Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[N:12][C:13]2[C:14]([C:4]=1[OH:20])=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=2)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 100 °C
Yield: 97.6 %

Procedure:
The solid 2-[(4-bromo-phenylamino)-methylene]-malonic acid diethyl ester (157 g, 458.8 mmol) was added to a hot diphenyl ether (260 g) and the mixture was heated to reflux for 5 h to afford a brown suspension. Then, the mixture was cooled to 100° C. and diluted with ethanol (˜200 mL). This suspension was refluxed for 10 min and then cooled to room temperature. The solids were collected by filtration and washed with diethyl ether. After drying in air, 132.59 g (97.6% yield) of 6-bromo-4-hydroxy-quinoline-3-carboxylic acid ethyl ester was isolated as a white solid: EI-HRMS m/e calcd for C8H6N2O (M+) 146.0480, found 146.0478.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[NH:6][C:5]=2[CH:4]=[C:3]([C:14]#[N:15])[CH:2]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:17]([CH:10]1[C:8]2[C:9]3[CH:1]=[CH:2][C:3]([C:14]#[N:15])=[CH:4][C:5]=3[NH:6][C:7]=2[CH2:13][CH2:12][CH2:11]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: N#Cc1ccc2c3c([nH]c2c1)CCCC3
Reactant: CCCCCCCCBr
Product: CCCCCCCCC1CCCc2[nH]c3cc(C#N)ccc3c21
Yield: 71.7 %

Procedure:
Using the procedure described in Example 9, 10.2 g of the carbonitrile from Example 2 was alkylated with 12.8 g of 1-bromooctane to give 11.5 g (68.5%) of 5,6,7,8-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrole-3-carbonitrile as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[CH:4]=[O:6])[CH:13]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1cccnc1
Product: O=Cc1cccnc1Nc1cccnc1

Procedure:
The procedure of Synthetic Example 1 or partly modified processes thereof were repeated using 2-chloronicotinic acid and 3-aminopyridine to obtain 2-(pyridin-3-ylamino)nicotinaldehyde.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:40]=[N:41][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:44]=3)[C:34]2=[O:49])[S:28][C:29]=1[C:30](O)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:40]=[N:41][C:42]([C:45]([F:47])([F:48])[F:46])=[CH:43][CH:44]=3)[C:34]2=[O:49])[S:28][C:29]=1[C:30]([NH2:7])=[O:31]
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)nc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)nc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 225-228° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.75 (br, 2H), 8.04 (d, J=8.1 Hz, 1H), 7.92-7.89 (m, 2H), 4.61 (s, 2H), 4.06-3.99 (m, 2H), 3.58-3.53 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 386.2 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([C:20]([O:22]C)=O)[CH:10]=2)=[CH:5][CH:4]=1.[Br:24][CH2:25]Br.C[Li]>C1COCC1>[Br:24][CH2:25][C:20]([C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:12]=1)=[O:22]
Reactant: BrCBr
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)n(-c2ccccn2)n1
Agent: [Li]C
Solvent: C1CCOC1
Product: CSc1ccc(-c2cc(C(=O)CBr)nn2-c2ccccn2)cc1
Reaction time: 1.5 h
Yield: 68.7 %

