Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:2]1.C1COCC1.[Li]CCCC.[Si:32](Cl)([CH3:35])([CH3:34])[CH3:33]>CCCCCC.O>[CH3:33][Si:32]([CH3:35])([CH3:34])[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:1]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:2]=2)([CH3:12])[CH3:11])=[CH:14]1
Reactant: CC(C)(C1=CCc2ccccc21)C1=CCc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C1=CC([Si](C)(C)C)c2ccccc21)C1=CC([Si](C)(C)C)c2ccccc21
Temperature: 25 °C
Yield: 95.1 %

Procedure:
3.3 g of 2,2-bis(3-indenyl)propane (20511/46, MW 272.39, 12.11 mmol) and 50 m of THF in a 100 mL flask were cooled to -70° C. while stirring. 17 mL of a 1.6 M solution of BuLi (27.2 mmol) in hexane were added dropwise. At the end of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The solution was cooled again to -70° C. and 3.4 mL of Me3SiCl (MW 108.64, d 0.856, 26.8 mmol) were added. At the end of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water is then added, the organic layer is separated and the water layer extracted twice with Et2O, all organic phases were combined and dried over MgSO4, then filtered and all volatiles removed in vacuo. 4.8 g (95%) of a mixture of rac/meso 2,2-bis(1-trimethylsilyl-3-indenyl)propane was obtained. 1H NMR (200 MHz, C2D2Cl4, 120° C., referenced to the peak of residual C2HDCl4 at 5.75 ppm): 7.1-7.3 (m, 4H, C6 ring), 6.75-6.95 (m, 4H, C6 ring), 6.3-6.4 (br s, 2H, C5 ring), 3.2-3.3 (m, 2H, C5 ring), 1.64, 1.62 (2 s, 6H, bridge methyls), -0.15, -0.17 (2 s, 18H, TMS methyls).
Reaction SMILES: C([O-])(=O)C.[K+].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[C:9]2[N:14]([CH3:17])[N:15]=[CH:16][C:8]=12.[C:18]([C:20]1[C:21]([F:29])=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>CN(C=O)C.C(#N)C>[Cl:6][C:7]1[CH:12]=[C:11]([C:22]2[C:21]([F:29])=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:18]#[N:19])[N:10]=[C:9]2[N:14]([CH3:17])[N:15]=[CH:16][C:8]=12
Reactant: Cn1ncc2c(Cl)cc(Cl)nc21
Reactant: N#Cc1cccc(B(O)O)c1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cn1ncc2c(Cl)cc(-c3cccc(C#N)c3F)nc21
Temperature: 125 °C
Yield: 26.8 %

Procedure:
Potassium acetate (4 mL, 1M, 4 mmol) was added to a mixture of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5 (0.115 g, 0.569 mmol), 3-cyano-2-fluorophenylboronic acid 14 (0.075 g, 0.455 mmol) in DMF (2 mL) and acetonitrile (2 mL). Nitrogen was bubbled through the mixture followed by the addition of 10 mole % tetrakis(triphenylphosphine) palladium (0) and the reaction was heated at 125° C. in a microwave for 20 minutes. Solvent was removed, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and brine (15 mL). The organic portions were pooled and dried over anhydrous sodium sulfate and the solvent was removed. The crude material was purified by reverse phase chromatography (Biotage) using ethyl acetate and hexanes as solvents to give 15 as white solid (0.035 g, 20%)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]([C:19]1([CH2:23][OH:24])[CH2:22][O:21][CH2:20]1)[CH3:18].O>CS(C)=O>[CH2:17]([C:19]1([CH2:23][O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:22][O:21][CH2:20]1)[CH3:18]
Reactant: CCC1(CO)COC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCC1(COc2ccc([N+](=O)[O-])cc2)COC1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
To a solution of 4-fluoronitrobenzene (3.76 mL, 35.4 mmol) in DMSO (35 mL) at room temperature was added cesium carbonate (7.09 mL, 89.0 mmol) followed by 3-ethyl-3-oxetanemethanol (4.48 mL, 42.5 mmol). The mixture was heated to 70° C. for 2 hours. After cooling water was added and the resulting precipitate was filtered, washed with water, and dried in a vacuum oven to provide the title compound (8.28 g, 98% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:31]([N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1)([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:37]5[CH:36]=[N:35][N:34]([CH:31]([CH3:33])[CH3:32])[CH:38]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)n1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), 