Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1.[CH3:17][O:18][C:19]1[C:34]([O:35][CH3:36])=[CH:33][C:22]2[CH2:23][C:24](=[O:32])[N:25]([CH2:28][CH2:29][CH2:30]Cl)[CH2:26][CH2:27][C:21]=2[CH:20]=1>>[CH3:17][O:18][C:19]1[C:34]([O:35][CH3:36])=[CH:33][C:22]2[CH2:23][C:24](=[O:32])[N:25]([CH2:28][CH2:29][CH2:30][N:2]([CH3:1])[CH:3]3[CH2:12][CH2:11][C:10]4[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[CH2:4]3)[CH2:26][CH2:27][C:21]=2[CH:20]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNC1CCc2cc(OC)c(OC)cc2C1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)CC2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 2-methylamino-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene with 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane. Mp: 236°-238° C.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:17][C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]2[C:19]=1[C:20](=[O:38])[N:21]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:22]=[N:23]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:59]1[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]1>C(Cl)Cl>[CH3:29][O:28][C:26]1[CH:25]=[C:24]2[C:19]([C:20](=[O:38])[N:21]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36])[CH:22]=[N:23]2)=[C:18]([O:17][CH:59]2[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]2)[CH:27]=1
Reactant: CN1CCC(O)CC1
Reactant: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC2CCN(C)CC2)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of di-tert-butyl azodicarboxylate (1.7 g) in methylene chloride (5 ml) was added to a stirred mixture of 5-hydroxy-7-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.5 g), triphenylphosphine (1.9 g), 4-hydroxy-1-methylpiperidine (0.675 g) and methylene chloride (20 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:10:1 mixture of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was washed with diethyl ether and dried under vacuum to give 7-methoxy-5-(N-methylpiperidin-4-yloxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.75 g); NMR Spectrum: (CDCl3): 1.2 (s, 9H), 2.05 (br s, 4H), 2.3 (s, 3H), 2.3–2.42 (m, 2H), 2.7–2.8 (m, 2H), 3.9 (s, 3H), 4.48 (m, 1H), 5.9 (s, 2H), 6.5 (d, 1H), 6.71 (d, 1H), 8.18 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[CH:14](O)=O>>[Cl:9][C:7]1[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:5][C:3]2[N:4]=[CH:14][NH:1][C:2]=2[CH:8]=1
Reactant: O=CO
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Product: NS(=O)(=O)c1cc2nc[nH]c2cc1Cl
Temperature: 100 °C

Procedure:
In a round bottomed flask equipped with a condenser 24.0 g of 2-amino-4-chloro-5-sulfamyl-aniline and 7.0 g of formic acid is refluxed at 100° C. for two hours. Concentrate under vacuum. Dissolve in hot methanol, stir, cool and filter off the solid wt.=11.0 gm. m.p. 243.8° C.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)([O:13][CH2:14][CH3:15])=[O:12].I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Cl.CN1CCCN(C)C1=O>O1CCCC1>[C:11]([C:16]1([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CSCc1ccc(OC)cc1
Reactant: ClCCCCCI
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C1(SCc2ccc(OC)cc2)CCCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 56.6 %

Procedure:
Cool lithium hexamethyldisilazane (8.4 mL of a 1.0M solution in tetrahydrofuran, 8.4 mmol) to -78° C. Add, by cannula transfer, a solution of 1-(carboethoxy)-1-(4-methoxybenzylthio)methane (2.0 g, 8.3 mmol) in tetrahydrofuran (8 mL). Stir for 45 minutes then add a solution of 1-iodo-5-chloropentane (1.94 g, 8.32 mmol) i n tetrahydrofuran (8 mL). Stir for 1 hour and add 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (1.21 mL, 10.0 mmol). Stir at 0° C. for 4 hours and at room temperature for 6 hours. Cool to -78° C., add lithium hexamethyldisilazane (8.4 mL, 8.4 mmol) and stir at room temperature overnight. Quench with saturated ammonium chloride (5 mL) and partition between ethyl acetate (50 mL) and water (50 mL). Separate the organic phase, dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (6:1 hexane/ethyl acetate) to give 1-(carboethoxy)-1-(4-methoxybenzylthio)cyclohexane as an colorless oil (1.45 g, 56%).
