Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14]([S:33]([C:36]1[C:37]([CH3:42])=[N:38][O:39][C:40]=1[CH3:41])(=[O:35])=[O:34])[CH2:13][CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[NH2:38][C:37]([CH3:42])=[C:36]([S:33]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[CH:15]1[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:24]=1)(=[O:35])=[O:34])[C:40](=[O:39])[CH3:41]
Reactant: Cc1noc(C)c1S(=O)(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)C(=C(C)N)S(=O)(=O)N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1
Yield: 75.5 %

Procedure:
A mixture of 6-benzyloxy-2-(3,5-dimethylisoxazole-4-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.036 g, 0.061 mmol), ammonium formate (0.077 g, 1.22 mmol), and 20% Pd(OH)2/C (0.020 g) in MeOH (20 ml) was refluxed under N2 for 1.5 hr, then filtered through Celite. The filtrate was evaporated in vacuo to a yellow residue that was suspended in a mixture of H2O(3 ml) and sat. NaHCO3 solution (3 ml), then extracted with CH2Cl2 (3×3 ml). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 0.023 g (76% yield) of yellow oil. Further purification by preparative TLC, eluting with SiO2, EtOAc:MeOH (1:1), gave 0.019 g (63% yield) of colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:36]([CH:35]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:6][CH:7]=1)[CH2:38][CH3:39])[CH3:37]
Reactant: CCC(Br)CC
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(CC)CC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and 3-bromopentane (1.40 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.98 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30]C4CCCCO4)[CH:27]=3)[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl>C(Cl)Cl.O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=3)[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13]
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-3-[1-(6-Fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazine (Stage 279.1, 250 mg, 0.511 mmol) was dissolved in DCM (5 mL). HCl in dioxane (4 N, 0.5 mL) was added and the RM was stirred 1 h at rt. It was then diluted with EtOAc and washed with a saturated NaHCO3 sol. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to afford the title compound as a white solid (tR 0.98 min (conditions 2), MH+=406, 1H-NMR in DMSO-d6: 8.39 (s, 1H); 8.07 (d, 2H); 8.01 (d, 1H); 7.69 (s, 1H); 7.61 (s, 1H); 7.51 (d, 1H); 7.47 (d, 1H); 7.23 (d, 1H); 4.95 (t, 1H); 4.76 (q, 1H); 4.18 (t, 2H); 3.78 (s, 3H); 3.75 (q, 2H); 1.79 (d, 3H)).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([C:16]([O:18]C)=[O:17])[N:6](C(OC)=O)[CH2:7]2.[ClH:20]>>[ClH:20].[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([C:16]([OH:18])=[O:17])[NH:6][CH2:7]2
Reactant: COC(=O)[C@H]1Cc2c(Br)cccc2CN1C(=O)OC
Agent: Cl
Product: O=C(O)[C@H]1Cc2c(Br)cccc2CN1
Yield: 84.6 %

Procedure:
Dissolve dimethyl (3R)-5-bromo-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylate (27.55 g, 84.0 mmol) in 5N hydrochloric acid (330.6 mL, 1.65 mol) and heat to reflux for three days. Concentrate under reduced pressure to give a white solid. Wash the solid with diethyl ether and dry under vacuum at 40° C. overnight to give (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1:1) (20.8 g, 71.1 mmol). Add acetyl chloride (50.6 mL, 711.0 mmol) to a 0° C. mixture of (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1:1) (20.8 g, 71.1 mmol) in methanol (474 mL). Warm to room temperature and stir for 36 hours. Concentrate under reduced pressure and dry to give the title compound (21.9 g, 71.4 mmol). MS (m/z): 270 (M+1).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25][C:24]=4[CH:31]=3)[N:13]=2)=[CH:7][CH:6]=1)(C)(C)C.[Li+].[OH-:33]>>[C:28]([C:26]1[O:27][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:14]3[N:13]=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][CH:5]=[C:6]([OH:33])[CH:7]=4)[C:17]([F:18])=[CH:16][N:15]=3)=[CH:31][C:24]=2[CH:25]=1)([OH:30])=[O:29]
Reactant: CC(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)CC(C(=O)O)O4)ncc2F)cc1
Reactant: [OH-]
Agent: [Li+]
Product: O=C(O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine, 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-4-pyrimidinediamine upon LiOH treatment gave N2-(2-carboxybenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.97 (bd, 2H), 7.60-7.44 (m, 4H), 7.20-7.05 (m, 3H), 6.69 (bd, 1H); 19F NMR (CD3OD): −21844; LCMS: ret. time: 16.77 min.; purity: 100%; MS (m/e): 381 (MH+).
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]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH: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.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:29][CH: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
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: C1CCNCC1
Product: Nc1ncnn2c(-c3ccc(CN4CCCCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 5 %

