Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[I-].[K+].Cl[CH2:46][C:47]([N:49]([CH3:51])[CH3:50])=[O:48]>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[O:32][CH2:31][CH:30]4[CH2:33][N:34]([CH2:46][C:47]([N:49]([CH3:51])[CH3:50])=[O:48])[CH2:35][CH2:36][N:29]4[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 65 °C
Reaction time: 2 h
Yield: 8.8 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.10 mmol), K2CO3 (28 mg, 0.21 mmol), and potassium iodide (19 mg, 0.11 mmol) in DMF (1 mL), 2-chloro-N,N-dimethylacetamide (14 mg, 0.11 mmol) was added at rt. The reaction was heated to 65° C. and allowed to stir for 2 hours. The mixture was allowed to cool and partitioned between ethyl acetate (50 mL) and saturated aqueous K2CO3 solution (30 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 5 mg (9%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.90 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.36 to 7.30 (m, 5H), 7.12 (dd, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.09 (dd, 1H), 3.76 (dd, 1H), 3.36-3.27 (m, 1H), 3.11 (d, 2H), 2.99-2.93 (m, 4H), 2.78-2.63 (m, 6H), 2.48-2.36 (m, 1H), 2.24-2.21 (m, 3H), 1.80 (t, 1H); LC-MS [M+H]+=566, RT=2.07 min.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH2:27](Br)[CH3:28]>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH3:28])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCBr
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C#N)(CC)c1cccc(Oc2ccccc2C)c1OC
Yield: 99 %

Procedure:
Sodium hydride (50%, 650 mg), ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (4 g) and ethyl bromide (3.35 g) were treated in a similar, manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]butyrate (4.3 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:11])([CH3:10])[CH2:4][CH2:5][S:6]([NH2:9])(=[O:8])=[O:7].Cl[C:13]1[C:14]([CH3:22])=[CH:15][C:16]2[N:17]([N:19]=[CH:20][N:21]=2)[N:18]=1>>[CH3:10][C:3]([CH3:11])([CH2:4][CH2:5][S:6](=[O:7])(=[O:8])[NH2:9])[CH2:2][O:1][C:13]1[C:14]([CH3:22])=[CH:15][C:16]2[N:17]([N:19]=[CH:20][N:21]=2)[N:18]=1
Reactant: CC(C)(CO)CCS(N)(=O)=O
Reactant: Cc1cc2ncnn2nc1Cl
Product: Cc1cc2ncnn2nc1OCC(C)(C)CCS(N)(=O)=O

Procedure:
Using 4-hydroxy-3,3-dimethyl-1-butanesulfonamide and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction was conducted as in Example 5 to produce the title compound. m.p. 214°-215° C.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=3[Cl:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([C:29]2[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=2[Cl:38])=[C:20]([CH2:19][N:15]2[C@@H:14]([CH3:39])[C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:41])([F:40])[F:1])[CH:4]=3)[O:17][C:16]2=[O:18])[CH:25]=1
Reactant: CC(C)c1ccc(Cl)c(-c2ccc([N+](=O)[O-])cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Solvent: CO
Product: CC(C)c1ccc(Cl)c(-c2ccc(N)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(2′-chloro-5′-isopropyl-4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (425 mg, 0.71 mmol) in methanol (10 mL) was subject to H2 (40 psi., Parr shaker) at 20° C. for 6 h. The crude mixture was filtered through a bed of Celite (521). The filtrate was evaporated in vacuo to afford a glass. The titled compound was obtained after a preparative TLC plate developed by 20% EtOAc in hexanes. LC-MS: 571.22 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 6:4 mixture of rotamers δ 7.82-7.86 (m, 1H), 7.65-7.71 (m, 2H), 7.34-7.38 (m, 1H), 7.11-7.17 (m, 2H), 7.02-7.06 (m, 1H), 6.76-6.82 (m, 1H), 6.68-6.74 (m, 1H), 5.58 (d, J=8.0 Hz, 0.4H), 5.51 (d, J=8.2 Hz, 0.6H), 4.82 (d, J=15.3 Hz, 0.6H), 4.70 (d, J=15.6 Hz, 0.4H), 3.69-4.00 (m, 4H), 2.84-2.94 (m, 1H), 1.19-1.28 (m, 6H), 0.45 (d, J=6.6 Hz, 1.2H), 0.40 (d, J=6.6 Hz, 1.8H).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[N:7]([C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)[C:8](=[O:21])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]=[O:20])[CH:12]=3)[C:5]=2[CH:4]=1)#[N:2].