Reaction SMILES: [CH2:1]=[CH:2]C(=C)C.[CH2:6]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:7]#[CH:8].C(Br)C>CCCCCC>[CH2:6]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:7]#[C:8][CH2:1][CH3:2]
Reactant: C#CCOC1CCCCO1
Reactant: C=CC(=C)C
Solvent: CCCCCC
Solvent: CCBr
Product: CCC#CCOC1CCCCO1
Reaction time: 0.25 h
Yield: 105.3 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 5 minutes to 100 ml (4 mol) of liquid ammonia at −38° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. Isoprene (5.94 g, 86 mmol) was added portion wise within 20 minutes. The reaction mixture was held at −38° C. for about 15 minutes. The end of the formation of Li-amide could be recognized by the de-coloration of the reaction mixture. 11.33 g (70 mmol) of 2-prop-2-ynyloxy-tetrahydropyran were added via a dropping funnel to the reaction mixture at −38° C. within 20 minutes. The reaction mixture was held at −38° C. for about 1 hour. Ethyl bromide 14.0 g (126 mmol) was added via a dropping funnel to the reaction mixture within 20 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml n-hexane was added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1.5 hours. 50 ml of water was added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The water layer was extracted twice with 50 ml n-hexane. The organic layer was dried over 5 g of anhydrous sodium sulfate. The solution was concentrated under reduced pressure (40° C., 60 mbar) and the crude product was analyzed by GC. Crude 2-pent-2-ynyloxy-tetrahydro-pyran (12.4 g) was obtained with a purity of 90.1% (94.3% yield based on 2-prop-2-ynyloxy-tetrahydropyran).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]2[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[N:12][O:13][CH2:14][C:9]=2[CH:8]=1.[CH2:24]([NH:27][CH3:28])[CH:25]=[CH2:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:24]([N:27]([CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]2[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[N:12][O:13][CH2:14][C:9]=2[CH:8]=1)[CH3:28])[CH:25]=[CH2:26]
Reactant: C=CCNC
Reactant: BrCC=CCOc1ccc2c(c1)CON=C2c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C)C/C=C/COc1ccc2c(c1)CON=C2c1ccc(Br)cc1

Procedure:
1.35 g of 7-(4-bromo-but-2-enyloxy)-4-(4-bromo-phenyl)-1H-benzo[d][1,2]oxazine are dissolved in 50 ml of acetone and treated with 3.83 ml of N-allyl-methyl-amine and 1.28 g of potassium carbonate. The mixture is stirred and subsequently filtered. After concentration the filtrate is chromatographed over silica gel with toluene/acetone/triethylamine (92:7:1). There are obtained 1.09 g of (E)-allyl-[4-[4-(4-bromo-phenyl)-1H-benzo[d][1,2]oxazin-7-yloxy]-but-2-enyl]-methyl-amine which is converted into the fumarate, MS: m/e 427 (M+H+, 1 Br).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[C@H:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl[C:31]1[N:32]=[N:33][CH:34]=[C:35]([Cl:37])[CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[Cl:37][C:35]1[CH:36]=[C:31]([C:11]2[CH:12]=[CH:13][C:8]([N:4]3[C@@H:3]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:2]([CH3:29])([CH3:1])[O:6][C:5]3=[O:7])=[CH:9][CH:10]=2)[N:32]=[N:33][CH:34]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: CC1(C)OC(=O)N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@H]1c1ccccc1
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: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(Cl)cnn3)cc2)[C@H]1c1ccccc1
Yield: 25.02 %

Procedure:
To a 0.5-2.0 mL microwave vial charged with (S)-5,5-dimethyl-4-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one (Intermediate J) (0.240 g, 0.610 mmol) and 3,5-dichloropyridazine (commercially available from ACES Pharma, Princeton, N.J.) (0.100 g, 0.671 mmol) were added dioxane (1.220 mL), and 2 M Na2CO3 (1.220 mL). Nitrogen was bubbled through the resulting suspension and then Pd(PPh3)4 (0.071 g, 0.061 mmol) was added. The resulting mixture was irradiated at 100° C. for 30 minutes. LC-MS indicated the formation of product as a major species (two close peaks with product mass, likely isomers) along with other impurities with consumption of starting material. The dark suspension was diluted with water, transferred to a separatory funnel, and extracted with EtOAc (2×). The combined organic layers were dried with Na2SO4, filtered, and dried under reduced pressure. The residual material was purified with a 40 g HP 15 μm spherical silica column (Interchim) ramping EtOAc in heptane from 0-100% leading to isolation of product (primarily one isomer) as the major species with 10-15% impurity. (S)-3-(4-(5-Chloropyridazin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.058 g, 0.153 mmol, 25.02% yield) was obtained as a white solid. Note: the regiochemistry of the product was not confirmed, but it was assumed that the major product would result from the more reactive chloride). m/z (ESI) 380.1 (M+H)+.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[O:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:21][CH:20]=1)[OH:18]>C(Cl)Cl>[O:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:23][CH:24]=1)=[O:18]
Reactant: OC(c1ccc(OC2CCCCO2)cc1)c1ncco1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ncco1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
PCC (14.5 mmol, 20% w/w on silica gel) was added to a solution of 10.1 (2.91 mmol) in DCM (20 mL). After 1 hour, the reaction mixture was chromatographed (silica gel, 1:2 EtOAc/hexane) to obtain compound 10.2 (2.41 mmol). MS ESI (pos.) m/e:296.0 (M+Na). 1H NMR (500 MHz) (DMSO-d6) δ 8.52 (s, 1H); 8.43 (d, J=9 Hz, 2H); 7.67 (s, 1H); 7.23 (d, J=9 Hz, 2H); 5.71 (m, 1H); 3.74-3.76 (m, 1H); 3.62-3.65 (m, 1H); 1.88-1.91 (m, 2H); 1.81-1.82 (m, 1H); 1.59-1.67 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:24])[C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[C@H](N(C)C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of (R)-methyl 3-(tert-butoxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (600 mg, 2.062 mmol, 1.0 eq.) in dry DMF (2 ml) was added to a stirred suspension of NaH (118 mg, 2.474 mmol, 1.2 eq., 50% in mineral oil) in DMF (3 ml) at 0° C. MeI (322 μl, 5.15 mmol, 2.5 eq.) was added to the reaction mixture at same temperature and it was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture diluted with ice-cold water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product as a brown sticky solid which was used in the next step without further purification. Yield: 90% (566 mg, 1.855 mmol).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>O1CCCC1.[Cu]I>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]([CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(=Cc1ccc(OC)cc1OC)C(=O)OCC
Reactant: CCCC[Mg]Br
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC(c1ccc(OC)cc1OC)C(C(=O)OCC)C(=O)OCC
Reaction time: 0.25 h

Procedure:
686 mg (3.60 mmol) of copper (I) iodide were added to 24.2 ml (36.3 mmol) of a 1.5 M butylmagnesium bromide solution in tetrahydrofuran, whilst cooling in an ice-salt bath, and the resulting mixture was stirred for 15 minutes to form a suspension. A solution of 7.47 g (24.3 mmol) of ethyl 3-(2,4-dimethoxyphenyl)-2-ethoxycarbonyl-2-propenoate (prepared as described in Preparation 1) in 25 ml of tetrahydrofuran was then added dropwise to this suspension at the same temperature over a period of 20 minutes, and the resulting mixture was stirred for 30 minutes. The reaction mixture was then neutralized with concentrated aqueous hydrochloric acid and the resulting mixture was filtered using a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in ethyl acetate. The resulting solution was washed three times with a saturated aqueous solution of ammonium chloride and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 100 g of silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 10:1 to 5:1 by volume as the eluent, to give 9.15 g (a quantitative yield) of diethyl 2-[1-(2,4-dimethoxyphenyl)pentyl]malonate as an oily substance.