Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)[C:12](Br)=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)[C:12]([C:39]3[CH:38]=[CH:37][C:36]([N:33]4[CH2:32][CH2:31][O:30][CH2:35][CH2:34]4)=[CH:41][CH:40]=3)=[CH:11][N:10]=2)[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 3, (R)-tert-butyl 3-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate with 4-morpholinophenylboronic acid to provide the title compound at 85% yield. 1H NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 7.36 (d, 2H), 6.92 (d, 2H), 5.16 (sb, 1H), 4.30-4.27 (m, 2H), 4.10-4.01 (m, 1H), 386-3.84 (m, 4H), 3.60-3.12 (m, 8H); 2.70-2.62 (m, 1H), 2.05-1.98 (m, 1H), 1.81-1.46 (m, 8H), 1.44 (s, 9H), 1.29-1.21 (m, 3H), 0.93 (d, 3H); MS (ESI) m/z: Found: 552.3 (M+1); Calc: 551.4 (M+).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: Cc1ccc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(NC(=O)[C@H](CC2CCC(=NO)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Solution of hydroxylamine hydrochloride (26.0 mg, 0.36 mmol) in methanol (0.7 mL) and 2,6-lutidine (0.7 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 64, 105 mg, 0.23 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water 1×5 mL), dried over magnesium sulfate, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 2/8 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-N-(5-methyl-pyridin-2-yl)-propionamide (67 mg, 63%) was a white foam; [α]23589=−7.84° (c=0.37 chloroform); EI-HRMS m/e calcd for C22H26ClN3O4S (M+H)+ 464.1406. found 464.1409.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]([CH3:33])[C:12]([N:15]2[CH2:32][CH2:31][C:18]3([C:22](=[O:23])[N:21]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1.CC(C)([O-])C.[K+]>CN(C)C1C=CN=CC=1.ClCCl.O1CCCC1>[OH:30][C@@H:27]1[CH2:26][CH2:25][C@H:24]([N:21]2[CH2:20][CH2:19][C:18]3([CH2:31][CH2:32][N:15]([C:12]4[C:11]([CH3:33])=[CH:10][C:9]([N:8]5[CH2:2][CH2:3][CH2:4][C:5]5=[O:6])=[CH:14][N:13]=4)[CH2:16][CH2:17]3)[C:22]2=[O:23])[CH2:29][CH2:28]1
Reactant: Cc1cc(N)cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Reactant: O=C(Cl)CCCBr
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(N2CCCC2=O)cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Reaction time: 3 h

