Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(=O)CCCCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CCCN=[N+]=[N-])cc1
Temperature: 70 °C
Yield: 94.7 %

Procedure:
To a solution of 4-chloro-4′-methoxybutyrophenone (Acros Organics) (22.45 g, 106 mmol) in DMF (300 mL) was added sodium azide (13.7 g, 211 mmol). The solution was heated under N2 (g) at 70° C. for 4 h. The milky reaction mixture was partitioned between ethyl acetate (700 mL) and water (500 mL). The organic layer was washed with another portion of water (500 mL), followed by saturated aqueous sodium bicarbonate (500 mL) and brine (500 mL). The organic layer was dried (sodium sulfate) and concentrated to give an oil (22 g, 95% yield) which solidifed slowly upon standing. MS m/e 220; HPLC retention time 3.09 min.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH2:25]([O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:35]N)[CH:30]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=1)[CH3:26]
Reactant: CCOC(=O)c1ccnc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CCOC(=O)c1ccnc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 2-hydrazino-isonicotinic acid ethyl ester according to example 43 gave the desired product. MS: M=466.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].IC.[C:14]([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[F:1][C:2]1[C:3]([O:11][CH3:14])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(F)ccc(F)c1O
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1c(F)ccc(F)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 3,6-difluoro-2-hydroxybenzaldehyde (2.450 g; 15.50 mmol), iodomethane (2.199 g; 15.50 mmol), and K2CO3 (2.570 g; 18.60 mmol) in anh. DMF (50 ml) was heated to 80° C., under nitrogen, for 4 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3,6-difluoro-2-methoxybenzaldehyde as a colorless solid. LC-MS (conditions A): tR=0.62 min.; no ionisation.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:13]1[CH:17]=[C:16]([CH:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[S:15][CH:14]=1)#[N:12].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[C:11]([C:13]1[CH:17]=[C:16]([C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[S:15][CH:14]=1)#[N:12]
Reactant: CC(C)C(O)c1cc(C#N)cs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(=O)c1cc(C#N)cs1
Temperature: -55 °C
Reaction time: 0.03 h
Yield: 49.3 %

Procedure:
Oxalyl chloride (0.70 ml) was dissolved in methylene chloride (10 ml), and then the mixture was cooled to −60 to −50° C. Dimethyl sulfoxide (0.57 ml) was added thereto, and the mixture was stirred for 2 minutes. Further, a methylene chloride solution (6 ml) of 3-cyano-5-(1-hydroxy-2-methylpropyl)thiophene (1.21 g) was added thereto at −60 to −50° C., and the mixture was stirred for 15 minutes. Then, triethylamine (4.65 ml) was added, and the temperature of the mixture was raised to a room temperature. Ethyl acetate was added, and the mixture was washed with water and further brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was recrystallized from ethanol, to give the title compound as pale yellowish white crystals (0.59 g) Further, the filtrate was purified by silica gel column chromatography (hexane/ethyl acetate system), to give the title compound (0.41 g, total yield: 1.00 g, 84%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=[O:5].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.C(N(CC)CC)C>CC(O)C>[CH3:1][N:2]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1)[CH2:3][C:4]([NH:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=[O:5]
Reactant: CNCC(=O)NC1CN(C(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(CC(=O)NC1CN(C(=O)OC(C)(C)C)C1)c1ncnc2ccc(C(F)(F)F)cc12

Procedure:
A mixture of tert-butyl 3-(2-(methylamino)acetamido)azetidine-1-carboxylate (348 mg, 1.43 mmol) as prepared in the previous step and commercially available 4-chloro-6-(trifluoromethyl)quinazoline (327 mg, 1.41 mmol) were stirred in anhydrous iPrOH and triethylamine at 90° C. under argon for 1 hour. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0%-5% MeOH/EtOAc) to give a yellow solid after drying under high vac.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)cc1

