Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1

Procedure:
An ethanol solution (30 ml) of tert-butyl 4-(4-nitrophenyl)-1-piperidinecarboxylate (1.7 g) was subjected to catalytic hydrogenation using 10% palladium carbon (0.2 g) as a catalyst under normal temperature and normal pressure. After the catalyst was filtered off, the filtrate was concentrated to give tert-butyl 4-(4-aminophenyl)-1-piperidinecarboxylate as a viscous oily substance. The titled compound (2.2 g) was obtained as colorless crystals, by carrying out the same operation as in Example 1, using the resulting oily substance and 4′-chloro[1,1′-biphenyl]-4-carboxylic acid (1.43 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:26][C:27]([F:38])([F:37])[C:28]1([CH2:31]OS(C)(=O)=O)[CH2:30][CH2:29]1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:31][C:28]5([C:27]([F:38])([F:37])[F:26])[CH2:30][CH2:29]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)cc1
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)O[C@@H](C2CCN(CC4(C(F)(F)F)CC4)CC2)C3)cc1

Procedure:
The title compound is prepared from (R)-5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 2. LC (method 1): tR=1.09 min; Mass spectrum (ESI+): m/z=481 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=[O:9].Br[CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=[O:9]
Reactant: O=C(c1ccccc1O)c1cccc2[nH]ccc12
Reactant: ClCCCBr
Product: O=C(c1ccccc1OCCCCl)c1cccc2[nH]ccc12

Procedure:
Using the procedure of Step E of Example 1, 10.9 g of the product of Step D and 18.17 ml of 1-bromo-3-chloro propane were reacted to obtain after chromatography on silica (eluant: methylene chloride - hexane (75-25)), 14.4 g of the desired product melting at 94° C., which was used as is for the following step.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=1.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>[F:34][C:33]([F:36])([F:35])[C:29]1[N:28]=[C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: FC(F)(F)c1cccc(Br)n1
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: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(-c3cccc(C(F)(F)F)n3)cc2C1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (190 mg, 0.52 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (10 mg, 0.5 mmol/g, 0.005 mmol) was added along with 2-Bromo-6-trifluoromethylpyridine (174 mg, 0.78 mmol) and 500 μl of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 95 mg of title compound were recovered as whitish solid (47%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-{(2S)-5-[6-(trifluoromethyl)-2-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:29]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30]>O1CCCC1>[Si:33]([O:10][CH2:9][C:5]1[C:4]([O:11][CH3:12])=[CH:3][C:2]([NH2:1])=[C:7]([F:8])[CH:6]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:35])[CH3:34]
Reactant: COc1cc(N)c(F)cc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(N)c(F)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (4-amino-5-fluoro-2-methoxyphenyl)methanol (intermediate 91; 1.49 g, 8.7 mmol) in tetrahydrofuran (117 mL) was added dimethylaminopiridine (0.1 g, 0.81 mmol) and triethylamine (3.4 mL, 24.3 mmol). Then the mixture was cooled to 0° C. and tert-butylchlorodimethylsilane (2.45 g, 16.2 mmol) was added under argon atmosphere. The mixture was stirred 2 hours at room temperature. The solvent was removed under reduced pressure and the crude obtained was purified by column chromatography with silica gel, eluting with hexane/ether (from 0% to 100%). The title compound was obtained as an pale-orange solid (82%).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][OH:15])=[CH:6][CH:5]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:15][CH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH:2]([F:16])[F:1])=[CH:5][CH:6]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(OC(F)F)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(OC(F)F)c2ccccc12

Procedure:
Prepared by reacting (4-difluoromethoxy-naphthalen-1-yl)-methanol with methanesulphonic acid chloride in methylene chloride in the presence of triethylamine.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6]1
Reactant: COc1ccc2c(c1)C(CN=[N+]=[N-])CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)C(CN)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in Step B (1.14 g) is dissolved in 100 ml of methanol and then palladium-on-carbon (120 mg) is added to the solution. The reaction mixture is stirred at ambient temperature and under hydrogen for 3 hours.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([C:29]([F:32])([F:31])[F:30])=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].[ClH:47]>C(Cl)Cl>[ClH:47].[CH3:28][C:23]1[C:22]([O:21][C:20]2[C:15]([NH:14][C:12]3[S:11][N:10]=[C:9]([CH:3]4[CH2:2][CH:1]5[N:8]([C:40](=[O:42])[CH3:41])[CH:5]([CH2:6][CH2:7]5)[CH2:4]4)[N:13]=3)=[N:16][CH:17]=[C:18]([C:29]([F:30])([F:31])[F:32])[CH:19]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1ncccc1Oc1cc(C(F)(F)F)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(C(F)(F)F)cc3Oc3cccnc3C)n1)C2
Yield: 47.5 %