Procedure:
4-Bromobutanoyl chloride (13.0 μL) was added to a mixture of 8-(5-amino-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (18.0 mg) and 4-dimethylaminopyridine (14.5 mg) in dichloromethane (1.0 mL). The mixture was stirred for 3 h. Then potassium tert-butoxide in tetrahydrofuran (1.0 M, 0.20 mL) was added. The mixture was stirred for an additional hour. The solvent was evaporated. The residue was dissolved in methanol (1.8 mL), and purified by prep.-HPLC under basic condition to afford 2-(cis-4-hydroxycyclohexyl)-8-[3-methyl-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-1-one. LCMS: (M+H)+=427.20.
Reaction SMILES: C[N:2](C)C=O.P(Cl)(Cl)(Cl)=O.[C:11]([C:14]1[N:15]=[C:16]([C@@H:19]2[CH2:23][C@@H:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][N:20]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[S:17][CH:18]=1)([OH:13])=O.O.N>O1CCCC1>[C:11]([C:14]1[N:15]=[C:16]([C@@H:19]2[CH2:23][C@@H:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][N:20]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[S:17][CH:18]=1)(=[O:13])[NH2:2]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](c2nc(C(=O)O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CN(C)C=O
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2nc(C(N)=O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
To a mixture of dimethylformamide (0.45 ml) and tetrahydrofuran (10 ml) was dropwise added phosphorus oxychloride (0.46 ml) at -5~5° C., and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of (2S,4R)-2-(4-carboxythiazol-2-yl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.54 g) in tetrahydrofuran (20 ml) at -5~5° C., followed by stirring at the same temperature for 30 minutes. The mixture was dropwise added to concentrated ammonia water (15 ml) at 0°-10° C. with stirring. The mixture was stirred at the same condition for 2 hours. Tetrahydrofuran was removed under reduced pressure to give a residue, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give (2S,4R)-2-(4-carbamoylthiazol-2-yl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.4 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[N:16]=[C:15]([C:17]4[S:21][C:20]([C:22]([C@H:26]5[CH2:31][CH2:30][C@H:29]([C:32]([O:34]C)=[O:33])[CH2:28][CH2:27]5)([OH:25])[CH2:23][CH3:24])=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:36])[CH:12]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[K+].CO.Cl>O.C(O)(C)C.C(Cl)(Cl)Cl>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[N:16]=[C:15]([C:17]4[S:21][C:20]([C:22]([C@H:26]5[CH2:27][CH2:28][C@H:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]5)([OH:25])[CH2:23][CH3:24])=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:36])[CH:12]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCC(O)(c1ncc(-c2cc(C)cc(Nc3cc(C4CC4)ccn3)n2)s1)[C@H]1CC[C@H](C(=O)OC)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CCC(O)(c1ncc(-c2cc(C)cc(Nc3cc(C4CC4)ccn3)n2)s1)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a flask containing methyl trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]-cyclohexanecarboxylate (198 mg, 0.391 mmol) and potassium hydroxide (88 mg, 1.563 mmol) was added methanol (1 mL) and water (1 mL). The reaction vessel was sealed and heated to 80° C. for a period of 14 hours. After cooling the reaction, aqueous hydrochloric acid (1.0 M, 1.56 mL, 1.56 mmol) was added. The cloudy solution was diluted with additional water (10 mL) and stirring was continued for one hour. Chloroform and isopropanol (4:1; 20 mL total) were added and the biphasic mixture was transferred to a separatory funnel. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic acid. MS ESI calc'd. for C27H33N4O3S [M+H]+ 493. found 493. 1H NMR (500 MHz, DMSO-d6) δ 11.60-10.74 (br s, 1H), 8.48 (s, 1H), 8.27 (s, 1H), 7.75-7.29 (m, 2H), 7.26 (m, 2H), 5.68-5.47 (m, 1H), 2.42 (s, 3H), 2.29-2.12 (m, 1H), 2.12-1.84 (m, 7H), 1.84-1.73 (m, 1H), 1.54-1.42 (m, 1H), 1.43-1.13 (m, 6H), 1.13-0.97 (m, 3H), 0.88 (t, J=7.3 Hz, 3H). rhSyk activity=+++.
Reaction SMILES: C(N(C(C)C)[C:5]([C:7]1[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([O:21]C)[C:14]=2[O:23]C)=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6])(C)C.B(Br)(Br)Br.CO.C(Cl)(Cl)Cl.O>C(Cl)Cl.C(O)(=O)C>[OH:19][C:16]1[CH:17]=[CH:18][C:13]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:5](=[O:6])[O:23][C:14]=2[C:15]=1[OH:21]
Reactant: COc1ccc(-c2ccccc2C(=O)N(C(C)C)C(C)C)c(OC)c1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1oc2c(O)c(O)ccc2c2ccccc12
Temperature: -78 °C
Yield: 76.6 %

Procedure:
N,N-Diisopropyl-2',3',4'-trimethoxy-2-biphenylcarboxamide (0.94 mmol) was dissolved in dry methylene chloride (40 ml). The solution was cooled down to -78° C., BBr3 (5.6 mmol) was added slowly. Reaction was allowed to warm to room temperature over a period of 22 hours. The mixture was again cooled down to -78° C. and methanol (3 ml) was added. The reaction was warmed to room temperature over a period of 2 hours. All solvent was evaporated. The solid was extracted with chloroform. Removal of solvent gave white fluffy solid which was dissolved in glacial acetic acid (10 ml) and refluxed over night. Removal of acetic acid gave a solid, which was worked up with chloroform-water, the aqueous layer was separated and was extracted several times with chloroform. The chloroform layer was washed with satd. NaHCO3 solution. Removal of chloroform gave 77% (0.72 mmol) of solid product, which was recrystallized from methanol (m.p. 252° C.-254° C.). NMR spectrum was analyzed to be: δ6.84 (d, 1H, J=8.7 Hz, Ar--H), 7.63 (d, 1H, J=8 Jz, Ar--H), 7.82-7.89 (m 1H, Ar--H), 8.17-8.24 (t, 2H, Ar--H), 9.27 (br s, 1H, OH [D2O exchangeable]), 9.89 (br s, 1H, OH [D2O exchangeable]); MS m/z (relative intensity) 229 (M+1, 13), 228 (M+, 100), 200 (6), 126 (11), 115 (26).
Reaction SMILES: FC1C=C(F)C=C(F)C=1C([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[N:8]=1)=O.Br.BrC1N=C(C(C2CCN(C)CC2)=O)C=CC=1>[Cu-]=O>[NH2:6][C:7]1[N:8]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:10]=[CH:11][CH:12]=1
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Agent: O=[Cu-]
Agent: Br
Agent: CN1CCC(C(=O)c2cccc(Br)n2)CC1
Product: CN1CCC(C(=O)c2cccc(N)n2)CC1