[BH4-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[N:7]([C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)[C:8](=[O:21])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][OH:20])[CH:12]=3)[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C#N)cc32)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C#N)cc32)cc1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyano-3-(3-formyl-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one (35.0 mg) in a mixture of ethanol (2 mL) and tetrahydrofuran (1 mL) was added sodium borohydride (3.27 mg) under ice cooling, and the mixture was stirred at 0° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with 1N-hydrochloric acid, water, saturated sodium bicarbonate solution and brine, successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by a preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (10:1). The crude product was triturated with diisopropyl ether to give 5-cyano-1-(trans-4-hydroxycyclohexyl)-3-(3-hydroxymethyl-4-methoxybenzyl)-1,3-dihydro-2H-benzimidazol-2-one as a colorless powder (20.0 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][O:10][CH2:9]2)[N:5]=[C:4]([NH2:13])[N:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].N1C=CC=CC=1>CCO>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:12][CH2:11][O:10][CH2:9]3)[N:5]=[C:4]([NH2:13])[N:3]=2)[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1nc(Cl)cc(C2CCOC2)n1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C3CCOC3)nc(N)n2)CC1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
A solution of 4-chloro-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine (500 mg, 2.51 mmol), N-BOC piperazine (960 mg, 5.15 mmol) and pyridine (500 uL, 6.1 mmol) in EtOH (10 mL) was heated at 90° C. for 4 h. Upon cooling to rt a thick precipitate formed which was collected by filtration. The material was rinsed with EtOAc to afford 125 mg of a white solid. The filtrate was concentrated and triturated with Et2O-EtOAc (1:1) to yield an additional 600 mg of material (82% combined). MS (ESI): mass calcd. for C17H27N5O3, 349.2; m/z found, 350.3 [M+H]+. 1H NMR (CDCl3): 5.86 (s, 1H), 4.70 (br s, 2H), 3.90-4.07 (m, 2H), 3.83-3.90 (m, 2H), 3.55-3.60 (m, 4H), 3.45-3.50 (m, 4H), 3.18-3.26 (m, 1H), 2.20-2.30 (m, 1H), 2.09-2.18 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])(=O)C.Cl.[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[S:8]([CH2:7][CH2:6][CH2:5][OH:4])(=[O:10])=[O:9]
Reactant: CNC
Reactant: CC(=O)OCCCS(=O)(=O)Cl
Agent: Cl
Product: CN(C)S(=O)(=O)CCCO

Procedure:
Using 3-acetoxypropane-1-sulfonyl chloride and dimethylamine hydrochloride, the same reaction as in Reference Example 44 and 46 was conducted to produce the title compound.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][CH3:32])[CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]3)=[N:8][CH:9]=1)=[S:3].Br[CH:34]([CH3:38])[C:35](=O)[CH3:36]>C(O)C>[CH3:38][C:34]1[N:1]=[C:2]([C:4]2[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][CH3:32])[CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]4)=[N:8][CH:9]=2)[S:3][C:35]=1[CH3:36]
Reactant: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(C(N)=S)cn1
Reactant: CC(=O)C(C)Br
Solvent: CCO
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(-c2nc(C)c(C)s2)cn1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
A mixture of ethyl ((1S)-5-{3-[[5-(aminocarbonothioyl)-2-pyridinyl]-(propyl)-amino]-propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 266) (90 mg, 0.20 mmol) and 3-bromo-2-butanone (40 mg, 0.26 mmol) in ethanol (9 mL) was heated under argon at 80° C. for 18 h. The solution was then concentrated and the residue purified by column chromatography (2:1 hexanes/EtOAc) to provide the title compound (0.1 g, 100%). 1H NMR (400 MHz, CD2Cl2) δ 8.54 (d, 1H), 7.89 (d, 1H), 7.06 (d, 1H), 6.79 (d, 1H), 6.71 (dd, 1H), 6.56 (d, 1H), 4.16 (q, 2H), 4.01 (t, 2H), 3.74 (t, 2H), 3.55-3.45 (m, 3H), 2.95-2.78 (m, 2H), 2.76-2.68 (m, 1H), 2.46-2.30 (m, 8H), 2.11 (qt, 2H), 1.72-1.62 (m, 3H), 1.28 (t, 3H), 0.97 (t, 3H).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](OCC)=[O:17])=[CH:11][C:10]=1[CH3:21])#[N:8]>O1CCCC1.O>[NH2:8][CH2:7][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=1[CH3:21]
Reactant: CCOC(=O)c1cc(C)c(C#N)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(C)c1CN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 233.3 %

Procedure:
