Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[O:12][CH3:13].[CH2:15]([O:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:21]1)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(CC(C)C)=O>[CH2:15]([O:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]2[CH2:30][CH2:31][N:32]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]([O:12][CH3:13])=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:14])[CH2:33][CH2:34]2)=[CH:21]1)[CH3:16]
Reactant: COC(=O)c1cc(CBr)ccc1OC
Reactant: CCOCCn1cc(C2CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOCCn1cc(C2CCN(Cc3ccc(OC)c(C(=O)O)c3)CC2)c2ccccc21
Temperature: 60 °C
Yield: 112.9 %

Procedure:
A solution of 1.9 g (0.0071 mol) of 5-bromomethyl-2-methoxy-benzoic acid methyl ester in 5 ml of methyl isobutylketone was added to a suspension of 1.8 g (0.065 mol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-indole and 1.8 g (0.013 mol) of potassium carbonate in 45 ml of methyl isobutylketone. The reaction mixture was heated at 60° C. for 20 h. The crude mixture was filtered to remove inorganic salts and the solvent was removed under reduced pressure affording 3.5 g of a crude oil. The crude mixture was purified by flash chromatography over silica gel affording 1.8 g (48% of yield) of 5-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidin-1-ylmethy}-2-methoxy-benzoic acid ethyl ester. This ester was dissolved in 18 ml of ethanol and hydrolysed with 2N NaOH at room temperature for 20 hours. The crude mixture was neutralised with 2N HCl aqueous solution and the solvent was removed under reduced pressure. The crude residue was extracted between dichloromethane and water. After drying, filtering and removing the solvent under reduced pressure, the residue obtained was recrystallised with ethanol affording 0.77 g (27% of overall yield) of the expected acid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][N:42]3[CH:44]=[C:45]([C:47]([OH:49])=O)[N:46]=[C:41]3[CH2:40][CH2:39]2)=[CH:34][C:33]=1[CH3:50].[F:51][C:52]([F:66])([F:65])[C:53]1[CH:54]=[C:55]([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:56]=[CH:57][CH:58]=1>CN(C=O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][N:42]3[CH:44]=[C:45]([C:47]([N:62]4[CH2:61][CH2:60][N:59]([C:55]5[CH:56]=[CH:57][CH:58]=[C:53]([C:52]([F:65])([F:66])[F:51])[CH:54]=5)[CH2:64][CH2:63]4)=[O:49])[N:46]=[C:41]3[CH2:40][CH2:39]2)=[CH:34][C:33]=1[CH3:50]
Reactant: Cc1cc(C2CCc3nc(C(=O)O)cn3C2)ccc1F
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C2CCc3nc(C(=O)N4CCN(c5cccc(C(F)(F)F)c5)CC4)cn3C2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (295 mg; 0.92 mmol) and N-methylmorpholine (253 μl; 232 mg; 2.3 mmol) were added to a solution of 6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.68 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (173 μl; 212 mg; 0.92 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and poured onto water. The precipitated solid was purified by column chromatography on silica gel (chloroform). Yield: 166 mg (50%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25](Cl)(=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:26][C:25](=[O:34])[NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(CNC(=O)OCc2ccccc2)c2ccccc2c1=O

Procedure:
The product of Example 42 and benzyl carbonochloridate were treated using a method similar to that described in Example 128 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.50-11.71 (m, 1H), 8.32 (dd, J=7.6, 1.5 Hz, 1H), 8.08-8.11 (m, 1H), 7.88-8.01 (m, 3H), 7.28-7.48 (m, 9H), 5.06-5.07 (bs, 2H), 4.54 (d, J=5.9 Hz, 2H), 3.68 (s, 2H); MS (ESI+) M/Z 494 (M+NH4)+.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25](Br)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([C:34]3[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)cn1

Procedure:
This compound is synthesized from compound 194 (see example 156) and (6-methoxy-pyridin-3-yl)-boronic acid analogously to the method described in Example 156.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[O:14])=[CH:7][CH:6]=1>C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[O:14])=[CH:9][CH:10]=1
Reactant: Cc1cc(C(=O)CC(c2ccc(C#CCO)cc2)c2ccccc2C)ccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)CC(c2ccc(CCCO)cc2)c2ccccc2C)ccn1
Yield: 101.4 %

