Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[CH:37]=[CH:36][S:35][CH:34]=1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[CH:37]=[CH:36][S:35][CH:34]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Brc1ccsc1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccsc1)OCC2c1ccc(C(C)C)cc1
Yield: 49 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 3-bromothiophene, the title compound was obtained in the same manner as in Example 107. Yield: 49%. Melting point: 172-174° C. (ethyl acetate-hexane).
Reaction SMILES: O[C@@H:2]1[CH2:6][N:5]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[C@H:4]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:42]([O:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C.C(OCC)(=O)C>[CH2:42]([O:49][NH:50][C@H:2]1[CH2:6][N:5]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[C@H:4]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:3]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NOCc1ccccc1
Reactant: C=CCOC(=O)[C@@H]1C[C@H](O)CN1C(=O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: C=CCOC(=O)[C@@H]1C[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of allyl (4S)-4-hydroxy-1-(trifluoroacetyl)-L-prolinate (844 mg, 3.16 mmol) in acetonitrile (16 mL) was cooled to −10° C. and 2,6-lutidine (0.62 mL, 5.32 mmol) was added followed by trifluoromethanesulfonic anhydride (0.85 mL, 5.15 mmol). After addition, the temperature was allowed to warm to 0° C. The reaction mixture was stirred at 0° C. for 1 hour then O-benzylhydroxylamine (1 mL, 8.67 mmol) was added followed by 2,6-lutidine (0.62 mL, 5.32 mmol). The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was then diluted with ethyl acetate and washed with 5% sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The tan oil residue (2.57 g) was chromatographed on silica gel eluted initially with 95:5 dichloromethane:ethyl acetate and finally with 80:20 dichloromethane:ethyl acetate to afford the title compound as a pale yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:32]=[CH:31][C:16]([CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29]C)=[O:28])[CH:25]=3)[NH:20][CH:19]=2)=[CH:15][CH:14]=1.CN1C2C(=CC=C(C(O)=O)C=2)C(CC2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=C1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:32]=[CH:31][C:16]([CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=3)[NH:20][CH:19]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc2[nH]cc(Cc3ccc(OCc4ccc5ccccc5n4)cc3)c2c1
Agent: Cn1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccc(C(=O)O)cc21
Product: O=C(O)c1ccc2[nH]cc(Cc3ccc(OCc4ccc5ccccc5n4)cc3)c2c1

Procedure:
This compound was prepared from the methyl ester (Example 13, part i) by the method described in Example 10, part iii, m.p. 227°-228° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2)(=[O:5])[CH3:4].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][C:23]=1[I:30]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.[Cl-].[NH4+]>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:12]2[C:13]3[C:9](=[CH:8][C:7]([O:6][C:3](=[O:5])[CH3:4])=[CH:15][CH:14]=3)[CH:10]=[C:11]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:24][C:23]=1[I:30]
Reactant: Clc1ccc(CBr)cc1I
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(I)c1
Reaction time: 0.25 h
Yield: 8.1 %

Procedure:
Sodium hydride (0.23 g of a 60% dispersion in oil) was added to a solution of ethyl 5-acetoxyindole-2 carboxylate (1.29 g) and tetra-n-butylammonium iodide (10 mg) in anhydrous DMF (25 ml) under a stream of argon. The reaction mixture was stirred for 15 minutes and a solution of 4-chloro-3-iodobenzyl bromide (1.9 g) in DMF (5 ml) was added. The mixture was stirred for 15 hours, then saturated aq. ammonium chloride (5 ml) was added. The residue obtained on removal of the solvent was diluted with saturated aq. ammonium chloride (50 ml) and extracted with ethyl actate (3×30 ml). The combined ethyl acetate extracts were washed with brine (100 ml) and dried. The residue obtained on removal of the solvent was purified by chromatography on silica eluting with a mixture of ethyl acetate and iso-hexane (1:9) to give the title compound (0.21 g). NMR (CD3SOCD3): d 1.1 (t, 3H), 2.2 (s, 3H), 4.3 (m, 2H), 5.8 (s, 2H), 6.9 (m, 1H), 7.1 (m, 1H), 7.35 (m, 1H), 7.4 (m, 2H), 7.6 (m 2H), 7.7 (m, 2H); m/z 497.5 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:26]=[CH:25][C:12]([C:13]([NH:15][C:16]3[S:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][N:20]=3)=[O:14])=[CH:11][C:10]=2[N+:27]([O-:29])=[O:28])=[CH:4][CH:3]=1.[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45](Cl)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45](=[O:46])[NH:1][C:2]3[CH:3]=[CH:4][C:5]([S:8][C:9]4[CH:26]=[CH:25][C:12]([C:13](=[O:14])[NH:15][C:16]5[S:17][C:18]([C:21]([CH3:24])([CH3:22])[CH3:23])=[CH:19][N:20]=5)=[CH:11][C:10]=4[N+:27]([O-:29])=[O:28])=[CH:6][CH:7]=3)[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)c1cnc(NC(=O)c2ccc(Sc3ccc(N)cc3)c([N+](=O)[O-])c2)s1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cnc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c([N+](=O)[O-])c2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A suspension of the product of Example 161B (226 mg, 0.5274 mmol) in anhydrous methylene chloride (5 mL) was treated with 9-fluorenylmethoxycarbonyl chloride (164 mg, 0.6329 mmol) and dry pyridine (0.085 mL, 1.055 mmol), and the resulting yellow solution stirred under a nitrogen atmosphere at ambient temperature for 3 hours. The reaction was diluted with ethyl acetate (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to provide the title compound as a yellow solid (338 mg, 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].II.[Br:15]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:15][C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:11])[C:2]([CH3:12])([CH3:1])[C:6]=2[CH:7]=1
Reactant: BrBr
Reactant: CC1(C)C(=O)Oc2ccccc21
Agent: [Fe]
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(=O)Oc2ccc(Br)cc21

