Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:13])=[CH2:12])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.CCO>[Pt].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: C=C(C)c1cc(Cl)cnc1C(=O)O
Agent: [Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1cc(Cl)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A sealable vial was charged with 5-chloro-3-(prop-1-en-2-yl)picolinic acid (373 mg, 1.887 mmol) and EtOH (100 mL). The solution was purged with Nitrogen. Pt on activated carbon (479 mg, 0.245 mmol) was added, followed by glacial acetic acid (0.4 mL). The reaction mixture was evacuated, backfilled with hydrogen and stirred for 30 min at rt. The reaction mixture was filtered through a pad of celite to obtain the title compound as a white solid. The product contained minor amounts of dehalogenated product. The product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][N:20]=1>>[CH3:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:22]1[CH:21]=[N:20][C:19]([NH2:18])=[N:24][CH:23]=1)=[N:3][C:4]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1cnc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21

Procedure:
4-(2-Chloro-9-methyl-9H-purin-6-yl)morpholine (95 mg) was reacted with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and purified via reverse phase HPLC to give 26.1 mg of 127 as a white solid. MS (Q1) 313.2 (M)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][CH2:47][Cl:48]>CN(C=O)C>[Cl:48][CH2:47][CH2:46][CH2:45][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:5]2
Reactant: ClCCCBr
Reactant: Cn1c(=O)c(-c2nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n2)cc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n2)cc2cc(OCCCCl)ccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a mixture of 6-hydroxy-1-methyl-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (600 mg, 1.22 mmol) and potassium carbonate (337 mg, 2.44 mmol), was added DMF (100 ml), and the resultant mixture was stirred. 1-Bromo-3-chloropropane (578 mg, 3.64 mmol) was then added thereto, followed by stirring at a bath temperature of 60° C. for four hours. The reaction mixture was concentrated under reduced pressure, and water was added thereto, followed by extraction with a mixture of chloroform-methanol (10:1). The residue was dried over sodium sulfate anhydrate, and the solvent was removed under reduced pressure, to thereby obtain the title compound (638 mg) in a crude form as yellow oily matter.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24](=[O:26])[CH3:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:25][C:24]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)=[O:26])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: COc1ccc(C(C)=O)cc1OC
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc1OC

Procedure:
The procedure described in Example 8 was repeated using 1.8 g of 3.4-dihydroxy-5-nitrobenzaldehyde and 1.8 g of 3',4'-dimethoxyacetophenone in 20 ml of methanol. Yield 1.7 g (50%), m.p. 206°-208° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:9][CH2:10][CH:11]([OH:26])[CH2:12][N:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>[Na].C(O)C>[ClH:9].[OH:26][CH:11]([CH2:10][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][N:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Sc1ccccc1
Reactant: OC(CCl)CN(C1CCCCC1)C1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: OC(CSc1ccccc1)CN(C1CCCCC1)C1CCCCC1
Yield: 63 %

Procedure:
One mol of thiophenol is dissolved in a solution of 46 g of sodium in ethanol. To the resulting solution there is progressively added 1 mol of an ethanolic solution of (3-chloro-2-hydroxy propyl) dicyclohexylamine hydrochloride. This mixture is then heated for two hours at reflux. After cooling the same, the reaction mixture is filtered and the filtrate evaporated to dryness. The resulting oily residue is taken up in sulfuric ether, through which there is then bubbled gaseous HCl. A white precipitate rapidly forms which is then filtered therefrom and recrystallized in ethanol for a 63 percent yield of white crystals melting at 181°C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[C:13]([O:15]CC)=O)=[C:8]([O:19][CH3:20])[CH:7]=1>C(O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13](=[O:15])[NH:3][CH2:2][CH2:1][N:4]=2)=[C:8]([O:19][CH3:20])[CH:7]=1
Reactant: CCOC(=O)C(=O)c1ccc(F)cc1OC
Reactant: NCCN
Solvent: CCO
Product: COc1cc(F)ccc1C1=NCCNC1=O
Yield: 79.2 %

Procedure:
Ethylenediamine (0.60 g, 10.0 mmol) was added to a solution of ethyl 2-(4-fluoro-2-methoxyphenyl)-2-oxoacetate (2.26 g, 10.0 mmol) in ethanol (30 ml) and refluxed 4 hr; After removal of the solvent under reduced pressure, residue was washed with ethanol-diethyl ether to give 5,6-dihydro-3-(4-fluoro-2-methoxyphenyl)pyrazinone (1.76 g, 79%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:33]([C:30]4[CH:29]=[CH:28][C:27]([C:24]5[CH:25]=[CH:26][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:22][CH:23]=5)=[CH:32][CH:31]=4)=[O:34])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(S(C)(=O)=O)cc4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4′-(methylsulfonyl)[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=O)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20](=[O:40])[CH2:21][N:22](C(C1C2C(=CC(OC)=CC=2)C(OC)=CC=1)=S)[CH3:23]>>[CH3:18][O:19][C:20](=[O:40])[CH2:21][N:22]([C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17])[CH3:23]
Reactant: COC(=O)CN(C)C(=S)c1ccc(OC)c2cc(OC)ccc12
Reactant: COc1ccc2c(C(=O)O)ccc(OC)c2c1
Product: COC(=O)CN(C)C(=O)c1ccc(OC)c2cc(OC)ccc12