Procedure:
3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (45 mg, 0.0973 mmol) was dissolved in CH2Cl2 (2 mL) and triethylamine (67.8 μL, 0.486 mmol) and acetic anhydride (13.8 μL, 0.146 mmol) were added. After 10 minutes the reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (10% methanol in EtOAc) to afford 1-(3-(5-(3-(2-methylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone hydrochloride (25 mg, 0.0462 mmol, 47.5% yield) as a solid after HCl salt formation. Mass spectrum (apci) m/z=505.2 (M+H—HCl).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:10][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC2CCN(C)CC2)cc1

Procedure:
1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), methyl 4-(aminomethyl)benzoate hydrochloride (2.0 g, 1.0 eq.).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([O:11]CC)=O.[C:14](#[N:16])[CH3:15].Cl>C1COCC1.C(OCC)(=O)C>[O:11]=[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH2:15][C:14]#[N:16]
Reactant: CCOC(=O)c1ccccn1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccccn1
Temperature: 65 °C
Yield: 100 %

Procedure:
To a mixture of sodium hydride (15 g, 60% in oil, 375 mmol) and ethyl 2-picolinate (50 g. 331 mmol) in anhydrous THF (250 mL) was added dropwise a solution of anhydrous acetonitrile (20 g, 487 mmol) in anhydrous THF (200 mL), at about 65° C. After complete addition the reaction mixture was heated at about 65° C., for about 5 h. After cooling to rt, ethyl acetate (500 mL) was added, followed by 1 M aqueous HCl (360 mL). The resulting layers were separated, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic layers were washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give crude 3-oxo-3-(2-pyridyl)propanenitrile (48.6 g, 331 mmol, 100%), which was used as such in the next step. 1H-NMR (CDCl3, Bruker 400 MHz) δ 4.39 (2H, s); 7.58 (1H, m); 7.91 (1H, dt, J=2 Hz, 10 Hz); 8.11 (1H, dt, J=2 Hz, 10 Hz); 8.70 (1H, s).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[N:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[S:26][C:25]=1[NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:33][C:25]3[S:26][C:27]4[C:32]([N:24]=3)=[CH:31][CH:30]=[CH:29][N:28]=4)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Nc1nc2cccnc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1nc2cccnc2s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Yield: 63.7 %

Procedure:
The compound of example A79 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.2 g, 0.58 mmol), thiazolo[5,4-b]pyridin-2-ylamine (0.133 g, 0.88 mmol), HOBt (0.119 g, 0.88 mmol), and EDCI (0.168 g, 0.88 mmol), N-methyl morpholine (0.178 g, 0.88 mmol) in DMF (10 mL) to provide the title compound (0.175 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[C:16]([I:17])=[C:15]([CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[CH:19]([O:22][C:23]1[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1)([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.O>[F:7][C:8]1[C:16]([I:17])=[C:15]([CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH:19]([CH3:21])[CH3:20])[CH:24]=1)=[O:12]
Reactant: CC(C)Oc1cccc(N)c1
Reactant: Cc1ccc(C(=O)O)c(F)c1I
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(OC(C)C)c2)c(F)c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
Oxalyl chloride (2 M in DCM) (1832 μl, 3664 μmol) was added to a suspension of 2-fluoro-3-iodo-4-methylbenzoic acid (684 mg, 2443 μmol) in DCM (20 mL) at 0° C. One drop of DMF (cat) was added. The mixture was stirred at RT for 3 h. Solvent was removed under vacuum. DCM (5 mL) was added to the residue and the mixture was added slowly to a mixture of 3-isopropoxybenzenamine (540 μL, 3664 μmol) and triethylamine (681 μL, 4885 μmol) in DCM (10 mL) at 0° C. The mixture was stirred at RT overnight and then water (50 mL) was added. The mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (100 mL) and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative TLC eluting with 10% EtOAc/hexane to give the title compound (683 mg, 68%). MS (M+H)+ 414.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([C:15](=O)[CH2:16][CH2:17][CH3:18])[C:10](OCC)=[O:11].Cl.[C:29](=[NH:32])([NH2:31])[CH3:30].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:11])[NH:32][C:29]([CH3:30])=[N:31][C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CC(=N)N
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1Cl)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1Cl
Yield: 73 %

Procedure:
To a suspension of 60% sodium hydride (0.40 g) in tetrahydrofuran (20 mL) was added dropwise a solution of ethyl butyrylacetate (2.13 g) in tetrahydrofuran (10 mL). After stirring for 30 min, 4′-(bromomethyl)-3′-chlorobiphenyl-2-carbonitrile (2.06 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(3-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(3-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (2.55 g), 28% sodium methoxide (7.80 g) in methanol (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (0.64 g, 73%) as a white solid.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[CH3:58][C:59]1[CH:60]=[C:61]([S:64](Cl)(=[O:66])=[O:65])[S:62][CH:63]=1>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:64]([C:61]3[S:62][CH:63]=[C:59]([CH3:58])[CH:60]=3)(=[O:66])=[O:65])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: Cc1csc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: Cc1csc(S(=O)(=O)Nc2cccc(-c3nc(C(C)(C)C)sc3-c3ccnc(N)n3)c2F)c1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 4-methyl-2-thiophenesulfonyl chloride (50 mg, 0.256 mmol), the title compound was obtained as a white solid (59 mg, 47% yield). MS (ESI): 504 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[C:4]([C:9](NC)=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1>ClC1C=CC=CC=1Cl>[C:13]1([CH:2]2[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:9](=[O:10])[O:1]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNC(=O)c1ccccc1C(O)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: O=C1OC(c2ccccc2)c2ccccc21