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C)C=O>ClCCl>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[O:19][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Oc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(1,4-dihydroindeno-[1,2-c]pyrazol-3-yl)phenol (2.4 g), anhydrous potassium carbonate (1.2 g), ethyl 2-bromoacetate (1.2 ml) and dry dimethylformamide (20 ml) was stirred at ambient temperature for 24 hours. The mixture was diluted with dichloromethane (200 ml), washed with water, then 1N sodium hydroxide solution. The organic layer was separated, dried, filtered and evaporated to give an oil which was purified by flash column chromatography on silica using ethyl acetate/petroleum ether b.p. 60-80° C. (1:2 as the mobile phase). Appropriate fractions were combined and evaporated to give ethyl 3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxyacetate, m.p. 134-136° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Cl:11]Cl.O>C(O)(=O)C>[Cl:11][C:4]1[C:5]([OH:10])=[C:6]([CH:9]=[C:2]([I:1])[CH:3]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(I)ccc1O
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cc(I)cc(Cl)c1O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To 24 g (96.8 mmole) of 5-iodosalicylaldehyde in 320 mL of acetic acid was added an excess of gaseous chlorine. After addition of about 10 g of Cl2, a white solid appeared in the solution. The mixture was heated to 70° C. and allowed to stir for 3 h. The heated solution was homogeneous and remained so after cooling to rt. The mixture was added to 1200 mL of water and allowed to stir for 1 h. The resultant solid was collected by filtration, washed with water, filtered and allowed to air dry to afford 27.3 g of a yellow solid. The solid was recrystallized by dissolving the material in 250 mL of hot methanol and adding 80 mL of H2O. After standing overnight, the crystalline solid was collected and air-dried to afford 20.3 g (74.2%) of a yellow solid. The product contained a minor impurity (approx. 9% by 1H NMR) and was used in the next step without further purification: 1H NMR (CDCl3/400 MHz) 7.78 (d, 1H, J=2.1 Hz), 7.88 (d, 1H, J=1.8 Hz), 9.83 (s, 1H), 11.40 (s, 1H); 13C NMR (CDCl3/100 MHz) 79.5, 122.8, 123.7, 140.3, 144.4, 156.9, 194.8; MS (ESI+) 283 (M+1, 100); HRMS (El) m/z calcd for (C7H4O2ICl) 281.8945, found 281.8899.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[O:10][C:11]1[C:16]([F:17])=[C:15](F)[N:14]=[CH:13][N:12]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=[N:35][O:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32]>C(#N)C>[Cl:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[O:10][C:11]1[N:12]=[CH:13][N:14]=[C:15]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30](=[N:35][O:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])[C:16]=1[F:17]
Reactant: Fc1ncnc(Oc2ccccc2Cl)c1F
Reactant: CON=C(C(=O)OC)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CON=C(C(=O)OC)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
40 g (0.29 mol) of ground potassium carbonate and 58 g (0.24 mol) of 4-(2-chlorophenoxy)-5,6-difluoropyrimidine are added to a solution of 50 g (0.24 mol) of methyl 2-(2-hydroxyphenyl)-2-methoxyiminoacetate in 600 ml of acetonitrile, and the mixture is stirred at 25° C. for 18 hours. The reaction mixture is poured into 3 l of ice-water and the resulting solid is filtered off with suction. This gives 102 g (98.7% of theory) of methyl 2-{2-[6-(2-chlorophenoxy)-5-fluoro-pyrimidin-4-yloxy]-phenyl}-2-methoxyiminoacetate.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)=[O:7].Br.C(OC(=O)C)(=O)C>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(C)c(OC)c2)cc1
Agent: Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)c2ccc(O)cc2)cc1O
Yield: 77.8 %

Procedure:
Demethylation of 114 g 3,4'-dimethoxy-4-methyl-benzophenone (0.445 mole) was effected by refluxing 15 hr. with a previously prepared mixture of 313.5 ml of 48% aqueous hydrobromic acid, 148 ml of acetic anhydride, and 148 ml of acetic acid. The isolated product melted at 173°-174° C. Recrystallization from ethanol/water yielded 79 g (0.346 mole) of 3,4'-dihydroxy-4-methylbenzophenone melting at 174°-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[N:11]#[C:12]Br.C(=O)(O)[O-].[Na+]>O>[F:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[NH:10][C:12]([NH2:11])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Step 1 The procedure used was similar to that reported in J. Med. Chem. 40:811-818, 1997. A solution of 1,2-diamino-4,5-difluorobenzene (500 mg, 3.47 mmol) in water (5 mL) was cooled to 0° C. and then treated with a solution of cyanogen bromide (0.83 mL, 4.16 mmol, 5 M in acetonitrile) and solid sodium bicarbonate (583 mg, 6.94 mmol). The solution was stirred at rt overnight and was then concentrated in vacuo. The dark residue was suspended in ethanol and heated at reflux for 15 minutes. The hot suspension was filtered, rinsing with hot ethanol, and the filtrate was concentrated in vacuo to afford 5,6-difluoro-1H-benzimidazol-2-amine (580 mg, 59%), which was used in the next step without further purification. LC-MS m/z 170.2 (MH+), ret. time 0.85 min; 1H NMR (300 MHz, DMSO-d6) δ 6.30 (br s, 2H), 7.06 (dd, 2H), 10.79 (br s, 1H).
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[CH3:11][C:12]1([CH3:24])[C:16]([CH3:18])([CH3:17])[O:15][B:14]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)[O:13]1.[H-].[Na+]>CN(C)C=O>[O:8]1[CH2:9][CH2:10][CH:6]([N:22]2[CH:23]=[C:19]([B:14]3[O:13][C:12]([CH3:24])([CH3:11])[C:16]([CH3:18])([CH3:17])[O:15]3)[CH:20]=[N:21]2)[CH2:7]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CS(=O)(=O)OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(C3CCOC3)c2)OC1(C)C
Temperature: 60 °C

Procedure:
Tetrahydrofuran-3-yl methanesulfonate was dissolved in N,N-dimethylformamide (0.5 mL) and added to a pre-stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.52 mmol) and sodium hydride (25 mg, 1.1 mmol) in N,N-dimethylformamide (1 mL). The mixture was heated to 60° C. for 2 d, cooled to RT, and purified by RP-HPLC to afford the desired product. LCMS: (M+H)=265.1.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[NH:41][C:18]4=[N:19][CH:20]=[C:21]([NH:23][C:24](=[O:40])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[C:27]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])[C:26]=5[F:39])[CH:22]=[C:17]4[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:4][O:3]1.Cl>C1COCC1.CO>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:41][C:18]3=[N:19][CH:20]=[C:21]([NH:23][C:24](=[O:40])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[C:27]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])[C:26]=4[F:39])[CH:22]=[C:17]3[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4cccc(OCC5COC(C)(C)O5)c4)cc3c2)c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4cccc(OCC(O)CO)c4)cc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
A solution of N-(2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (22 mg, 36 mmol) in 2:1 THF/MeOH (3 mL) was treated with 1N HCl (1 mL) and the mixture stirred at room temperature for 16 hours. The volatiles were removed via rotary evaporation, and the resulting residue was partitioned between EtOAc and aqueous NaHCO3. The layers were separated, and the organic layer was dried (MgSO4), filtered and concentrated to a solid. The solid was triturated with DCM and collected via vacuum filtration to afford N-(2-(3-(2,3-dihydroxypropoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (13 mg, 64%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.16 (s, 1H), 10.89 (s, 1H), 9.80 (s, 1H), 8.40-8.33 (m, 2H), 7.58-7.49 (m, 3H), 7.40-7.34 (m, 1H), 7.31-7.24 (m, 1H), 7.00-6.90 (m, 2H), 5.00-4.96 (m, 1H), 4.72-4.67 (m, 1H), 4.12-4.07 (m, 1H), 4.01-3.99 (m, 1H), 3.88-3.81 (m, 1H), 3.52-3.47 (m, 1H), 3.16-3.10 (m, 2H), 1.82-1.74 (m, 2H), 1.04-0.97 (m, 3H); m/z (APCI-pos) M+1=561.2.