Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]#[N:13])=[CH:5][C:4]=1[CH3:14].[CH2:15](N)[CH2:16][NH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>[NH:13]1[CH2:15][CH2:16][N:17]=[C:12]1[CH:9]1[C:10]2[C:6](=[CH:5][C:4]([CH3:14])=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1
Reactant: COc1cc2c(cc1C)CCC2C#N
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2c(cc1C)CCC2C1=NCCN1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixture of 2.4 grams (0.013 mole) of 6-methoxy-5-methylindanecarbonitrile (iv) and 11.2 grams (0.045 mole) of the ethylenediamine salt of p-toluenesulfonic acid was stirred and heated to about 140° C.-160° C. where it was maintained for about 4.5 hours. The reaction mixture was then cooled to ambient temperature and dissolved in a mixture of aqueous 5% potassium carbonate and methylene chloride. The organic layer was removed, and the aqueous layer was extracted with two portions of methylene chloride. The combined extracts and organic layer were washed with one portion of aqueous 5% potassium carbonate. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was purified by column chromatography on Grade II basic alumina (3% water) using mixtures of methylene chloride and methanol as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding about 2.1 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)S(O[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(Cl)c2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 59.9 %

Procedure:
A mixture of (3-chloro-2-(trifluoromethyl)phenyl)boronic acid (0.453 g, 2.02 mmol), tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.669 g, 2.02 mmol), tetrakis(triphenylphosphine)palladium (0.117 g, 0.1 mmol), sodium carbonate (2 M, 5 mL), and 1,2-dimethoxyethane (10 mL) was heated at 80° C. under microwave irradiation for 1 h. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-30% EtOAc in hexanes) to give tert-butyl 4-(3-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as colorless oil (0.438 g, 60%): 1H NMR (300 MHz, CDCl3) δ 7.44-7.34 (m, 2H), 7.09 (m, 1H), 5.49 (br, 1H), 4.01 (br, 2H), 3.60 (br, 2H), 2.30 (br, 2H), 1.50 (s, 9H); MS (ESI+) m/z 306 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:18][OH:19].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:19][NH:18][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(C)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(c2ncc(C(=O)NO)s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15a (125 mg, 0.518 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (360 mg, 5.18 mmol) and a freshly prepared solution of sodium methoxide in methanol (178 mg, 7.72 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16a. HPLC: (Rt=10.74 min).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH:12]([NH:16][C:17]([O:19][CH3:20])=[O:18])[CH:13](C)C)[CH:7]([C:22]2[NH:23][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[NH:42][C:43]([CH:46]6[CH2:50][CH2:49][CH2:48][N:47]6[C:51](=[O:61])[CH:52]([NH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]([CH3:55])[CH3:54])=[N:44][CH:45]=5)=[CH:37][CH:36]=4)=[CH:29][CH:28]=3)[N:26]=2)[CH2:6]1)=[O:4].N[C@H](C(O)=O)C(C)C.C(=O)([O-])N.N[C@H](C(O)=O)C>>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH:12]([NH:16][C:17]([O:19][CH3:20])=[O:18])[CH3:13])[CH:7]([C:22]2[NH:23][CH:24]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[NH:42][C:43]([CH:46]6[CH2:50][CH2:49][CH2:48][N:47]6[C:51](=[O:61])[CH:52]([NH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]([CH3:55])[CH3:54])=[N:44][CH:45]=5)=[CH:37][CH:36]=4)=[CH:31][CH:32]=3)[N:26]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)NC(C(=O)N1CCN(C(=O)OC)CC1c1nc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c[nH]1)C(C)C
Agent: CC(C)[C@H](N)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: NC(=O)[O-]
Product: COC(=O)NC(C)C(=O)N1CCN(C(=O)OC)CC1c1nc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c[nH]1

Procedure:
was prepared in a similar fashion to 4-(2-Methoxycarbonylamino-3-methyl-butyryl)-3-{4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-piperazine-1-carboxylic acid methyl ester (example DP), replacing the valine derived carbamate with the corresponding alanine derived carbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:9])=[C:6]([OH:8])[CH:7]=1.CC(C)([O-])C.[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na]>CN(C)C=O>[CH2:16]([O:8][C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[Br:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: Nc1ccc(Br)c(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 106.9 %

