Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH:19][C:20]1[CH:72]=[C:23]2[N:24]=[C:25]([CH3:71])[C:26]([C@H:60]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[C:61]([O:63][CH2:64][CH3:65])=[O:62])=[C:27]([N:28]3[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([O:42][Si:43]([C:56]([CH3:59])([CH3:58])[CH3:57])([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH3:41])([CH3:34])[CH2:30][CH2:29]3)[N:22]2[N:21]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:67]([O:66][C@@H:60]([C:26]1[C:25]([CH3:71])=[N:24][C:23]2[N:22]([N:21]=[C:20]([CH2:19][CH2:18][CH2:17][C:10]3[CH:11]=[C:12]([F:16])[CH:13]=[C:14]([F:15])[C:9]=3[OH:8])[CH:72]=2)[C:27]=1[N:28]1[CH2:29][CH2:30][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([O:42][Si:43]([C:56]([CH3:59])([CH3:57])[CH3:58])([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH3:41])([CH3:34])[CH2:32][CH2:33]1)[C:61]([O:63][CH2:64][CH3:65])=[O:62])([CH3:68])([CH3:69])[CH3:70]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3cc(F)cc(F)c3OCc3ccccc3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3cc(F)cc(F)c3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Yield: 80.5 %

Procedure:
To a solution of (S)-ethyl 2-(2-(3-(2-(benzyloxy)-3,5-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (190 mg, 0.190 mmol) in Ethanol (4 mL) was added 10% Pd—C (40.4 mg, 0.038 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered through a pad of celite, concentrated and dried under high vac to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(3,5-difluoro-2-hydroxyphenyl)propyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (140 mg, 0.153 mmol, 81% yield) as thick paste. Used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J=7.3 Hz, 4H), 7.45-7.34 (m, 6H), 6.75-6.63 (m, 2H), 6.34 (s, 1H), 5.90 (br. s., 1H), 4.33-4.10 (m, 3H), 3.95-3.79 (m, 1H), 3.35 (br. s., 2H), 2.92-2.76 (m, 3H), 2.73 (br. s., 1H), 2.61 (s, 3H), 2.16-2.04 (m, 3H), 1.92 (br. s., 1H), 1.87 (br. s., 1H), 1.53-1.46 (m, 3H), 1.45-1.26 (m, 9H), 1.24 (s, 9H), 1.07 (s, 9H). LCMS (M+H)=913.9.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Al](Cl)(CC)CC.[O:11]([C:18]1[C:27]2[CH:28]=[CH:29][S:30][C:26]=2[C:25]2[CH:24]=[CH:23][C:22]([C:31]#[N:32])=[CH:21][C:20]=2[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al](N=[N+]=[N-])(CC)CC.[OH-].[Na+].N([O-])=O.[Na+].Cl>>[O:11]([C:18]1[C:27]2[CH:28]=[CH:29][S:30][C:26]=2[C:25]2[CH:24]=[CH:23][C:22]([C:31]3[NH:32][N:3]=[N:2][N:1]=3)=[CH:21][C:20]=2[N:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)nc(Oc1ccccc1)c1ccsc12
Agent: CC[Al](CC)N=[N+]=[N-]
Agent: CC[Al](Cl)CC
Agent: Cl
Product: c1ccc(Oc2nc3cc(-c4nnn[nH]4)ccc3c3sccc23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In an oven dried flask, under nitrogen atmosphere, was charged sodium azide (1.4 eq, 84 mg). Et2AlCl (1.4 eq, 1.08 ml of 1.8 M solution in toluene) was added through syringe. The mixture was stirred at room temperature for 4 hours. 4-phenoxythieno[3,2-c]quinoline-7-carbonitrile (1.0 eq, 20 mg) was charged in a vial. Et2AlN3 solution (0.15 ml) was added and the resulting mixture stirred at 80° C. for 5 days. The mixture was treated by a solution of NaOH and some sodium nitrite was added (pH=13-14). The pH was adjusted to 1.5 with HCl 6N. The material was extracted with ethyl acetate. The material was extracted from the organic phase using a saturated aqueous solution of K2CO3. The pH was adjusted to 2.5 with HCl 6N and the material was extracted with ethyl acetate. The solvent were evaporated to afford 4-phenoxy-7-(1H-tetrazol-5-yl)thieno[3,2-c]quinoline. LCMS (ES)>95% pure, m/z 303 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=1>CCO>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CC(=O)Nc1cccc(Sc2ccc(C)cc2N)c1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3cccc(NC(C)=O)c3)ccnc2n1
Temperature: 80 °C
Yield: 74.7 %

Procedure:
