NH:49][C:50]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:51])=[CH:45][CH:44]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:53]([NH:52][C:50]([NH:49][C:46]1[CH:45]=[CH:44][C:43]([C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:59]=[CH:60][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:61])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:63][CH:62]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])=[CH:48][CH:47]=1)=[O:51])[CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCCNC(=O)Nc1ccc(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)Nc1ccc(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 50 %

Procedure:
N-[4-({4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}carbonyl)phenyl]-N′-hexylurea (0.160 g, 0.180 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.06 g, 0.09 mmol).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:23][CH2:24]1
Reactant: ICCC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CCC4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and (2-iodoethyl)cyclohexane.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=1[CH:8]=[O:9].[NH4+].[Cl-]>C1COCC1>[CH:1]([CH:8]([C:7]1[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:6]=1[F:5])[OH:9])=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
52.6 ml (0.0526 mol) of a 1M solution of vinylmagnesium bromide in THF are added dropwise at a temperature below 25° C. to a solution of 10.1 g (0.0526 mol) of 2-fluoro-5-(trifluoromethyl)benzaldehyde (prepared according to Example P) in 53 ml of anhydrous THF. The mixture is then stirred for 2 h 30 at room temperature. Hydrolysis is carried out with a saturated aqueous NH4Cl solution while cooling between 10° and 20° C.; extraction is carried out with ether and the extract is washed with water, dried over Na2SO4, filtered and evaporated under vacuum. The residue is used without subsequent purification in the following stage. Yd.: 11.6 g (quantitative)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:22]([CH2:33][CH3:34])[C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH:27](Br)[C:26]1=O)=[O:24])[CH3:21]>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:33]([N:22]([CH2:20][CH3:21])[C:23]([CH:25]1[C:26]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=3)[N:12]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:27]=2[CH2:28][CH2:29][CH2:30]1)=[O:24])[CH3:34]
Reactant: CCN(CC)C(=O)C1CCCC(Br)C1=O
Reactant: O=C(COCc1ccccc1)Nc1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 3.6 %

