Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[CH2:10][C:9](=O)[C:8]=2[CH:19]=1)([O-:3])=[O:2].C[Si]([C:24]#[N:25])(C)C.P(Cl)(Cl)(Cl)=O.Cl>[I-].[Zn+2].[I-].N1C=CC=CC=1.C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[CH:10]=[C:9]([C:24]#[N:25])[C:8]=2[CH:19]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1=CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
To a mixture of 3.08 g of 3,4-dihydro-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-one and 40 ml of dried benzene was added 1.8 ml of trimethylsilyl cyanide with stirring under ice-cooling. 1.22 g of zinc iodide was added therein and the resultant mixture was stirred at room temperature for 19 hours. 6 ml of pyridine and 3.1 ml of phosphorus oxychloride were added therein and the mixture was refluxed with heating for 5.5 hours. Ice water was added to the residue, and the residue was acidified to be hydrochloric acid and extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.28 g of 6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-carbonitrile with a melting point of 175°-176° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:30][C@H:31]5[CH2:33][O:32]5)[CH2:22][CH2:21]4)[C:14]3=[O:34])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:36][NH2:37]>>[CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:30][C@H:31]([OH:32])[CH2:33][NH:37][CH3:36])[CH2:22][CH2:21]4)[C:14]3=[O:34])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@H]3CO3)CC2)c1=O
Product: CNC[C@@H](O)COc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1

Procedure:
The title compound was prepared using a similar method to that described for Example 299b from (R)—N-cyclopropyl-4-methyl-3-(3-(1-(2-(oxiran-2-ylmethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)benzamide (Example 299a) and methylamine.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH3:54])([CH3:53])[C:45]1=[O:55]>CC(=O)CC>[CH3:54][C:46]1([CH3:53])[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:44]([CH2:43][CH2:42][CH2:41][N:9]2[CH2:8][CH2:7][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=4[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C:2]3=[O:1])[CH2:11][CH2:10]2)[C:45]1=[O:55]
Reactant: CC1(C)C(=O)N(CCCCl)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCN3C(=O)C(C)(C)c4ccccc43)CC2)C1=O
Temperature: 78 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.175 g, 0.42 mmol), sodium iodide (0.019 g, 0.13 mmol) and potassium carbonate (0.087 g, 0.63 mmol) in 2-butanone (5 mL), was added 1-(3-chloropropyl)-3,3-dimethylindolin-2-one (0.098 g, 0.42 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.18 g, 69%); 1H NMR (DMSO-d6): δ 1.26 (s, 6H), 1.57 (s, 9H), 1.67 (d, 2H, J=12.4 Hz), 1.75-1.76 (m, 2H), 2.32-2.33 (m, 2H), 2.50-2.72 (m, 6H), 3.74 (t, 2H, J=6.4 Hz), 4.61 (s, 2H), 4.84 (s, 2H), 6.76 (t, 1H, J=7.2 Hz), 6.84 (d, 2H, J=8 Hz), 7.02 (t, 1H, J=6.8 Hz), 7.13 (d, 1H, J=7.6 Hz), 7.23-7.31 (m, 4H), 7.34 (d, 1H, J=6.8 Hz), 7.41 (t, 1H, J=7.2 Hz), 7.57 (t, 1H, J=8.8 Hz), 7.82 (d, 1H, J=7.2 Hz); MS for C38H46N4O4 m/z 623.28 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[C:14]2[CH:13]=[C:12]([N:15]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5](B1OC(C)(C)C(C)(C)O1)=[CH:6][CH:7]=2.I[C:41]1[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][N:42]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:47][C:44]1[CH:45]=[CH:46][C:41]([C:5]2[CH:4]=[C:3]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([N:15]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)[C:16]5[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=5)=[CH:13][C:14]=4[C:2]3([CH3:1])[CH3:39])=[CH:7][CH:6]=2)=[N:42][CH:43]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c(c2)C(C)(C)c2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)cc1
Reactant: Brc1ccc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c(c2)C(C)(C)c2cc(-c4ccc(Br)cn4)ccc2-3)cc1
Temperature: 90 °C
Yield: 77 %