Procedure:
To a stirred solution of methyl 5-(4-methylthiophenyl)-1-(2-pyridyl)pyrazole-3-carboxylate (prepared as described in Penning, T. D. et al. J. Med. Chem. 1997, 40, 1347–1365.; 0.39 g, 1.2 mmol) and dibromomethane (0.17 mL, 2.4 mmol) in THF (10 mL) at −78° C. under nitrogen atmosphere was added methyllithium (1.6 M in ether, 1.4 mL, 2.2 mmol). After being stirred at the same temperature for 90 minutes, the solution was quenched with aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Chromatography of the residue on silica gel (2:1 EtOAc:hexane) gave the title compound (0.32 g, 69% yield) as a white foam. 1H NMR (300 MHz, CDCl3) δ 8.42–8.40 (m, 1H), 7.83 (m, 1H), 7.55–7.51 (m, 1H), 7.17–7.09 (m, 4H), 7.02 (s, 1H), 4.70 (s, 2H), 2.46 (s, 3H); LRMS (API-TIS) m/z 388 and 390 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24](O)=[O:25])=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:24](=[O:25])[CH2:23][NH:22][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:32][CH2:31]1
Reactant: OC1CCNCC1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC(O)CC3)ccc21
Yield: 64.2 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]amide (77 mg) was prepared by following General Procedure F starting from {[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (100 mg), 4-hydroxypiperidine (27 mg), HBTU (109 mg), and DIEA (63 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 499.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.48 (t, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.81 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.39 (d, 1H), 4.80 (d, 1H), 4.15 (d, 2H), 3.98-3.88 (m, 1H), 3.76-3.68 (m, 2H), 3.63 (s, 3H), 3.20 (t, 1H), 3.05 (t, 1H), 1.85-1.65 (m, 2H), 1.46-1.20 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].CS(O[C@H:11]([CH3:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=O)=O>CN(C)C=O>[C:1]([O:4][C@@H:11]([CH3:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C[C@H](COc1ccc(Oc2ccccc2)cc1)OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H](C)COc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 70.7 %

Procedure:
A mixture of anhydrous sodium acetate (82 mg, 1.0 mmol), (R)-1-methyl-2-(4-phenoxyphenoxy)ethyl methanesulfonate (250 mg, 0.78 mmol; ee.: 99.4%) and dimethylformamide (5 ml) was stirred at an inner temperature of 100° to 110° C. for 5 hours. After allowed to cool, ice-water was added thereto, and the reaction mixture was extracted with toluene three times. The toluene layer was dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by thin layer chromatography using silica gel to give (S)-(-)-1-methyl-2-(4- phenoxyphenoxy)ethyl acetate (158 mg). [α]D23 =-30.6° (CHCl3, c=1). ee.: 88.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cn1
Yield: 74 %

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (112 mg) was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as in General Procedure 4B to give the title compound as a brown solid (74% yield). m.p.=156° C., LCMS: m/z=408.25 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.48 (2H, m), 3.65 (2H, m), 3.87 (3H, s), 4.58 (2H, s), 5.06 (1H, s), 6.45 (1H, s), 7.36 (2H, m), 7.49 (2H, m), 7.63 (2H, m).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:16]([C:19]1[S:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])[CH3:17].C(=O)([O-])O.[Na+].O>C(COC)OC.O>[CH3:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([C:22]3[S:23][C:19]([C:16](=[O:18])[CH3:17])=[CH:20][CH:21]=3)[CH:3]=[CH:4][CH:5]=2)[CH:14]=1
Reactant: Cc1ccnc(Nc2cccc(Br)n2)c1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1ccc(-c2cccc(Nc3cc(C)ccn3)n2)s1
Temperature: 130 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
A suspension of (6-bromopyridin-2-yl)-(4-methylpyridin-2-yl)amine (1.00 g, 3.79 mmol), 5-acetylthiophene-2-boronic acid (644 mg, 3.79 mmol), tetrakis triphenylphosphine palladium (440 mg, 0.38 mmol), sodium hydrogen carbonate (480 mg, 5.68 mmol) in dimethoxyethane-water (12 ml) was heated and stirred in an Ar stream at 130° C. for 12 hours. Water was added to the reaction solution and extracted with ethyl acetate. After the organic layer was washed with a saturated brine and dried over anhydrous magnesium sulfate, the residue obtained by concentration in vacuo was washed with tetrahydrofuran-ethyl acetate (1:1), dried, and the title compound (426 mg, 36%) was obtained.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([CH2:33][CH:34]3C[CH2:37][CH2:36][N:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)N=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([O-])=O.[NH4+:56]>CO.[Pd]>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:56]=[C:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)[N:18]([CH:33]3[CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:34]3)[CH:19]=2)=[CH:23][C:24]=1[C:29]([F:30])([F:32])[F:31]
Reactant: CC(C)(C)OC(=O)N1CCCC1Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a solution of 4-[1-(1-tert-butoxycarbonyl-pyrrolidin-2-ylmethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (200.00 mg; 0.32 mmol; 1.00 eq.) in methanol 5 ml added trifluoro-acetic acid (54.24 mg; 0.48 mmol; 1.50 eq.), stirred at RT for 5 min, added ammonium formate (199.96 mg; 3.17 mmol; 10.00 eq.) and 200 mg wet 10% Pd/C, stirred at RT for 1 hr, lc-ms showed clean desired. Removed off solvent, added EA 50 ml, washed with Brine and 5% NaHCO3, dried, removed off solvent, got title compound 110 mg, yield 70%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[O:15][CH:14]=[N:13][CH:12]=1)[C:5]([OH:7])=O.C(OC([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][CH:30]2[CH2:32][CH2:31]2)[CH2:25][CH2:24]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:30]1([N:29]([CH:26]2[CH2:27][CH2:28][NH:23][CH2:24][CH2:25]2)[C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)=[C:2]([F:1])[CH:3]=2)[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(-c2cnco2)c(F)c1)N(C1CCNCC1)C1CC1