Procedure:
To a solution of 5-amino-2-bromo-phenol (35.2 g, 0.187 mol) in N,N-dimethylformamide (350 mL) was added potassium tert-butoxide (22.9 g, 0.204 mol). After 15 min, benzyl chloride (25.5 mL, 0.222 mol) was added within 2 min. The reaction was stirred during 4 h and then poured onto an aqueous solution of sodium hydrogenocarbonate and extracted with ethyl acetate. The combined organic phases were washed with brine and water then dried over sodium sulfate, filtered, and evaporated under vacuum. 55.6 g of the title compound were obtained. Black solid, ISP-MS: m/e=279.1 ([M+H]+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:15]=[C:13]([CH3:14])[C:11](=[O:12])[NH:10][C:8]1=[O:9].Br[CH2:17][CH2:18][CH2:19][CH2:20][B:21]([OH:23])[OH:22]>CN(C)C=O>[OH:22][B:21]([OH:23])[CH2:20][CH2:19][CH2:18][CH2:17][N:7]1[CH:15]=[C:13]([CH3:14])[C:11](=[O:12])[NH:10][C:8]1=[O:9]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: OB(O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(CCCCB(O)O)c(=O)[nH]c1=O
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Potassium carbonate (0.6 g, 4.4 mmol) was added to a solution of thymine (0.56 g, 4.4 mmol) in dimethylformamide (15 mL) and stirred for 30 minutes. To this reaction mixture, 4-bromobutyl boronic acid (0.4 g, 2.2 mmol) dissolved in dimethylformamide (5 mL) was added dropwise, and stirring was continued 2 days at room temperature. After the potassium carbonate was filtered, the dimethylformamide was evaporated under high vacuum. The residue was purified on a silica gel column eluting with a discontinuous gradient of chloroform/methanol (95:5, 85:15). The appropriate TLC-homogenous fractions were pooled and evaporated to give 0.22 g of pure product. Yield 44%; mp 130°-132° C.; 1H NMR (DMSO-d6) 0.55-0.68 (t, B CH2), 1.22-1.35 (m, B CH2 CH2), 1.42-1.60 (m, B CH2 CH2 CH2), 1.72-1.78 (s, CH3 C5 thymine), 3.52-3.63 (CH2 CH2 N), 7.40-7.43 (s, (HO)2 B), 7.48-7.51 (s, H C6 thymine), 11.12-11.18 (s, HN thymine). Elemental Analysis (C9H15BO4N2); Calcd. C, 47.82%; H, 6.69%; N, 12.40%; Found C, 47.71%; H, 6.72%; N, 12.35%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][CH2:33][C@H:34]1[N:38]([CH3:39])[C:37](=[O:40])[CH2:36][CH2:35]1.O[C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>O1CCCC1>[CH3:39][N:38]1[C@H:34]([CH2:33][O:32][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[CH2:35][CH2:36][C:37]1=[O:40]
Reactant: Oc1cccnc1
Reactant: CN1C(=O)CC[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@H]1COc1cccnc1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 1.57 g (6.0 mmole) triphenylphosphine in 30 ml dry tetrahydrofuran under argon atmosphere at −15° C. 0.95 ml (1.05 g, 6.0 mmole) diethyl azodicarboxylate was added, drop by drop for 5 minutes, then 0.517 g (4.0 mmole) (S)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one in 5 ml dry tetrahydrofuran and 0.40 g (4.2 mmole) 3-hydroxypyridine were added and stirred for 10 minutes, then kept overnight in a refrigerator at −20° C. The solution was evaporated at 35° C. in good vacuum; the residue was dissolved in 15 ml of dichloromethane and washed with 1×7 and 2×2 ml of 1M hydrochloric acid. To the combined acidic solutions 20 ml saturated aqueous sodium bicarbonate solution was carefully added and then further 1 g of solid sodium bicarbonate was added, and this was extracted with 5×10 ml dichloromethane. The combined organic solutions were dried over magnesium sulfate, evaporated on a rotavapor at 35° C. and the residue was purified by column chromatography on 30 g silica gel, and developing with benzene containing 30% of diethylamine; this furnished 0.252 g (31%) of pure product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([C:14]1[N:15]=[C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][N:27]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[N:28]3)[CH2:21][CH2:20]2)[S:17][CH:18]=1)=[N:12][OH:13].[C:38](Cl)(=[O:40])[CH3:39].C(N(CC)CC)C.Cl>ClCCl>[C:38]([O:13][N:12]=[C:11]([C:14]1[N:15]=[C:16]([CH:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:37])[CH2:26][N:27]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]([F:35])([F:36])[F:34])=[N:28]3)[CH2:23][CH2:24]2)[S:17][CH:18]=1)[CH:10]=[CH:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])(=[O:40])[CH3:39]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(C=Cc3c(F)cccc3F)=NO)cs2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ON=C(C=Cc1c(F)cccc1F)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1

