Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([CH2:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:22]=2[CH3:29])=[CH:16][C:15]=1[F:30])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O.O>[C:1]([O:5][C:6](=[O:31])[N:7]([CH2:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:33])[NH2:28])=[CH:23][C:22]=2[CH3:29])=[CH:16][C:15]=1[F:30])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C#N)ccc1-c1cc(F)c(CN(CCC(C)C)C(=O)OC(C)(C)C)c(F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C(N)=O)ccc1-c1cc(F)c(CN(CCC(C)C)C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
(4′-Cyano-3,5-difluoro-2′-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1d: 30 g) was dissolved in 150 mL dimethyl sulfoxide and combined with potassium carbonate (20 g) and 20 mL of a 30% hydrogen peroxide solution in water. After stirring at room temperature for 12 hours, the reaction mixture was quenched with water and extracted using ethyl acetate (250 mL). The organic layer was washed with water (2 times), brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica eluting with 50% ethyl acetate in heptane to provide 28 g of the title compound (I-1e).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M83) (0.17 g, 0.32 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (98 mg, 74%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].CN(C)C(Cl)=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:27][CH3:28])=[C:18]([CH:20]2[O:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])[CH:19]=1.[Na].ClC1C=CC(OC)=C(C2OC(=O)N(C(=O)N(C)C)C2=O)C=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:27][CH3:28])=[C:18]([CH:20]2[O:24][C:23](=[O:25])[N:22]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:21]2=[O:26])[CH:19]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Agent: CN(C)C(=O)Cl
Agent: COc1ccc(Cl)cc1C1OC(=O)N(C(=O)N(C)C)C1=O
Agent: [Na]
Product: CCOC(=O)N1C(=O)OC(c2cc(Cl)ccc2OC)C1=O

Procedure:
By the same method, but replacing ethyl chloroformate with an equivalent amount of dimethylcarbamoyl chloride, sodium 5-(5-chloro-2-methoxyphenyl)oxazolidine-2,4-dione is converted to 5-(5-chloro-2-methoxyphenyl)-3-dimethylcarbamoyloxazoldine-2,4-dione.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].Cl[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:21][C:22]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([O:15][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)c1cc(O)cc(OCC)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC)cc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of ethyl 3-ethoxy-5-hydroxybenzoate (3.00 g), 4-chloromethyl-5-methyl-2-phenyloxazole (3.26 g), potassium carbonate (2.17 g) and N,N-dimethylformamide (60 ml) was stirred at 80° C. for 2 hrs. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl 3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzoate (5.40 g, 99%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2.Cl>C(O)(C)C>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cc1OCc1ccccc1
Yield: 96 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (5 g, 16.6 mmol), (prepared as described for the starting material in Example 1), 5-aminoindole (2.4 g, 18.2 mmol) in isopropanol (60 ml) containing 5N hydrogen chloride in isopropanol (260 μl, 1.6 mmol) was refluxed for 90 minutes. After cooling the volatiles were removed under vacuum. The solid was triturated with isopropanol, filtered, washed with isopropanol followed by ether and dried under vacuum to give 7-benzyloxy-4(indol-5-ylamino)-6-methoxyquinazoline hydrochloride (6.9 g, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[O:14])[N:10]=[C:9]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[C:4]([Cl:28])[CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[Cl:28][C:4]1[CH:3]=[C:2]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[O:14])[N:10]=[C:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(CO)NC(=O)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CO)NC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2ccccc2Cl)n1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To a 100 mL round bottom flask attached with condenser column and magnetic stir bar was added 1-(4-bromo-2-chlorophenyl)-2-(2-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-1H-imidazole-4-carboxamide (956 mg, 1.98 mmol), 3-methylsulfonylphenyl boronic acid (435 mg, 2.18 mmol), PdCl2dppf (150 mg, 10 mol %), K2CO3 (830 mg, 6.00 mmol), 1,2-dimethoxyethane (50 mL) and H2O (13 mL). The reaction solution was allowed to stir at 80° C. for 2.5 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 5% EtOAc to 100% EtOAc to afford 885 mg (80% yield) of the title compound. MS (ESI) 556.3, 558.3, 560.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (t, J=1.7 Hz, 1H), 8.06-8.13 (m, 2H), 8.03 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.82 (dd, J1=7.3 Hz, J2=1.5 Hz, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.38-7.48 (m, 3H), 5.18 (br s, 1H), 3.45 (s, 2H), 3.36 (br s, 1H), 3.31 (s, 3H), 1.37 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1.[Li]CCCC.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[C:14]=1[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1