Procedure:
By following serially the procedures of examples 2 and 3 and using an equivalent amount of 4,6-dimethoxy-1-naphthalenecarboxylic acid of example 61 instead of 5-bromo-1-naphthalenecarboxylic acid; N-[(4,6-dimethoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester (I, R1 and R2 =CH3, R3 =4-CH3O, R4 =6-CH3O and R5 =H); mp 105°-107° C.; NMR(CDCl3) δ3.05 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 4.0 (s, 3H), 4.8 (2d, J=20 Hz, 2H), 7.3 (m, 5H); was obtained via N-[(4,6-dimethoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester; NMR(CDCl3) δ2.75 (s, 3H), 3.7 (s, 3H), 3.9 (s, 3H), 4.0 (s, 3H), 4.35 (s, 2H), 7.4 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:34][C:35](OC(C)=O)=[O:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[N:12]([CH:8]2[CH2:9][C:10]3[CH:11]=[C:2]([NH:1][C:35](=[O:36])[CH3:34])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7]2)[CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)CC(N(CCCN1CCN(C)CC1)C(=O)Nc1ccc(F)c(Cl)c1)CC2
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea (from Preparative Example 27, 0.033 g, 0.070 mmol) in CH2Cl2 (0.2 mL) at 0° C. were added Ac2O (0.0066 mL, 0.070 mmol) and DIEA (0.036 mL, 0.21 mmol). The mixture was stirred from 0° C. to room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 0.030 g (83%) of N-(7-{3-(3-chloro-4-fluoro-phenyl)-1-[3-(4methyl-piperazin-1-yl)-propyl]-ureido}-5,6,7,8-tetrahydro-naphthalen-2yl)-acetam ide as a light yellow gum. 1H NMR (300 MHz, CD3OD): δ 7.60 (dd, 1H, J=6.9, 2.4 Hz), 7.38 (d, 1H, J=2.1 Hz), 7.30 (ddd, 1H, J=9.0, 4.2, 2.4 Hz), 7.20 (dd, 1H, J=8.4, 2.1 Hz), 7.15 (t, 1H, J=9.0 Hz), 7.05 (d, 1H, J=8.4 Hz), 4.31 (m, 1H), 3.60 (m, 8H), 3.47 (m, 2H), 3.24 (t, 2H, J=7.2 Hz), 2.97 (m, 7H), 2.14-2.00 (m, 7H). MS-ESI: 516.1 (M+H+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:35]([CH3:41])[C@H:36]([C:38]([OH:40])=O)[CH3:37])([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCN(C(C)C)C(C)C.[NH2:51][CH:52]([C:78]([CH3:81])([CH3:80])[CH3:79])[C:53]([N:55]1[CH2:59][CH2:58][CH:57]2[N:60]([CH:72]3[CH2:77][CH2:76][O:75][CH2:74][CH2:73]3)[CH2:61][CH:62]([O:63][C:64]3[CH:69]=[CH:68][C:67]([F:70])=[C:66]([F:71])[CH:65]=3)[CH:56]12)=[O:54]>CN1C(=O)CCC1>[CH2:28]([O:27][C:25](=[O:26])[N:35]([CH:36]([C:38](=[O:40])[NH:51][CH:52]([C:53]([N:55]1[CH2:59][CH2:58][CH:57]2[N:60]([CH:72]3[CH2:77][CH2:76][O:75][CH2:74][CH2:73]3)[CH2:61][CH:62]([O:63][C:64]3[CH:69]=[CH:68][C:67]([F:70])=[C:66]([F:71])[CH:65]=3)[CH:56]12)=[O:54])[C:78]([CH3:80])([CH3:79])[CH3:81])[CH3:37])[CH3:41])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(N)C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
HATU (126 mg, 0.33 mmol) and Cbz-N(Me)Ala-OH (79 mg, 0.33 mmol) were dissolved in NMP (0.5 mL) and DIPEA (70 μL, 0.39 mmol) was added. The reaction mixture was cooled to 0° C. and a solution of 26 (125 mg, 0.30 mmol) in NMP (2 mL) was added. The reaction mixture was warmed to ambient temperature. After 12 h, the reaction mixture was quenched with 1N NaOH (0.5 mL) and diluted with water. The product was extracted with 10:1 Et2O/EtOAc, and the combined organic extracts were washed successively with water, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 160 mg of 27 as a beige-colored foam that was used without further purification. Mass spectrum, m/z [657.2] (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[C:22]([O:26][NH:27][S:28]([CH:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]1=[C:38]=[O:39])(=[O:30])=[O:29])([CH3:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:22]([O:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[S:28]([CH:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]1=[C:38]=[O:39])(=[O:30])=[O:29])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)CC[C@@H](CCCCO)CCCc1cccnc1
Reactant: CC(C)(C)ONS(=O)(=O)C1C=CC(Cl)=CC1=C=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CC[C@@H](CCCCN(OC(C)(C)C)S(=O)(=O)C1C=CC(Cl)=CC1=C=O)CCCc1cccnc1
Reaction time: 1 h