Procedure:
3-[4-(3-Hydroxy-prop-1-ynyl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 85, step 1; 40 mg) in ethyl acetate (6 mL) was hydrogenated in the presence of Pd (5% on carbon, 7 mg) at room temperature for 1.5 hours. The solution was filtered over decalite, the filter residue was washed with ethyl acetate, and the solution was evaporated to yield 3-[4-(3-hydroxy-propyl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (41 mg, 64%) as a colorless oil, which was directly subjected to the next step.
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[OH:10][C:11]1[CH:16]=[C:15]([CH3:17])[O:14][C:13](=[O:18])[CH:12]=1.[Cl-].[Na+]>C1C=CC=CC=1>[OH:10][C:11]1[CH:16]=[C:15]([CH3:17])[O:14][C:13](=[O:18])[C:12]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: ClSc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1cc(O)c(Sc2ccccc2)c(=O)o1
Yield: 100 %

Procedure:
Benzenesulfenyl chloride (7.2 g., 0.050 mol) dissolved in benzene (15 ml.) was added to a rapidly stirred slurry of the monosodium salt of 4-hydroxy-6-methyl-2-pyrone (7.4 g., 0.050 mol) in benzene (110 ml.) over a period of 12 minutes. The reaction temperature was maintained at 25°-27°C. with cooling during the addition; then the reaction mixture was heated at reflux for 30 minutes. The benzene was removed by distillation in vacuo and the residue triturated with water (100 ml.) to remove the by-product sodium chloride. The crude product was removed by filtration, 10.9 g., m. 158°-163°C., 93 percent yield. A portion was recrystallized from ethanol, m. 164.5°-165.5°C. Evaporation of the aqueous filtrate to dryness in vacuo produced 2.9 g. (100 percent yield) of the by-product sodium chloride.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12](F)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[C:22]([C@@H:28]([NH2:30])[CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=1>>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:30][C@H:28]([C:22]4[C:21]([F:20])=[CH:26][C:25]([F:27])=[CH:24][N:23]=4)[CH3:29])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](N)c1ncc(F)cc1F
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1F
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ncc(F)cc1F

Procedure:
Following a similar procedure to the synthesis of Example 1, the title compound was synthesized from 6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,5-difluoronicotinonitrile (Method 32) and (S)-1-(3,5-difluoropyridin-2-yl)ethanamine (Method 50). 1H NMR (400 MHz) δ 0.68 (m, 2H), 0.95 (m, 2H), 1.45 (d, J=6 Hz, 3H), 1.87 (m, 1H), 5.48 (m, 1H), 6.19 (s, 1H), 6.69 (m, 1H), 7.63 (d, 1H), 7.98 (m, 1H), 8.51 (s, 1H), 9.58 (s, 1H), 12.15 (s, 1H). MS: Calcd.: 399. Found: [M+H]+ 400.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([OH:23])=[O:22])[C:17]=3[CH:24]=2)[C:3]1=[O:25].[CH3:26]O>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([O:23][CH3:26])=[O:22])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 75.3 %

Procedure:
To a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid (0.300 g, 0.000809 mol) in methanol is added sulfuric acid (98%, 5 drops) at room temperature. The resultant mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is taken up in methylene chloride, washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography of the residue on silica gel with methylene chloride:ethyl acetate gives the title compound as a white solid (0.235 g, 75.3%, mp 153-156° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:29]([OH:31])=O)=[CH:25][CH:26]=4)[NH:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:32]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:29](=[O:31])[NH2:32])=[CH:25][CH:26]=4)[NH:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4cc(C(=O)O)ccc4c23)CCO1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4cc(C(N)=O)ccc4c23)CCO1
Reaction time: 0.5 h

