Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]2[CH2:17][S:16][C:15](=[O:18])[NH:14][NH:13]2)=[CH:6][CH:5]=1)([O-])=O>N1C=CC=CC=1.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]2[CH2:17][S:16][C:15](=[O:18])[NH:14][NH:13]2)=[CH:6][CH:5]=1
Reactant: O=C1NNC(C=Cc2ccc([N+](=O)[O-])cc2)CS1
Solvent: c1ccncc1
Solvent: O
Product: Nc1ccc(C=CC2CSC(=O)NN2)cc1

Procedure:
To a solution containing 7.5 g of 5-[2-(4-nitrophenyl)ethenyl]-5,6-dihydro-1,3,4-thiadiazin-2(3H)one (Example 46) in 300 ml of pyridine 18.0 g sodium dithionite in 150 ml of water was gradually added. The mixture was refluxed for 5 h. The organic phase was separated and evaporated to dryness in vacuo. The residue was treated with water and the product was filtered. Yield 4.0 g (60%), mp. 188°-196° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](O)([CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:20]S(O)(=O)=O>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([CH3:18])[CH2:10][C:9]1=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(C)(O)c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CC(=O)N(C(=O)OC(C)(C)C)c2ccccc21
Yield: 92 %

Procedure:
A solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4hydroxy-4-methylquinoline (109 mg, 0.41 mmol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (10 mg) and a trace of conc. H2SO4 at rt for 7 h. Filtration over Celite™ afforded 93 mg (92%) of 1-tert-Butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinolinone. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.62(d, J=8.1, 1H), 7.16 (d, J=7.8, 1H), 7.11 (ddd, J=7.8, 7.8, 1.6, 1H), 7.01 (ddd, J=7.7, 7.5, 1.0, 1H), 3.71 (m, 2H), 2.87 (ddq, J=6.8, 6.8, 6.8, 1H), 2.04 (dddd, J=7.4, 7.4, 7.4, 6.1, 1H), 1.61 (m, 1H), 1.51 (s, 9H), 1.3 (d, J=6.8, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:29]=[CH:28][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=3[F:27])=[C:13]([N+:30]([O-])=O)[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:29]=[CH:28][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=3[F:27])=[C:13]([NH2:30])[CH:12]=2)=[O:10])=[CH:33][CH:34]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2[N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2N)c(F)c1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3-fluorophenyl)acetate (100 mg, 0.205 mmol) was diluted with THF (2 mL) followed by the addition of Zn dust (13.4 mg, 0.205 mmol) and saturated aq. NH4Cl (1 mL). After stirring for 1 hour, the reaction was diluted with ethyl acetate and 10% aq sodium carbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-aminophenoxy)-3-fluorophenyl)acetate (93 mg, 99.1% yield).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([OH:14])=[O:13])#[N:2].Cl>[Pd].C(O)C>[NH2:2][CH2:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([OH:14])=[O:13]
Reactant: N#Cc1ccc(C(=O)O)cc1C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(C(=O)O)cc1C(=O)O

Procedure:
A pressure flask was charged with 4-cyanoisophthalic acid 204 (1.40 g, 7.33 mmol), ethanol (100 mL), Pd/C (10%) (0.50 mg), and concentrated HCl (1.5 mL). The mixture solution was hydrogenated at 50 PSI overnight. The solid impurities were removed by filtration. Removal of solvent gave quantitative yield of 4-aminomethylisophthalic acid 205: 1H NMR (400 MHz, CD3OD) δ 4.46 (s, 2H), 7.69 (d, J=8 Hz, 1H), 8.26 (dd, J=2 Hz, J=8 Hz, 1H), 8.76 (d, J=1.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>>[CH3:1][C:2]1[S:3][C:4]([C:14]2([OH:17])[CH2:15][CH2:16][C:11]3([O:10][CH2:9][CH2:8][O:7]3)[CH2:12][CH2:13]2)=[CH:5][N:6]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1nccs1
Product: Cc1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from 2-methyl-thiazole (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][C:4]#[N:5].C1CCN2C(=NCCC2)CC1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:30][C:31]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=2)[CH:22]=[C:23]([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[CH:24]=1>C(#N)C>[CH3:1][C:2]([N:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=3)[CH:20]=[C:19]([CH3:18])[CH:24]=2)[CH:29]=[N:28]1)([CH3:6])[CH2:3][C:4]#[N:5]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Reactant: CC(C)=CC#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C(C)(C)CC#N)c2)c1
Temperature: 75 °C