Procedure:
2,3-Dihydro-3,3-dimethylbenzofuran-2-one (1.62 g, 0.01 mole), in carbon tetrachloride (25 ml) containing catalytic amounts of iron filings and iodine was treated with bromine (1.6 g, 0.01 mole) and the mixture boiled under reflux for 1 hour. The solvent was removed under vacuum and the residue taken up in petroleum ether (b.p. 60°-80° C.). The solution was decanted from a little insoluble residue and washed with aqueous sodium metabisulphite and water, dried over magnesium sulphate and run down. The title product was obtained as a white solid m.p. 49°-53° C. and was shown by NMR to be a slightly impure sample of the product obtained in Example 3(b).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[C:26]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[F:34][C:31]([F:32])([F:33])[C:30]([C:26]1[CH:25]=[C:24]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)[CH:29]=[N:28][CH:27]=1)([OH:36])[CH3:35]
Reactant: CC(O)(c1cncc(Br)c1)C(F)(F)F
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)(c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1)C(F)(F)F
Temperature: 90 °C

Procedure:
In a sealed tube which contains the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 ml 1,4-dioxane, 0.78 mmol) is added 2-(5-bromo-pyridin-3-yl)-1,1,1-trifluoro-propan-2-ol (253 mg, 0.94 mmol.), Na2CO3 (166 mg, 1.56 mmol) and water (1.0 ml). The mixture is bubbled with Ar for 5 min. Then PdCl2(DPPF) DCM complex (64 mg, 0.078 mmol) is added. The mixture is then bubbled with Ar for 5 min. The cap is sealed and the mixture is heated at 90° C. in oil bath for 1 h and then is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is separated by flash silica gel column (EtOAc/heptane 0 to 100% gradient, then 100%). The fractions which contain the desired product are combined, concentrated and further purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 65% gradient over 10 min run). The desired fractions are combined and basified by 1N Na2CO3 to pH=10, and is extracted by DCM. The DCM phases are combined and concentrated under vacuum to obtain 69 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Br:10][CH2:11][C:12](O)=[O:13]>C(Cl)Cl>[Br:10][CH2:11][C:12]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:13]
Reactant: O=C(O)CBr
Reactant: Cc1cccc(C)c1N
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CBr
Temperature: 25 °C
Yield: 112.1 %