Procedure:
A mixture of 2-benzyloxy-N-(4-fluoro-phenyl)-acetamide (33) (5.3 g, 22 mmol) and 3-bromo-2-oxo-cyclohexanecarboxylic acid diethylamide (35) (3.0 g, 13 mmol)) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (30 mL) and dry zinc chloride (9.0 g, 66 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with 2 N HCl (100 mL), water (2×100 mL) and aqueous potassium carbonate solution (2×100 mL) then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10-50% B, 100 g) to afford 196 mg (11%) of 9-(2-benzyloxy-ethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (36) as a white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.14 (3H, t, J=7 Hz, N(CH2CH3)2), 1.30 (3H, t, J=7 Hz, N(CH2CH3)2), 1.60-2.60 (4H, m, 2- and 3-CH2), 2.70-2.85 (2H, m, 1-CH2), 3.10-3.65 (4H, m, N(CH2CH3)2 and NCH2CH2OBn), 3.66-3.75 (1H, m, 4-CH), 4.00-4.25 (2H, m, NCH2CH2OBn), 4.41 (2H, s, OCH2Ph), 6.75-6.95 (2H, m, NCCHCHCFCH), 7.05-7.15 (1H, m, NCCHCHCFCH), and 7.16-7.25 (5H, m, Ph).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][N:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c3nnsc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (60 mg, 0.14 mmol) in CH2Cl2 (3 mL) was added triethylamine (43 mg, 0.42 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (31 mg, 0.21 mmol) and DMAP (5 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (75 mg, 100% yield). 1H NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.75-7.73 (d, 2H), 7.34 (m, 1H), 3.34 (m, 1H), 1.68 (m, 2H), 0.85 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH2:14]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccccc2CC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of 528 mg (3.0 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) in 45 mL of absolute methanol at room temperature was treated with 4.5 g of powdered 3A molecular sieves followed by dropwise addition of a solution of 954 mg (9.0 mmol, 3 eq.) of benzaldehyde in 15 mL of methanol. The pH of the mixture was adjusted to 7 by addition of trifluoroacetic acid then stirred at room temperature for 2 hours. Sodium cyanoborohydride (18 mL of 1.0M THF solution; 18 mmol, 6 eq.) was added and the mixture stirred at room temperature for 18 hours. The mixture was filtered and the filtrate treated with 3 mL of trifluoroacetic acid with stirring for 3 hours, then all volatiles removed under vacuum and the residue dissolved in 50 mL of ethyl acetate. The ethyl acetate solution was washed with water (3×15 mL), saturated aqueous sodium bicarbonate (2×15 mL) and 15 mL of brine then dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by chromatography on silica, eluting with ethyl acetate/hexane (70:30), to afford 410 mg (1.54 mmol, 51%) of the product. 1H NMR (200 MHz,CDCl3): 2.05 (m,1H), 2.5-3.0 (m,3H), 3.37 (dd;7,11 Hz;1H), 3.57 (d,12 Hz,1H), 3.90 (d,12 Hz,1H), 7.05 (d,8 Hz,1H), 7.1-7.4 (m,8H), 7.75 (br s,1H). FAB-MS: calculated for C17H18N2O 266; found 267 (M+H,75%).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][S:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>O1CCCC1.C(OCC)(=O)C>[CH3:14][S:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:3][C:1]#[N:2])=[CH:18][CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CSc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(C=CC#N)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl cyanomethylphosphonate (5.3 ml) in tetrahydrofuran (10 ml) was added dropwise to an ice-cooled mixture of sodium hydride (60%, 1.3 g) in tetrahydrofuran (40 ml). The mixture was stirred at 5° C. for 15 minutes. To the resulting mixture was added a solution of 4-(methylthio)benzaldehyde (5 g) in tetrahydrofuran (10 ml) at 5 to 10° C. The mixture was stirred at ambient temperature for 5 hours, diluted with ethyl acetate, and washed with water. The organic layer was dried and concentrated under reduced pressure. The residue was washed with a small amount of ether and dried to give pale brown crystals of 3-[4-(methylthio)phenyl]acrylonitrile (4.7 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13](CS([O-])(=O)=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].[Cl:21][C:22]1[C:23]([OH:29])=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:21][C:22]1[C:23]([O:29][CH:13]2[CH2:12][CH2:11][N:10]([C:7]3[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=3)[CH2:15][CH2:14]2)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1
Reactant: CCCc1cnc(N2CCC(CS(=O)(=O)[O-])CC2)nc1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3Cl)CC2)nc1
Temperature: 120 °C

Procedure:
A mixture of 1-(5-propylpyrimidin-2-yl)piperidin-4-ylmethanesulfonate (800 mg, 2.67 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (389 mg, 2.67 mmol, AK Scientific) and cesium carbonate (2612 mg, 8.02 mmol) in DMF (20 mL) was heated at 120° C. for 6 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and washed with H2O (3×). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The residue was purified by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2) to give the desired product as a yellow solid. MS (ESI) 379 (M+H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:7]=[CH:8][C:9](/[C:14](/[C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=2)=[CH:15]/[C@@H:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:19](=[O:32])[CH2:18][CH2:17]2)=[N:10][C:11]=1[O:12][CH3:13])(=[O:5])[CH3:4].O>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33](/[C:14](/[C:9]2[CH:8]=[CH:7][C:6]([CH:3]([OH:5])[CH3:4])=[C:11]([O:12][CH3:13])[N:10]=2)=[CH:15]\[C@@H:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:19](=[O:32])[CH2:18][CH2:17]2)=[CH:34][CH:35]=1)([CH3:40])([CH3:41])[CH3:42]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)=O)c(OC)n2)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)O)c(OC)n2)c(OC)c1
Reaction time: 0.67 h

Procedure:
Sodium borohydride (108 mg) was added to a solution of (5R)-5-[(E)-2-(5-acetyl-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Example 4-175(1) (773 mg) in methanol under ice-cooling, followed by stirring for 40 minutes. The reaction solution was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→1:1) to give (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(1-hydroxyethyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless amorphous (388 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:38])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:6]([CH:12]([O:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3COCC[Si](C)(C)C)[CH3:13])=[N:7]2>CO.Cl>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:38])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:6]([CH:12]([O:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][NH:19]3)[CH3:13])=[N:7]2
Reactant: Cc1cccc2nc(C(C)Oc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl
Solvent: CO
Product: Cc1cccc2nc(C(C)Oc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 40 °C