Procedure:
3-Methylbut-2-enenitrile (179 mg, 1.57 mmol) and DBU (143 mg, 0.94 mmol) were added to a stirred solution of N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (250 mg, 0.73 mmol) in acetonitrile (3.9 mL). The mixture was heated to 75° C. overnight and concentrated under reduced pressure The residue was purified by column chromatography on silica gel to afford 3-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]butanenitrile. MS ESI calcd. for C20H20F3N6 [M+H]+ 401. found 401. 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.27 (s, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 7.26 (d, J=4.9 Hz, 1H), 7.15 (s, 1H), 3.24 (s, 2H), 2.31 (s, 3H), 1.67 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C(=O)=O.CO.CCO.CC(O)C.[NH4+].[OH-]>[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH:18]=[CH:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Nc1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CO
Solvent: CCO
Solvent: CC(C)O
Product: O=c1[nH]ccc2[nH]c(-c3cccc4ccc(Nc5ccccc5Cl)nc34)cc12
Yield: 13.9 %

Procedure:
A solution of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 53.5 mg, 0.180 mmol), 2-chloroaniline (94 μl, 0.898 mmol), and LHMDS (1.0 M in THF; 898 μl, 0.898 mmol) was stirred in a sealed flask at 65° C. for 4 h. The mixture was then partitioned between DCM (50 mL) and saturated aq. NH4Cl (30 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by supercritical-fluid chromatography (Chiralcel OJ-H (250×21 mm, 5 μm), 55% liquid CO2/45% 1:1:1 MeOH:EtOH:IPA (+20 mM aq. NH4OH), 75 mL/min) separately provided 2-(2-((2-chlorophenyl)amino)-quinolin-8-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (107; 9.7 mg, 0.025 mmol, 14% yield; first-eluting compound) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.47 (1H, br. s.), 9.73 (1H, br. s.), 8.17 (2H, t, J=8.9 Hz), 8.06 (1H, d, J=9.0 Hz), 7.59 (2H, t, J=7.6 Hz), 7.39 (3H, quin, J=7.8 Hz), 7.22 (1H, t, J=7.6 Hz), 6.99 (2H, d, J=8.6 Hz), 6.94 (1H, s), 6.08 (1H, d, J=7.0 Hz). m/z (ESI, +ve) 387.0 (M+H)+: and 2-(2-((2-chlorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (108; 14.0 mg, 0.036 mmol, 20% yield; second-eluting compound) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.16 (1H, s), 8.04 (3H, t, J=8.7 Hz), 7.53 (2H, d, J=8.0 Hz), 7.35-7.41 (1H, m), 7.31 (2H, t, J=7.8 Hz), 7.09-7.18 (2H, m), 6.95 (1H, d, J=8.8 Hz), 5.32 (1H, br. s.), 3.53-3.60 (2H, m), 2.68 (2H, br. s.). m/z (ESI, +ve) 389.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[C:12]([CH3:28])=[CH:11][C:10]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[CH:5][N:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[N:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[C:12]([CH3:28])=[CH:11][C:10]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[CH:7][N:8]=1
Reactant: COc1ncc(-c2nc(C(=O)N3CCC(N4CCCC4)CC3)c(C)cc2-c2cccc(C(F)(F)F)c2)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cnc(O)nc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 10C, [6-(2-methoxy-pyrimidin-5-yl)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 44) was reacted with boron tribromide in dichloromethane to give the title compound as light yellow solid. MS: 512.2 (MH+).
Reaction SMILES: N1C(C)=CC=CC=1C.[Si:9]([O:16]S(C(F)(F)F)(=O)=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([F:36])[CH2:33][C@@H:32]1[C@@H:37](O)[C@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:39]([N:41]1[C@@H:45]([CH:46]([CH3:48])[CH3:47])[CH2:44][O:43][C:42]1=[O:49])=[O:40])=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl>ClCCl>[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([F:36])[CH2:33][C@@H:32]1[C@@H:37]([O:16][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])[C@H:38]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:39]([N:41]1[C@@H:45]([CH:46]([CH3:47])[CH3:48])[CH2:44][O:43][C:42]1=[O:49])=[O:40])=[O:30])([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](Cc1ccccc1)[C@H](O)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](Cc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Add 2,6-lutidine (5.3 mL, 54 mmol) and tert-butyl-dimethylsilyl-trifluoromethylsulfonate (1.62 mL, 7.08 mL) to a solution of 2-(R)-[2-(S)-benzyl-1-(S)-hydroxy-3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)-3-oxopropyl]-4-(R)-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (2.585 g, 5.4 mmol) in dichloromethane (40 mL) at −78° C. Stir 3 h, warm to room temperature, stir 5 min and cool in an ice bath. Add 1 N HCl (100 mL), wash with 1 N HCl (2×100 mL), saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a white foam (2.779 g, 87%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([Sn:24]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])/[C:25](/[CH3:29])=[CH:26]\[CH2:27][OH:28])[CH2:21][CH2:22][CH3:23].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH:49]=[CH:48][C:47](O)=[N:46]2)=[CH:41][CH:40]=1>C1COCC1>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([N:45]2[CH:49]=[CH:48][C:47]([O:28][CH2:27]/[CH:26]=[C:25](\[Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH3:37])/[CH3:29])=[N:46]2)=[CH:43][CH:44]=1
Reactant: CCCC[Sn](CCCC)(CCCC)/C(C)=C\CO
Reactant: Oc1ccn(-c2ccc(Cl)cc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(C)=C\COc1ccn(-c2ccc(Cl)cc2)n1
Temperature: -75 °C