Procedure:
A mixture of 9,9-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-di-p-tolyl-9H-fluoren-2-amine (Compound 33) (5.0 g, 9.7 mmol), 2-iodo-5-bromo-pyridine (8.26 g, 29.1 mmol), Pd(PPh3)4 (0.56 g, 0.48 mmol) and K2CO3 (5.36 g, 38.8 mmol) in dioxane/water (65 mL/13 mL) was degassed and heated at about 90° C. overnight. The resulting mixture was worked up with ethyl acetate and brine. The organic phase was dried over Na2SO4, loaded on silica gel, purified by flash column (hexanes/dichloromethane 5:1 to 1:3 to dichloromethane). The desired fraction was collected, concentrated and recrystallized in dichloromethane/hexanes to give a white solid (Compound 34) (4.085 g, in 77% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)=O>[CH:1]([NH:8][C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH2:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(N)(CC)c1ccccc1
Solvent: O=CO
Product: CCOC(=O)C(CC)(NC=O)c1ccccc1
Reaction time: 15 h
Yield: 100 %

Procedure:
12.72 mL of formic acid then 25.38 mL of acetic anhydride were added dropwise, under stirring, to 2.49 g (12.03 mmol) of amine 6. After 15 h at room temperature, solvents were removed under reduced pressure to give 3.09 g of 7 as a green viscous oil (100% yield).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][N:15]1[C:19]([CH2:20][OH:21])=[CH:18][C:17]([C:22]([F:25])([F:24])[F:23])=[N:16]1.[CH3:26][O:27][C:28](=[O:41])[CH2:29][C:30]1[C:34]2[C:35]([CH3:40])=[CH:36][C:37](O)=[CH:38][C:33]=2[S:32][CH:31]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:26][O:27][C:28](=[O:41])[CH2:29][C:30]1[C:34]2[C:35]([CH3:40])=[CH:36][C:37]([O:21][CH2:20][C:19]3[N:15]([CH3:14])[N:16]=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:18]=3)=[CH:38][C:33]=2[S:32][CH:31]=1
Reactant: Cn1nc(C(F)(F)F)cc1CO
Reactant: COC(=O)Cc1csc2cc(O)cc(C)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)cc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a mixture of tri-n-butylphosphine (0.162 mL), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (90 mg), methyl(6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetate (118 mg) and THF (5.0 mL) was added ADDP (164 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated. To the residue was added IPE, the precipitate was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) and then silica gel column chromatography (EtOAc/hexane) to give the title compound (148.4 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:19])=[C:4]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24].COCC(O)=O.S(Cl)(Cl)=O>CC(N(C)C)=O>[OH:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[C:4]1[C:5]([I:12])=[C:6]([C:10]([I:11])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][O:21][CH3:20])[C:3]=1[I:19])[C:7]([OH:9])=[O:8]
Reactant: COCC(=O)Cl
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCCO)c1I
Agent: COCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCCO)c1I

