Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(c3cccc(Cl)c3)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1cccc(Cl)c1)Oc1ccc(Br)cc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A mixture of 6-bromo-2-(3-chlorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (470 mg, 1.16 mmol) and Lawesson's Reagent (468 mg, 1.16 mmol) in 1,4-dioxane (16 mL) was stirred at 110° C. overnight. The solvent was removed in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (350 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:17])[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[I:18]Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:17])[C:11]3[N:12]([C:14]([I:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: ClI
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2ccnc12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Yield: 79 %

Procedure:
Prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine (example C.21 step 1) (6.65 g, 27 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as an off-white solid (8.0 g, 79%). MS (ISP) 369.0 [(M+H)+], 371 [(M+2+H) +].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.C(O[C:45]([N:47]1[CH2:53][CH2:52][CH2:51][N:50]([C:54](=O)[CH2:55]Cl)[CH2:49][CH2:48]1)=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:55][CH2:54][N:50]1[CH2:51][CH2:52][CH2:53][N:47]([CH3:45])[CH2:48][CH2:49]1)[CH2:5][N:7]([CH:33]([CH3:34])[CH3:35])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:17][CH2:18][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:24]=2[CH2:25]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)CCl)CC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCN(C)CC3)c(F)c2)C(C)C)c1
Yield: 59.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 4-(2-chloroacetyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (26 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (16 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12.Cl.[CH3:18][NH2:19].[OH-].[Na+]>C(O)(C)C.O>[CH3:18][NH:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12
Reactant: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CNc1ccnc2cc(-c3cn(C)cn3)sc12
Temperature: 130 °C
Yield: 99.7 %

Procedure:
A stirred suspension of 10 (500 mg, 2 mmol) and methylamine hydrochloride (15 g, 222 mmol) in isopropanol (50 ml) was heated at 130° C. in a sealed flask for four days, then cooled to room temperature. The reaction mixture was poured in water, and the pH was adjusted to ˜10 with 1N NaOH. After extraction of the aqueous phase with AcOEt, the combined organic layer was concentrated and directly purified by flash column chromatography (eluents 2% of NH4OH in methanol/CH2Cl2: 10/90 to 40/60) to afford title compound 344 (487 mg, 99% yield, hydrate form) as a beige solid. MS (m/z): 245.0 (M+H)+..
Reaction SMILES: [NH2:1][NH2:2].C(O)(=O)C.[Cl:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]([C:18](=O)[CH3:19])[C:16]#[N:17])=[C:10]([CH3:21])[CH:9]=1>C1(C)C=CC=CC=1>[NH2:17][C:16]1[NH:2][N:1]=[C:18]([CH3:19])[C:15]=1[C:11]1[C:12]([CH3:14])=[CH:13][C:8]([Cl:7])=[CH:9][C:10]=1[CH3:21]
Reactant: CC(=O)C(C#N)c1c(C)cc(Cl)cc1C
Reactant: NN
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(C)c1-c1c(C)n[nH]c1N
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
Dissolve anhydrous hydrazine (0.91 g, 0.90 mL) in 20 mL toluene. Add glacial acetic acid (2.25 mL) and allow to stand at ambient temperature for 10 minutes until solution becomes cloudy white. Add a solution of 2-(4-chloro-2,6-dimethylphenyl)-3-oxobutanenitrile in 10 mL toluene, rinsing out the ketonitrile flask with an additional 5 mL toluene. Heat to reflux under N2 (130° C.) with Dean-Stark trap attached. Water will begin to accumulate after 10 minutes or so. After 2 hours, evaporate down and partition between 1.0 N NaOH (100 mL) and EtOAc (100 mL). Extract aqueous layer with EtOAc (2×100 mL), then pool the organic layers and dry over Na2SO4. Filter and evaporate to yellow oil (1.75 g). Use without further purification. LCMS=236.5 (M+); 234.5 (M−)
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:20][C:21]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.CC([O-])=O.[Na+]>CC(O)=O>[OH:20][C:21]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[CH:1][C:2]1[N:11]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc(-n2c(C)nc3ccccc3c2=O)c1
Reactant: COc1cccc(C=O)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(C=Cc2nc3ccccc3c(=O)n2-c2cccc(C)c2)c1O
Yield: 96.4 %

Procedure:
In a 50 mL round-bottom flask a mixture of 50 (0.5 g, 002 mol), 2-hydroxy-3 methoxybenzaldehyde (0.4 g, 0.0025 mol) and NaOAc (0.233 g, 0.002 mol) in AcOH was heated under reflux for 10 hours. After cooling the precipitate formed was filtered off, washed with water, dried and recrystallized from acetic acid to yield 51 (0.74 g, 85%). M. Wt. 384. LCMS [M+H]+=385.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:5](OCC)=[O:6].[C:17]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH2:30])=[N:27][CH:28]=1)([CH3:20])([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:17]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:5](=[O:6])[C:4]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:3][NH:30]2)=[N:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Reactant: CC(C)(C)OCc1ccc(NN)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)(C)OCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Temperature: 25 °C