Procedure:
To 8.09 g (30.8 mmol) triphenylphosphine in 200 ml THF have been added with stirring at −75° C. 6.23 g (30.8 mmol) azodicarbonic acid diisopropyl ester. The mixture has been stirred at this temperature for 5 min. Then 10.39 g (28.8 mmol) (Z)-3-tributylstannanyl-but-2-en-1-ol have been added dropwise and stirred for 5 min at −75° C. After addition of 4.00 g (20.6 mmol) 1-(4-chlorophenyl)-3-hydroxypyrazole at −75° C. a red suspension was formed. The mixture was allowed to warm up to ambient temperature and stirred for 3 d. After removal of the solvents in vacuo 29 g oil have been collected and purified by chromatography on 120 g silica with MTBE/heptane. Yield 8.3 g (75%) oil. δ=0.85 (m); 0.95 (m); 1.30 (m); 1.50 m); 2.00 (s); 4.65 (d); 5.90 (d); 6.43 (t); 7.35 (d); 7.52 (d); 7.68 (d).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:12]=[C:11]([NH2:21])[CH:10]=2)[CH2:4][CH2:3]1.Br[C:23]1[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:12]=[C:11]([NH:21][C:23]3[N:24]=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=3)[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(Nc2cc(N)ncc2-c2ccccc2)CC1
Reactant: N#Cc1cnc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CN1CCC(Nc2cc(Nc3cnc(C#N)cn3)ncc2-c2ccccc2)CC1
Temperature: 90 °C
Yield: 17.3 %

Procedure:
A solution of N4-(1-methylpiperidin-4-yl)-5-phenylpyridine-2,4-diamine (0.050 g, 0.17 mmol), 2-bromo-5-cyanopyrazine (0.022 g, 0.12 mmol), BINAP (0.003 g, 0.01 mmol), sodium tert-butoxide (0.016 g, 0.16 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.005 g, 0.01 mmol) in toluene (0.7 mL) was stirred at r.t. under nitrogen for 10 min before being heated under microwave irradiation for 30 min at 90° C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (0.5 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by preparative thin layer chromatography eluting with methanol/dichloromethane (1/9) to give the desired compound as a yellow solid (0.008 g, 17%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-])=O)=[CH:7][C:6]=1[Cl:15]>[Ni].CO>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:6]([Cl:15])=[CH:7][C:8]([NH2:12])=[CH:9][C:10]=1[Cl:11]
Reactant: COC(=O)Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CO
Product: COC(=O)Cc1c(Cl)cc(N)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A suspension of (2,6-dichloro-4-nitro-phenyl)-acetic acid methyl ester (12.7 g, 47.13 mmol) and Raney Nickel (3 g) in MeOH (500 mL) is stirred for 3.5 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a yellow solid: ESI-MS: 232.0/234.0 [M-H]−; tR=3.11 min (System 2).
Reaction SMILES: CN1CCOCC1.[NH2:8][C@@H:9]([CH:12]([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH2:10][OH:11].[Cl:21][C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1.O>C(OC(C)C)(=O)C.CCCCCCC>[Cl:21][C:22]1[S:26][C:25]([S:27]([NH:8][C@H:9]([CH2:10][OH:11])[CH:12]([C:13]([F:14])([F:15])[F:16])[C:17]([F:18])([F:19])[F:20])(=[O:29])=[O:28])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: N[C@H](CO)C(C(F)(F)F)C(F)(F)F
Solvent: CC(=O)OC(C)C
Solvent: CCCCCCC
Solvent: CN1CCOCC1
Product: O=S(=O)(N[C@H](CO)C(C(F)(F)F)C(F)(F)F)c1ccc(Cl)s1
Temperature: 22.5 °C
Reaction time: 0.12 h
Yield: 67.8 %