Procedure:
Compound 182 (0.053 g, 0.1 mmol) was dissolved in a mixture of methanol (2 mL) and 4M HCl (2 mL). The mixture was stirred and heated to 40° C. for 3 h. The reaction mixture was removed from the heat source and allowed to cool. The reaction mixture was then filtered through a plug of GFA (glass fiber) filter paper and the filtrate concentrated to only remove the methanol. The residue was adjusted to pH 10 by addition of 10% potassium carbonate solution. The resulting solid was collected by filtration and purified by RP-HPLC (C18 Luna column, 10×250 mm, 4.7 mL/min, 10-90% CH3CN in water in 18 min, with all solvents containing 0.05% formic acid) to give compound 176 as a fluffy white solid after lyophilization. 1H NMR (400 MHz, d6-DMSO) δ13.40, br s, 1H; 8.40, s, 1H; 8.35, s, 1H; 7.66, t, J=7.8 Hz, 1H; 7.48-7.58, m, 4H; 7.31-7.36, m, 2H; 7.20-7.23, m, 1H; 5.65, q, J=6.6 Hz, 1H; 2.73, s, 3H; 1.65, d, J=6.6 Hz, 3H. ESI-MS m/z=399 (MH+). The reaction described above and compound 176 are shown below.
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=12.[F:13][C:14]1[CH:36]=[CH:35][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27]O)[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[C:29]1([CH:26]([N:23]2[CH2:22][CH2:21][CH:20]([C:18](=[O:19])[C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:36][CH:35]=3)[CH2:25][CH2:24]2)[CH2:27][N:5]2[C:4](=[O:8])[N:3]3[CH2:9][CH2:10][CH2:11][CH2:12][C:2]3=[N:1][C:6]2=[O:7])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(C(CO)c2ccccc2)CC1
Reactant: O=c1nc2n(c(=O)[nH]1)CCCC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(C(Cn2c(=O)nc3n(c2=O)CCCC3)c2ccccc2)CC1

Procedure:
In the manner described in Example 1-2), 6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione obtained in Example 1-1) and 4-(4-fluorobenzoyl)-1-(1-phenyl-2-hydroxyethyl)piperidine were condensed in N,N-dimethylformamide in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:25][C:24]([NH:28][C:29]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:5]2[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]4[NH:14][CH:15]=[CH:16][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:18][CH:19]=1)=[O:30])([CH3:27])[CH3:26]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: CC(C)(C)N=C=O
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)NC(C)(C)C)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and tert-butyl isocyanate provided the title compound. ESMS [M+H]+: 403.2
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[CH:4][N:3]=1.[Cl-].[NH4+:16]>C(O)C.N>[NH2:16][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Clc1ncncc1Oc1ccccc1
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: Nc1ncncc1Oc1ccccc1