Procedure:
The present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a salt thereof, comprising the step of: reacting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrobromide with >0.02 wt % copper(I)oxide at less than 80° C. to yield (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][N:7]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:5][C:2]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)([CH3:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=1
Reactant: CC(C)(CN)c1cc(-c2ccccc2)[nH]n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1cc(-c2ccccc2)n[nH]1
Yield: 11 %

Procedure:
This compound was synthesized from 2-methyl-2-(5-phenyl-1H-pyrazol-3-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (10 mg, yield 11%). 1H NMR (CDCl3) δ 8.52 (s, 1H) 8.20 (d, J=7.4, 1H), 8.05 (d, J=7.4, 1H), 7.64-7.52 (m, 3H), 7.46-7.32 (m, 3H), 6.47 (s, 1H), 3.70 (d, J=4.5, 2H), 1.44 (s, 6H). MS (ESI) m/z: Calculated for C23H20F3N5O2: 455.16. found: 456.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[O:18][C:19]=3[CH:20]([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:31])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CC(C)=O>[CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[O:18][C:19]=3[CH:20]([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][C:5]=1[O:31][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:2]=[CH2:3]
Reactant: CCOC(=O)CBr
Reactant: C=CCc1c(O)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1c(OCC(=O)OCC)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Reaction time: 20 h
Yield: 80.7 %

Procedure:
The obtained 7-allyl-6-hydroxy-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-1,2-benzisoxazole (45 mg, 0.098 mmol) and potassium carbonate (20 mg, 0.147 mmol) was suspended in acetone (5.0 mL). An acetone solution of ethyl bromoacetate (25 mg, 0.147 mmol) was added to the suspension while cooling with ice. The mixture was allowed to room temperature, and stirred for 20 hours. After insoluble was filtered off, the filter cake was washed with acetone. The filtrate and washings were combined, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (4/1) to give the desired compound (43 mg) as colorless oil (yield 80%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][C:2]2=[O:7])=[N:10][CH:11]=1
Reactant: O=C1COCCN1
Reactant: Brc1ccc(Br)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1COCCN1c1ccc(Br)cn1
Temperature: 100 °C
Yield: 64.2 %

Procedure:
Morpholin-3-one (500 mg, 4.94 mmol) and 2,5-dibromopyridine (1.76 g, 7.42 mmol) were dissolved in toluene, to which was added cesium carbonate (2.42 g, 7.42 mmol). The resulting mixture was flushed with argon for 3 times. Then Pd2(dba)3 (226 mg, 0.247 mmol) and xantphos (171 mg, 0.296 mmol) were added, followed by flushing again with argon. The reaction mixture was heated to 100° C. and allowed to react overnight. After the reaction completed, the mixture was filtered. Column chromatography afforded 815 mg of white solid (compound 19a), yield 64%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH2:19])[S:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:34]([C:37]1[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH:19][C:43](=[O:44])[CH2:42][O:41][C:40]3[CH:46]=[CH:47][C:37]([CH:34]([CH3:35])[CH3:36])=[CH:38][CH:39]=3)[S:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Reactant: CC(C)c1ccc(OCC(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)c1ccc(OCC(=O)NCc2nc(C(=O)NCCc3cccc(Cl)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.9 %

Procedure:
2-Aminomethyl-thiazole-4-carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide (50 mg, 0.17 mmol) was dissolved in DMF (1 mL). EDC (38 mg, 0.2 mmol) and HOBt (27 mg, 0.2 mmol) where added and the mixture was stirred at ambient temperature for 10 minutes. (4-Isopropyl-phenoxy)-acetic acid (33 mg, 0.17 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. DI water was added and the mixture was extracted with ethyl acetate ×3. The combined organic layers were washed with 1 N hydrochloric acid ×2, 2 N sodium hydroxide ×2, 1 N sodium bicarbonate ×2, DI water ×2 and brine ×1, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography using silica (1:1 Ethyl acetate:Hexanes) to give the title compound as a semi-solid (16.8 mg, 21%). 1H NMR (400 MHz, d6-DMSO): 9.02 (t, 1H), 8.41 (t, 1H), 8.11 (s, 1H), 7.27 (m, 3H), 7.16 (m, 3H), 6.88 (d, 2H), 4.61 (d, 2H), 4.56 (s, 2H), 3.48 (q, 2H), 2.83 (m, 3H), 1.17 (d, 6H); MS (ESI-LCMS) for C24H27ClN3O3S: 472 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:29]=[C:14]3[C:15]4[C:20]([CH2:21][CH2:22][N:13]3[C:12](=[O:30])[CH2:11][N:10]=2)=[C:19]([C:23]#[C:24][Si](C)(C)C)[CH:18]=[CH:17][CH:16]=4)[CH:6]=[CH:7][CH:8]=1.BrC1C=CC=C2C=1CCN1C(=O)CN=C(C3C=CC=C(OC)C=3)C=C12.C[Si](C#C)(C)C>N1CCCCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:23]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH2:21][CH2:22][N:13]1[C:12](=[O:30])[CH2:11][N:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:29]=[C:14]12)[CH3:24]
Reactant: COc1cccc(C2=NCC(=O)N3CCc4c(C#C[Si](C)(C)C)cccc4C3=C2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCc1cccc2c1CCN1C(=O)CN=C(c3cccc(OC)c3)C=C21
Temperature: 80 °C