Procedure:
The title compound is prepared from 3-fluoro-4-oxazol-5-yl-benzoic acid and 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described for Intermediate 1. The deprotection step is accomplished by using trifluoroacetic acid in dichloromethane. LC (method 2): tR=0.98 min; Mass spectrum (ESI+): m/z=330 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:19](N(OC)C)=[O:20])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:25][Mg]Cl.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:19](=[O:20])[CH3:25])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CON(C)C(=O)c1nc2cccc(C)n2c1-c1cc(F)cc(F)c1
Reactant: C[Mg]Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1nc2cccc(C)n2c1-c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 3-(3,5-difluorophenyl)-N-methoxy-N,5-dimethylimidazo[1,2-a]pyridine-2-carboxamide (0.43 g, 1.3 mmol) in tetrahydrofuran (5.2 mL) at 0° C. was treated with 3 M methylmagnesium chloride in tetrahydrofuran (1.3 mL, 3.9 mmol) dropwise and stirred at 0° C. for 30 min. The reaction mixture was treated with additional 3 M methylmagnesium chloride in tetrahydrofuran (1.3 mL, 3.9 mmol) dropwise and stirred at 0° C. for another 30 min. The reaction mixture was quenched with 1 M hydrogen chloride (5.2 mL, 5.2 mmol), poured into saturated sodium bicarbonate (25 mL), and extracted with ethyl acetate (75 mL). The organic layer was separated, washed with brine and water, and dried with sodium sulfate, filtered, and concentrated to a crude solid. Purification by flash column chromatography gave the desired product (0.29 g, 78%). LCMS for C16H13F2N2O (M+H)+: m/z=287.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18](=O)[CH2:19][CH2:20][C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:17]=[C:18]([CH2:19][CH2:20][C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#CCCC(=O)CBr
Reactant: Nc1ncccc1OCc1ccccc1
Product: C[Si](C)(C)C#CCCc1cn2cccc(OCc3ccccc3)c2n1