Procedure:
4-methyl morpholine (2.7 mL, 24.6 mmol) was added to a suspension of (2S)-2-amino-4,4,4-tri-fluoro-3-(trifluoromethyl)butan-1-ol (2 g, 8.1 mmol) in isopropyl acetate (10 mL). The mixture was stirred at about 20-25° C. for about 5-10 minutes and then 5-chlorothiophene-2-sulfonyl chloride (2.0 g, 9.2 mmol) was added. The reaction mixture was stirred at 20-25° C. for 6-18 hours. Water (10 mL) was then added to the reaction mixture, whereby the solids dissolved. The two layers were then separated and the organic layer was washed with a solution of 10% NaHCO3 (10 mL) and 10% NaCl (10 mL). Heptane (10 mL) was added to the isopropyl acetate layer (about 10 mL). The mixture was then distilled down to about half of its original volume under atmospheric distillation. While the solution remained at about 80-90° C., heptane (10 mL) was added over 5-10 minutes, during which time solids formed. After the addition of heptane, the mixture was cooled to 20-25° C., stirred for about 1-2 hours, and then further cooled to about 5-10° C. for 1 hour. The solid was then collected by filtration, washed with heptane (5 mL), and oven-dried to give 2.15 g (67%) of the product as an off-white solid. 98 area% HPLC purity and >99% chiral purity by HPLC.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>COCCOC.O>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)N1CCC(N(Cc2ccccc2)Cc2ccccc2)C(OC)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of racemic ethyl 4-amino-3-methoxypiperidine-1-carboxylate (1 part by mole) in DME were added benzyl bromide (about 2.2 part by mole), potassium carbonate (about 2.4 part by mole) and potassium iodide (about 0.2 part by mole) respectively. The reaction was heated to about 80° C. (in the specification, delta, or “A,” refers to heat). After about 6 hours, the reaction was slowly diluted with water (about 12 parts by volume) and extracted with, for example, ethyl acetate. The organic layer was washed with brine and then dried over anhyh. Na2SO4. Subsequent filtration and concentration of the solvent provided the 1 as the yellow-orange oil (1 part by mole).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:34][C:31]1[CH:32]=[CH:33][C:24]([N:23]=[CH:11][C@@:10]([OH:17])([C:13]([F:16])([F:14])[F:15])[CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:22])[C:4]=2[O:20][CH3:21])[CH2:18][CH3:19])=[C:25]2[C:30]=1[NH:29][C:28](=[O:35])[CH:27]=[CH:26]2
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Reactant: Nc1ccc(F)c2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1ccc(F)c2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 300 mg (0.93 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 165 mg (0.93 mmol) of 5-amino-8-fluoroquinolin-2(1H)-one and 0.58 ml of titanium tert-butoxide are reacted to give 8-fluoro-5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one. 280 mg of chromatographically purified imine (silica gel, hexane/ethyl acetate 0-75%) are cyclized in the same way as in Example 130 at −30° C. with 4.6 ml (4.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-100%) yields 230 mg of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[O:5][CH2:6][C:7]([OH:9])=O.[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([CH3:40])[CH:30]=1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[O:5][CH2:6][C:7]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([CH3:40])[CH:30]=1)=[O:9]
Reactant: O=C(O)COc1ccc(C(F)(F)F)c(Cl)c1
Reactant: Cc1cc(CN)ccc1NS(C)(=O)=O
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: Cc1cc(CNC(=O)COc2ccc(C(F)(F)F)c(Cl)c2)ccc1NS(C)(=O)=O
Yield: 66.5 %

Procedure:
[3-Chloro-4-(trifluoromethyl)phenoxy]acetic acid (127 mg, 0.5 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (97 mg, 0.6 mmol), triethylamine (0.33 ml) and N{4-(aminomethyl)-2-methylphenyl]methanesulfonamide hydrochloride (151 mg, 0.6 mmol) were treated in the same procedure described in Example 2(b). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (3/1 to 1/1) to furnish 150 mg (67% yield) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[F:26][C:27]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:25][C:4]1[N:3]=[C:2]([C:33]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:26])[CH:34]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=1
Reactant: COc1ccc2[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)nc2c1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)nc2c1
Yield: 97.1 %

Procedure:
To a solution of 4-chloro-6-{2-[5-(methyloxy)-1H-benzimidazol-2-yl]-4-morpholinyl}-2-pyrimidinamine (150 mg, 0.416 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (134 mg, 0.540 mmol) and Na2CO3 (110 mg, 1.039 mmol) in 1,4-dioxane (1.8 mL) and water (0.6 mL) stirred under nitrogen at room temperature was added solid Pd(PPh3)4 (48.0 mg, 0.042 mmol) in one charge. The reaction vessel was sealed and heated in Biotage Initiator using initial high to 140° C. for 1 hour. The reaction mixture was partitioned between EtOAc/THF 25/25 mL and water 50 mL. The organic phase was washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was added to a silica gel column and was eluted with Hexanes/EtOAc to afford the title compound (180 mg). LC-MS (ES) m/z=446 [M+H]+.