Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])([CH3:3])[CH3:2]>CO.[BH4-].[K+]>[OH:9][CH:8]1[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:14])[N:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC(C)N1C(=O)c2ccccc2C1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 150.9 %

Procedure:
3-Hydroxy-2-isopropyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 4.0 g of N-isopropylphthalimide in 20 cm3 of methanol and 1.1 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The solvent is then evaporated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 6.1 g of 3-hydroxy-2isopropyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white wax. (Rf=0.65, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (30/70 by volume)).
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH:31]([CH2:39][N:40]([CH3:42])[CH3:41])[CH2:30]2)=[O:28])=[CH:21][CH:20]=1.CC1C=CC(B(O)O)=CC=1.O>C1(C)C=CC=CC=1.C(O)C.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>[C:7]1([CH3:17])[CH:8]=[CH:9][C:10]([S:13]([OH:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1.[CH3:41][N:40]([CH2:39][CH:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:29]([C:27](=[O:28])[CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([CH3:1])=[CH:20][CH:21]=2)[CH2:30]1)[CH3:42]
Reactant: CN(C)CC1Cc2ccccc2N(C(=O)CCc2ccc(Br)cc2)C1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(B(O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(CCC(=O)N2CC(CN(C)C)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2M Aqueous sodium carbonate solution (1.25 ml) was added to a suspension of 1-[3-(4-bromophenyl)propanoyl]-3-(N,N-dimethylamino)methyl-1,2,3,4-tetrahydroquinoline p-toluenesulfonate (400 mg) in toluene (10 ml) and ethanol (1.25 ml), which was stirred at room temperature for 10 minutes. 4-Methylbenzene boronic acid (123 mg) and tetrakis(triphenylphosphine)palladium (24 mg) were added to the reaction mixture, which was heated under reflux under an argon atmosphere for 14 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: hexane/ethyl acetate=10/1 to 2/1), which was converted into its p-toluenesulfonate. The mixture was recrystallized from ethyl acetate to give the entitled compound (296 mg).
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=O)[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:33]([N:35](C(OC(C)(C)C)=O)[NH2:36])[CH3:34].C(O)=O>C(O)(=O)C>[CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[N:35]([CH2:33][CH3:34])[N:36]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCN(N)C(=O)OC(C)(C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Solvent: CC(=O)O
Solvent: O=CO
Product: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C
Temperature: 35 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
A mixture of (Z)—N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 74B, 70 mg, 0.155 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (49.6 mg, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (1 mL) was added and the reaction mixture stirred at 60° C. for 6 h. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The material was further purified by preparative HPLC to afford N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-methyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (38 mg, 53.4% yield) as an off-white solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([OH:19])(=[O:18])[CH2:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1>CC#N>[CH2:26]([O:15][C:14]1[CH:16]=[CH:17][C:9]([CH2:8][C:7]([O:19][CH2:8][C:9]2[CH:17]=[CH:16][CH:14]=[CH:11][CH:10]=2)=[O:18])=[CH:10][C:11]=1[O:12][CH3:13])[C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(CC(=O)OCc2ccccc2)ccc1OCc1ccccc1

Procedure:
Cs2CO3 (17.88 g; 54.9 mmol) was added to a solution of homovanillic acid (2.0 g; 11 mmol) in CH3CN, whereafter BnBr (4.3 g; 24.15 mmol) was added dropwise over 10 minutes. The mixture was refluxed overnight, filtered through Hyflo and concentrated. The resulting mixture was dissolved in EtOAc (100 mL), water (30 mL) was added, and the aqueous layer was separated. The organic phase was washed with citric acid solution (5%, 1×20 mL) and brine, dried (Na2SO4), and evaporated to yield 4.25 g (quant.) of the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1>C(Cl)(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-difluorobenzoyl chloride (5.25 g) in chloroform (30 mL) at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (3.2 g) followed by pyridine (5.8 mL) dropwise. The mixture was stirred at r.t. for 2 hr, diluted with EtOAc, washed with HCl 1N, with H2O, saturated NaCHO3 sol., brine, dried (MgSO4) and the solvents evaporated to give the title product.
Reaction SMILES: O=[C:2]([NH:8][CH2:9][C:10](=[O:12])[CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:10]1[O:12][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8][CH:9]=1
Reactant: CCOC(=O)C(=O)NCC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(C)o1
Yield: 44.7 %