Procedure:
The title compound was prepared in accordance with the general method of Example 223(D), from 3-(benzyloxy)pyridin-2-amine (274 mg, 1.37 mmol) and 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (compound 223(C), 750 mg, 3.0 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: from 98/2 to 95/5 as eluent) to afford 331 mg of 8-(benzyloxy)-2-(4-(trimethylsilyl)but-3-ynyl)H-imidazo[1,2-a]pyridine (Yield: 69%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:8]=3[NH:7][C:6]=2[N:19]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[C:11](=[O:12])[N:10]([CH3:23])[C:9]3[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:8]=3[NH:7][C:6]=2[N:19]=1
Reactant: CI
Reactant: Cc1cc(C)c2c(n1)Nc1cc(C)c(C)cc1NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(n1)Nc1cc(C)c(C)cc1N(C)C2=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 6.7 gm of 6,11-dihydro-2,4,8,9-tetramethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 150 ml of dimethyl formamide and 1.4 gm of 50% sodium hydride in mineral oil was stirred at 50° C. in a nitrogen atmosphere for 30 minutes. Thereafter, a solution of 7.1 gm of methyl iodide in 30 ml of dimethyl formamide was added dropwise at room temperature. The resulting mixture was heated on an oil bath at 120° C. for 1 hour, and was then evaporated in vacuo. The residue was admixed with water, the aqueous mixture was made alkaline with ammonia, and it was then extracted with chloroform. After separation of the 2,4,6,8,9,11-hexamethyl compound which had simultaneously formed in a silica gel column, the product was recrystallized from petroleum ether (b.p. 100°-140° C.), yielding 63% of theory of the compound named in the heading, which had a melting point of 225°-227° C.
Reaction SMILES: [F:1][C:2]1[C:24]([S:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]2)=[O:26])=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=[O:37].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[C:24]([S:25]([CH:27]2[CH2:28][CH2:29][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:32]2)(=[O:37])=[O:26])=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)(=O)C4CCN(C(C)C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 41.7 %

Procedure:
To an ice-cooled solution of 8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidine-4-sulfinyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 210 (51 mg, 0.102 mmol) in DCM (8 mL) was added TFA (24 μL, 0.306 mmol) followed by a slow addition of a solution of m-CPBA (21 mg, 0.122 mmol) in DCM (1 mL) and the resulting mixture was stirred for 2.5 h at 0° C. Additional m-CPBA (9 mg) in DCM (0.5 mL) was added and the mixture was stirred for 1 h at RT. Volatiles were then removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. Further purification by column chromatography (Si-PCC, gradient 5-10% MeOH in DCM) afforded 211 as a white solid (22 mg, 41%). LCMS: RT 2.76 min [M+H]+ 517.1. 1H NMR (DMSO, 400 MHz): δ 8.88 (1H, d, J=8.22 Hz), 7.94 (1H, s), 7.25 (1H, d, J=11.17 Hz), 5.67-5.55 (1H, m), 4.73-4.54 (4H, m), 3.28-3.15 (1H, m), 2.89-2.79 (2H, m), 2.72-2.60 (1H, m), 2.26 (3H, s), 2.13 (2H, bt, J=11.43 Hz), 1.89 (2H, bd, J=12.04 Hz), 1.58-1.41 (8H, m), 0.91 (6H, d, J=6.55 Hz)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:37]=[CH:36][C:35]=2[C:45]2[C:50]([O:51][CH3:52])=[CH:49][CH:48]=[CH:47][C:46]=2[O:53][CH3:54])=[CH:30][C:29]=1O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[N:39]=[C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:37]=[CH:36][C:35]=2[C:45]2[C:50]([O:51][CH3:52])=[CH:49][CH:48]=[CH:47][C:46]=2[O:53][CH3:54])=[CH:32][C:33]=1[O:7][CH:4]1[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]1
Reactant: CCOC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(O)c2)n1
Reactant: CN1CCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(OC3CCN(C)C3)c2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
Add 88 mg (0.87 mmol) of 1-methyl-3-hydroxypyrrolidine, 246 mg (1.09 mmol) of triphenylphosphine and 0.01 mL (0.07 mmol) of TEA to a solution of 300 mg (0.72 mmol) of ethyl 6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in 2.5 mL of anhydrous THF cooled to 0° C. and placed under argon. After dissolution, add dropwise, at 0° C., a solution of 0.24 mL (1.09 mmol) of DIAD in 2.5 mL of anhydrous THF. Bring the reaction mixture to RT, stir for 18 h, then take up in 50 mL of EtOAc. Wash the organic phase successively with 20 mL of a saturated aqueous solution of sodium bicarbonate (NaHCO3) then 20 mL of water. After drying over Na2SO4 and concentration under reduced pressure, purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 20% of methanol. After concentration under reduced pressure, we obtain 250 mg of ethyl 6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in the form of oil.
Reaction SMILES: OO.[F:3][CH2:4][CH2:5][O:6][CH:7]1[C:16]2[C:11](=[C:12]([CH3:21])[CH:13]=[C:14]([C:18]([OH:20])=[O:19])[C:15]=2[CH3:17])S[CH2:9][CH2:8]1.[S:22]([O-:25])(O)=[O:23].[Na+]>C(O)(=O)C>[F:3][CH2:4][CH2:5][O:6][CH:7]1[C:16]2[C:11](=[C:12]([CH3:21])[CH:13]=[C:14]([C:18]([OH:20])=[O:19])[C:15]=2[CH3:17])[S:22](=[O:25])(=[O:23])[CH2:9][CH2:8]1
Reactant: O=S([O-])O
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC2OCCF
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2OCCF
Yield: 85 %