The title compound was prepared from the product of Example 2g (750 mg, 3.63 mmol), and the product of Example 199c (988 mg, 3.63 mmol) combined in 10 mL of EtOH and heated to 80° C. for 40 hrs. After cooling to room temperature the solvent was removed under vacuum giving the title compound (1.2 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13](=[O:29])[N:14]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13](=[O:29])[N:14]([CH2:21][C:22]([OH:24])=[O:23])[C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(S(=O)(=O)Nc2ccc(C(C)C)n(CC(=O)OC(C)(C)C)c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C(C)C)n(CC(=O)O)c2=O)c1
Yield: 67 %

Procedure:
3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.24 g, 2.95 mmol), as prepared in the preceding step, was dissolved in methylene chloride (20 mL) and reacted with trifluoroacetic acid (8 mL) at ambient temperature for 2 hours. After evaporation in vacuo, the crude product was dissolved in methylene chloride, washed with pH 7 buffer and brine, dried over MgSO4, and filtered. Evaporation of the filtrate gave the title compound (0.72 g, 67%) as a light yellow solid. Mass spectrum (LCMS, ESI) calcd. for C17H20N2O5S: 365.4 (M+H). Found: 365.1.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH3:45])[CH2:39][CH2:38]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH3:45])[CH2:41][CH2:42]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: CCCN1CCN(CCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCN1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a solution mixture of methyl 2-(2-(benzyloxy)-5-(2-(4-propylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.081 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.081 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Chloroform was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.043 g of methyl 2-(2-hydroxy-5-(2-(4-propylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as an orange solid.
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]1[C:7]([N:23]([CH3:25])[CH3:24])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH3:25][N:23]([CH3:24])[C:7]1[C:6](/[CH:5]=[CH:4]/[CH2:3][OH:2])=[C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COC(=O)/C=C/c1c(N(C)C)nc2ccccc2c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CN(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1/C=C/CO
Reaction time: 1 h
Yield: 108.9 %

Procedure:
(E)-Methyl-3-[2-(dimethylamino)-4-(4-fluorophenyl)-3-quinolinyl]-2-propenoate (4.60 g) is dissolved in 40 ml of dichloromethane at -78° C. under an atmosphere of nitrogen. A 1 M solution of diisobutylaluminum hydride (DIBAL) (29 ml, 2.2 equivalents), in dichloromethane is added dropwise, the reaction stirred for one hour, and quenched by adding 15 ml of an aqueous saturated solution of sodium sulfate and removing the cooling bath. The reaction mixture is filtered through Celite and the filtrate dried (magnesium sulfate) and evaporated to give 4.61 g of (E)-3-[2-(dimethylamino)-4-(4-fluorophenyl)-3-quinolinyl]-2-propen-1-ol as an orange oil; 1H NMR (chloroform-d): δ 7.72 (d, 1H), 7.50-7.30 (m, 1H), 7.20-6.98 (m, 6H), 6.31 (d, 1H), 5.72 (dt, 1H), 3.99 (bd, 2H), 2.96 (s, 6H), 1.54 (bs, 1H) ppm.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[NH:19]1[CH:23]=[N:22][C:21]([C:24](O)=[O:25])=[N:20]1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:24]([C:21]2[N:22]=[CH:23][NH:19][N:20]=2)=[O:25])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)c1nc[nH]n1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2nc[nH]n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.30 g, 1.03 mmol), 1H-1,2,4-triazole-3-carboxylic acid (0.12 g, 1.08 mmol), triethylamine (0.22 g, 2.16 mmol), EDCI (0.21 g, 1.08 mmol) and HOBt (0.17 g, 1.08 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water, and the suspension of white precipitate in ethyl acetate was washed with 10% sodium hydrogen carbonate solution, water, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford white solid. This solid was triturated with diisopropyl ether to give the title compound (0.18 g, 56%) as a white solid, mp 295° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1CCCCC=1>C(OCC)(=O)C.