Procedure:
See FIG. 2, Formula T2. 8.1 Preparation of 2-bromo-N-(2, 60-dimethylphenyl)acetamide DCC (14.5 g; 70 mmol) was added to a cold solution of 2,6-dimethylaniline (8.5 g; 70 mmol) and bromoacetic acid (9.75 g; 70 mmol) in dry CH2Cl2 (400 mL) in portions over 30 min. The mixture was allowed to warm to room temperature overnight with stirring. It was then filtered, and the filtrate evaporated to dryness. The residual solid was dissolved in EtOAc (200 mL) and CH2C2 (200 mL). The mixture was filtered, and the filtrate evaporated to dryness to yield 2-bromo-N-(2,6-dimethylphenyl)acetamide (19 g). 8.2 Preparation of 1-(2,6-dimethylphenyl)-2,8,8-trioxo-1,4-diaza-7,8-dithianonane
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]2[CH2:14][CH2:13]2)[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:15][CH2:16][CH3:17].[Na+].O>C(O)C>[CH:12]1([C:4]2[C:5]3[N:6]([C:8]([NH2:11])=[N:9][N:10]=3)[N:7]=[C:2]([O:15][CH2:16][CH3:17])[CH:3]=2)[CH2:14][CH2:13]1
Reactant: Nc1nnc2c(C3CC3)cc(Cl)nn12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C2CC2)c2nnc(N)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
6-Chloro-8-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.010, 77 mg) was initially charged in ethanol (10 ml) while stirring at RT and admixed with sodium ethoxide (67 mg). After stirring for 4.5 h, the mixture was left to stand overnight and then the solvent was drawn off. The residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 91 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][CH:2]([C@@:4]12[C@@H:19]([OH:20])[C@:18]34[O:21][C@H:17]3[CH2:16][C@@H:15]3[C@:10]([CH3:26])([CH2:11][CH2:12][C:13]5[C:24](=[O:25])[O:23][CH2:22][C:14]=53)[C@:8]34[O:9][C@H:7]3[C@@H:5]1[O:6]2)[CH3:3].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1.CCCCCC>N1C=CC=CC=1>[CH3:3][CH:2]([C@@:4]12[C@@H:19]([OH:20])[C@:18]34[O:21][C@H:17]3[CH2:16][C@@H:15]3[C@:10]([CH3:26])([CH2:11][CH2:12][C:13]5[C:24](=[O:25])[O:23][CH2:22][C:14]=53)[C@:8]34[O:9][C@H:7]3[C@@H:5]1[O:6]2)[CH3:1].[C:27]([O-:32])(=[O:33])[CH2:28][CH2:29][C:30]([O-:6])=[O:31]
Reactant: O=C1CCC(=O)O1
Agent: CC(C)[C@]12O[C@H]1[C@@H]1O[C@]13[C@]1(O[C@H]1C[C@H]1C4=C(CC[C@@]13C)C(=O)OC4)[C@@H]2O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: O=C([O-])CCC(=O)[O-]
Reaction time: 30 h

Procedure:
Triptolide (100 mg) in 10 ml of pyridine was treated with succinic anhydride (150 mg) at room temperature. The reaction was carried out at 85° C. for 30 hours under a nitrogen atmosphere. Hexane (50 ml) was added to the resultant mixture to precipitate a crude product, which was collected by filtration and washed with hexane. The crude product was recrystallized from ether/hexane to yield 90 mg (70%) of triptolide succinate (YM-262), m.p. 111°-113° C.
Reaction SMILES: F.[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](O)(=[O:11])[CH3:10]>>[OH:8][C:2]1[CH:7]=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)O
Agent: F
Product: CC(=O)c1ccc(O)cc1
Yield: 40 %

Procedure:
Simons et al, Journal of the American Chemical Society, 61, 1795 and 1796 (1939) teach the acylation of aromatic compounds using hydrogen fluoride as a condensing agent and in Table 1 on page 1796 show the acetylation of phenol with acetic acid to produce p-hydroxyacetophenone (4-HAP) in 40% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:27]=[CH:26][N:25]=4)[CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:38]([OH:46])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:27]=[CH:26][N:25]=4)[CH:17]=3)=[O:14])=[CH:36][CH:37]=2)[CH2:4][CH2:3]1.[C:38]([O-:46])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)c1ccccc1
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: Cc1ccccc1C
Product: O=C([O-])c1ccccc1