Procedure:
4-Chloro-5-phenoxy pyrimidine is dissolved in absolute ethanol saturated with ammonia and added ammonium chloride, and heated in a stainless steel pressure bomb at about 160°C. for approximately 6 hours. The ethanol is removed under vacuum, and the oily residue taken up in ether. Concentration of the ether extract gives 4-amino-5-phenoxy pyrimidine as a yellow solid which is taken up in hot ethyl acetate, treated with activated charcoal, filtered and cooled to provide white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:21]=[C:22]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:23]([C:24](O)=[O:25])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:40][C:38]=2C=1.CCN=C=NCCCN(C)C.CN.Cl.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:21]=[C:22]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:23]([C:24]([NH:40][CH3:38])=[O:25])=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)O)c2cc1OCc1ccccc1)S(C)(=O)=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(C)S(C)(=O)=O)c(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
5-(benzyloxy)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylic acid (3 g, 6.4 mmol), HOBT (1.3 g, 9.6 mmol) and EDCI (2.5 g, 12.8 mmol) in DMF (50 mL) was allowed to stir at room temperature. After 30 minutes, CH3NH2.HCl (857 mg, 12.8 mmol) and Et3N (1.3 g, 12.8 mmol) were added to the mixture, and the mixture was allowed to stir overnight at room temperature. After the solvent was removed, H2O and NaHCO3 (aq.) were added and the mixture was stirred at room temperature for 1 hour. After filtration, the cake was washed with H2O and dried to give pure 5-(benzyloxy)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (3 g, yield: 97%). 1H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 7.86 (s, 1H), 7.56˜7.59 (m, 2H), 7.35˜7.44 (m, 5H), 7.16 (t, J=8.8 Hz, 2H), 5.41 (br s, 1H), 5.15 (s, 2H), 3.22 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 2.71 (s, 3H). MS (M+H)+: 483.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[OH:14][C:15]1([CH3:31])[CH:20]2[CH2:21][NH:22][CH2:23][CH:16]1[CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2>C(#N)C.O>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:22]2[CH2:21][CH:20]3[C:15]([OH:14])([CH3:31])[CH:16]([CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[CH2:23]2)=[CH:7][CH:8]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)C2(C)O
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)C2(C)O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
4-[(2S)-Oxiranylmethoxy]benzonitrile (from step (v) above, 247 mg, 1.4 mmol) was added to a stirred solution of tert-butyl 9-hydroxy-9-methyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (iv) above, 328 mg, 1.28 mmol) in acetonitrile:water (4:1). The reaction was heated to 60° C. for 12 h, after which stirring was continued at rt for a further 48 h.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:30]1([CH2:36][C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=3)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A suspension of 6.9 g (30 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 12.6 ml (90 mmol) of triethylamine, and 300 ml of dichloromethane is stirred at 0°-5° and 12 ml (94.5 mmol) of chlorotrimethylsilane is added. The reaction mixture is stirred at room for 1 hr and is cooled with a dry ice-acetone bath and 4.6 ml (35 mmol) of phenylacetyl chloride is added. The solution is stirred overnight while warming to room temperature. The dichloromethane is evaporated and water is added. The solid is filtered, washed with water and ether, and dried to give 7.0 g of 6-[4-(phenylacetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>280° after crystallization from 100 ml of N,N-dimethylacetamide.
Reaction SMILES: [C:1]1([P:7]([Cl:9])Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+]#N)=[CH:14][CH:13]=1)#[N:11].F[B-](F)(F)F.[Al]>>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[Cl:9])=[CH:14][CH:13]=1)#[N:11]
Reactant: ClP(Cl)c1ccccc1
Reactant: N#Cc1ccc([N+]#N)cc1
Agent: F[B-](F)(F)F
Agent: [Al]
Product: N#Cc1ccc(P(Cl)c2ccccc2)cc1
Yield: 47 %

Procedure:
In this process, the reaction product of phenyldichlorophosphine and p-cyanophenyl-diazonium-tetrafluoroborate has to be subjected to a reduction with aluminum in order to obtain the p-cyanophenyl-phenylchlorophosphine. The yield is 47 % of the theoretical yield. This process can be carried out only with difficulty on a large scale, and the formation of large amounts of fluorine containing waste secondary products creates the problem of the pollution-free destruction thereof.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CC(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:19]1[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=1)[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1ccc(COc2ccc3c(c2)CCN3)cc1
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc(OCc5ccccc5)ccc43)c2cc1OC
Yield: 90 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 90% yield from 5-benzyloxy-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 181°-182° C.; LC-MS: 415 (MH+); anal. RP18-HPLC RT: 4.78 min.).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.Br[C:19]1[C:20]2[N:21]([C:26]([F:29])=[CH:27][N:28]=2)[N:22]=[C:23]([Cl:25])[CH:24]=1>CCO>[Cl:25][C:23]1[CH:24]=[C:19]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:20]2[N:21]([C:26]([F:29])=[CH:27][N:28]=2)[N:22]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Fc1cnc2c(Br)cc(Cl)nn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2cc(Cl)nn3c(F)cnc23)cc1
Temperature: 80 °C

Procedure:
p-Phenetidine (0.044 ml, 0.34 mmol) and triethylamine (0.1 ml, 0.75 mmol) were added to a mixture of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine (0.085 g, 0.34 mmol) from 1a in EtOH (1.7 mL). The mixture was heated to 80° C. and stirred for 16 hors. The solution was then concentrated in vacuo to give crude 6-chloro-N-(4-ethoxyphenyl)-3-fluoroimidazo[1,2-b]pyridazin-8-amine.