Procedure:
A solution of 3-(2,6-difluorophenyl)-1-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolyl]-2-propen-1-one 1-oxime (i.e. the product of Example 2, Step B) (0.10 g, 0.189 mmol), acetyl chloride (0.017 g, 0.22 mmol) and triethylamine (0.022 g, 0.22 mmol) in dichloromethane (5 mL) was stirred for 2 hr and shaken with 1 mL of 1 N hydrochloric acid. The mixture was poured onto a Celite® extraction tube, eluted with dichloromethane and concentrated to give 0.11 g of crude material which was purified via silica gel chromatography (hexanes-ethyl acetate gradient) to provide 0.11 g of the title compound.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([S:10][CH3:11])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].Br.[O:13]=[C:14]1[CH2:18][NH:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15]1.C(SCCC(N1CC(=O)C[C@H]1C(O)=O)=O)(=O)C>>[C:1]([S:4][CH2:5][CH:6]([S:10][CH3:11])[C:7]([N:17]1[CH2:18][C:14](=[O:13])[CH2:15][C@H:16]1[C:19]([OH:21])=[O:20])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C1CN[C@H](C(=O)O)C1
Reactant: CSC(CSC(C)=O)C(=O)Cl
Agent: Br
Agent: CC(=O)SCCC(=O)N1CC(=O)C[C@H]1C(=O)O
Product: CSC(CSC(C)=O)C(=O)N1CC(=O)C[C@H]1C(=O)O

Procedure:
The 3-(acetylthio)-2-(methylthio)propionic acid chloride is reacted with 4-keto-L-proline, hydrobromide according to the procedure of Example 1 (d) to yield 1-[3-(acetylthio)-2-methylthio-1-oxopropyl]-4-oxo-L-proline.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][S:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)(=[O:15])=[O:14])[N:3]=1.[CH3:24][C:25]1[O:26][C:27]2[C:33]([NH2:34])=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1>O1CCOCC1>[F:23][C:18]1[CH:17]=[C:16]([S:13]([NH:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:34][C:33]2[C:27]4[O:26][C:25]([CH3:24])=[CH:29][C:28]=4[CH:30]=[CH:31][CH:32]=2)=[N:3]3)(=[O:15])=[O:14])[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1cc(F)cc(F)c1
Reactant: Cc1cc2cccc(N)c2o1
Solvent: C1COCCO1
Product: Cc1cc2cccc(Nc3ccc4c(NS(=O)(=O)c5cc(F)cc(F)c5)cccc4n3)c2o1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
N-(2-Chloro-quinolin-5-yl)-3,5-difluoro-benzenesulfonamide (150 mg, 0.423 mmol) was dissolved in 3 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. (2-Methyl-1-benzofuran-7-yl)amine (245 mg, 1.33 mmol), sodium tert.-butylate (230 mg, 2.40 mmol), 1,1′-bis(diphenylphosphin)ferrocen (36 mg, 0.06 mmol) and 1,1′-bis(diphenylphosphin)ferrocen-palladium(II)chloride (17 mg, 0.02 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 16 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->60:40 gradient). The title compound was obtained as a light brown solid (164 mg, 83%), MS: m/e=466.0 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14](F)[CH:13]=2)=[O:9])=[C:6]([CH3:20])[CH:5]=[C:4]([Cl:21])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([SH:30])[CH3:29].O>CN(C=O)C>[Cl:21][C:4]1[N:3]=[C:2]([S:30][CH2:28][CH3:29])[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[O:9])=[C:6]([CH3:20])[CH:5]=1
Reactant: CCS
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A solution of 4.0 g (12.8 mmol) 2,6-dichloro-N-(3,5-difluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide in DMF (30 ml) was treated with 2.6 g (19.2 mmol) K2CO3 and 1.2 ml (16.0 mmol) ethanethiol, followed by stirring in a closed vessel at RT for 16 h. Then water (35 ml) was added and the mixture was extracted with EtOAc (2×70 ml). The combined organic layers were washed with water, a 2M aq. NaOH sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 3.3 g (9.7 mmol, 76%) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:4]>O1CCOCC1.CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)C=Cc1c[nH]c2cc(C(=O)OC)ccc12
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCc1c[nH]c2cc(C(=O)OC)ccc12
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 82.5 %