Reactant: Fc1cc(F)cc(OC2CCCOC2)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2c(F)cc(OC3CCCOC3)cc2F)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(3,5-difluorophenoxy)tetrahydro-2H-pyran (1.42 g, 6.63 mmol) in THF (26 mL) at −78° C., a solution of n-BuLi in hexanes (1.6 M; 10.4 mL, 16.6 mmol) was added slowly through a dripping funnel. When addition was complete, the mixture was kept at −78° C. for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.06 mL, 19.9 mmol) was then added in one portion. The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched with NaHCO3 solution and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give sub-title compound as a colorless oil. LCMS calc. for C17H24BF2O4 (M+H)+ m/z=341.2. found: 341.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: CSc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(SC)cc32)CC1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
In accordance with the general procedure described in the foregoing Examples, 14.0 grams of 8-methylthio-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with 12.2 grams of caprylyl chloride (octanoyl chloride) in a mixture of 20 milliliters of chloroform and 60 milliliters of benzene. After the reaction mixture had been allowed to stand for 4 days at room temperature, the reaction mixture was heated to a temperature of 60°C and further treated as described in the preceding Example. The recovered crude 8-methylthio-10-[4-(3-octanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was thereafter converted into the crystalline di(hydrogen maleate) as described in the foregoing Example. The salt was recovered in a yield of 13.7 grams and, after recrystallization from acetone, had a melting point of 122°-123°C. The pure base was recovered in the form of a viscous oil by treatment of the pure salt with a dilute aqueous solution of ammonium hydroxide as described in the foregoing Example.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:39]=[CH:38][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:47]([O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:48]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:47]([O:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[O:48])=[O:22])=[CH:38][CH:39]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCN)cc2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCNC(=O)Oc3ccccc3)cc2)cc1
Reaction time: 18 h
Yield: 63.9 %

Procedure:
A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-aminopentyloxy)phenyl]benzamide (750 mg) in dichloromethane (30 ml) was treated with pyridine (681 mg) and phenyl chloroformate (675 mg). After 18 hours, the solvent was removed and the residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (SiO2; 50 g, 1% methanol in dichloromethane) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-phenoxycarbonylaminopentyloxy)phenyl]benzamide (590 mg).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OCC)(=[O:17])[CH2:15][OH:16].CO.C[O-].[Na+]>CCOCC>[CH2:1]([NH:13][C:15](=[O:16])[CH2:14][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(=O)CO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCCCCCNC(=O)CO
Yield: 74.9 %

Procedure:
181.4 g (1.0 mol) of dodecylamine, 104.1 g (1.0 mol) of ethyl glycolate and 7.5 g (40 mmol) of a methanol solution containing 28% sodium methylate were fed into a 500-ml four-necked flask equipped with a stirrer and a thermometer. The obtained mixture was stirred under a stream of nitrogen gas, and the temperature thereof was elevated to 100° C. At this temperature, the reaction mixture was stirred for 2 hr while distilling off formed methanol. The obtained reaction mixture was dissolved in 500 ml of ether at room temperature. The ether solution thus obtained was transferred to a separatory funnel, and washed with water. The ether phase was separated, and concentrated. The solid remaining after concentration was dried in a reduced pressure to thereby obtain 182.3 g of white powdery N-dodecylglycolamide (yield: 74.9%). The hydroxyl value of this N-dodecylglycolamide was 229.4 (calculated value: 230.5).