Procedure:
To a solution of methyl (R)-8-hydroxy-4-[3-(3-pyridyl)propyl]octanoate (1.09 g 3.7 mmol), N-t-butoxy-carbonyl-p-chlorophenylsulfonamide (1.52 g, 5.2 mmol) and triphenylphosphine (1.92 g, 7.3 mmol) in methylene chloride (17 ml) is added dropwise diethyl azodicarboxylate (0.82 ml, 5.2 mmol). The reaction mixture is allowed to stir or 1 hour and the solvent is evaporated. The residue is purified by flash chromatography on silica gel using 1:1 ethyl acetate/hexane to obtain methyl (R)-8-[N-t-butoxy-carbonyl-p-chlorophenylsulfonamido]-4-[3-(3-pyridyl)propyl]octanoate; IR (CH2Cl2): 1730, 1356, 1154 cm- 1.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH:32]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]2)[CH2:31][CH2:30]1>C(Cl)Cl>[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH:32]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][CH:44]([NH:47][C:11]([CH:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)=[O:13])[CH2:43][CH2:42]2)[CH2:31][CH2:30]1
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: NC1CCN(CCC2CCOc3ccccc32)CC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCC2CCOc3ccccc32)CC1)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (176 mg, 1 mmol) and triethylamine (0.25 ml) in methylene chloride (5 ml), isobutylchloroformate (136 mg, 1 mmol) was added. After 5 minutes N-[1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-aminopiperidine (260 mg, 1 mmol) in methylene chloride was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with 2N potassium hydroxide solution. The organic layer was separated, washed with distilled water and dried (Na2SO4). Evaporation of the solvent gave a white solid which was crystallized from diethyl ether to afford the title compound (140 mg, 33%), m.p.=130°-2°, Anal C27H34N2O2. 0.25 H2O, Calc, C, 76.65; H, 8.22, N, 6.62; Found C,76.34; H, 8.32; N, 6.59.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([O:7]C)=O.[NH2:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([NH:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:7]
Reactant: Cc1ncccc1N
Reactant: COC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncccc1NC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
To a mixture of methyl 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.14 g, 0.34 mmol, Example #E.1) and 3-amino-2-methylpyridine (0.04 g, 0.37 mmol) in anhydrous THF (10 mL), was added lithium bis(trimethylsilyl)amide solution (1.3 mL, 1 M in THF, 1.3 mmol), at about −40° C. The resulting mixture was stirred for about 30 min, at about −40° C., and then quenched by the addition of water (10 mL) and ethyl acetate (130 mL). The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/methanol 100:0 to 0:100) and preparative HPLC (Table 2, Method a) to afford 3-chloro-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydro-pyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide (0.0162 g, 0.03 mmol, 9%): LC-MS (Table 1, Method b) Rt=3.70 min, m/z 491 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 2.56 (3H, s), 2.70-2.90 (2H, m), 3.26-3.35 (1H, m), 3.63-3.71 (1H, m) 3.60-4.00 (1H, br s) 3.84 (3H, s) 6.91 (1H, s) 7.09 (1H, ddd, J=1.2, 4.8, 7.9 Hz) 7.21 (1H, dd, J=4.8, 8.2 Hz) 7.44 (1H, d, J=8.0 Hz) 7.58-7.64 (3H, m) 7.80 (1H, d, J=8.0 Hz) 7.92 (1H, d, J=2.0 Hz) 8.28-8.34 (2H, m) 8.48-8.51 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][C:22]=1[F:29].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)([CH3:11])[CH:9]([C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([F:29])[CH:23]=1)[OH:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc([Mg]Br)ccc1Cl
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(c1ccc(Cl)nc1)C(O)c1ccc(Cl)c(F)c1
Reaction time: 1 h
Yield: 84 %

