Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([CH:40]=[CH:41][CH:42]=2)[C:16]([NH:18][CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])=[O:17])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:43][C:44]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([CH2:56][C:57]2[CH:58]=[C:59](B(O)O)[CH:60]=[CH:61][CH:62]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])[CH3:45].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>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][NH:18][C:16]([C:15]3[CH:14]=[C:13]([CH2:12][N:10]([CH2:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:59]5[CH:60]=[CH:61][CH:62]=[C:57]([CH2:56][N:53]6[CH2:54][CH2:55][N:50]([C:48]([O:47][C:44]([CH3:46])([CH3:45])[CH3:43])=[O:49])[CH2:51][CH2:52]6)[CH:58]=5)[CH:3]=4)[CH3:11])[CH:42]=[CH:41][CH:40]=3)=[O:17])[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(Br)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
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: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 150 °C
Yield: 82 %

Procedure:
To a solution of 3-{[[(3-bromo-4-fluorophenyl)methyl](methyl)amino]methyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (0.37 g, 0.58 mmol) in p-dioxane/H2O (4.5/1.5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (0.279 g, 0.87 mmol), Pd(PPh3)4 (33.6 mg, 0.029 mmol), and K2CO3 (0.32 g, 2.32 mmol). The mixture was heated with a microwave at 150° C. for 15 min. The organic layer was separated and concentrated. The residue was redissolved in EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, concentrated and the concentrate purified by CombiFlash chromatograph to afford the title compound 0.396 g (82%). LC-MS m/z 833 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.[H-].[Na+].Br.Cl[C:12]1[CH:13]=[C:14]([CH3:22])[C:15]2[N:16]([C:18]([NH2:21])=[N:19][N:20]=2)[N:17]=1.O>CN(C=O)C>[CH3:22][C:14]1[C:15]2[N:16]([C:18]([NH2:21])=[N:19][N:20]=2)[N:17]=[C:12]([O:7][CH2:6][C:2]2([CH3:1])[CH2:5][O:4][CH2:3]2)[CH:13]=1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: CC1(CO)COC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC2(C)COC2)nn2c(N)nnc12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
(3-Methyloxetan-3-yl)methanol (1.74 g) was initially charged in DMF (30 ml), admixed under argon with sodium hydride (408 mg) and stirred at 45° C. for 0.5 h. Subsequently, 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g) was dissolved in DMF (30 ml) and one equivalent of the alkoxide solution (10 ml) was added. After stirring at 45° C. for 30 min, a further 0.5 equivalent of alkoxide solution was added, followed by 0.5 eq. each after a further 30 and 60 min. Then the mixture was admixed with water, and the reaction mixture was dried and purified using silica gel (80 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 758 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[O:27])[CH:21]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:36]\[OH:37])=[C:4]([F:34])[CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2cccc(C(=O)N3CCOCC3)c2)c2ccc(Cl)cc2F)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2cccc(C(=O)N3CCOCC3)c2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-fluorophenyl)-3-(3-(morpholine-4-carbonyl)phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid containing 7% of the corresponding Z isomer, MS (ESI+): m/z=498.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:16])(=[O:15])[CH:7]2[CH:8]3[CH2:13][CH2:12][CH:11]([CH:6]2[C:5](=[O:14])[NH:4]1)[CH:10]=[CH:9]3.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5](=[O:14])[CH:6]2[CH:11]3[CH2:12][CH2:13][CH:8]([CH:7]2[S:3]1(=[O:15])=[O:16])[CH:9]=[CH:10]3
Reactant: BrCCCCBr
Reactant: O=C1NS(=O)(=O)C2C3C=CC(CC3)C12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C2C3C=CC(CC3)C2S(=O)(=O)N1CCCCBr
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 15.9 %

Procedure:
A solution of 456 mg (19 mmol) of sodium hydride (prepared from 760 mg of 60% sodium hydride in mineral oil by pentane wash) in 40 ml of dimethylformamide is treated portionwise with 4.05 g (19 mmol) of 3a,4,7,7a-tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H)-one-1,1-dioxide at 0° C. The resulting solution is added dropwise to a solution of 12.3 g (57 mmol) of 1,4-dibromobutane in 40 ml of dimethylformamide. The mixture is maintained with stirring at room temperature for 22.5 hours. The solvent is removed under high vacuum and the residue partitioned between methylene chloride and water. The combined methylene chloride extracts are washed with brine and dried over MgSO4. Filtration and removal of solvent in vacuo gives an oily solid which is triturated with ethyl ether and filtered to give 1.05 g of the title compound, mp 118°-122° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.[C:28]1([C:34](=O)[CH2:35][CH2:36][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCO>[C:28]1([C:34]2[N:1]([CH2:2][C:3]3[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=3)[C:37]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCC(=O)c1ccccc1)c1ccccc1
Reactant: NCc1cccc(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cccc(Cn2c(-c3ccccc3)ccc2-c2ccccc2)n1

