Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[C:8](Cl)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>CCOCC.O>[C:8]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(=O)Cl
Reactant: CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCC(=O)NC(C)(C)C(=O)O
Yield: 48.7 %

Procedure:
2-Aminoisobutyric acid (2.0 g, 19.4 mmol) and n-hexanoyl chloride (3.0 g, 22.4 mmol) were reacted in the presence of NaOH (1.6 g, 40 mmol) in a mixture of ether and water using the method described in Example 5, Part A. The title compound (1.90 g, 49%) was obtained after crystallization from benzene, m.p. 141°-143° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[N:6]=[C:5]2[CH3:22].N1C=CC=CC=1.[C:29](Cl)(Cl)=[O:30]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N:11]=[C:29]=[O:30])[N:7]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[N:6]=[C:5]2[CH3:22]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N)cc32)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N=C=O)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (138 mg, 0.36 mmol) was dissolved in 5 ml of toluene at room temperature. DMAP (1 eq, 44 mg), pyridine (1.3 eq, 0.04 ml) were added followed by phosgene (1.33 eq, 0.24 ml of a 20% solution in toluene). The mixture was allowed to stir at room temperature for 2 hours, forming a fine white precipitate. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated in vacuo again to give 5-bromo-6-isocyanato-3-methyl-1-(toluene-4-sulfonyl)-1H-indazole (150 mg, quantitative) as a white crystalline solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6](CN)=[C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:4]=1.FC1C=CC([C:21]#[N:22])=C(N2C=NC=N2)C=1.Cl>C(O)C.[Pd]>[N:11]1([C:5]2[CH:6]=[CH:7][C:8]([C:21]#[N:22])=[C:3]([F:2])[CH:4]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: NCc1ccc(F)cc1-n1cncn1
Reactant: N#Cc1ccc(F)cc1-n1cncn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(-n2cncn2)cc1F
Yield: 99 %

Procedure:
(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride). Intermediate 67, 4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile, (2.46 g, 13.13 mmol) was dissolved in hot ethanol (150 mL). To this was added 1N HCl (15 mL) followed by 10% Pd—C (200 mg). The mixture was treated with H2 at 55 psi for 4 h in a Parr shaker then filtered over Celite and the solvent removed under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The aqueous phase was separated and lyophilized to afford the title compound as a white powder (2.96 g, 99% yield). 1H NMR (500 MHz, CD3OD) δ ppm: 9.51 (1H, s), 8.63 (1H, s), 7.85 (1H, dd, J=8.5, 5.8 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 7.49 (1H, td, J=8.3, 2.4 Hz), 4.20 (2H, s). LCMS (M+H) calcd for C9H10N4F: 193.08. found: 193.16.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([OH:23])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:24])[CH:12]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:24])[CH:12]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c12
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Sodium hydride (54 mg, 1.35 mmol) was added to a solution of 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (380 mg, 1.08 mmol) and DMSO (20, ml) room temperature under N2. After 1 h, ethyl 6-bromohexanoate (770 mg, 3.45 mmol) was added, and the mixture was heated at 30° C. for 5 h. The reaction was quenched with drops of water, poured into 0.5 M KH2PO4, and extracted with ethyl acetate (100 mL×3). The combined extracts were washed with water and then brine, dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate: pet. ether) to give ethyl 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoate: MS (ESI): 494.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[CH:9]1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([O:15][C:33]2[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)=[O:14])[N:10]=[CH:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)O)c3)c(F)c2)C(=O)O1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-carboxyimidazol-1-y l)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (181 mg, 0.5 mM), 4-nitrophenol (139 mg, 1 mM), dicyclohexylcarbodiimide (144 mg, 0.7 mM) and 4-dimethylaminopyridine (61 mg, 0.5 mM) were dissolved in N,N-dimethylformamide (2 ml). The mixture was stirred at ambient temperature for 17 hours, diluted with dichloromethane (20 ml), washed with 1M aqueous sodium dihydrogen phosphate (10 ml), water (2×10 ml), and dried over magnesium sulfate. After filtration and evaporation to a suitable volume, the solution was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give title product (210 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(OC(C)(C)C)=O)=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)c2c(N)ncnn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)c1cc(-c2ccc(N)cc2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 99.5 %