Procedure:
4 ml of acetic acid and 6.24 g (56.7 mmol) of a 30% hydrogen peroxide aqueous solution as an oxidizing agent were added to 5.37 g (18.9 mmol) of the 4-(2-fluoroethoxy)-5,8-dimethylthiochroman-6-carboxylic acid, and the mixture was allowed to react at 80° C. for2hours. After the reaction mixture was allowed to cool, a 2% sodium hydrogensulfite aqueous solution was added to the reaction mixture, excessive hydrogen peroxide was removed, and a precipitated crystal was recovered by filtration and dried to give 5.08 g (yield 85%) of 4-(2-fluoroethoxy)-5,8-dimethylthiochroman-6-carboxylic acid-1,1-dioxide (corresponding to compound of the formula (II-2)).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:14][C:15](/[CH:18]=[C:19]3/[C:20](=[O:28])[NH:21][C:22]4[C:27]/3=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:17]=2)[CH:8]=1)=[O:5].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN1C(=O)CCC1>[O:28]=[C:20]1[NH:21][C:22]2[C:27](/[C:19]/1=[CH:18]\[C:15]1[O:14][C:13]([C:9]3[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:12]=[CH:11][CH:10]=3)=[CH:17][CH:16]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: C1CCNC1
Reactant: O=C(CCCl)Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1
Solvent: CN1CCCC1=O
Product: O=C(CCN1CCCC1)Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1

Procedure:
A solution of (E)-3-chloro-N-(3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)phenyl)propanamide (25 mg, 0.06 mmol) and pyrrolidine (0.025 mL) in NMP (0.75 mL) was heated in microwave (100° C., 5 min). The reaction mixture was purified by RHPLC to yield the desired (E)-N-(3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)phenyl)-3-(pyrrolidin-1-yl)propanamide LCMS (ES): m/z 428 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc(F)cc1F)c1cc(Br)ccc1OCc1ccc(F)cc1F
Yield: 99.7 %

Procedure:
To a solution of 5-bromo-2-hydroxybenzoic acid (2.5 g, 11.52 mmol) in acetone (100 ml) was added potassium carbonate (3.98 g, 28.8 mmol) and 1-(bromomethyl)-2,4-difluorobenzene (3.25 ml, 25.3 mmol). The mixture was heated to reflux for 4 hours. On cooling the mixture was filtered to remove the carbonate, the solid was washed with acetone (50 ml). The organics were evaporated under reduced pressure to give a white solid 5.39 g. No attempt was made to purify this compound it was taken on as is.