Procedure:
Analogously to Example 1(c), 90.3 g. (150 mmol) of 5-amino-N-(2-hydroxyethyl)-2,4,6-triiodoisophthalamic acid and methoxyacetyl chloride, freshly prepared from 45.5 ml. of methoxyacetic acid/43.5 ml. of thionyl chloride, are reacted in dimethylacetamide; yield: 84.7 g. (84%) m.p. 285° C., with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C@@H:27]2[CH2:30][C@H:29]([C:31]([O:33]C)=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:26][C@@H:27]2[CH2:30][C@H:29]([C:31]([OH:33])=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: COC(=O)[C@H]1C[C@@H](Nc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1C[C@@H](Nc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl cis-3-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)cyclobutanecarboxylate (2.0 mg, 4.2 μmol) was dissolved in THF (42 μl) before 0.1 N sodium hydroxide (42 μl, 4.2 μmol) was added and stirred at ambient temperature for 16 h. The reaction mixture was acidified with 2 N HCl, diluted with THF, separated, dried over sodium sulfate, and was concentrated to give the title compound. MS (ESI) m/z: Calculated: 459.1; Observed: 460.0 (M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:28]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])(=[O:30])[NH2:29]>>[F:25][C:24]([F:27])([F:26])[C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:28]([NH2:29])(=[O:31])=[O:30])[CH:37]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C(F)(F)F)c2)cc1
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.81) (0.200 g, 0.448 mmol) and 3-sulfamoyl-benzeneboronic acid (example F.2) (0.100 g, 0.488 mmol) according to the general procedure VI. Obtained as a white solid (0.040 g, 15%). MS (ISP) 523.3 [(M+H)+]; mp 187° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:15])=[CH:11][CH:12]=2)[C:7]1=[O:16].[Br:17]Br.Cl>ClCCl>[Br:17][C:12]1[CH:11]=[C:10]([CH3:15])[CH:9]=[C:8]2[C:13]=1[CH2:14][CH:6]([CH3:5])[C:7]2=[O:16]
Reactant: BrBr
Reactant: Cc1ccc2c(c1)C(=O)C(C)C2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(Br)c2c(c1)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 334 g (2.50 mol) of anhydrous AlCl3 (powder) in 400 ml of dry dichloromethane, a solution of 160 g (1.00 mol) of 2,6-dimethylindan-1-one in 200 ml of dichloromethane was added dropwise while vigorously stirring for 30 min at 0° C. This mixture was stirred for 1 h at ambient temperature, and then a solution of 51.6 ml (161 g, 1.01 mol) of bromine in 800 ml of dichloromethane was added while vigorously stirring for 2 h. The resulting mixture was stirred for 12 h and then poured on 700 cm3 of ice. The mixture was acidified by saturated HCl to pH 1, the organic layer was separated, and the aqueous layer was extracted with 3×350 ml of dichloromethane. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. From the residue, 71.0 g of the starting indanone was distilled off in vacuum (bp 89-91 mm Hg), and the solid material left in the rectification flask was recrystallized from 600 ml of hot hexanes. Crystals that precipitated at room temperature were collected. The pure title product was then isolated by flash chromatography on Silica Gel 60 (40-63 um, d 50 mm, l 1200 mm, eluent: hexanes-dichloromethane, 10:1, vol.). Yield 44.0 g (18%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][C:20]1([CH3:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][C:20]1([CH3:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:21]1
Reactant: CC1(C)CNc2ccccc21
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.7 %

Procedure:
The product is prepared according to the procedure described in example 5, using 177 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 236 mg of 3,3-dimethylindoline (which can be prepared according to T. W. Ramsay et al., Synth. Commun. 1995, 25, 4029) and 169 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.11 ml of pyridine and 5 ml of N,N-dimethylformamide. The reaction mixture is stirred for 15 h at ambient temperature and then concentrated to dryness under reduced pressure. 40 ml of water are added to the residue and triturated with a spatula at ambient temperature. The precipitate formed is filtered off, and then solubilized with a dichloromethanemethanol mixture and dried. After concentration to dryness under reduced pressure, the crude product is purified by chromatography on a 30 g silica (0.02-0.045 mm) column, eluent: 90/10 v/v dichloromethanemethanol. After the various fractions have been evaporated, the pink solid residue is triturated from 10 ml of diisopropyl ether, filtered off, and then dried under a bell jar (1h40° C./20 mbar). 134 mg of 2-[2-(3,3-dimethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are thus obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:18]4[C:17]([OH:20])=[CH:16][N:15]=[CH:14][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:69][O:70][C:71]1[CH:72]=[C:73]([CH:75]=[CH:76][C:77]=1[O:78][CH3:79])[NH2:74]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:69][O:70][C:71]1[CH:72]=[C:73]([NH:74][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[S:19][C:18]5[C:17]([OH:20])=[CH:16][N:15]=[CH:14][C:13]=5[CH:12]=4)=[CH:9][N:10]=3)[N:7]=2)[CH:75]=[CH:76][C:77]=1[O:78][CH3:79]
Reactant: COc1ccc(N)cc1OC
Reactant: Oc1cncc2cc(-c3cnc4ccc(Cl)nn34)sc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc3ncc(-c4cc5cncc(O)c5s4)n3n2)cc1OC
Temperature: 110 °C