[Pd]>[F:16][C:10]1([CH2:9][O:8][C:7]2[N:6]=[CH:5][C:4]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:3][CH:2]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCOCC2)c(Br)c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(OCC2(F)CCOCC2)nc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide (200 mg) and cyclohexene (0.549 mL) in ethyl acetate (10 mL) was added 10% palladium on carbon (57.6 mg). The suspension was stirred for 60 minutes at 120° C. The reaction mixture was filtered and concentrated. The product was purified by reverse-phase flash chromatography (C18, 150 g, 10%-100% acetonitrile/H2O/trifluoroacetic acid 0.1%).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:22])([F:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([CH2:19]O)[CH:16]=[N:15]2)=[CH:10][CH:9]=1>CCOCC>[Br:2][CH2:19][C:17]1[CH:16]=[N:15][N:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]([F:22])([F:21])[F:5])=[CH:9][CH:10]=2)[CH:18]=1
Reactant: OCc1cnn(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(-n2cc(CBr)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
PBr3 (76 μL, 0.81 mmol) was added to a solution of alcohol 117 (0.210 g, 0.813 mmol) in ether (10 mL) at 0° C. The mixture was stirred at room temperature for 2 h, then cooled to 0° C., quenched with ice, and partitioned between Et2O and water. Column chromatography of the organic portion on silica gel (eluting with CH2Cl2) gave 4-(bromomethyl)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole (118) (0.212 g, 81%) as a white solid: mp 50-51° C.; 1H NMR (CDCl3) δ 7.94 (d, J=0.5 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J=9.1 Hz, 2H), 7.31 (d, J=9.1 Hz, 2H), 4.50 (s, 2H). APCI MS m/z 321, 323 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>ClCCl.CO>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]1=[O:30]
Reactant: C[C@@](CCn1ccc(CCc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@@](CCn1ccc(CCc2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A solution of hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(2-phenylethyl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (14 mg, 0.029 mmol) in 5:1 dichloromethane-methanol (1.2 mL) at 0° C. After 2 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with 1:1 pentane-dichloromethane, filtered, washed with pentane, and dried under reduced pressure to provide a light pink solid (8 mg, 70%). MS (APCI) m/z 393.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (s, 3H) 2.00-2.14 (m, 1H) 2.24-2.36 (m, 1H) 2.63-2.74 (m, 2H) 2.78-2.88 (m, 2H) 3.06 (s, 3H) 3.58-3.73 (m, 1H) 3.94-4.08 (m, 1H) 6.16-6.26 (m, 2H) 7.11-7.32 (m, 5H) 7.55 (d, J=7.41 Hz, 1H) 11.14 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CC(C)([O-])C.[Na+].Br[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1>C1COCC1.C(OCC)(=O)C>[CH3:52][O:51][C:48]1[CH:49]=[CH:50][C:45]([NH:1][C:2]2[C:7]3[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:46][CH:47]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cn1c(=O)[nH]c2cccc(N)c21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Nc2cccc3[nH]c(=O)n(C)c23)cc1
Temperature: 60 °C
Yield: 41.8 %

Procedure:
A mixture of 0.183 g (1.12 mmol) of 7-amino-1-methyl-1,3-dihydrobenzimidazol-2-one, 0.037 g (0.11 mmol) of biphenyl-2-yl-dicyclohexylphosphane, 0.237 g (2.47 mmol) of sodium tert-butoxide and 0.041 g (0.045 mmol) of tris(dibenzylidineacetone)dipalladium in 6 mL of THF was treated with 0.14 mL (1.12 mmol) of 4-bromoanisole and heated to 60° C. for 18 h. The crude reaction mixture was diluted with ethyl acetate, filtered through a pad of celite and purified by flash chromatography eluting with a 97% dichloromethane/methanol mixture to give 0.126 g (42%) of the title compound as a tan powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:12][CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OCC)=O.O.[OH-].[Na+]>O1CCCC1>[CH3:7][NH:12][CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)NC(Cc1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(Cc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred suspension of lithium aluminum hydride (12.4 g, 0.032 mol) in 300 ml of tetrahydrofuran at 0° C. under nitrogen was added dropwise a solution of N-carboethoxy-1,2-diphenylethylamine (35.0 g, 0.13 mmol) in 200 ml of tetrahydrofuran. The mixture was heated to reflux for 8 hours. The mixture was cooled in an ice-water bath and water (13 ml), 15% NaOH (13 ml) and water (39 ml) were carefully added to the mixture. The mixture was warmed to ambient temperature and the precipitated salts were removed by filtration through celite. Removal of solvent gave N-methyl-1,2-diphenylethylamine, 26.8 g as a colorless oil.