To a solution of aluminum lithium hydride (2.1 g) in tetrahydrofuran (20 ml) was added a solution of ethyl 4-cyanomesitylenate (2.9 g) in tetrahydrofuran (30 ml) at 0° C. and the mixture was refluxed under heating for 6 hr. To this reaction mixture was added 50% (v/v) tetrahydrofuran in water under ice-cooling. This mixture was stirred at room temperature for 30 min and the catalyst was filtered off using Celite. The solvent was evaporated and the obtained residue was recrystallized from methanol-isopropyl ether to give the title compound (5.5 g) as white crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([C:34](=[N:36]O)[NH2:35])[CH:30]=[CH:31][C:32]=1[F:33]>>[Cl:26][C:27]1[CH:28]=[C:29]([C:34]2[N:36]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH2:12]3)[O:24][N:35]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1ccc(F)c(Cl)c1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)c(Cl)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 41 mg (0.22 mmol, 1.1 eq.) of 3-chloro-4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 51 mg (51% of theory)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH:30]2[CH2:39][CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31]2)(=O)=O)=CC=1>>[CH2:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:38][CH2:39][CH:30]1[CH2:29][N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3C2)cc1
Product: O=C(N[C@H]1CCN(CC2CCc3ccccc3C2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide and (1,2,3,4-tetrahydronaphthalen-2-yl)methyl p-toluenesulfonate were reacted under the same conditions as in Example 6 to give (S)-N-(1-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:32]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(Cl)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-chloro-benzoic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:20]=[CH:19][C:12]2[S:13][C:14]([C:16](O)=[O:17])=[CH:15][C:11]=2[CH:10]=1)[CH3:2].[NH3:23].C(OCC)(=O)C>O1CCCC1>[CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:20]=[CH:19][C:12]2[S:13][C:14]([C:16]([NH2:23])=[O:17])=[CH:15][C:11]=2[CH:10]=1)[CH3:2]
Reactant: N
Reactant: CCN(CC)CCOCCc1ccc2sc(C(=O)O)cc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)CCOCCc1ccc2sc(C(N)=O)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 30 mL of tetrahydrofuran is dissolved 2.18 g of 5-{2-[2-(diethylamino)ethoxy]ethyl}benzo[b]-thiophene-2-carboxylic acid, to which is added 1.98 g of N,N′-carbonyldiimidazole. The resulting mixture is stirred at ambient temperature for one hour. Then, 50 mL of 25% aqueous ammonia is added to the mixture and the resulting mixture is stirred at ambient temperature for one hour. Ethyl acetate is added to the mixture, the organic layer is separated, washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent:chloroform:methanol to chloroform:methanol:ammonia=5:1 to 100:10:1). Thus, 2.00 g of 5-{2-[2-(diethylamino)ethoxy]ethyl}benzo[b]-thiophene-2-carboxamide is obtained as a colorless crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:8]([C@@H:18]([NH:23][C:24]1[C:25]3[N:33]=[CH:32][CH:31]=[CH:30][C:26]=3[N:27]=[CH:28][N:29]=1)[C:19]([F:22])([F:21])[F:20])=[CH:7]2.[H-].[Na+].[CH3:36]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:8]([C@@H:18]([N:23]([C:24]1[C:25]3[N:33]=[CH:32][CH:31]=[CH:30][C:26]=3[N:27]=[CH:28][N:29]=1)[CH3:36])[C:19]([F:22])([F:21])[F:20])=[CH:7]2
Reactant: FC(F)(F)[C@H](Nc1ncnc2cccnc12)c1cc2cccc(Cl)c2nc1-c1cccnc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ncnc2cccnc12)[C@H](c1cc2cccc(Cl)c2nc1-c1cccnc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.9 %

Procedure:
A stirred solution of Example 1 (92 mg, 0.197 mmol) in DMF (10 mL) was cooled to 0° C. NaH (60%; 9 mg, 0.217 mmol) was added and the mixture was stirred at 0° C. for 5 minutes. Methyl iodide (30 mg, 0.207 mmol) was added and the mixture was stirred at r.t. for 16 h. Water (0.5 mL) was added and the mixture was evaporated in vacuo. The residue was partitioned between DCM and water. The aqueous phase was extracted with further DCM, the combined organic fractions were washed with brine and dried Na2SO4), then the solvent was evaporated in vacuo. The residue was purified twice by column chromatography (SiO2, 0-35% MeOH in EtOAc) to give the title compound (16 mg, 17%) as an off-white solid. δH (DMSO-d6) 9.00 (d, J 1.7 Hz, 1H), 8.77 (dd, J 4.8, 1.6 Hz, 1H), 8.73-8.70 (m, 2H), 8.27 (dt, J 7.8, 1.8 Hz, 1H), 8.11 (dd, J 8.3, 1.2 Hz, 1H), 8.01 (s, 1H), 7.98 (dd, J 7.5, 1.2 Hz, 1H), 7.85 (dd, J 8.5, 1.2 Hz, 1H), 7.71 (dd, J 8.5, 4.4 Hz, 1H), 7.66-7.56 (m, 2H), 5.93 (q, J 7.7 Hz, 1H), 3.53 (s, 3H). LCMS (ES+) 481 (M+H)+, RT 2.31 minutes.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[C:33]([CH3:34])=[CH:32][N:31]=[C:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:34][C:33]1[C:28]([CH3:27])=[N:29][C:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:31][CH:32]=1