Procedure:
A mixture of 76.5 g. of α-hydroxy-N-methyl-α-phenyl-o-toluamide and (0.314 mole) 150 ml. o-dichlorobenzene is heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting solid triturated with cold ether to give 3-phenyl phthalide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Br)CC1
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(CC2CCCCC2)c2ccccc2Br)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.60 mmol) was dissolved in dry N,N-dimethylformamide (10.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 127.3 mg, 3.18 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C., bromomethyl-cyclohexane (0.55 g, 3.13 mmol). The reaction mixture was stirred at 0° C. for one hour, then at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was then added into an excess of water-ice and a solid precipitated. The solid was filtered by suction, washed with water and dried to yield a crude solid. The crude solid was purified via flash chromatography (25% ethyl acetate/hexanes) to yield the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]2=[O:23].C(NCC1CCNC1)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[CH:11]=1)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]2=[O:23]
Reactant: O=C(O)c1cn(-c2ccccc2)c2c(F)c(F)c(F)cc2c1=O
Agent: CCNCC1CCNC1
Solvent: CC#N
Product: O=C(O)c1cn(-c2ccccc2)c2c(F)cc(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.88 g (2.75 mmol) of the 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.418 g (1.05 equivalents) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.32 g (1.0 equivalent) of 3-[(ethylamino)methyl]-pyrrolidine. The reaction was refluxed for one hour and was stirred overnight at room temperature. The mixture was filtered to give 0.75 g of 7-[3-(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxylic acid, mp 258°-260° C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@H:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)=[CH:6][CH:5]=1)([O-])=O.O.[ClH:18].[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[ClH:18].[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@H:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1N[C@@H](Cc2ccc([N+](=O)[O-])cc2)CO1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1ccc(C[C@H]2COC(=O)N2)cc1

Procedure:
A suspension of the product from step (c) (0.79 g) and 10% palladium on carbon (0.26 g) in a mixture of ethanol (15 ml), water (11 ml), ethyl acetate (2.0 ml) and aqu. 2N HCl (2.3 ml) was stirred under 1 atmos. pressure of hydrogen until uptake ceased. The mixture was filtered through Hyflo and the filtrate evaporated in vacuo to give the desired product as a pale yellow foam (0.79 g).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([O:13][C:14]([F:17])([F:16])[F:15])[CH:6]=1.C1COCC1.CO.O[Li].O>O>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:18])=[O:2])=[CH:6][C:7]=1[O:13][C:14]([F:15])([F:17])[F:16])#[N:12]
Reactant: COC(=O)Cc1ccc(C#N)c(OC(F)(F)F)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(CC(=O)O)cc1OC(F)(F)F

Procedure:
To a solution of methyl(4-cyano-3-trifluoromethoxyphenyl)acetate (2.15 g, 8.3 mmol) in 1:1 THF:MeOH (10 mL each) was added LiOH—H2O (0.42 g, 10.0 mmol) in water (30 mL). The reaction mixture was stirred at room temperature for 12 hours at which time the starting ester was consumed by TLC (25% ethyl acetate/hexanes). The mixture was concentrated in vacuo and acidified to pH<3 by dropwise addition of 12N HCl. The acidified solution was then extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo to yield the crude title product. LC-MS (IE, m/z): 246 [M+1]+. 1H-NMR (500 MHz, CDCl3) δ ppm 3.81 (s, 2H), 7.39 (d, J=7.5 Hz, 1H), 7.40 (s, 1H), 7.75 (d, J=7.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2cc(Cl)ccc2Cl)c([N+](=O)[O-])c1
Yield: 81.8 %

Procedure:
2,5-Dichlorophenol (17.86 g, 109.54 mmol) and 4-chloro-3-nitrobenzonitrile (10.00 g, 54.77 mmol) were combined with K2CO3 (37.85 g, 273.85 mmol) in THF (300 mL). The reaction mixture was refluxed for 48 hrs and then the solid was filtered over a bed of Celite. After rinsing the residue with copious amounts of DCM, the filtrate was concentrated to produce a yellow solid. The solid was triturated with minimal DCM and collected via vacuum filtration to yield compound 34 (13.84 g, 81.7% yield, 100.0% pure). 1H NMR (500 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.12 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.73 (d, J=9 Hz, 1H), 7.65 (d, J=2 Hz, 1H), 7.48 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.21 (d, J=9 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:29])=O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[C:13]=1[O:14][CH3:15])[C:8]([Cl:29])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1S(C)(=O)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc(C(=O)Cl)cc1S(C)(=O)=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-t-butyl-4-methoxy-5-methylsulfonyl benzoic acid (200 mg), toluene (4 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (80 μL) were added to the solution, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (f).