Procedure:
A solution of 8.2 g. of p-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hrs. The solution is concentrated to ca. 50 ml. by distillation of the solvent and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate, dried and evaporated to yield ethyl p-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 1-bromohexadecane, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated to 80° C. for 7 hours. The mixture is then cooled, diluted with water and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl (4-hexadecylaminophenyl)acetate.
Reaction SMILES: BrC1C=C(O)C=CC=1.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][C:16](=[O:20])[O:17]2)=[CH:12][CH:11]=1.CC(C)=CC(O)=O.[H-].[Na+].[C:30]1([O:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)Cl.O1CCCC1>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][C:16](=[O:20])[O:17]2)=[CH:12][CH:11]=1.[O:40]=[C:37]1[CH2:38][CH2:39][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:36]1
Reactant: C=CC(=O)Oc1ccccc1
Agent: CC(C)=CC(=O)O
Agent: O=C1CCc2ccc(Br)cc2O1
Agent: Oc1cccc(Br)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CCc2ccccc2O1

Procedure:
Thus, in accordance with Reaction Scheme 6, 3-bromo phenol, or a 3-bromo phenol substituted in the 4 (para) position by an alkyl substituent (Compound 7) is acylated with an acylating agent, such as the acid chloride (compound 11) derived from 3,3-dimethylacrylic acid or from another appropriately substituted acrylic acid (R1 ' and R2 ' is either H or lower alkyl). The acylation of the 3-bromo-phenol (Compound 7) with the acid chloride (Compound 11) is preferably conducted in the presence of a strong base (e.g. sodium hydride) in an inert solvent (such as tetrahydrofuran). The resulting phenyl-acrylate (Compound 12) is ring closed under Friedel-Crafts type reaction conditions (e.g. AlCl3 catalyst, in an inert solvent such as methylene chloride) to provide two positional isomers (Compound 13) and (Compound 14) of the 2-oxo-chroman derivative, each of which bears, in the 4-position, the CH2R1 ' and CH2R2 ' substituents and where R5 is hydrogen or lower alkyl. As described previously for Reaction Scheme 5, the mixture is then separated by conventional means to obtain the desired 7-bromo-2-oxo-chroman (Compound 13). 1t should be noted that as also described previously in connection with Reaction Scheme 5 the 7-bromo-2-oxo chroman (Compound 11) can be separated from the potential regio-isomeric impurities at the carboxylic acid stage or at the final coupling stage. The 2-oxo-7-bromo-chroman (Compound 13) is thereafter reduced with lithium aluminum hydride or an appropriate reducing agent to provide the 7-bromo-diol (Compound 15). The diol (Compound 15) is then mono-mesylated at the primary alcohol position followed by intramolecular nucleophilic displacement of a mesyl leaving group, to give the 7-bromo-chroman (Compound 8) which bears the desired CH2 --R1', CH2R2 ' and R5 substituents. The carboxylic acid function is introduced into the 7-position in the same manner as described previously in Reaction scheme 5 to give the 7-carboxy chroman (Compound 10).
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[CH:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]2[C@H:26]3[CH2:27][CH2:28][C@H:23]([CH2:24][N:25]3C(OC(C)(C)C)=O)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)([CH3:10])[CH3:9]>C(Cl)(Cl)Cl>[ClH:1].[CH:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]2[C@H:26]3[CH2:27][CH2:28][C@H:23]([CH2:24][NH:25]3)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(C(=O)OC(C)(C)C)C3)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2NC3)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 100 %

Procedure:
A 4 N-hydrochloric acid-ethyl acetate solution (8.1 mL) was added to a chloroform (10 mL) solution of the compound (1.26 g, 3.24 mmol) synthesized in (3), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was then concentrated under reduced pressure to obtain the title compound (1.15 g, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([S:15]([NH:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23]C(C)(C)C)=[O:22])(=[O:17])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([S:15]([NH:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([OH:23])=[O:22])(=[O:16])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NS(=O)(=O)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1NS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzylsulfonamido)-4-phenethylbenzoate and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 65-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 5.1 mg of 2-(benzylsulfonamido)-4-phenethylbenzoic acid as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11].[CH3:15][C:16]([CH3:20])([CH3:19])[C:17]#[CH:18].C(N(CC)CC)C.[Cl-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C)C=O>[CH3:15][C:16]([CH3:20])([CH3:19])[C:17]#[C:18][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)NCc1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cc(C#CC(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.8 %