Reactant: Cc1cnc(-c2ccccc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(-c2ccccc2)ncc1CBr
Yield: 92 %

Procedure:
5.54 g (31.1 mmol) of N-bromosuccinimide (NBS) and 6 mg of dibenzoyl peroxide were added to a solution of 5.53 g (30 mmol) of 4,5-dimethyl-2-phenylpyrimidine in 110 ml of CCl4, and the mixture was warmed to the boiling point for 5 minutes with stirring and irradiation with a daylight lamp with increased short-wave content (type: Osram UltraVitalux, 300 W, GUR 53). The NBS had then been consumed and converted into specifically light succinimide. It was filtered off under suction at room temperature and washed with a little CCl4. The filtrate was evaporated in vacuo, the residue was dissolved in 100 ml of diisopropyl ether, the solution was clarified over kieselguhr, and the clear filtrate was again evaporated in vacuo. 7.70 g, 94.5% purity according to the 1H NMR spectrum, of 5-bromomethyl-4-methyl-2-phenylpyrimidine (=92% yield), melting point 65°-66° C., were obtained, analysis: C12H11BrN2 (MW 263.15) calc. C 54.77, H 4.21, Br 30.37, N 10.65; found C 53.5, H 3.9, Br 31.3, N 10.0%.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH:8]1[C:17]2[C:12](=[CH:13][C:14]([N:18]3[CH2:34][CH2:33][C:21]4([CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH2:20][CH2:19]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH2:25]1[C:21]2([CH2:20][CH2:19][N:18]([C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[CH:8]=[N:9][CH:10]=[CH:11]4)[CH2:34][CH2:33]2)[CH2:22][CH2:23][NH:24]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc4cnccc4c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2cc(N3CCC4(CCNC4)CC3)ccc2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (2 ml) was added to a cooled (0° C.) solution of tert-butyl 8-(isoquinolin-6-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.544 mmol, 1.0 eq.) in methylene chloride (10 ml) and the reaction mixture was stirred at room temperature for 1 h. When the reaction was complete, the solvent was removed on a rotary evaporator. The crude product was employed directly in the next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:11][CH:12]([F:25])[O:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:25][CH:12]([F:11])[O:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1
Reactant: Fc1ccc(C(F)(F)F)cc1OC(F)F
Reactant: Oc1ccc2ccoc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)Oc1cc(C(F)(F)F)ccc1Oc1ccc2ccoc2c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-benzofuran-6-ol (13.4 g, 100 mmol) and 2-(difluoromethoxy)-1-fluoro-4-trifluoromethylbenzene (29.9 g, 130 mmol) in DMF (300 mL) was added cesium carbonate (65.2 g, 200 mmol). The reaction mixture was stirred at 75° C. for 16 hours (or at 110° C. for 2 hours). After cooling to room temperature, it was diluted with ethyl acetate, washed with water (2×) and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified on a silica gel column, eluting with ethyl acetate (0-20%) in hexanes. The final product was collected as a colorless oil. 1H NMR (CDCl3, δ ppm): 6.7 (t, 1H, J=74 Hz), 6.8 (s, 1H), 7.0 (m, 2H), 7.2 (s, 1H), 7.4 (d, 1H), 7.6 (m, 3H).
Reaction SMILES: O1CCCC1.[CH3:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10].[H-].[Na+].[Br:14][C:15]1[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]2[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=2[C:16]=1[CH2:41]Br>O>[Br:14][C:15]1[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]2[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=2[C:16]=1[CH2:41][O:11][CH:8]([CH2:9][CH3:10])[CH2:7][CH3:6]
Reactant: CCC(O)CC
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To 15 ml of dehydrated tetrahydrofuran solution containing 1.90 ml of 3-pentanol was added 0.38 g of sodium hydride (55% dispersed material in mineral oil) under cooling in ice-bath, and the mixture was stirred at room temperature for 3 hours. Then, 0.99 g (1.75 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added to the mixture, and the mixture was stirred at 45° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.66 g of the title compound as a slightly yellowish oil. (Yield: 65%)