Procedure:
To a solution of ethyl 2-oxo-2-(2-oxopropylamino)acetate (1.7 g, 9.8 mmol) in toluene (10 mL) was added phosphorus oxychloride (2 mL). The mixture was heated to reflux for 3 h. The reaction was concentrated to dryness and the residue was taken up in ethyl acetate (20 mL). This organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried and concentrated to give a crude product which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (4:1) to give ethyl 5-methyloxazole-2-carboxylate (0.68 g, 44.1% yield) as yellow syrup. 1H-NMR (CDCl3) δ 6.97 (s, 1H), 4.44-4.49 (q, 2H), 2.43 (s, 3H), 1.42-1.46 (t, 2H). LCMS retention time 0.643 min; LCMS MH+ 156.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([N:1]([S:33]([CH3:32])(=[O:35])=[O:34])[C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N(S(C)(=O)=O)S(C)(=O)=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 98.7 %

Procedure:
To a solution of ethyl 3-amino-6-chloro-2-(3-chlorobenzoyl)-]-1H-indole-1-carboxylate (step 1 of Example 4, 507 mg, 1.25 mmol) in dichloromethane (15 ml) was added pyridine (0.32 ml, 4.04 mmol) and methanesulfonyl chloride (0.16 ml, 2.02 mmol). After stirring for 19 h, additional pyridine (1.3 ml, 16.2 mmol) and methanesulfonyl chloride (0.32 ml, 4.04 mmol) were added and the mixture heated at reflux for 17 h and then cooled to room temperature. The mixture was concentrated, and partitioned between ethyl acetate (200 ml) and 2 M aqueous HCl (100 ml). The organic layer was separated and washed with 2 M aqueous HCl (100 ml×2), saturated aqueous sodium bicarbonate (100 ml×3), and dried (Na2SO4). After removal of solvent the residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:4) to afford the title compound (532 mg, 74%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9](COC(=O)C(C)(C)C)[CH:8]=[N:7][C:6]=2[N:5]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[C:3]1=[O:4].Cl>[OH-].[Na+]>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:3]1=[O:4]
Reactant: CCOC(=O)CCCn1c(=O)n(C)c(=O)c2c1ncn2COC(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)c2[nH]cnc2n(CCCC(=O)O)c1=O

Procedure:
An oily suspension of 1-methyl-3-(carboethoxypropyl)-7-(pivaloyloxymethyl)xanthine (508 mg) in 2N NaOH(36.2 ml) was heated under nitrogen at 95°-100° for 2 hrs. The oil dissolved and the reaction was shown to be complete by TLC. After cooling the reaction mixture, it was acidified to pH 2-3 with 15 ml 12% hydrochloric acid and the solution extracted with 3×5 ml chloroform to remove the pivalic acid. After washing the chloroform extracts with 5 ml 0.5 N HCl, the aqueous solutions were combined and stripped to dryness and the residue dried in vacuo at room temperature. The crude product was dissolved in about 22 ml hot water, decolorized and concentrated to 15 ml, at which time 159 mg of a crystalline product was obtained upon cooling. m.p. 220°-221°.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[F:5][C:6]1[C:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[C:8]([CH:16]=[CH:17][C:18]=1[F:19])[C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10]>>[NH2:4][CH2:1][C:2]#[C:3][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:7]2[C:6]([F:5])=[C:18]([F:19])[CH:17]=[CH:16][C:8]=2[C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10])=[C:22]([F:28])[CH:23]=1
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C#CCN
Product: NCC#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 100 %

Procedure:
The title compound was prepared by Sonogashira reaction of propargyl amine and 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide by the general procedure of Example 1, Step A. The orange oil resulting from workup was purified by chromatography on silica gel (10% MeOH/CH2Cl2 as eluant), to give 2-[4-(3-amino-1-propynyl)-2-fluoroanilino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a pale orange solid (100%); m.p. (Et2O) 72–76° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.14 (v br s, 1 H), 7.49–7.44 (m, 1 H), 7.21 (dd, J=12.3, 1.7 Hz, 1 H), 7.24–7.14 (m, 1 H), 7.08 (dd, J=8.4, 1.6 Hz, 1 H), 6.77 (ddd, J=8.8, 8.8, 5.1 Hz, 1 H), 5.45 (br s, 2 H), 3.83 (t, J=4.8 Hz, 2 H), 3.55 (t, J=5.0 Hz, 2H), 3.41–3.32 (m, 2H, obscured by H2O). Not all exchangeable protons observed. CRL10671. Await HRMS. Anal. calcd. for C28H16F3N3O3: C, 57.0; H, 4.3; N, 11.1. Await Found. HRMS (EI+) calcd for C18H16F3N3O3 379.1144 (M+), found 379.1140.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]([NH2:15])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=2[N:21]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:9]1([CH2:8][CH:7]([NH:15][C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=3[N:21]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Cc1ccc2oc(Cl)nc2c1
Reactant: N[C@@H](CC1CCCCC1)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2oc(NC(CC3CCCCC3)c3ccccn3)nc2c1