Procedure:
To a suspension of butyl 4-amino-5-{4-[(tert-butoxycarbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (174.5 mg, 0.41 mmol) in dichloromethane (4 mL) was added TFA (2 mL). The solution was stirred at rt for 6.5 h and then the volatiles were evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and then this solution was washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfate, and concentrated to dryness under reduced pressure to afford 132.7 mg (99%) of the title compound. 1H-NMR (DMSO-d6) δ 8.10 (bs, 1H), 8.02 (s, 1H), 7.10 (d, J=8.3 Hz, 2H), 7.08 (s, 1H), 6.64 (d, J=8.4 Hz, 2H), 5.55 (bs, 1H), 5.34 (s, 2H), 4.24 (t, J=6.5 Hz, 2H), 1.70-1.63 (m, 2H), 1.46-1.37 (m, 2H), 0.93 (t, J=7.4, 3H); MS [M+H]+=326.3; LCMS RT=2.07 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cu](C#N)[C:12]#[N:13]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[C:12]#[N:13]
Reactant: N#C[Cu]C#N
Reactant: COc1ccc(Br)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C#N)cc1F
Temperature: 25 °C
Yield: 78 %

Procedure:
20 g of the 2-fluoro-4-bromoanisole thus obtained and 9.8 g of copper cyanide were dissolved in 100 ml of dimethyl formamide and heated under reflux for ten hours. To the reaction mixture, was added an aqueous solution of 20 g of ferric chloride in 100 ml of water. The reaction mixture was allowed to cool to room temperature and the reaction product was extracted with toluene. The organic layer was successively washed with water, a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of common salt. Then the organic layer was separated. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=10:1) and further recrystallized from ethanol. Thus 10.0 g of 3-fluoro-4-methoxybenzonitrile was obtained. Yield: 68%.
Reaction SMILES: Cl.[NH2:2]O.C([O-])=O.[Na+].[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]=O)[CH:19]=2)=[N:15][C:14]=1[CH3:27])=[O:12])[CH3:9].O>C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]#[N:2])[CH:19]=2)=[N:15][C:14]=1[CH3:27])=[O:12])[CH3:9]
Reactant: NO
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(C=O)c2)nc1C
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(O)c(C#N)c2)nc1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (35.82 g, 0.515 mol) and sodium formate (46.73 g, 0.687 mol) were added to a solution of ethyl-2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate (100 g, 0.343 mol) in formic acid (anhydrous, 300 mL) and the reaction mixture was heated to a temperature of about 100° C. for about 8 hours. After completion of reaction, the reaction mixture was cooled to about 40° C. and water was added to it. The reaction mixture was cooled to about 25° C. and stirred for about 1 hour. The solid obtained was filtered, washed with water and dried. The solid was then dissolved in acetone at about 50° C. and water was added slowly over a period of about 30 minutes. The mixture was cooled to about 25° C. and again stirred for about 1 hour. The solid thus obtained was filtered, washed with acetone:water (1:1) mixture and dried to obtain the title product. (Yield: 85 g, 85.9%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[N:12](CCOC[Si](C)(C)C)[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:7]=1.Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1CCOC[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(F)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