Procedure:
To a solution of methyl 3-(2-methoxycarbonylethenyl)-indole-6-carboxylate (213 mg) in a mixture of 1,4-dioxane (2 ml) and methanol (3 ml) was added 10% palladium on carbon (40 mg) and the mixture was stirred under hydrogen at 20° C. for 6.5 hours. The resulting mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 3-(2-methoxycarbonylethyl)indole-6-carboxylate (177 mg).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[F:12][CH:13]([F:31])[N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:15]1=[O:30].[H-].[Na+]>CN(C=O)C.CO>[F:31][CH:13]([F:12])[N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[N:3]=3)=[CH:25][CH:24]=2)[C:15]1=[O:30]
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(Oc2ccc(-n3c(=O)n(C(F)F)c4cccnc43)cc2)nc2ccccc21
Temperature: 180 °C
Yield: 46.7 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (70 mg) was added to a solution of 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (122 mg) and NaH (25.2 mg) in DMF (3 mL) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-(difluoromethyl)-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (80 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([NH:27][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)[CH3:26])=[N:3][CH:4]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 175 °C
Yield: 75 %

Procedure:
A mixture of 2,5-dichloro-4-(5-cyclopropyl-1H-pyrazole-3-ylamino)pyrimidine (Method 7; 0.064 g, 0.235 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 0.030 g, 0.214 mmol), and DIEA (0.045 ml, 0.257 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 175° C. for 20 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a white solid (0.060 g, 75%). 1H NMR (400 MHz) 12.51 and 12.09 (s, 1H), 9.70 and 9.64 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.02 and 7.93 (b, 1H), 7.63 (m, 1H), 7.40 (m, 1H), 5.93 and 5.80 (s, 1H), 5.06 (m, 1H), 1.83 (m, 1H), 1.45 (d, J=6.8 Hz, 3H), 0.94 (m, 1H), 0.84 (m, 1H), 0.74 (m, 1H), 0.63 (m, 1H). MS: Calcd.: 373. Found: [M+H]+374.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Cl:11].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCOCC2)cc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A mixture of 2-chloro-4-fluoro-benzoic acid methyl ester (3.51 g, 18.6 mmol), morpholine (1.95 mL, 22.3 mmol) and potassium carbonate (5.12 g, 37.1 mmol) in N-methylpyrrolidinone (20 mL) was stirred at 120° C. for 5 h. The reaction was cooled, diluted with ethyl acetate and filtered through Celite. The filtrate was washed four times with water, once with brine, was dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 2:8 ethyl acetate:hexanes to provide 2-chloro-4-morpholin-4-yl-benzoic acid methyl ester (3.08 g, 65% yield) as a white solid. 1H-NMR (CDCl3, 500 MHz) 7.79 (d, 1H), 6.81 (d, 1H), 6.67 (dd, 1H), 3.81 (s, 3H), 3.78 (m, 4H), 3.20 (m, 4H) ppm; MS (FIA) 256.1 (M+H); HPLC (Method A) 3.275 min.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH:19]1[C:24]([N:25]=[C:26]=[O:27])=[CH:23][C:22]2[C:28]([F:35])([F:34])[O:29][C:30]([F:33])([F:32])[O:31][C:21]=2[CH:20]=1>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:18]=[CH:17][C:15]([NH:16][C:26]([NH:25][C:24]3[CH:19]=[CH:20][C:21]4[O:31][C:30]([F:33])([F:32])[O:29][C:28]([F:34])([F:35])[C:22]=4[CH:23]=3)=[O:27])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C=Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)cc2)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
To a slurry of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (143 mg, 0.59 mmol) in DCM (1 mL) at 0° C. was added dropwise a solution of 2,2,4,4-tetrafluoro-6-isocyanato-1,3-benzodioxene (150 mg, 0.60 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 12 h. The resulting precipitate was filtered and washed with DCM to afford the desired product (125 mg, 41%) as a white solid.
Reaction SMILES: [CH2:1]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C([Li])CCC.[CH2:21]1[O:23][CH2:22]1>O1CCCC1.CCCCCC>[CH:4]1[C:3]2[CH2:2][CH2:1][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:9]([CH2:21][CH2:22][OH:23])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C1CO1
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 58.3 g of dibenzosuberane in 750 ml of tetrahydrofuran, stirred under argon, is cooled to about 10° in an ice-bath and treated dropwise with 190 ml of an about 2M solution of butyl lithium in hexane. The dark red solution is heated to boiling under reflux for 2 hours. Ethylene oxide is conducted for 15 minutes into the solution, cooled to about 10°, subsequently the mixture is stirred at room temperature for 1 hour and finally heated to boiling under reflux for an additional 30 minutes. The cooled mixture is poured into 300 ml of ice-cold 3N hydrochloric acid and extracted twice with 2 l of ether each time. The organic extracts are washed with 500 ml of 2N potassium bicarbonate solution, combined, dried over magnesium sulfate and evaporated. The residue is boiled up three times with 50 ml of pentane each time. There is obtained 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ethanol in the form of a very viscous, yellowish oil, Rf: 0.25 (toluene/ethyl acetate, 9:1).