Reaction SMILES: [C:1]([NH:3][CH3:4])#[CH:2].[Cl:5][C:6]1[C:11]([CH:12]=O)=[C:10]([F:14])[C:9]([CH3:15])=[CH:8][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:5][C:6]1[C:11]([CH2:12][N:3]([C:1]#[CH:2])[CH3:4])=[C:10]([F:14])[C:9]([CH3:15])=[CH:8][CH:7]=1
Reactant: Cc1ccc(Cl)c(C=O)c1F
Reactant: C#CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C#CN(C)Cc1c(Cl)ccc(C)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethynyl-methylamine (98 uL, 1.16 mmol) and 6-chloro-2-fluoro-3-methyl-benzaldehyde (200 mg, 1.16 mmol) in CH2Cl2 (3 mL) was added sodium triacetoxyborohydride (369 mg, 1.74 mmol) and acetic acid (7 uL, 0.12 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, and concentrated to afford the title compound as yellow oil.
Reaction SMILES: COCCOC.Cl[C:8]1[S:12][N:11]=[C:10]([S:13][CH3:14])[N:9]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:14][S:13][C:10]1[N:9]=[C:8]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)[S:12][N:11]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1nsc(-c2cccc(Cl)c2)n1
Yield: 57.3 %

Procedure:
To 25 ml of 1,2-dimethoxyethane were added about 2.0 g of 5-chloro-3-methylthio-1,2,4-thiadiazole, 2.25 g of 2-chlorophenylboronic acid, 694 mg of tetrakistriphenylphosphine palladium and 25 ml of a 2 M aqueous sodium carbonate solution, and the mixture was heated under reflux for 3 hours in a nitrogen atmosphere. Then, the reaction mixture was poured into water, and the mixture was extracted with t-butyl methyl ether. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by concentration was subjected to silica gel column chromatography to obtain 1.67 g of 3-methylthio-5-(3-chlorophenyl)-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([CH2:7][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH2:9])[CH2:4][O:3]1.[F:15][C:16]1[C:21]([F:22])=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])[C:19]([NH2:32])=[C:18]([O:33][CH3:34])[CH:17]=1>N1C=CC=CC=1>[F:22][C:21]1[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:19]([NH:32][S:10]([C:8]([CH2:7][C@H:5]2[CH2:4][O:3][C:2]([CH3:14])([CH3:1])[O:6]2)=[CH2:9])(=[O:12])=[O:11])[C:18]([O:33][CH3:34])=[CH:17][C:16]=1[F:15]
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Reactant: C=C(C[C@H]1COC(C)(C)O1)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: C=C(C[C@H]1COC(C)(C)O1)S(=O)(=O)Nc1c(OC)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(S)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)prop-1-ene-2-sulfonyl chloride (1 eq) is dissolved in pyridine and 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine (1 eq) added. The solution is stirred at 100° C. for 2 hours and then partitioned with water and ethyl acetate. The organic layer is washed with brine, dried (MgSO4), concentrated under reduced pressure and purified by flash column chromatography on silica (30% ethyl acetate/hexanes eluant).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]Br>C(O)(=O)C.C(O)(C(F)(F)F)=O>[Br:13][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8](=[O:12])[O:9][CH2:10][C:11]=2[C:2]=1[CH3:1]
Reactant: Cc1cccc2c1COC(=O)N2
Reactant: BrBr
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(Br)ccc2c1COC(=O)N2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-1,4-dihydro-benzo[d] [1,3]oxazin-2-one (0.695 g, 4.3 mmol) in acetic acid (5 mL), Br2 (0.805 g=5 mmol) solution in TFA (5 mL)+acetic acid (5 mL) was added at 10° C. Reaction mixture was stirred for 2 hours and poured over ice water. Yellow precipitate was filtered and dried at 120° C.