Procedure:
A mixture comprising 1.00 g of methyl N-(5-bromo-2-fluorobenzyl)carbamate, 0.75 g of 3,3-dimethyl-1-butyne, 0.06 g of dichlorobis(triphenylphosphine)palladium, 0.02 g of copper(I) iodide, 1.29 g of triethylamine and 2.7 ml of N,N-dimethylformamide, was stirred at room temperature for 48 hours in a nitrogen atmosphere. This reaction solution was poured into a saturated sodium chloride aqueous solution and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.40 g of methyl N-[5-(3,3-dimethyl-1-butynyl)-2-fluorobenzyl]carbamate as brown crystals.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33]COC)=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1>CO.Cl.[OH-].[OH-].[Pd+2]>[CH3:22][C:17]1[N:16]([C:12]2[N:11]=[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[C:9]([OH:8])=[C:14]([CH3:15])[N:13]=2)[C:20]([CH3:21])=[CH:19][CH:18]=1
Reactant: COCOCCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-n2c(C)ccc2C)nc(CCCCCCCCCCO)c1O

Procedure:
To a stirred solution containing 240 mg (0.48 mmol) of 5-(Benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(10-(methoxymethoxy)decyl)-6-methylpyrimidine in 10 mL of methanol were two drops of concentrated HCl and the mixture was stirred at reflux overnight. To the mixture were added 10 mg of 20% palladium hydroxide on carbon (Degussa type E101 NE/E). The reaction mixture was stirred at 23° C. under hydrogen atmosphere for 15 min. The reaction mixture was filtered through celite and the filtrated was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (13×3 cm). Elution with 2:1 toluene-ethyl acetate afforded the expected product as colorless oil: yield 13 mg (8%); silica gel TLC Rf 0.40 (2:1 toluene-ethyl acetate); 1H NMR (methanol-d4) 61.29-1.35 (m, 12H), 1.49 (m, 2H), 1.71 (m, 2H), 2.11 (s, 6H), 2.45 (s, 3H), 2.80 (dd, 2H, J=7.2, 7.2 Hz), 3.50 (t, 2H, J=6.4 Hz) and ˜5.74 (s, 2H); 13C NMR (methanol-d4) δ 11.96, 11.96, 17.50, 25.49, 27.27, 28.93, 29.05, 29.12, 29.18, 29.22, 31.00, 32.22, 61.56, 106.34, 106.34, 128.37, 128.37, 146.20, 148.84, 155.40 and 158.94; mass spectrum (APCI), m/z 360.2659 (M+H)+ (C21H34N3O2 requires 360.2651).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[N:22]=[C:23]([CH:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36](C)(C)C)=[O:34])[CH2:29][CH2:28]5)[NH:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.CC1C=CC(C(N2CC(C3C=CC(C#N)=CC=3)C2)=O)=CC=1C1NC(C2CCNCC2)=NC=1C.C(N(C(C)C)CC)(C)C.ClC(OC)=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[NH:22][C:23]([CH:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]5)=[N:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Agent: COC(=O)Cl
Agent: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCNCC2)nc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCC(c2nc(C)c(-c3cc(C(=O)N4CC(c5ccc(C#N)cc5)C4)ccc3C)[nH]2)CC1
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3, 227 mg, 0.42 mmol) in CH2Cl2 (10 mL), was added trifluoroacetic acid (2 ml). The reaction was stirred for 1.5 hours and concentrated under reduced pressure. The reaction mixture was neutralized with 2 mL Na2CO3 (1M) to afford the crude intermediate after lyophilization. A mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (185 mg, 0.42 mmol) and diisopropyl ethylamine (363 μL, 2.1 mmol) were dissolved in DMF (6 mL). Methyl chloroformate (36 μL, 0.46 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was concentrated, diluted with saturated NaH2PO4 (20 mL) and extracted with EtOAc (3×20 ml). The organic phase was washed by brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative TLC with 10% methanol in dichloromethane and lyophilized to give 141 mg (67%, over 2 steps) of the title compound as a white solid. m/z (ES+) 498 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11](=O)[CH2:12][Cl:13])=[C:4]([F:15])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17].P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]=[C:11]([Cl:17])[CH2:12][Cl:13])=[C:4]([F:15])[CH:3]=1
Reactant: COc1cc(NC(=O)CCl)c(F)cc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(N=C(Cl)CCl)c(F)cc1Cl
Reaction time: 1 h
Yield: 78.3 %