Procedure:
661 mg (3.0 mmol) of the compound from Example 2A and 586 mg (3.0 mmol) of the compound from Example 17A are initially charged in 10 ml of ethanol. 114 mg (0.6 mmol) of p-toluenesulfonic acid are added, and the mixture is stirred under reflux for 16 h. The mixture is then allowed to cool to RT, and the solid formed is filtered off, washed once with ethanol and dried under high vacuum. The solid is then stirred in tert-butyl methyl ether for 30 min, filtered off again and dried under high vacuum (batch 1). The filtrates and wash solutions obtained beforehand are combined and concentrated, and the residue is stirred in saturated sodium bicarbonate solution. The solid obtained is filtered off and washed once with water, and the filter residue is then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA to the water). The product fractions are combined and concentrated (batch 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K+].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH-:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN1CCCC1=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:9][CH3:10])[N:5]=[C:6]([NH:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH:7]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: [NH-]S(=O)(=O)c1ccc(F)cc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(F)cc2)n1
Yield: 55.9 %

Procedure:
0.46 g (0.0026 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and 1.1 g (0.0051 mol) of 4-fluoro-benzenesulfonamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone in 150° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was saturated with sodium chloride, evaporated briefly in a vacuum and made acid with 4N HCl, with a precipitate separating. The mixture was suctioned filtered, the extract and the solid were combined and chromatographed over silica gel with cyclohexane/ethyl acetate 2:1 as the eluent. The product was recrystallized from ethyl acetate/n-hexane. There was obtained 0.46 g (56%) of N-(6-chloro-2-methylamino-pyrimidin-4-yl)-4-fluoro-benzenesulfonamide as white crystals; m.p. 121-123° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[Br:14]Br.Br>C(Cl)(Cl)(Cl)Cl>[Br:14][C:2]([CH3:13])([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11][CH3:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: BrBr
Reactant: CSc1ccc(C(=O)C(C)C)cc1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(C(=O)C(C)(C)Br)cc1
Temperature: 25 °C

Procedure:
369.2 g (1.9 mols) of 2-methyl-1-[4-(methylthio)phenyl]-propan-1-one are dissolved in 400 ml of carbon tetrachloride. 303.7 g (1.9 mols) of bromine, diluted with 270 ml of carbon tetrachloride, are added dropwise slowly to this solution, with cooling, at room temperature. The dissolved HBr gas is then driven off by blowing with nitrogen. The solution is concentrated and is then reacted further as described below.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:31]=[N:32][C:27]([O:26][CH2:24][CH3:25])=[CH:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCOc1ccc(B(O)O)cn1
Product: CCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 60 mg, 0.161 mmol) and 6-ethoxypyridine-3-boronic acid (ABCR, Karlsruhe, Germany, 36 mg, 0.211 mmol) to give the title compound as a white solid. (HPLC: tR 2.69 min (Method A); M+H=415 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.32-8.24 (m, 1H), 8.15-8.05 (m, 2H), 7.92-7.85 (m, 1H), 7.79-7.72 (m, 1H), 7.47 (s, 1H), 6.94-6.87 (m, 1H), 4.32 (q, 2H), 3.90 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.32 (t, 3H))
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:13][CH2:14][CH:15](N)[CH3:16].[C:18]([C:20]1[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=1[N+:27]([O-:29])=[O:28])#[N:19]>ClC1C=CC=CC=1Cl>[CH3:25][N:24]1[C:20]([C:18]2[NH:13][CH2:14][CH:15]([CH3:16])[N:19]=2)=[C:21]([N+:27]([O-:29])=[O:28])[C:22]([CH3:26])=[N:23]1
Reactant: CC(N)CN
Reactant: Cc1nn(C)c(C#N)c1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1nn(C)c(C2=NC(C)CN2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
p-Toluenesulfonic acid monohydrate (15.2 g, 0.08 mol) is added in portions with stirring to 6 g (0.08 mol) of 1,2-diaminopropane under nitrogen. To the resulting melt (ca 100° C.) is added in portions 12.6 g (0.076 mol) of 5-cyano-1,3-dimethyl-4-nitropyrazole (mp 93° C.); the mixture is stirred and heated to 120° C. and 25 ml of o-dichlorobenzene is added; stirring is continued at 120°-130° for 0.5 hours then at 160° C. for three hours. The cooled mixture is extracted with 75 ml of 3N HCl. The aqueous extract is made strongly basic with a large excess of concentrated NH4OH and the mixture is extracted thoroughly with methylene dichloride. Evaporation of the extract gives 14.3 g (84%) of 2-(1,3-dimethyl-4-nitropyrazol-5-yl)-4-methylimidazoline, mp 98°-101°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[OH:19])([CH3:8])([CH3:7])[CH3:6].[CH2:20]1[O:23][CH:21]1[CH3:22]>C1(C)C=CC=CC=1>[C:15]([C:11]1[CH:12]=[C:13]([CH:21]([CH3:22])[CH2:20][OH:23])[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]=1[OH:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC1CO1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(CO)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To a stirred slurry of 66.7 g (0.5 mole) aluminum chloride in 250 ml toluene, 103.0 g (0.5 mole) 2,6-di-tert-butylphenol dissolved in 250 ml toluene was slowly added through a dropping funnel under a nitrogen atmosphere and under dry ice/acetone bath cooling so as to maintain the temperature of the mixture at -25° C. to -20° C. The addition was complete in 10 minutes. To the resulting orange-yellow slurry, 87.0 g (1.5 mole) propylene oxide dissolved in 250 ml toluene dropwise with stirring was slowly added over a period of 1.5 hours while maintaining the temperature at -35° C. to -30° C. After stirring for an additional 0.5 hours, the mixture was worked up as described in Example 1 to give 21.2 g (16% yield) of the desired product as colorless needles. This product proved identical to that obtained in Example 1 based on IR and NMR analysis.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[N:12]([CH2:25][O:26][CH3:27])[C:13](Br)=[N:14][C:15]=3[N:16]([CH2:21][CH2:22][CH3:23])[C:17]2=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:29][SH:30].O>CN(C)C=O>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[N:12]([CH2:25][O:26][CH3:27])[C:13]([S:30][CH3:29])=[N:14][C:15]=3[N:16]([CH2:21][CH2:22][CH3:23])[C:17]2=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(Br)n2COC
Reactant: CS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(SC)n2COC
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.3 %