Procedure:
6-(Aminomethyl)pyridin-2-amine (0.050 g, 0.4 mmol) was dissolved in EtOH (2 mL) and Toluene (10 mL) was added. To this mixture was added pTSA (5 mg) and 1,4-diphenyl-1,4-butanedione (0.124 g, 0.4 mmol). The solution was heated to reflux overnight. The solvent was removed and the residue was purified by flash chromatography (20:1 CHCl3: MeOH) to yield 6-[(2,5-diphenyl-1H-pyrrol-1-yl)methyl]pyridin-2-amine as a white solid. mp 143-144° C.; 1H NMR (500 MHz, DMSO-d6) δ: 5.06 (s, 2H), 5.50 (d, 1H, J=7.3 Hz), 5.82 (s, 2H), 6.16 (d, 1H, J=8.1 Hz), 6.34 (s, 2H), 7.18 (t, 1H, J=7.47 Hz), 7.28 (t, 2H, J=8.5 Hz), 7.36 (m, 4H), 7.40 (m, 4H); MS (ES) m/z 326.3.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18]CC3C=CC=CC=3)=[CH:15][CH:16]=2)[C:11]([OH:26])=[CH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)(=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([OH:26])=[CH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(O)c2cc(OCc3ccccc3)ccc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=c1cc(O)c2cc(O)ccc2n1Cc1ccccc1

Procedure:
1-Benzyl-4-hydroxy-6-benzyloxy-2(1H)-quinolinone (Step (1) of Example 7) was subjected to hydrogenolysis using a palladium catalyst and acetic acid as a solvent to produce 1-benzyl-4,6-dihydroxy-2(1H)-quinolinone.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1.[CH:13]1(CO)CCC1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2][CH2:13]1
Reactant: Nc1cc(OCC2CC2)ncn1
Reactant: OCC1CCC1
Product: Nc1cc(OCC2CCC2)ncn1
Yield: 89 %

Procedure:
This was prepared in a manner analogous to 6-(cyclopropylmethoxy)pyrimidin-4-amine, where cyclobutylmethanol was used as the alcohol. 6-(cyclobutylmethoxy)pyrimidin-4-amine (0.245 g, 1.367 mmol, 89% yield) was obtained as a white solid. m/z (ESI) 180.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[O:15]COC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cnccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cnccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A mixture of 0.7 g of 4-benzyloxy-3-methoxymethoxypyridine and 1N hydrochloric acid was stirred for 2 hours at 60° C. The mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated to obtain 0.547 g of 4-benzyloxy-3-hydroxypyridine.
Reaction SMILES: [C:1]([C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:9]2=[N:8][C:7]=1[CH3:16])([O:3][CH2:4][CH3:5])=[O:2].[CH2:17]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21]Cl)[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(#N)C>[C:1]([C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:21][C:20]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:17][CH3:18])[C:9]2=[N:8][C:7]=1[CH3:16])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCc1cccc(C)c1CCl
Reactant: CCOC(=O)c1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc2c(OCc3c(C)cccc3CC)cccn12
Yield: 68 %

Procedure:
A stirred mixture of 3-carboethoxy-8-hydroxy-2-methylimidazo[1,2-a]pyridine (0.92 g, 4.2 mmol), (0.7 g, 4.2 mmol) 2-ethyl-6-methylbenzylchloride (0.7 g, 4.2 mmol), sodium carbonate (1.0 g, 9.4 mmol) and a catalytic amount of potassium iodide in acetonitrile (40 ml) was refluxed for 4 h. After filtration and evaporation of the solvent under reduced pressure the residue was purified by column chromatography on silica gel using methylene chloride:ethylacetate as eluent to give 1.0 g, (68%) of the title compound.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:18][O:19][C:20]([CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])=[O:21]>>[CH2:1]([N:6]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:20]([O:19][CH3:18])=[O:21])[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNCCc1c[nH]c2ccccc12
Reactant: COC(=O)CCCC(=O)Cl
Product: CCCCCN(CCc1c[nH]c2ccccc12)C(=O)CCCC(=O)OC
Yield: 71.5 %