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:16][O:17][CH3:18])[C:11]([O:13]CC)=[O:12])[N:5]=1)=O.[OH-].[Na+].Cl>C(O)C>[NH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:16][O:17][CH3:18])[C:11]([OH:13])=[O:12])[N:5]=1
Reactant: CCOC(=O)C(=NOC)c1nccc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (4.3 g.) and 10N aqueous solution of sodium hydroxide (6.1 ml.) in ethanol (100 ml.) was stirred for 3 hours at ambient temperature. To the reaction mixture was gradually added concentrated hydrochloric acid with stirring, whereby said mixture was adjusted to pH 3. The precipitates were collected by filtration and washed successively with ethanol and diethyl ether and then dried to give white crystals of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
At 0° C., 859 ml (859 mmol) of a 1M solution of borane/tetrahydrofuran complex in tetrahydrofuran are added dropwise to 110 g (573 mmol) of 5,6-dichloronicotinic acid in 250 ml of tetrahydrofuran. The mixture is warmed to room temperature and stirred at this temperature for 3 hours. After cooling to 0° C., the reaction mixture is made alkaline using saturated aqueous potassium carbonate solution, most of the tetrahydrofuran is removed on a rotary evaporator and the residue is extracted repeatedly with ethyl acetate. The combined organic phases are washed with water and saturated aqueous sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressured and purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:2) gives 62 g (61% of theory) of (5,6-dichloropyridin-3-yl)methanol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COC(=O)c1c(CNC(=O)c2cccc(OC)c2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
7-Methoxy-3-[(3-methoxy-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester was prepared starting from intermediate K and 3-methoxybenzoyl chloride. MS calcd. for C27H24N2O6 [(M+H)+] 473.2, obsd. 473.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25]O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][O:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cc([N+](=O)[O-])ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-5-nitro phenol (10 g, 63.497 mmol), N-boc-4-piperidine methanol (13.67 g, 63.49 mmol), and PPh3 (16.63 g, 63.49 mmol) in 130 mL THF, cooled at −20° C. was added dropwise over 1.5 h a 50 mL THF solution containing DIAD (12.75 ml, 64.76 mmol). The mixture turned a deep red. The reaction was warmed gradually to RT and stirred for 18 h. The mixture was concentrated in vacuo, dissolved in Et2O, washed once with water, then NaHCO3 (sat). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was treated with a mixture of hexanes and EtOAc (1:1) and the solid was filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography to yield the title compound as a yellow solid. MS (MH+)=NA; Calc'd 370.13 for C17H23ClN2O5.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[O:21]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=[CH:29][C:22]1=2>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:30]([C:27]2[CH:28]=[CH:29][C:22]3[O:21][CH2:25][CH2:24][C:23]=3[CH:26]=2)=[O:31])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc2c(c1)CCO2
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc2c(c1)CCO2)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2,3-dihydrobenzo(B)furan-5-carboxylic acid.
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:36]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (135.0 mg, 0.29 mmol), 3-methyltetrahydro-4H-pyran-4-one (100 mg, 0.88 mmol) and triethylamine (0.1.6 mL, 1.2 mmol) in methylene chloride (10 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 and isomer 2. MS calculated for C24H36F3N5O2: (M+H) 484; found 484.1.