Reaction SMILES: [Cl-].[NH4+].O[N:4]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38])[C:27](O)=[O:28]>CN(C)C=O.COC(C)(C)C>[Cl:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38])[C:27]([NH2:4])=[O:28]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Ammonium chloride (3.23 g), 1-hydroxybenzotriazole (2.45 g), IPEA (13.7 mL) and benzotriazol-1-yloxytris(pyrrolidino)phosphonimn hexafluorophosphate (9.43 g) were sequentially added to a solution of 5-chloro-2-(4-chloro-2-trifluoromethylphenyl)pentanoic acid (4.75 g) in N,N-dimethylformamide (45 mL). The mixture was stirred at room temperature overnight. Ice water and tert-butyl methyl ether were added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with tert-butyl methyl ether. The combined organic layers were sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel™ C-200; elution solvent:heptane:ethyl acetate=4:1→3:1) to obtain 3.89 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(O)c(N)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a mixture of 4-hydroxy-3-nitrobenzonitrile (4 g, 0.0244 mol) in ethanol (180 mL) and water (90 mL) was added sodium thiosulfate (17 g, 0.0976 mol) at room temperature. The heterogeneous mixture was stirred at 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture was cooled to room temperature, and ethanol was removed under reduced pressure. The yellow solid was filtered, washed with water, and dried under reduced pressure to yield 3-amino-4-hydroxybenzonitrile (1.46 g, 0.011 mol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:33])[NH:18][C:19]2[CH:20]=[N:21][C:22]([O:25][C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][CH:24]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]I.CO>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:33])[N:18]([CH3:36])[C:19]2[CH:20]=[N:21][C:22]([O:25][C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][CH:24]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1ncccc1Oc1ccc(NC(=O)c2cn(C(=O)OC(C)(C)C)c3ccccc23)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1ncccc1Oc1ccc(N(C)C(=O)c2cn(C(=O)OC(C)(C)C)c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.7 %

Procedure:
The 1H-indole-3-carboxylic acid[6-(2-methyl-pyridine-3-yloxy)-pyridine-3-yl]-amide (0.2 g, 0.58 mmol) in Example 6 was dissolved in dichloromethane (10 ml), and Boc2O (0.15 g, 0.7 mmol) and triethylamine (0.12 g, 1.16 mmol) were added to the solution. The reaction solution was stirred at room temperature for 2 hours, and then the product was washed, filtered, and dried to obtain tert-butyl-3-(6-(2-methylpyridine-3-yloxy)pyridine-3-ylcarbamoyl)-1H-indole-1-carboxylate (0.27 g, 0.52 mmol). The tert-butyl-3-(6-(2-methylpyridine-3-yloxy)pyridine-3-ylcarbamoyl)-1H-indole-1-carboxylate (0.27 g, 0.52 mmol) was dissolved in THF (10 ml), and NaH (21 mg, 0.54 mmol) and methyl iodide (0.95 g, 0.67 mmol) were added to the solution. The reaction solution was stirred at room temperature for 5 hours, and then the product was washed and filtered to yield tert-butyl-3-(methyl(6-(2-methylpyridine-3-yloxy)pyridine-3-yl)carbamoyl)-1H-indole-1-carboxylate (40 mg, 0.087 mmol) by chromatography (methanol:dichloromethane=1:20).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[ClH:14]>O.S>[Cl:14][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cl
Reactant: Nc1cccnc1CO
Agent: O=N[O-]
Agent: S
Agent: [Na+]
Solvent: O
Product: OCc1ncccc1Cl

Procedure:
A solution sodium nitrite (2.38 g) in water (10 ml) was added dropwise to a stirred mixture of 3-amino-2-hydroxymethylpyridine (4.8 g) in aqueous hydrochloric acid (48% 10 ml) and water (5 ml) at 0°-5° C. This solution of the diazonium salt was added to a hot solution of cuprous chloride (2.5 g) in conc. hydrochloric acid and following cessation of nitrogen evolution the mixture was heated on the steam bath for 0.5 hours, diluted with water and saturated with hydrogen sulphide. Filtration, concentration to low bulk and extraction with chloroform yielded 3-chloro-2-hydroxymethylpyridine (3.7 g), m.p. 42°-44° (from n-pentane). This was dissolved in aqueous hydrobromic acid (48% 50 ml), cysteamine hydrochloride (3.22 g) added and the solution obtained was heated under reflux for 6 hours. Concentration, followed by recrystallisation from aqueous ethanol afforded 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine dihydrobromide (6.0 g), m.p. 250°.