Procedure:
Using a procedure similar to that of Example 282 (step 2) with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and piperidine as starting materials, 12 mg (5%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.50 (s, 2 H) 2.30 (m, 4 H), 1.80 (m, 2 H), 1.55 (m, 4 H), 1.40 (m, 2 H); ES-MS m/z 514.04 [M+H]+, HPLC RT (min) 2.34.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].[C:25]1([CH2:31][CH2:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:23]([O:22][C:19](=[O:21])[CH2:20][C:33]([OH:37])([CH2:32][CH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:34][CH2:35][CH3:36])[CH3:24]
Reactant: CCOC(C)=O
Reactant: CCCC(=O)CCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(O)(CCc1ccccc1)CC(=O)OCC
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (32.2 ml, 230 mmol) in tetrahydrofuran (240 ml) at −58° is added 2.63 M n-butyl lithium in hexane (87.4 ml, 230 mmol) over one hour. Ethyl acetate (21.4 ml, 220 mmol) is then added and the reaction mixture stirred for 1 hour during which time the reaction mixture was cooled to −70°. 1-Phenyl-3-hexanone (I, 35.2 g, 200 mmol) is added slowly over 30 minutes and the reaction mixture stirred cold for 1 hour. The mixture was quenched with aqueous ammonium chloride (100 ml) and warmed to 20-25°. The mixture is then acidified with hydrochloric acid (4 M). The desired product is extracted into methyl t-butyl ether dried over magnesium sulfate and concentrated to give the title compound, TLC Rf=0.71 (ethyl acetate/hexane, 30/70); NMR (CDCl3) 7.28-7.12, 4.13, 3.60, 2.73-2.63, 2.50, 1.83-1.77, 1.58-1.53, 1.41-1.36, 1.24 and 0.93 L; CMR (CDCl3) 173.0, 143.2, 128.5, 128.4, 128.3, 128.1, 125.8, 72.8, 60.6, 42.9, 41.3, 30.1, 17.0, 14.6 and 14.2 L; MS (CI, ammonia) m/z (relative intensity) 282 (100), 264 (63), 247 (10), 194 (13), 172 (5), 159 (5).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])[NH2:28].[F-].[Cs+]>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].C1(P(C2C=CC=CC=2)CCCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]([C:34]1[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=1)[C:27]([NH2:28])=[O:29])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OC2=CC3CCC(C2)N3Cc2ccccc2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Product: NC(=O)c1cccc(C2=CC3CCC(C2)N3Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 64.4 %

Procedure:
To a 100 mL round bottom flask was added toluene-4-sulfonic acid 8-benzyl-8-azabicyclo[3.2.1]oct-2-en-3-yl ester (0.75 g, 2 mmol), 3-carbamoylphenyl boronic acid (0.36 g, 2.2 mmol), Pd2 dba3 (0.055 g, 0.06 mmol), 1,5-bis(diphenylphosphino)pentane (0.053 g, 0.12 mmol) and CsF (0.91, 6 mmol). The reaction mixture was purged with nitrogen for 5 min, and THF (8 mL) and 1.5 mL DMF (1.5 mL) were added. The suspension was stirred at room temperature and purged with nitrogen for another 5 min, then heated to 68° C. After 21 h at 68° C., the reaction mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and 1 N NaOH (20 mL). The organic layer was washed with 1:1 brine:water (2×20 mL) and dried over Na2SO4. The organic layer was concentrated to 7 to 8 mL, resulting in a slurry that was filtered to provide the title compound (0.41 g, 64% yield) as off-white solids. (m/z): [M+H]+ calcd for C21H22N2O, 319.18. found 319.4.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: [O-]B([O-])Oc1ccc(F)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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(F)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.0 g), 4-fluorophenyl borate (0.465 g) and potassium carbonate (0.84 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.17 g), and the mixture was refluxed for 20 hours, cooled, extracted with ethyl acetate, saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:1) and recrystallized from ethyl acetate/hexane=1:1 to give pale yellow crystals of methyl 7-(4-fluorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (656.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1F)[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[F:16]C1C=CC(F)=CC=1C(Cl)=O>>[F:16][C:12]1[CH:13]=[CH:14][C:2]([F:1])=[CH:3][C:4]=1[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: O=C(O)CNC(=O)c1ccc(F)c(F)c1
Product: O=C(O)CNC(=O)c1cc(F)ccc1F