Procedure:
To a solution of 132.8 g (0.65 moles) 1-(+)-(S)-(2-pyridyl)-2-cyclohexylethylamine in 550 mL methylene chloride was added 109 g (0.65 moles) 2-chloro-5-methylbenzoxazole followed by 168 g (1.3 moles) diisopropylethylamine. The reaction mixture was heated to reflux for 5-40 hours, cooled and concentrated under reduced pressure. The mixture was dissolved in 2 L of ethanol. Addition of 2-3 L of water gave crude [(2-cyclohexyl-1-(2-pyridyl)ethylamino]-5-methylbenzoxazole. Recrystallization from ethanol/water gave 190 g (83%) as a hydrate; mp 80°-86° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][CH:5]=[C:4]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[NH:3]1.Cl>CC(N)CC>[CH3:13][CH:4]([NH:3][C:8]([C:7]1[C:2](=[O:1])[NH:3][C:4]([C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])=[CH:5][CH:6]=1)=[O:10])[CH2:5][CH3:6]
Reactant: CCOC(=O)c1ccc(C(F)(F)C(F)(F)F)[nH]c1=O
Agent: CCC(C)N
Agent: Cl
Product: CCC(C)NC(=O)c1ccc(C(F)(F)C(F)(F)F)[nH]c1=O

Procedure:
At room temperature, 160 mg (0.56 mmol) of ethyl 2-oxo-6-(pentafluoroethyl)-1,2-dihydropyridine-3-carboxylate were stirred in 5 ml of 2-butylamine for 14 h. The pH was then adjusted to 2 by addition of 1N hydrochloric acid, which resulted in the precipitation of a colorless solid. Filtration with suction and drying gave 160 mg (91% of theory) of the product.
Reaction SMILES: [F:1]C(F)(F)C1C=CC(OC2C=CC=CC=2CC2CCNCC2)=CC=1.Cl.C([C:34]1[CH:53]=[CH:52][C:37]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:36][CH:35]=1)(=O)C1C=CC=CC=1>>[F:1][C:34]1[CH:53]=[CH:52][C:37]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:36][CH:35]=1
Reactant: FC(F)(F)c1ccc(Oc2ccccc2CC2CCNCC2)cc1
Reactant: O=C(c1ccccc1)c1ccc(Oc2ccccc2CC2CCNCC2)cc1
Agent: Cl
Product: Fc1ccc(Oc2ccccc2CC2CCNCC2)cc1

Procedure:
(−)-4-[(4-trifluoromethylphenoxy)phenyl]methyl-piperidine, sulfate (96% ee, m.p.=85° C. (d), [α]365−15.5, c=0.508, CHCl3)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23]>C(OCC)(=O)C.O.CN(C)C(=O)C>[CH2:28]([O:27][C:20]1[CH:19]=[CH:18][C:17]([N:16]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1cc(N)ccc1OCc1ccccc1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.54 g), potassium iodide (0.11 g), and bis(2-chloroethyl)ether (0.22 mL) were sequentially added to an N,N-dimethylacetamide (3.2 mL) solution of methyl 5-amino-2-(benzyloxy)benzoate (0.40 g), followed by stirring at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 85-60% hexane/ethyl acetate] to obtain 0.27 g of methyl 2-(benzyloxy)-5-(morpholin-4-yl)benzoate as a light yellow oily substance.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:1])=[O:15])[CH:11]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1
Reactant: O=C(O)c1cc(Cl)nc(OCc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)nc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
With cooling with ice, oxalyl chloride (5.8 mL) and DMF (3 drops) were added to a CHCl3 (40 mL) solution of 2-chloro-6-benzyloxypyridine-4-carboxylic acid, and stirred at that temperature for 1 hour. DMF (3 drops) was added to it, and stirred overnight at room temperature, then oxalyl chloride (2.9 mL) and DMF (3 drops) were added to it, and stirred at room temperature for 3 hours. The solvent was evaporated away, CHCl3-MeOH was added to the residue, and stirred at room temperature for 30 minutes. Sodium bicarbonate water was added to the reaction solution, extracted with chloroform, and the organic layer was washed with water, saturated sodium bicarbonate water and saturated saline water, and dried with anhydrous sodium sulfate. This was filtered, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[C:50]([CH2:52][N:53]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54]2)[CH:51]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:58][C:55]1[CH:56]=[CH:57][N:53]([CH2:52][C:50]2[CH:51]=[C:46]([Cl:45])[CH:47]=[CH:48][C:49]=2[O:59][CH2:60][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[N:54]=1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: Nc1ccn(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2cc(Cl)ccc2OCc2ccccc2)n1)c1c(F)cccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-chloro-6-fluorobenzoic acid (18 mg, 0.1 mmol, Aldrich) in DMF (0.1 ml) was added a solution of HATU (38 mg, 0.1 mmol) in DMF (0.2 ml). After 5 min, DIPEA (0.050 ml, 0.27 mmol) was added to the mixture. To the mixture was added a solution of 1-({5-chloro-2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-amine (for a preparation see Intermediate 55)(0.1 mmol) in DMF (0.1 ml). After shaking for 10 min, the resulting solution was allowed to stand for 16 h at ambient temperature. The solvent was removed using a genevac. The sample was dissolved in 1:1 MeOH:DMSO (0.6 ml) and purified by MDAP on a C18 column using Acetonitrile-Water with a TFA modifier (Method D). The solvent was evaporated in vacuo using the Genevac to give the title compound; LCMS (System 3) MH+=470/472, tRET=1.32 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41](=[O:52])([O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[O:42][CH2:43]Cl>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.CCOC(C)=O>[C:41](=[O:52])([O:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[O:42][CH2:43][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1
Reactant: O=C(OCCl)Oc1ccccc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)Oc3ccccc3)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.8 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol), TBAB (132 mg, 0.4 mmol) and Et3N (114 μL, 0.8 mmol) in DMF (1 mL) was added chloromethyl phenyl carbonate (46 mg, 0.25 mmol). The reaction was stirred at rt for 12 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1) to afford the title compound as a white solid (10 mg, 7.7%). The title compound was characterized by LCMS and 1H NMR as shown below:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=3)[N:21]=[CH:20]2)[N:4]=1.[CH2:33]([O:35]CC)[CH3:34]>C(OC(=O)C)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([NH:30][C:33](=[O:35])[CH3:34])=[N:28][CH:29]=3)[N:21]=[CH:20]2)[N:4]=1
Reactant: CCOCC
Reactant: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cn1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cn1
Yield: 84 %