Procedure:
13.4 g of N-pentyl-tryptamine and 10.5 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 14.9 g of N-pentyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-pentyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. Yield: 71.9%
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH3:4])=[C:2]([OH:1])[CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C)c(O)c1
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A solution of 2-hydroxy-4-methoxy-benzaldehyde (5.00 g, 32.86 mmol) and palladium under carbon (10%) (3.50 g, 3.28 mmol) in ethanol (32 mL) and acetic acid (3 mL) is stirred under 60 psi of hydrogen. After stirring overnight, the mixture is filtered off through Celite and washed with methanol. The mixture is concentrated under reduced pressure, and purified by flash chromatography by eluting with hexane:ethyl acetate 2:1 to afford the title compound (3.96 g, 87%). Rf=0.58 (hexane:ethyl acetate 2:1). δ1HNMR (300 MHz, CDCl3): 2.18 (s, 3H), 3.75 (s, 3H), 6.42 (m, 2H), 7.00(d, 1H, J=8.9 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Product: CCCCNC(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1

Procedure:
2-Amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and butyl isocyanate were treated in the same manner as in Example 29 to obtain 2-(butylcarbamoyl)amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:10][CH2:11][CH2:12][CH2:13][C@:14]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:18]([C:19](=[O:24])[C@@H:20]([O:22]C)[CH3:21])[N:17]=[C:16]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[S:15]1>>[NH2:10][CH2:11][CH2:12][CH2:13][C@:14]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:18]([C:19](=[O:24])[C@@H:20]([O:22][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH3:21])[N:17]=[C:16]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[S:15]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Product: C[C@H](OCC(=O)OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1

Procedure:
Prepared as previously described in Example 71 using tert-butyl 2-bromoacetate in place of methyl iodide. MS ESI (+) m/z 520 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.50 (m, 1H), 7.46 (d, 2H, J=8 Hz), 7.34 (m, 2H), 7.27 (m, 1H), 7.13 (m, 2H), 4.93 (q, 1H, J=6 Hz), 4.18 (d, 1H, J=16 Hz), 3.96 (d, 1H, J=16 Hz), 3.30 (m, 1H), 2.96 (m, 2H), 2.45 (m, 1H), 2.01 (m, 1H), 1.63 (m, 1H), 1.50 (d, 3H, J=6 Hz), 1.46 (s, 9H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[H-].[K+].C([Li])(C)(C)C.CN(C)[CH:27]=[O:28]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[CH:27]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1)=[O:28]
Reactant: CN(C)C=O
Agent: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CC=C(c2c[nH]c3ccc(C=O)cc23)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of 10.0 gm (34.3 mMol) 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 150 mL tetrahydrofuran was added dropwise to a stirring suspension of 7.2 gm (36 mMol) potassium hydride in 150 mL tetrahydrofuran at 0° C. After 30 minutes, the reaction mixture is cooled to -78° C. and to it was added 44.5 mL (75.6 mMol) of a precooled (-78° C.) solution of tert-butyllithium (1.7 M in tetrahydrofuran) via cannula. After 15 minutes 4.0 mL (51.5 mL) dimethylformamide was added via cannula and the reaction mixture was allowed to warm slowly to room temperature. The reaction mixture was quenched by the addition of 5N sodium hydroxide and the reaction mixture extracted well with diethyl ether. The organic extracts were combined, washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluting with 4% methanol in dichloromethane. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 3.8 gm (46%) of the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24](B(O)O)[CH:25]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:29])=[C:22]([C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[C:4]([CH3:18])[CH:3]=2)[CH:21]=1
Reactant: OB(O)c1cc(F)ccc1O
Reactant: Cc1cc(Br)ccc1C(=O)OCc1ccccc1
Product: Cc1cc(-c2cc(F)ccc2O)ccc1C(=O)OCc1ccccc1