Procedure:
To a solution of 2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-ol (50 mg, 0.165 mmol, 1.0 equiv), xantphos (19 mg, 0.0330 mmol, 0.2 equiv), palladium acetate (4 mg, 0.0165 mmol, 0.1 equiv), and potassium carbonate (456 mg, 3.30 mmol, 20 equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (38 mg, 0.248 mmol, 1.5 equiv) and heated to 110° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 30 mg, of the brown solid, 43%.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][CH:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]1[N:17]([CH2:18][CH:19]([OH:21])[CH3:20])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: COc1ccc2c(c1)CC(CC=O)C2=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)Cc1ccn(CC(C)O)c1-2
Reaction time: 0.58 h
Yield: 67.2 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-5-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.94 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). There were obtained 1.6 g (67%) of (RS)-1-(6-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[N:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].CN.Cl.F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:43]2C=CC=CC=2N=N1.CCN(CC)CC>>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([NH:39][CH3:43])=[O:23])=[N:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(=O)N1Cc2nc(-c3ccccc3C(=O)O)ccc2C=Cc2ccccc21
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccccc1-c1ccc2c(n1)CN(C(C)=O)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of 61A, MeNH2.HCl (20 mg, 0.30 mmol), BOP (37 mg, 0.084 mmol) and Et3N (50 μl, 0.036 mmol) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography (SiO2, 100% CH2Cl2 then 100% EtOAc) to give 61B (11.1 mg, 48% for two steps). HPLC Rt=2.063 min; LCMS Found: (M+H)+=384.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:14](OC)=[O:15])([O-])=O.O>C(OCC)(=O)C.CO>[O:15]=[C:14]1[CH:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:12][C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3]1
Reactant: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
Sodium borohydride (1.10 g) was added to the mixed solution of dimethyl 2-[(2-nitrophenyl)methylidene]malonate (15.2 g) in ethyl acetate (50 ml) and methanol (200 ml) at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes. Water was added to the mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. 5% Palladium-carbon (6.26 g) was added to the mixed solution of the residue in THF (100 ml) and methanol (100 ml), and catalytic hydrogenation was conducted at room temperature under atmospheric pressure for 3 days. The catalyst was removed by filtration, and the filtrate was concentrated. The obtained crude crystals were washed with a mixed solution of ethyl acetate/hexane=1/4 to give the entitled compound (9.487 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:27].[Na+].Cl([O-])=O.[Na+]>O.CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:18]=[C:19]([CH2:23][C:24]([OH:27])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCc1cccc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)Cc1cccc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 95.5 %

Procedure:
To a solution of 2.0 g of 3-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetaldehyde and 1.0 g of sodium dihydrogenphosphate in 10 ml of water and 50 ml of dimethyl sulfoxide was added a solution of 2.0 g of sodium chlorite in water (10 ml) and the resulting mixture was reacted at room temperature for 20 minutes. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 2.0 g of crude 3-[1-(benzyloxycarbonyl)piperidin-4-yl]phenylacetic acid was obtained as a colorless oily substance. To a solution of 2.0 g of this oily substance in 50 ml of methanol was added 0.47 ml of thionyl chloride at 0° C. and the resulting mixture was reacted at room temperature for 2 hours. The reaction mixture was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.2 g of the title compound as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:21]1([CH2:26]Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([CH2:26][N:14]2[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrCC1CCCC1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC2CCCC2)c1=O
Yield: 72 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and cyclopentylmethyl bromide {J. Org. Chem., 36, 3103 (1971)} were reacted to yield the title compound as yellow needles (yield: 72.0%).
Reaction SMILES: [CH3:1][SiH:2]([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[Br:9]Br.Br>>[CH3:1][Si:2]([CH:6]([CH3:8])[CH3:7])([CH:3]([CH3:5])[CH3:4])[Br:9]
Reactant: CC(C)[SiH](C)C(C)C
Reactant: BrBr
Agent: Br
Product: CC(C)[Si](C)(Br)C(C)C
Reaction time: 1 h

Procedure:
20.8 g (0.16 mol) of the methyldiisopropylsilane prepared under Example 2, above was placed in a 50 mL three-neck flask equipped with a reflux condenser, thermometer, and addition funnel. 25 g bromine (0.16 mol) was cautiously dripped in while cooling with ice and stirring with a magnetic stirring bar. A strong exothermic reaction developed and hydrogen bromide was evolved. After addition of the entire quantity of bromine, the reaction was allowed to stand for 1 hour at room temperature and was then distilled in vacuo. 26.3 g (0.13 mol) of the target methyldiisopropylbromosilane (bp=92 degrees Centigrade/50 mmHg) was obtained.