Procedure:
4-[2-(tert-Butoxycarbonylamino-methyl)-morpholin-4-yl]-9H-pyrimido[4,5-b]indole-7-carboxylic acid (6 mg, 0.014 mmol) was stirred in DMF (0.25 mL) at 0° C. Carbonydiimidazole (2.5 mg, 0.016 mmol) was added and the reaction allowed to proceed to room temperature for 30 minutes. Ammonia (28% aqueous, 0.04 mL) was added. The reaction mixture was concentrated to dryness and then the reaction was repeated to afford a complete conversion. The reaction mixture was concentrated to give the title compound as a yellow solid (5 mg, 0.012 mmol), which was deprotected without further purification. LC-MS (1) Rt 1.48 min; m/z 427 (ES+).
Reaction SMILES: Cl[C:2]1[C:3]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([NH2:24])[C:12]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][C:14]=2[O:15][CH3:16])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:68]([Zn]C#N)#[N:69].CC(N(C)C)=O>CCOC(C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl.CO>[NH2:24][C:11]1[C:12]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[C:2]([C:68]#[N:69])=[CH:7][N:6]=2)[CH:10]=1
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2c[nH]c3ccccc23)n1
Temperature: 95 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
N′-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 74, 268 mg, 0.58 mmol), zinc powder (3.78 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (52.9 mg, 0.06 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’, 55.1 mg, 0.12 mmol), and dicyanozinc (40.7 mg, 0.35 mmol) were placed in a flask under N2 and then degassed DMA (3 mL) was added. The resulting suspension was stirred for 3 h at 95° C. The mixture was then diluted with EtOAc and washed 5 times with water and then brine. The solution was then dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated with diethyl ether and the resulting solid was collected by filtration and washed with diethyl ether to give crude product. This crude material was dissolved into CH2Cl2/CH3OH and concentrated in vacuo onto silica. Purification by FCC, eluting with 1.5-8% 7N methanolic ammonia in CH2Cl2 provided a solid which was washed with CH3OH (0.2 mL) to give the title compound (48 mg, 18%) as a beige crystalline solid; 1H NMR: 2.26 (3H, s), 2.53 (4H, m), 2.91 (4H, s), 3.65 (3H, s), 4.38 (2H, d), 6.74 (1H, s), 6.85 (1H, s), 6.99 (1H, s), 7.19 (1H, s), 7.48 (1H, d), 8.01 (1H, s), 8.52 (1H, s), 8.65 (1H, s), 9.21 (1H, s), 11.97 (1H, s); m/z: ES+ MH+ 455.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[C@@H:4]([NH:12]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.CO.CNC.CO>C1COCC1>[NH2:12][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)[C:3]([N:2]([CH3:31])[CH3:1])=[O:30]
Reactant: CN(C)C(=O)[C@H](Cc1ccncc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CNC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)[C@@H](N)Cc1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
To a solution of 1.61 g of the compound obtained in Step 83-1 in a mixed solution of MeOH and THF (25 ml 4:1; v/v) was added a solution of 2 mol/L dimethylamine MeOH (5.8 ml) and the reaction mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under vacuum, and the obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=9/1 to 5/1; v/v) to obtain 0.59 g of the title compound (brown oil).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([Cl:16])[CH:11]=[CH:10][CH:9]=2)=[O:4].[CH2:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20].CCCCCCC>CO>[CH2:19]([N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([Cl:16])[CH:11]=[CH:10][CH:9]=2)=[O:4])[CH3:20]
Reactant: CCNc1ccccc1
Reactant: COC(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O
Solvent: CCCCCCC
Solvent: CO
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 98 %