1-isopropylpyrazole-4-boronic acid pinacol ester (153 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (217 mg, 68%) in an orange oily form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[CH2:49][C:50]([CH3:53])([OH:52])[CH3:51])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:49][C:50]([OH:52])([CH3:53])[CH3:51])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(C)(O)CCn1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 825 mg, 2.50 mmol) was suspended in methylene chloride (12.5 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (1.25 mL, 2.5 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (582 μL, 5.00 mmol) was added. The reaction continued to stir at 0° C. for 10 min. 4-(3-Amino-pyrazol-1-yl)-2-methyl-butan-2-ol (424 mg, 2.50 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to the reaction. The reaction continued to stir at 0° C. for 10 min. The reaction was diluted with methylene chloride (50 mL), washed with water (15 mL), saturated aqueous brine solution (10 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 35% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-3-methyl-butyl)-1H-pyrazol-3-yl]-propionamide (653 mg, 54%) as a white foamy solid: ESI-LRMS m/e calcd for C23H32ClN3O4S [M+] 481.18, found 482.35 [M+H+], 464.22 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.23 (m, 2H, CH2), 1.29 (s, 6H, 2×CH3), 1.46-1.94 (m, 8H, 4×CH2), 1.94-2.04 (m, 2 H, CH2), 2.18-2.29 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.55 (t, J=7.5 Hz, 1H, CH), 3.00-4.25 (m, 2H, NCH2), 6.65 (d, J=2.3 Hz, 1H, Ar), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.47 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.61 (d, Jm=1.7 Hz, 1H, Ar), 8.10 (d, Jo=8.2 Hz, 1H, Ar), 8.12 (s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(N(C)C)=O)=NC(N(C)C)=O.[C:28](O)(=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.C(P(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A solution of Intermediate 35 (21.06 g), 1,1′-azobis(N,N-dimethylformamide) (64.11 g) and p-anisic acid (23.03 g, Tokyo Kasei Kogyo) in tetrahydrofuran (400 ml) was added with tri(n-butyl)phosphine (35.6 ml) at room temperature and stirred at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, then added with ethyl acetate (200 ml) and successively washed with saturated aqueous sodium hydrogencarbonate twice (200 ml each) and 0.1 N aqueous sodium hydroxide (50 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (32.92 g).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24](O)=[O:25])[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>>[F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([NH:38][S:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH3:28])(=[O:36])=[O:37])=[O:25])[O:21][C:22]=3[CH3:23])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: Cc1oc(C(=O)O)cc1CSc1ccc(-c2ccc(OC(F)F)cc2)cc1
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(CSc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1

Procedure:
Compound (154) was prepared from compound (153) and 2-D methyl-benzenesulphonamide by adapting the procedure of Example 34(c). LC/MS System D; Rt=11.61 mins, m/z (ES+)=544 (M+H for C27H23F2NO5S2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:32])[CH:10]([C:12]2[CH:13]=[C:14]([C:29](O)=[O:30])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.CN1CCOCC1.[NH:40]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:32])[CH:10]([C:12]2[CH:13]=[C:14]([C:29]([N:40]3[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]3)=[O:30])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1CCNCC1