Procedure:
2-(3-methoxyphenyl)-9-((trimethylsilyl)ethynyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 37-1. A mixture of 9-bromo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 20) (1.0 g, 2.52 mmol), Pd(PPh3)2Cl2 (88 mg, 0.13 mmol) and CuI (48 mg, 0.25 mmol) in piperidine (15 mL) was degassed (sonication) with a flux of Ar, and trimethylsilylacetylene (1.06 mL, 7.55 mmol) was then added. The mixture was heated to 80° C. for 18 h. Additional trimethylsilylacetylene (1.00 mL, 7.12 mmol) and Pd(PPh3)2Cl2 (88 mg, 0.13 mmol) were added and the mixture was heated to 80° C. for another 24 h. After cooling to RT, the reaction was diluted with AcOEt, and washed with H2O. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, hexane to hexane/AcOEt 1:1) afforded the title compound (700 mg) as a brown solid UPLC-MS: MS 415.3 (M+H+); UPLC rt 1.43 min.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:20]([C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N#Cc1cccc(Oc2ccccc2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(Oc3ccccc3)n2)sc2ccccc12
Yield: 27.1 %

Procedure:
A mixture of methyl thiosalicylate (0.34 g, 2.0 mmol), 2-cyano-6-phenoxypyridine (0.40 g, 2.0 mmol), triethylamine (0.45 ml, 3.1 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.18 g, 26%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:22])[CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CCO.[OH-].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:22])[CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A 3-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a dropping funnel, and a nitrogen inlet/outlet adapter was charged with ethyl 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoate (128.0 g, 370.2 mmol), EtOH (1.29 L), and KOH (27.7 g, 1444.2 mmol). The resulting mixture was stirred at 20° C. for 24 h. Additional KOH (1.12 g, 0.04 eq.) was added and the reaction was stirred for an additional 6 h. The resulting yellowish thick slurry was dissolved in deionized water (1.2 L) and then poured into a 12-L 4-neck flask equipped with an overhead stirrer that contained ice-water (6 L) in an ice-water bath. The aqueous pH was adjusted to pH 2-3 using 2 N aqueous HCl solution with fast stirring at 8-10° C. for 20 min. The solid in the resulting milky slurry was collected by filtration, washed with deionized water (100 mL), dried under air-suction for 20 h and then in a vacuum oven at 60° C. under hi-vacuum (20 mmHg) for 72 h to yield 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoic acid as a yellowish solid, which was used in the next step without further purification. (ES, m/z) 318, 320 (M+H)+
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=1>CO>[C:25]([C:21]1[CH:20]=[C:19]([NH:18][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: COCCOCCn1ccc2c(Cl)ncnc21
Reactant: C#Cc1cccc(N)c1
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3c2ccn3CCOCCOC)c1
Yield: 81 %

Procedure:
Utilizing a procedure analogous to that described in Example 47, this product was prepared in 81% yield from 4-chloro-7-[2-(2-methoxy-ethoxy)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq) and m-aminophenyl acetylene (1.2 eq) in methanol. M.P. 240-241° C.; LC-MS: 336 (M+); RP18HPLC RT: 4.29 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[CH2:26]1[NH:31][CH2:30][CH2:29][N:28]2[CH2:32][CH2:33][CH2:34][CH:27]12>>[CH2:26]1[N:31]([C:2]2[CH:7]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:5]=[C:4]([NH2:25])[N:3]=2)[CH2:30][CH2:29][N:28]2[CH2:32][CH2:33][CH2:34][CH:27]12
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Reactant: C1CC2CNCCN2C1
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCN3CCCC3C2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and octahydropyrrolo[1,2-a]pyrazine (Oakwood, Cat. No. 032034). LCMS (M+H)+: m/z=445.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(F)cc4F)cc3c2C1
Yield: 81.2 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) 2,4-difluorobenzoyl chloride, 13.8 mg (81%) of the title compound were recovered as a beige solid.