Procedure:
In accordance with the method of Example 1-3, the compound of Example 15-1 was used instead of the compound of Example 1-2, and 5-fluoro-2-hydroxyphenylboronic acid was used instead of 2-hydroxyphenylboronic acid to afford benzyl 5′-fluoro-2′-hydroxy-3-methylbiphenyl-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34](O)=[O:35].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([F:37])([F:25])[F:38]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1C(F)(F)F)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), [2-(trifluoromethyl)phenyl]acetic acid (120 mg, 0.58 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) were added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with 5% aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solid was washed with ethyl acetate/heptane to give the title compound (120 mg, 79%) as a colorless powder.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([NH:17]C(=O)OC(C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>C(O)(C)C>[N:1]1([C:7]2[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:10]=[C:9]([NH2:17])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)O
Product: Nc1cc(N2CCOCC2)cc(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 90b; 1.7 g, 5 mmol) is treated with a solution of hydrogen chloride in isopropanol (30 mL of 4 M) and heated at 60° C. for 5 h. The solvent is evaporated off under reduced pressure and the residue is treated with aqueous sodium hydrogen carbonate solution (80 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed with brine (2×50 mL), dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ether-hexane to afford the title compound as yellow crystalline solid, m.p. 96-97° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[NH2:17][CH:18]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:19]1[CH:33]=[CH:32][C:22]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:1][C:2]1[C:7]([C:8]([NH:17][CH:18]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:19]2[CH:20]=[CH:21][C:22]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH:32][CH:33]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Reactant: CCOP(=O)(Cc1ccc(C(N)c2ccc(OC)cc2)cc1)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(NC(=O)c2cnc(-c3cccnn3)nc2O)c2ccc(OC)cc2)cc1)OCC
Temperature: 50 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (325 mg, 1.5 mmol) and diethyl 4-(amino(4-methoxyphenyl)methyl)benzylphosphonate, 32-f, (540 mg, 1.5 mmol) was dissolved in DMF (5 ml), HATU (570 mg, 1.5 mmol) and DIEA (590 mg, 4.5 mmol) were then added, the reaction mixture was stirred for 2 h at 50° C. under nitrogen. The resulting mixture was cooled to ambient temperature, diluted with water (10 ml), filtered, the residue was washed with water for 3 times, a brown solid was obtained, 32-g, (500 mg, 60% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.14-1.18 (t, J=4.2 Hz 6H), 3.16-3.23 (d, J=21.3 Hz 2H), 3.73 (s, 3H) 3.89-3.98 (m, 4H), 6.20-6.22 (d, J=7.8 Hz, 1H), 6.89-6.92 (m, 2H), 7.20-7.24 (m, 6H), 7.99-8.02 (m, 1H), 8.49-8.58 (m, 2H), 9.48-9.50 (m, 1H), 14.00 (s, 1H). LC-MS 564 [MH]+.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>C(O)C>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][NH:21][CH2:18][CH2:19][CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCC(c1ccccc1)c1ccccc1
Reactant: CCCN
Solvent: CCO
Product: CCCNCCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 15.0 g. of 1,1-diphenyl-4-chlorobutane and 35 cc. of propylamine in 75 cc. of ethyl alcohol was heated in a sealed bomb at 100° C. for 16 hours. After cooling the reaction mixture to about 25° C., the solvent was removed under reduced pressure. The product was dissolved in 100 cc. of diethyl ether and washed with 5 N sodium hydroxide, and the product was extracted with 2 N hydrochloric acid. The aqueous acidic extracts were combined and the pH was adjusted to 11 by the addition of 5 N sodium hydroxide. The product was insoluble in the aqueous basic solution and was extracted therefrom into diethyl ether. The ethereal extracts were combined, washed with water and dried, and hydrogen chloride gas was added to the ethereal solution. The hydrochloride salt of 1,1-diphenyl-4-n-propylaminobutane crystallized and was collected by filtration. m.p. 94°-96° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]2[C:11](=[CH:12][CH:13]=1)[CH:10]([C:14]#[N:15])[CH2:9]2)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6]1[CH:7]=[C:8]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][NH2:15])[CH2:9]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc2c(c1)CC2C#N
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)Oc1ccc2c(c1)CC2CN
Reaction time: 8 h

Procedure:
1.1 g (5.46 mmoles) of the product of Step 1 are dissolved in 30 mL of methanol (MeOH). 30 mL of (7N) ammoniacal methanol solution and 0.5 g of Raney nickel are added. The reaction mixture is hydrogenated overnight under a pressure of 1 bar, at ambient temperature. The catalyst is then filtered off and the filtrate is evaporated to dryness. The expected product is obtained in the form of an oil.