To a solution of N-(5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (330 mg, 0.68 mmol) in 14 mL ethanol was added HCl (1.0 mL of a 6 M solution in water, 6.0 mmol). The reaction mixture was then stirred at 70° C. for 6 hours. After cooling to room temperature, a light yellow precipitate formed, which was filtered off and rinsed with methanol and diethyl ether. The filtrate was reduced in volume to precipitate more product, which was filtered off. The combined collected solids were dried under vacuum to yield 220 mg (92%) of N-(5-(5-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=353.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.32 (dd, 1H), 8.77 (dd, 1H), 8.63 (s, 1H), 8.19 (s, 1H), 7.30 (m, 4H), 3.82 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH2:28]([O:30][C:31](=[O:46])[CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:28]([O:30][C:31](=[O:46])[CH2:32][CH2:33][N:34]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[C:25](=[O:26])[CH2:24][NH:23][C:21](=[O:22])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:29]
Reactant: CCOC(=O)CCNCc1ccc(OC)c(OC)c1
Reactant: COc1cc(CC(=O)NCC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(Cc1ccc(OC)c(OC)c1)C(=O)CNC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
Step 1. A solution of ({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetic acid [50 g, Reference Example 3] and 3-(3,4-dimethoxy-benzylamino)-propionic acid ethyl ester [36 g, Reference Example 2(a)] in dimethylformamide (500 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate] (53.2 g) and diisopropylethylamine (59 ml). After stirring at ambient temperature for 3 hours the reaction mixture was evaporated to dryness and the residue was treated with water (3L). The mixture was extracted twice with ethyl acetate (1L) and then concentrated to dryness. The residue was subjected to flash chromatography on silica eluting initially with ethyl acetate and then with a mixture of ethyl acetate and methanol (9:1, v/v) to give 3-[N-(3,4-dimethoxybenzyl)-2-{2-[3-methoxy-4-(3-o-tolylureido)phenyl]acetylamino}acetamido]propionic acid ethyl ester as a yellow oil (49 g).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1.[CH3:20][S:21]SC.CCOCC>C1COCC1>[Cl:6][C:7]1[C:8]([S:21][CH3:20])=[C:9]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC1(C)COC(c2cccc(Cl)c2)=N1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSc1c(Cl)cccc1C1=NC(C)(C)CO1
Temperature: -65 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
n-Butyllithium (2.5M in hexane, 4.2 ml) was added to a solution of 2-(3-chlorophenyl)-4,4-dimethyloxazoline (2 g) in THF while maintaining the temperature below -45° C. The mixture was stirred at -65° C. for 3 hours. Dimethyl disulphide (1.0 g) was added and the mixture was stirred at -65° C. for 2.5 hours and allowed to warm to room temperature. Ether was added and the mixture was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-(3-chloro-2-methylsulphenylphenyl)-4,4-dimethyloxazoline (2.35 g) as a yellow oil NMR (CDCl3) 2.0(s,6H) 3.0(s,3H) 4.65(s,2H) 7.5-8.1(m,3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][S:27]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31]1)(=[O:29])=[O:28].N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:39]/[C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CS(=O)(=O)n1cc(C=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(C)(=O)=O)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (2 mL) was added with 1-(methanesulfonyl)-1H-indole-3-carboxaldehyde (0.0641 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(6-hydroxy-2-{[1-(methylsulfonyl)-1H-indol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.104 g, 66%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:9]1[CH:8]=[C:7](/[CH:6]=[CH:5]/[CH2:4][CH2:3][CH2:2][N:19]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[O:15][CH3:16]
Reactant: COc1cc(/C=C/CCCBr)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(/C=C/CCCN2CCCNCC2)cc(OC)c1OC