Procedure:
A tetrahydrofuran (20 ml) solution of the compound (6.47 g, 22.7 mmol) obtained in Step 3 above was added dropwise to 4-chloro-3-fluorophenyl magnesium bromide (0.5 M tetrahydrofuran solution) (100 ml, 50.0 mmol) under ice cooling and the resulting mixture was stirred at the same temperature for 1 hour. An aqueous solution of saturated ammonium chloride was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. An n-hexane/ethyl acetate mixed solvent was added to the residue obtained and the resulting precipitate was collected by filtration and dried to give the title compound (7.92 g, 84%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[F:16][C:17]1[C:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: OB(O)c1cccc(-c2cccnc2)c1F
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Fc1c(-c2cccnc2)cccc1-c1ccnc2nc(C(F)(F)F)ccc12
Yield: 44.3 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-fluoro-3-(pyridin-3-yl)benzeneboronic acid (61 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(2-fluoro-3-pyridin-3-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (36 mg, 45%). δH (360 MHz, CDCl3) 7.40-7.55 (3H, m), 7.65-7.70 (2H, m), 7.84 (1H, d, J 8.4), 7.93 (1H, dq, J 8.1 and 1.9), 8.37 (1H, dd, J 2.3 and 8.6), 8.67 (1H, dd, J 1.6 and 4.7), 8.86 (1H, s), 9.34 (1H, d, J 4.6). m/z (ES+) 370 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30](O)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:10][CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[CH:5]=3)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(N)cc1OCCN1CCCC1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: COc1ccc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)cc1OCCN1CCCC1
Yield: 74 %

Procedure:
Acylation of 4-methoxy-3-(2-(pyrrolidin-1-yl)ethoxy)benzenamine from step A with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid to generate the title compound in 74% yield was achieved via the procedure described in step C of Example 1. MS (ESI) 440 (M+H)+.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22]3[CH:23]=[C:24]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH:18]=2)[CH2:13]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:11][C@@H:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22]3[CH:23]=[C:24]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH:18]=2)[CH2:13]1
Reactant: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](NC(=O)OCc2ccccc2)C3)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](N)C3)cc(C(F)(F)F)c1

Procedure:
A suspension of (S)-methyl 3-((2-(benzyloxycarbonylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)benzoate (0.254 mmol, 123 g) and palladium hydroxide (0.064 mmol, 45 mg) in ethanol (9 mL) was treated under hydrogenation conditions (2 bar hydrogen) for 30 minutes. The reaction mixture was filtered through celite and the pad washed with EtOH & EtOAc before the filtrate was concentrated under reduced pressure to give a light brown film (82 mg, 92%). MS (ESI): m/z [M+H]+ 350.0
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14](N2CCOC2=O)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.NO.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30]N=C1)=[O:26]>C(Cl)(Cl)Cl.ClCCl>[O:26]1[CH2:30][CH2:31][N:27]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:25]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCOC2=O)CC1
Agent: NO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C1CCN(N2CCOC2)CC1

Procedure:
1-Benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine. A solution of the amino alcohol (1.7 g) and 1,1′-carbonyldiimidazole (2.4 g) in chloroform (30 mL) was heated at reflux for 6 hours. The reaction mixture was diluted with dichloromethane and washed with 1 N sodium hydroxide and water. The separated organic phase was dried and evaporated to give the oxazolidin-3-yl piperidine as a viscous oil (1.9 g); NMR: 7.35 (m,5), 5.13 (s,2), 4.34 (m,4), 3.89 (m,1), 3.49 (m,2), 2.86 (m,2), 1.78 (m,2), 1.58 (m,2); MS: m/z=305(M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:24]1[N:25]=[CH:26][C:27]([C:30]([N:32]([CH2:34][CH3:35])[CH3:33])=[O:31])=[N:28][CH:29]=1>C(#N)C.C(OC(=O)C)C>[CH2:34]([N:32]([CH3:33])[C:30]([C:27]1[N:28]=[CH:29][C:24]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[N:25][CH:26]=1)=[O:31])[CH3:35]
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: CCN(C)C(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)CC)cn2)c2cc(C)oc2c1
Temperature: 100 °C

Procedure:
Ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1c: 2.25 g, 10.22 mmol), potassium carbonate (2.1 g, 15.3 mmol), 5-chloro-N-ethyl-N-methylpyrazine-2-carboxamide (SM-4: 2.04 g, 10.2 mmol) were mixed in acetonitrile (30 ml). The mixture was heated at 100° C. over night, after which time, the reaction mixture was diluted with ethylacetate (50 ml) and filtered. The organic layer was concentrated and purified by column chromatography on silica gel eluting with ethylacetate in heptanes 20-100% to afford ethyl 4-(5-(ethyl(methyl)carbamoyl)pyrazin-2-yloxy)-2-methylbenzofuran-6-carboxylate (I-7a: (3.9 g, 99.5%) as a gum.