Procedure:
2-(2,5-difluorobenzamido)acetic acid was prepared in the same manner as 2-(3,4-difluorobenzamido)acetic acid described above, except that 2,5-difluorobenzoyl chloride was used in place of 3,4-difluorobenzoyl chloride. LCMS (+ESI) m/z 216.2 [M+H]+. 1H-NMR (dmso d6) δ 12.69 (br s, 1H), 8.66 (bdd, 1H), 7.55-7.30 (m, 3H), 7.75 (m, 1H), 3.93 (d, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[CH:4][C:5]1[NH:6][C:7](=[O:29])[C:8]2[C:9]3[N:18]([CH3:19])[C:17]([NH:20][C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:28])=[N:16][C:10]=3[CH:11]=[CH:12][C:13]=2[C:14]=1[CH3:15].[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:17]1[N:18]([CH3:19])[C:9]2[C:8]3[C:7](=[O:29])[NH:6][C:5]([CH2:4][CH:3]=[CH:2][NH:1][C:37]([NH:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:38])=[C:14]([CH3:15])[C:13]=3[CH:12]=[CH:11][C:10]=2[N:16]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1c(C=CCN)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Solvent: CN(C)C=O
Product: Cc1c(CC=CNC(=O)Nc2ccccc2)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Yield: 86.8 %

Procedure:
A solution of the product of Example 28 (50 mg, 0.12 mmol) and phenyl isocyanate (17 mg, 0.13 mmol) in DMF (2 mL) was heated at 60° C. for 10 h. The resulting precipitate was filtered, triturated with MeOH/CH2Cl2 (90:10), and dried to provide the title compound (57 mg, 89%) mp>290° C.; MS (ES) 547 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1>CS(C)=O>[NH:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: Nc1cc(Cl)ncn1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.1 %

Procedure:
Sodium hydride (400 mg, 10.0 mmol) was suspended in dimethyl sulfoxide (20 ml) under nitrogen atmosphere, and 5-hydroxyindole (1.33 g, 10.0 mmol) was gradually added while the reaction mixture was stirred at room temperature. After 20 minutes, 6-chloropyrimidin-4-ylamine (1.04 g, 8.00 mmol) was added thereto, the reaction mixture was heated at 100° C. and stirred for 1 hour. After the reaction mixture was naturally cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=3:1) to yield the title compound (1.07 g, 4.73 mmol, 59%) as a brown oil.
Reaction SMILES: [O:1]=[C:2]([CH2:26][O:27]C(=O)C)[CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10].[BH4-].[Na+].C([O-])([O-])=O.[Na+].[Na+].Cl>C(O)C.CO.O>[OH:1][CH:2]([CH2:26][OH:27])[CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10]
Reactant: CC(=O)OCC(=O)CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCCC(O)CO)c1Oc1ccccc1
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
A slurry of 3-(γ-oxo-δ-acetoxybutylamino)-4-phenoxy-5-sulfamylbenzoic acid (1.5 g) in ethanol (10 ml) was treated with sodium borohydride (0.5 g) and the mixture was heated on the steam bath with occasional swirling until a clear solution had formed. Water and aq. Na2CO3 were added and heating on the steam bath continued for about 10 min. The solution was cooled and carefully acidified with 3 N aqueous HCl. Some methanol was added and the solution was concentrated to ca. 20 ml under reduced pressure. Partial neutralization with aq. Na2CO3 caused the product to separate as a gum, which soon solidified. The product was filtered, washed with water, and air-dried to give 1.1 g (80%) of 3-(γ, δ-dihydroxybutylamino)-4-phenoxy-5-sulfamylbenzoic acid as a colorless powder. A sample was recrystallized from methanol/water to give needles with mp 235°-238°; ir (Nujol) 3500, 3400, 2700 (broad) 1710, 1625, 1600, and 1525 cm-1 ; nmr (d 6 -DMSO) 1.5 (m, broad, 2H), 3.0-3.5 (m, broad, 5 H), 5.13 (s, broad, NH), 6.7-7.3 (m, C6H5), 7.17 (s, SO2NH2), 7.31 (d, J=2, CH), and 7.66 ppm, d, J=2, CH); mass spectrum m/e 378, 396 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:38])[CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]=[C:24]3[C:27]3([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:30][CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CC(O)C>ClCCl>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:27]2([C:24]3[C:25]4[C:20](=[CH:19][CH:18]=[C:17]([O:16][CH2:15][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:38])[CH:26]=4)[CH2:21][CH2:22][N:23]=3)[CH2:30][CH2:29][CH2:28]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc3c(c2)C(C2(c4ccc(Cl)cc4)CCC2)=NCC3)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(COc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)N1CCNCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-(2-{1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (690 mg, 1.28 mmol) was dissolved in dichloro-methane. A 5 M solution of HCl in 2-propanol (5 mol) was added and the mixture was stirred for 14 h at RT. The solvent was removed and the residue (230 mg) was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[O-2].[Mn+2]>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:1]
Reactant: N#Cc1cnc2ccc(CO)cc2c1-c1ccccc1
Agent: [Mn+2]
Agent: [O-2]
Product: N#Cc1cnc2ccc(C=O)cc2c1-c1ccccc1