Procedure:
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) is added to a solution of benzoic acid (Fluka, Buchs, Switzerland; 1.22 g, 10 mmol) in xylene (50 mL). The mixture is heated and the resulting hot solution is filtered. Upon cooling, the product crystallizes and is filtered and dried to afford 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, benzoate as a pale-brown crystalline solid, having the following analytical properties: Analysis found: C, 70.13; H, 6.12; N, 16.24%. Calculated for C36H37O3: C, 70.22; H, 6.06; N, 15.92%.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[C:8]([C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28](O)=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1)#[N:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[C:8]([C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:26])([CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: CC1(C)CC(c2cccc(C#N)c2)Nc2ccc(C(=O)O)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C#N)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of methanesulfonamide (160 mg, 1.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (66 mg, 1.65 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A33. A solution of 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (110 mg, 0.66 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B33. Solution B33 was added to Solution A33 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (25 mg, 20%) as a white solid: MS (ESI) M+1=384.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH3:29])[CH:25]=5)[N:20]([CH3:30])[C:19]4=[O:31])[CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:32][CH3:33].[CH2:34](I)[CH2:35][CH3:36]>>[CH3:33][O:32][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:34][CH2:35][CH3:36])[N:9]=[CH:8][N:7]=[C:6]2[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH3:29])[CH:25]=3)[N:20]([CH3:30])[C:19]2=[O:31])[CH2:14][CH2:13]1
Reactant: COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2cc1O
Reactant: CCCI
Product: CCCOc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 223.5 mg (0.50 mmol) of Compound 89 obtained in Example 79 was used in place of Compound 24 and propyl iodide was used in place of methyl iodide. As a result, a free base of Compound 91 was obtained, which was then converted to the hydrochloride in the similar manner as in Example 41 to give 229.9 mg (yield: 87%) of the hydrochloride of Compound 91 as white crystals.
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([F:36])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[F:36][C:28]1[CH:27]=[C:26]([C:24]2[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]3[C:9]4[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=4[CH:23]=[C:24]3[CH3:26])[S:22][CH:23]=2)[CH:31]=[CH:30][C:29]=1[C:32]([F:35])([F:34])[F:33]
Reactant: O=C(CBr)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)cs1
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (45 mg, 0.232 mmol) with 2-bromo-N-{4-[3-fluoro-4-trifluoromethylphenyl]-1,3-thiazol-2-yl}acetamide (107 mg, 0.279 mmol) in the presence of NaH (13 mg, 0.555 mmol) in dry DMF (5.0 mL) to give 35 mg of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.27 (s, 3H), 3.17 (s, 3H), 3.36 (s, 3H), 5.34 (s, 2H), 6.07 (s, 1H), 7.85-7.91 (m, 1H), 7.94-8.05 (m, 3H), 12.82 (br s, 1H); ESI-MS (m/z) 496.23 (M+H)+.
Reaction SMILES: Cl[C:2]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)=[O:3].[CH3:35][O:36][CH2:37][CH2:38][NH2:39].ClCCl.O>CO>[CH3:35][O:36][CH2:37][CH2:38][NH:39][C:2]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)Cl)cc2)CC1
Reactant: COCCN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COCCNC(=O)c1ccc(CN2CCC(CNC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 1-[4-(chloroformyl)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (0.042 mmol) with 2-methoxyethylamine (3.8 mg, 0.050 mmol), a piperidinomethylpolystyrene (46 mg) and dichloromethane (1.5 mL) was stirred at room temperature for 17 hours. Water (0.020 mL) was then added to the mixture, and the resulting mixture was stirred for 30 minutes. Methanol (1 mL) was then added to the obtained mixture, and the resulting mixture was loaded onto a Varian™ SCX column and washed with methanol (10 mL). The obtained crude product was eluted with a 2 M methanol solution of NH3 and concentrated to thereby provide 1-[4-[N-(2-methoxyethyl)carbamoyl]benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 1612) (26.7 mg, 100%). The purity was determined by RPLC/MS (92%). ESI/MS m/e 535.2 (M++H, C27H33F3N4O4).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[C:28](I)=[CH:27][C:24]([C:25]#[N:26])=[C:23]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:22]=1)=[C:5]([CH3:19])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:7]2.[CH3:36][O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[N:42][CH:43]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[C:28]([C:40]3[CH:41]=[N:42][CH:43]=[C:38]([O:37][CH3:36])[CH:39]=3)=[CH:27][C:24]([C:25]#[N:26])=[C:23]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:22]=1)=[C:5]([CH3:19])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:7]2
Reactant: COc1cncc(B(O)O)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)c(C#N)cc1I
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cncc(-c2cc(C#N)c(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
4-(5,7-Difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-iodo-2-morpholinobenzonitrile (65.2 mg, 0.11 mmol), 5-methoxypyridin-3-ylboronic acid (26.6 mg, 0.17 mmol), tricyclohexylphosphine (5.9 mg, 0.021 mmol), and tris(dibenzylideneacetone)dipalladium (0) (9.7 mg, 10.6 μmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aqueous 1.3M potassium phosphate tribasic (0.26 mL, 0.34 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-50% of a premixed solution of 89:9:1 DCM:methanol:ammonium hydroxide in DCM) to afford a yellow film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concd then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a yellow solid as 4-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-ylamino)-5-(5-methoxypyridin-3-yl)-2-morpholinobenzonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 8.73 (1H, m), 8.41 (2H, d, J=2.0 Hz), 7.94 (2H, m), 7.64 (1H, m), 7.47 (3H, m), 7.25 (1H, m), 6.99 (1H, m), 6.87 (1H, m), 6.18 (1H, s), 3.96 (3H, s), 3.85 (4H, m), 3.16 (4H, m), 2.27 (3H, s). Mass Spectrum (pos.) m/e: 565.2 (M+H)+.