Reactant: CC(c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CC(c1cc(C(=O)N2CCC(O)CC2)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (113 mg, 0.35 mmol) was added to a stirred solution of 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (130 mg, 0.29 mmol), 4-methylmorpholine (0.080 mL, 0.73 mmol) and piperidin-4-ol (36 mg, 0.35 mmol) dissolved in NMP (1.2 mL). The resulting solution was stirred at 23° C. for 2 hrs. The reaction mixture was purified by preparative HPLC using a Waters SunFire system. The fractions containing the desired compound were evaporated, triturated with ether and dried to afford 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-6-(4-hydroxypiperidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (90 mg, 58%) as a white solid. Mass Spectrum: M+H+ 528. NMR Spectrum (DMSOd6 at 323° K): 1.38 (bs, 2H), 1.57 (d, 3H), 1.75 (bs, 2H), 2.66 (s, 3H), 3.23-3.30 (m, 2H), 3.30-3.38 (m, 2H), 3.61 (m, 4H), 3.65 (bs, 4H), 3.71-3.79 (m, 1H), 4.66 (d, 1H), 5.52 (s, 1H), 5.54 (q, 1H), 6.36 (t, 1H), 6.50 (d, 2H), 7.62 (d, 1H), 7.87 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C[O-].[Na+].Cl>CO.CCOC(C)=O>[CH3:4][O:3][C:1](=[O:2])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:13](=[O:15])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-carbomethoxybenzaldehyde (79 mg, 0.48 mmol) and acetophenone (56 L, 0.48 mmol) in anhydrous methanol (1.6 mL), was added neat sodium methoxide (26 mg, 0.48 mmol). The mixture was stirred at room temperature overnight then heated to reflux for 1 hour, cooled down to room temperature and added HCl 1N and EtOAc. The layers were separated and the organic layer dried over anhydrous MgSO4 and filtered. The solvent was evaporated under vacuum to afford a yellow solid, which was recrystallized from acetonitrile/water to give a pale yellow crystalline solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:20])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
6-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation, see Intermediate 63) (2.05 g, 4.82 mmol), morpholine (2.084 mL, 24.09 mmol), HATU (2.015 g, 5.30 mmol) and DIPEA (2.52 mL, 14.45 mmol) were combined in DMF (25 mL) and the reaction stirred at room temperature for 90 mins. The mixture was concentrated in vacuo before being dissolved in DCM and loaded onto an aminopropyl SPE column (70 g). The column was eluted with 10% MeOH in DCM, and the appropriate fractions combined and concentrated to dryness in cavuo. The residue was purified by chromatography (100 g column, EtOAc/cyclohexane gradient) to give tert-butyl ((2S,4R)-1-acetyl-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (2.05 g, 4.14 mmol, 86% yield).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([CH:17]2[CH2:19][CH2:18]2)=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.[NH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[NH2:21].NN>C(O)C.CCCCCCC.Cl>[CH:17]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:6]=2[C:4](=[O:5])[N:20]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=2)[N:21]=3)[CH2:18][CH2:19]1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1c(C2CC2)nc2ccccc2c1Cl
Agent: Cl
Agent: NN
Solvent: CCCCCCC
Solvent: CCO
Product: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Yield: 80.2 %

Procedure:
4-chloro-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (1.15 g, 0.0041 mols) and 4-hydrazino-benzoic acid (1.0 g, 0.0068 mols) were stirred in ethanol (30 ml) at reflux for 16 h. The bright yellow suspension was diluted with heptane, filtered, washed with cold t-butylmethyl ether and left to dry under suction to yield crude solid containing hydrazine. This solid was suspended in 1 M HCl, filtered, washed with water and then dried in vacuo to yield 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (1.135 g, 80%) as a yellow solid, LCMS m/z 346.20 [M+H]+ @ RT 1.05 min: 96% purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH2:15][C:16]([C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:21]=[C:20]([C:31]#[N:32])[CH:19]=1)=[O:17].S(O)(O)(=O)=[O:34].C(OCC)(=O)C>O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH2:15][C:16]([C:18]1[N:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:21]=[C:20]([C:31]([NH2:32])=[O:34])[CH:19]=1)=[O:17]
Reactant: COc1ccc(-n2nc(C#N)cc2C(=O)Cc2ccc(-n3ccccc3=O)cc2F)cc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(C(N)=O)cc2C(=O)Cc2ccc(-n3ccccc3=O)cc2F)cc1
Reaction time: 2 h
Yield: 41 %