Procedure:
Similar procedure as described in example 61i was used, starting from 6-hydroxymethyl-4-phenyl-quinoline-3-carbonitrile (example 62b), and activated manganese oxide to give 6-formyl-4-phenyl-quinoline-3-carbonitrile. LC-MS m/e 259 (MH+).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[CH2:13][CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC[C@@H]1CCCC[C@@H]1c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC[C@@H]1CCCC[C@@H]1c1ccccc1
Reaction time: 2 h
Yield: 50.5 %

Procedure:
A solution of 2-(cis-2-phenylcyclohexyl)ethanol (3 g.) in methylene chloride (6 ml.) was added rapidly to a stirred suspension of pyridinium chlorochromate (4.8 g.) in methylene chloride (6 ml.). The mixture was stirred for 2 hours and diluted with ether (75 ml.). The supernatant solution was decanted from the black tar and filtered through diatomaceous earth. The residual tar was washed thoroughly with ether. The combined ethereal filtrate and washings were evaporated. The pale yellow oil obtained, was purified by flash chromatography on silica eluting with hexane/ether (2:1 v/v) to give (cis-2-phenylcyclohexyl)acetaldehyde (1.5 g.) as a semi-solid; NMR (CDCl3): 1.1-2.35 (10H, m), 2.4-2.7 (1H,m), 2.75-3.0 (1H,m), 7.0-7.4 (5H,m) and 9.3 (1H, br s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13](F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([NH2:34])[CH2:31][CH2:32][NH2:33]>>[O:28]=[S:20]1(=[O:29])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH2:31][CH2:30][NH2:34])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=2)[CH2:18][CH2:19]1
Reactant: NCCCN
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Product: COc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro-6-methoxyquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methoxyquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 8.01-7.99 (d, J=8 Hz, 1 H), 7.83-7.81 (d, J=7.2 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.52-7.50 (d, J=7.6 Hz, 2 H), 7.30-7.27 (d, J=9.2 Hz, 1 H), 5.90 (s, 1 H), 5.25 (s, 2 H), 4.46 (s, 2 H), 3.83 (s, 3 H), 3.66 (s, 2 H), 3.56 (s, 2 H), 3.08-3.07 (t, J=7.2 Hz, 2 H), 2.09-2.06 (d, J=5.2 Hz, 2 H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:31][CH2:30][CH2:29][N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:11][N:8]([CH:37]3[CH2:36][CH2:35][C:34]([OH:33])([C:41]4[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=4)[CH2:39][CH2:38]3)[CH2:9]2)=[O:32])=[N:17]1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(CCO)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 74, Step A) and 4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.