Procedure:
First, 2.00 g of N-(4-chloro-2-fluoro-5-methoxyphenyl)-2-chloroacetamide was mixed with 1.66 g of phosphorus pentachloride, and the stirring was continued for 1.0 hr at 60° C. After letting the mixture stand to cool the same, the produced phosphorus oxychloride was distilled out under reduced pressure. Then, the residue was refined by vacuum distillation to obtain 1.68 g of N-(4-chloro-2-fluoro-5-methoxyphenyl)-2-chloroacetimidoylchloride. The boiling point was 121° C./0.5 mm Hg.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[S:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:10]=1
Reactant: NCc1cc(F)ccc1S(=O)(=O)N1CCCC1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)N1CCCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
(Step 2) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.87 g), 1-[5-fluoro-2-(pyrrolidin-1-ylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 1 (1.15 g) and potassium carbonate (1.54 g) in ethanol (10 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH2:11].C(O)C>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:11][CH3:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNCc1ccc(Cl)nc1
Temperature: 20 °C

Procedure:
A mixture of the product of Example 4(b), 2-chloro-5-chloromethylpyridine, (8.1 g, 0.05 mol), methylamine (60 ml of a 30% w/v solution in water, 0.5 mol) and ethanol (100 ml) was heated, with stirring, under reflux for 5 hours. The reaction mixture was then cooled to ambient temperature (20° C.) and the solvent removed by evaporation under reduced pressure to give a brown oil. The product, N-(6-chloro-3-pyridylmethyl)-N-methylamine, was isolated from this oil by flash chromatography using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), with 10% v/v methanol/dichloromethane as eluent, as a brown oil (5.96 g, 76.1%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])/[CH:4]=[CH:5]/[C:6]([OH:8])=O)[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][C:45]1[CH:54]=[C:53]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[C:52]2[C:47](=[CH:48][C:49]([C:61]([F:64])([F:63])[F:62])=[CH:50][CH:51]=2)[N:46]=1>CN(C=O)C>[CH2:9]([CH:3]([CH2:1][CH3:2])/[CH:4]=[CH:5]/[C:6]([N:58]1[CH2:59][CH2:60][N:55]([C:53]2[C:52]3[C:47](=[CH:48][C:49]([C:61]([F:64])([F:62])[F:63])=[CH:50][CH:51]=3)[N:46]=[C:45]([CH3:44])[CH:54]=2)[CH2:56][CH2:57]1)=[O:8])[CH3:10]
Reactant: Cc1cc(N2CCNCC2)c2ccc(C(F)(F)F)cc2n1
Reactant: CCC(/C=C/C(=O)O)CC
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: CCC(/C=C/C(=O)N1CCN(c2cc(C)nc3cc(C(F)(F)F)ccc23)CC1)CC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 320 %

Procedure:
(E)-4-Ethyl-hex-2-enoic acid (21.3 mg, 0.15 mmol) was dissolved in DMF (350 μl), diisopropylethylamine was added (26 μl, 0.15 mmol) followed by HATU (57 mg, 0.15 mmol dissolved in 0.25 ml DMF). The mixture was stirred at room temperature for 15 minutes, then 2-methyl-4-piperazin-1-yl-7-(trifluoromethyl)quinoline (44 mg, 0.15 mmol, dissolved in 1 ml DMF) was added and stirring was continued overnight. The mixture was evaporated under reduced pressure, the residue was dissolved in dichloromethane, the solution was washed with 5% sodium bicarbonate solution and water, evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 20.3 mg (0.48 mmol, 32.3%) of a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=[C:37]2B1OC(C)(C)C(C)(C)O1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:37]3[C:36]4[C:40](=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=4)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reactant: COc1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and tert-butyl 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (Example 93A) (262 mg, 0.702 mmol) in N,N-dimethylformamide (2.63 mL) was added saturated aqueous bicarbonate solution (880 μL) followed by bis(triphenylphosphine)palladium dichloride (17.26 mg, 0.025 mmol). The mixture was heated to 70° C. for 3 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 689.3 [M+H]+.