Procedure:
Part I. To 5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)-phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carbonitrile (75 mg, 0.175 mmol) was added concentrated aqueous dihydrogen sulfate (4.5 mL). After 2 h, the reaction was poured into ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, and concentrated to dryness. The resulting residue was purified by radial chromatography (2% methyl alcohol in dichloromethane) to afford 5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide (32 mg, 41%) as a white solid upon lyophilization from 10% acetonitrile in water. LC/MS (ESI+): 448.2 (M+H)+. 1H NMR (CD3OD) δ 7.70 (s, 1H), 7.60 (m, 2H), 7.43 (t, 1H), 7.16-7.32 (m, 4H), 6.97 (d, 2H), 6.60 (d, 1H), 6.45 (t, 1H), 4.40 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C@@:18]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:19](O)=[O:20])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].CN1CCOCC1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][NH2:41].O>CC1OCCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C@@:18]([CH3:26])([S:22]([CH3:25])(=[O:23])=[O:24])[C:19]([NH:41][O:40][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][O:34]3)=[O:20])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@@](CCn1cc(C#Cc2cccc(C#N)c2)cn1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Solvent: CN1CCOCC1
Solvent: CC1CCCO1
Solvent: O
Product: C[C@@](CCn1cc(C#Cc2cccc(C#N)c2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of (2R)-4-{4-[(3-cyanophenyl)ethynyl]-1H-pyrazol-1-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (0.360 g, 0.969 mmol) in 2-MeTHF (30 mL) was added N-methyl morpholine (0.139 g, 1.36 mmol, 1.4 eq), followed by CDMT (0.204 g, 1.16 mmol, 1.2 eq). The reaction mixture was allowed to stir for one hour. O-Tetrahydro-2H-pyran-2-yl-hydroxylamine (0.136 g, 1.16 mmol, 1.2 eq) was added, and the reaction mixture and was allowed to stir for an additional two hours. Water (20 mL) was added, and the solution was extracted with 2-MeTHF (100 mL). The aqueous layer was re-extracted with 2-MeTHF (150 mL), and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude was purified by flash chromatography, eluting with 30%-100% ethyl acetate/heptane to yield (2R)-4-{4-[(3-cyanophenyl)ethynyl]-1H-pyrazol-1-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (209 mg, 46% yield) as a colorless oil. LC-MS M−H 469.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[C:17]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:23]=4)=[O:21])[CH:16]=[CH:15][C:14]=3[CH3:34])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:35][CH3:36].C1(C)C=CC(S(O[CH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>O>[CH3:36][O:35][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 100 °C
Yield: 12.2 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline (250 mg), 3-methylsulphonylpropyl 4-toluenesulphonate (150 mg), cesium carbonate (501 mg) and N,N-dimethylacetamide (5 ml) was stirred and heated to 100° C. for 1 hour. After cooling the reaction mixture to ambient temperature, water was added and the precipitated solid was isolated and dried under vacuum. The material so obtained was purified by column chromatography on silica using a 10:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (38 mg); NMR: 2.14 (s, 3H), 2.13 (m, 2H), 3.02 (s, 3H), 3.24 (m, 2H), 3.49 (m, 4H), 3.68 (m, 4H), 3.93 (s, 3H), 4.29 (t, 2H), 7.08 (d, 1H), 7.16 (s, 1H), 7.21 (s, 1H), 7.27 (d, 1H), 7.58 (d, 1H), 7.76 (s, 1H), 7.83 (s, 1H), 8.25 (d, 1H), 8.27 (s, 1H), 9.4 (s, 1H), 10.28 (s, 1H); m/s: M+H+ 607.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13]>N1CCCCC1.C(O)C>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:30]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c1C
Temperature: 90 °C
Yield: 68.1 %

Procedure:
A mixture of 5-Chloro-1,3-dihydro-indol-2-one (335 mg, 2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90° C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 565 mg (68%) of the title compound as an orange solid.