Procedure:
5-Chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (3.0 g), N-ethylaniline (2 eq. 2.88 ml), and heptane (60 ml) were heated and the volatiles, mainly heptane and formed methanol, (32 ml) distilled off during 6 hours and 35 minutes. After cooling to room temperature the crystalline suspension was filtered and the crystals were washed with heptane and dried in vacuum to yield the crude title compound (3.94 g, 98 %) as white to off-white crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[CH3:22].[OH-].[K+].Cl>CO.O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])/[CH:20]=[CH:1]/[C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])=[CH:15][C:14]=1[CH3:22]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)/C=C/c2cccc(C(=O)O)c2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Commercially available 3-formylbenzoic acid (15.0 g, 0.1 mol) and commercially available 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol) were dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (28.0 g, 0.5 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, filtered, washed with water (200 mL), methanol (100 mL) and dried in the air. 19 g (67%) of a yellowish solid was obtained. 1 H NMR (400 MHz, DMSO-d6): δ 13.18 (br, 1H), 10.39 (s, 1H), 8.38 (s, 1H), 8.15 (m, 1H), 7.95 (m, 4H), 7.75 (d, 1H), 7.60 (m, 1H), 6.95 (d, 1H), 2.20 (s, 3H). MS (EI): 283 (MH+).
Reaction SMILES: CO.[OH-].[Na+].[O:5]([C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:14]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH:37]=[CH:36][CH:35]=[CH:34]3)[CH:28]=2)[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>C(OCC)(=O)C.O1CCOCC1>[O:5]([C:12]1[CH:24]=[CH:23][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH:37]=[CH:36][CH:35]=[CH:34]3)[CH:28]=2)[CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(-n2cccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1cccc(-n2cccc2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
1.0 mL of methanol and 0.5 mL of 2.0 mol/L aqueous sodium hydroxide were added to 1.0 mL of dioxane solution containing 20 mg of tert-butyl 4-phenoxy-2-(3-(1H-pyrrol-1-yl)benzamido)benzoate at room temperature and stirred at 50° C. for 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. Diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 7.6 mg of 4-phenoxy-2-(3-(1H-pyrrol-1-yl)benzamido)benzoic acid as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl.[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22].[OH-].[Na+]>O.C(O)C>[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)c1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5-methoxyaniline hydrochloride (56 mg, 0.290 mmol) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture was cooled to room temperature and then basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and isolated as a brown solid (28 mg, 38%). 1H NMR (CDCl3): 8.50–8.47 (m, 2H), 7.99 (d, J=3.0 Hz, 1H), 7.53–7.47 (m, 3H), 7.36 (d, J=9.0 Hz, 1H), 7.29 (s, 1H), 6.91 (s, 1H), 6.71 (dd, J=3.0, 9.0 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)[CH2:13][CH2:14][O:15][CH3:16])=[CH:8][C:6]=2[N:7]=1.[NH2:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1>CCOCC>[CH:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:3][C:2]([C:36]4[CH:35]=[N:34][C:33]([NH2:32])=[N:38][CH:37]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14][O:15][CH3:16])[CH2:18][CH2:19]1)([CH3:25])[CH3:24]
Reactant: Nc1ncc(B(O)O)cn1
Reactant: COCCN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCN(C(C)C)CC1
Solvent: CCOCC
Product: COCCN(Cc1cc2nc(-c3cnc(N)nc3)nc(N3CCOCC3)c2s1)C1CCN(C(C)C)CC1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-isopropyl-piperidin-4-yl)-(2-methoxy-ethyl)-amine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Acid/base work-up and trituration with ether yielded 334. 400 MHz, 1H NMR CDCl3: 9.30 (s, 2H), 7.26 (s, 1H), 5.22 (br s, 2H, NH2), 4.06 (s, 2H), 4.05 (t, 4H, J 4.4), 3.90 (t, 4H, J 4.6), 3.50 (t, 2H, J 6.0), 3.32 (s, 3H), 2.94 (d, 2H, J 11.2), 2.85 (t, 2H, J 6.1), 2.75-2.68 (m, 1H), 2.61-2.55 (m, 1H), 2.10 (t, 2H, J 11.4), 1.85 (d, 2H, J 12.0), 1.65-1.53 (m, 2H), 1.03 (d, 6H, J 6.4). LC-MS (m+1)=527.41
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[CH3:24])=[C:6]([CH3:26])[C:5]([OH:27])=[CH:4][CH:3]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([CH3:26])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:13]=[C:12]([CH3:23])[C:11]=1[CH3:24]
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2C)c1C
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2C)c1C
Temperature: 60 °C
Yield: 83.4 %

Procedure:
To a solution of N-(6-fluoro-3-hydroxy-2-methyl-phenyl)-5-(3-fluorophenyl)-2,3-dimethyl-benzamide (290 mg, 0.78 mmol, 1.0 eq) in THF (10 mL) was added a solution of BH3 (1M in THF, 5 mL, 5.0 mmol, 6.4 eq) under nitrogen. The mixture was heated at 60° C. overnight then the reaction quenched by addition of methanol. The mixture was evaporated in vacuo and the residue obtained purified by column chromatography (petroleum ether:EtOAc, 400:1 to 20:1) to give the title compound as a pale red oil (230 mg, 85%).
Reaction SMILES: [Cl-].[CH2:2]1[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N+:5]=2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C1(CCNC(=O)CCCCl)C=CC=CC=1.C(O)(C)C.ClCCl.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:2]1[CH:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: c1ccc2c(c1)CC[N+]1=C2CCC1
Agent: O=C(CCCCl)NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)O
Product: c1ccc2c(c1)CCN1CCCC21
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 2,3,5,6-tetrahydro-1H-pyrrolo[2,1-a]isoquinolinium chloride (prepared by the method of S. Akaboshi, T. Kutsuma, and K. Achiwa, J. Pharm. Bull., 1960, 8, 14, from N-(2-phenylethyl)-4-chlorobutyramide (56.4 g, 0.25 mol) and extracted into isopropanol-dichloromethane) in methanol (700 ml) and acetic acid (50 ml) at 0° C. was added portionwise sodium cyanoborohydride (19 g) over 1 h. After stirring overnight, the solvent was concentrated in vacuo. The residue was dissolved in dilute sodium hydroxide and was extracted twice with dichloromethane. The dried (magnesium sulfate) organic phase was concentrated to give an oil which was distilled using a Kugelrohr distilling apparatus, b.p. 100° C. at 0.25 mm, to give the title compound (30.4 g, 70%) as a pale yellow oil.