Procedure:
A stirred solution of 5-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-pyridin-2-ylamine (example 13) (0.314 g, 0.7 mmol) in acetic acid anhydride (6 ml) was heated at 120° C. for 1 h. To the cooled reaction mixture was added diethyl ether (10 ml), the precipitate was collected by filtration and dried to yield the title compound as a light yellow solid (0.29 g, 84%). MS (ISP) 493.3 [(M+H)+]; mp 314° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:11][N:12]1[C:16](=[O:17])[CH2:15][NH:14][C:13]1=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:15]2[NH:14][C:13](=[O:18])[N:12]([CH3:11])[C:16]2=[O:17])[CH:8]=[CH:9][CH:10]=1
Reactant: CN1C(=O)CNC1=O
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(C=C2NC(=O)N(C)C2=O)c1
Yield: 73.8 %

Procedure:
Prepared according to the procedure described in Example 93 using 3-methoxybenzaldehyde (3.5 ml, 28 mmoles) and 3-methyl hydantoin (3.0 g, 21 mmoles), to afford the product (3.6 g), mp 203°-205° C.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][NH:6][CH2:7]2.[BrH:12]>>[BrH:12].[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][NH:6][CH2:7]2
Reactant: COc1cccc2c1CNC2
Agent: Br
Product: Oc1cccc2c1CNC2
Temperature: 25 °C
Yield: 78 %

Procedure:
4-Methoxyisoindoline (4.4 g, 29.53 mmol) in 48% aqueous hydrobromic acid (50 ml) was stirred and held at reflux for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-hydroxyisoindoline hydrobromide (5.0 g, 78%) as a pale orange solid. 1H NMR (DMSO-d6) 9.95 (1H, br s), 9.37 (2H, br s), 7.19 (1H, t), 6.84 (1H, d), 6.80 (1H, d), 4.48 (2H, t), 4.40 (2H, t). MS: [M+H]+ 136.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH3:22][O:23][C:24]1[C:29]2[CH:30]([NH2:33])[CH2:31][O:32][C:28]=2[CH:27]=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[C:29]2[CH:30]([NH:33][C:20]3[O:8][CH2:9][C:10]4[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][C:11]=4[N:19]=3)[CH2:31][O:32][C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc2c1C(N)CO2
Reactant: CC(C)(C)[Si](C)(C)OCc1c(N=C=S)cccc1[N+](=O)[O-]
Product: COc1cccc2c1C(NC1=Nc3cccc(N)c3CO1)CO2

Procedure:
The title compound, MS (ISP) m/e=312.0 [(M+H)+], was prepared from tert-butyl-(2-isothiocyanato-6-nitro-benzyloxy)-dimethyl-silane (intermediate 2) and 4-methoxy-2,3-dihydro-benzofuran-3-ylamine according to the procedure described for example 1 and 2.