Procedure:
(E)-5-Bromo-1-(3,4,5-trimethoxyphenyl)-1-pentene (434 mg) and homopiperazine (276 mg) were reacted in the same manner as in Preparation Example 4 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]2=[O:29])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[N:4][C:3]=1[N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]2=[O:29])[CH2:17][CH2:18]1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1

Procedure:
The title compound was prepared from 5,6-dichloronicotinic acid (2.2 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (3.0 g) using the method of example 115 step (ii). Yield 0.037 g
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:17])[NH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1.[Na].FC1C=C(C=CC=1)CO.FC1C=C2[C:35]([C:36](=[O:42])[NH:37]C=N2)=CC=1.Cl>O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:17])[N:12]([CH2:35][C:36]([NH2:37])=[O:42])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=c1[nH]cnc2cc(OCc3cccc(F)c3)ccc12
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: Cl
Agent: OCc1cccc(F)c1
Agent: [Na]
Solvent: O
Product: NC(=O)Cn1cnc2cc(OCc3cccc(F)c3)ccc2c1=O
Temperature: 25 °C
Yield: 61 %

Procedure:
7-(3-Fluoro-benzyloxy)-3H-quinazolin-4-one: Sodium (1.8 g, 78.6 mmol) was added portionwise to 3-fluorobenzyl alcohol and the resulting mixture heated at 80–90° C. for 4 h under Argon. The resulting suspension was cooled to rt and 7-fluoro-3H-quinazolin-4-one (3.2 g, 19.5 mmol) was added and the resulting mixture heated at 130–140° C. for 14 h. The solid formed was then dissolved with water (400 mL) and the mixture acidified to pH 3–4 with HCl (4 N). The resulting precipitate was then filtered off, washed with water (100 mL) and diethylether (100 mL). Recrystallisation from tetrahydrofuran: ethylacetate (1:1) afforded the title compound (3.2 g, 61%) as white crystals. MS: m/e=271.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([C:20]1[CH:25]=[CH:24][N:23]2[C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:27][N:28]=[C:22]2[N:21]=1)([CH3:19])[CH3:18]>>[F:16][C:17]([C:20]1[CH:25]=[CH:24][N:23]2[C:26]([C:2]3[N:7]=[C:6]([C:8]4[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:27][N:28]=[C:22]2[N:21]=1)([CH3:19])[CH3:18]
Reactant: N#Cc1cccnc1-c1cccc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(C)F)ccn12
Product: CC(C)(F)c1ccn2c(-c3cccc(-c4ncccc4C#N)n3)cnc2n1

Procedure:
6′-Chloro-2,2′-bipyridinyl-3-carbonitrile was coupled to 7-(1-fluoro-1-methylethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine (prepared according to Example 25) by the method of Example 1 to give 6′-[7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridinyl-3-carbonitrile: δH (400 MHz, CDCl3) 1.78 (3H, s), 1.84 (3H, s), 7.42 (1H, dd, J 2.0, 7.0), 7.55 (1H, dd, J 4.7, 7.8), 7.95 (1H, d, J 1.2), 7.99 (1H, t, J 7.8), 8.06-8.08 (1H, m), 8.24 (1H, dd, J 1.6, 7.8), 8.39 (1H, s), 8.94 (1H, dd, J 1.6, 4.7), 10.36 (1H, d, J 7.0); m/z 359 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:14]=1)[CH:12]=[O:13].P([O-])(O)(O)=[O:34].[Na+].Cl[O-].[Na+].OO>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:14]=1)[C:12]([OH:34])=[O:13]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C=O)c2)c(OC)c(OC)c1OC
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Yield: 89.8 %

Procedure:
To a solution of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (5.60 g, 0.0128 mol) in acetonitrile (30.0 ml) were added an aqueous solution (10.0 ml) of sodium dihydrogen phosphate (12.0 g, 0.100 mol), an aqueous solution (30.0 ml) of sodium hypochlorite (5.19 g, 0.0577 mol) and an aqueous hydrogen peroxide (1.701 ml, 30%) and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrosulfite (Na2S2O4) and a saturated saline, dried and concentrated to give the title compound (5.20 g, 0.0115 mol, 90%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH:10]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]([C:22]3[S:23][C:24]([C:28](O)=[O:29])=[C:25]([CH3:27])[N:26]=3)[C:18](=[O:31])[CH:17]=2)[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]([C:22]3[S:23][C:24]([C:28]([NH:7][CH2:6][C:5]4[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=4)=[O:29])=[C:25]([CH3:27])[N:26]=3)[C:18](=[O:31])[CH:17]=2)[CH2:12][CH2:11]1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 30 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 4-fluorobenzylamine in place of benzylamine to react with 2-(4-(2-cyclopropylethoxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 30% yield: mp 172-174° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=8.1 Hz, 1H), 8.32-8.27 (m, 2H), 7.05-7.00 (m, 2H), 6.17-6.08 (m, 2H), 5.97 (t, J=2.5 Hz, 1H), 4.54 (d, J=5.7 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 2.67 (s, 3H), 1.68 (q, J=6.6 Hz, 2H), 0.87-0.93 (m, 1H), 0.54-0.46 (m, 2H), 0.13-0.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.9, 163.9, 162.2, 160.6, 153.6, 152.4, 133.6, 131.3, 129.6, 122.0, 115.8, 104.2, 96.6, 69.1, 43.3, 33.6, 17.3, 7.5, 4.2; MS (ES+) m/z 428.2 (M+1).