Procedure:
6-Methylthio-3-(n-propyl)-7H-purin-2(3H)-one (Compound B8, 11.8 g, 52.5 mmol), which was obtained by the method described in Journal of Heterocyclic Chemistry (J. Heterocycl. Chem.), 30, p. 241, 1993, was dissolved in N,N-dimethylformamide (200 mL). To the solution was added sodium hydride (1.51 g, 63.0 mmol, 1.2 equivalents) and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added chloromethyl methyl ether (4.85 mL, 63.9 mmol, 1.2 equivalents) and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous ammonium chloride, the mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was evaporated, and to the resulting residue was added diethyl ether. The deposited crystals were collected by filtration to obtain a methoxymethyl adduct. (R)-8-Benzyl-2-bromo-7,8-dihydro-1-methoxymethyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 36a, 2.81 g, 6.52 mmol), which was obtained from the methoxymethyl adduct in a manner similar to that in Example 35, was dissolved in N,N-dimethylformamide (26 mL), to the solution was added an about 15% aqueous solution of methylmercaptan sodium salt (6.10 mL, 13.1 mmol, 2.0 equivalents), and the mixture was stirred at room temperature for three days. To the reaction solution was added water, the mixture was extracted with chloroform, then the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated. The reaction residue was purified by silica gel column chromatography (chloroform:methanol=98:2) and the eluent was concentrated. To the residue was added acetonitrile, and the deposited crystals were collected by filtration to obtain the title compound (2.17 g, 84%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[O:15].[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[NH:26][C:25]3=[O:32])=[CH:19][CH:18]=1.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[NH:26][C:25]3=[O:32])=[CH:33][CH:34]=1)=[O:15]
Reactant: Nc1ccc(Oc2ccc3c(c2)C(=O)NC3=O)cc1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(Oc2ccc3c(c2)C(=O)NC3=O)cc1
Reaction time: 12 h
Yield: 90.3 %

Procedure:
To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH2Cl2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CH2Cl2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a 1N HCl solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO4) and concentrated under reduced pressure to afford N-(2-methoxy-5-(trifluoromethyl)phenyl-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) Rf 0.50; 1H NMR (DMSO-d6) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3 Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M+H)+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:4]>O1CCOCC1.CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)C=Cc1c[nH]c2cc(C(=O)OC)ccc12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCc1c[nH]c2cc(C(=O)OC)ccc12
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 82.5 %

Procedure:
To a solution of methyl 3-(2-methoxycarbonylethenyl)-indole-6-carboxylate (213 mg) in a mixture of 1,4-dioxane (2 ml) and methanol (3 ml) was added 10% palladium on carbon (40 mg) and the mixture was stirred under hydrogen at 20° C. for 6.5 hours. The resulting mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 3-(2-methoxycarbonylethyl)indole-6-carboxylate (177 mg).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[N:10]([CH2:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][C:18]([C:24](=O)[CH3:25])=[CH:17]4)[N:11]=[N:12][C:7]2=[N:6][CH:5]=1)(=O)[CH3:2].[NH2:27][O:28][CH2:29][CH2:30][OH:31]>CO.C(O)(=O)C>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:24](/[C:18]1[CH:19]=[N:20][C:21]2[C:16]([CH:17]=1)=[CH:15][C:14]([CH2:13][N:10]1[C:8]3=[N:9][C:4](/[C:1](=[N:27]/[O:28][CH2:29][CH2:30][OH:31])/[CH3:2])=[CH:5][N:6]=[C:7]3[N:12]=[N:11]1)=[CH:23][CH:22]=2)\[CH3:25]
Reactant: CC(=O)c1cnc2ccc(Cn3nnc4ncc(C(C)=O)nc43)cc2c1
Reactant: NOCCO
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\OCCO)c1cnc2ccc(Cn3nnc4ncc(/C(C)=N/OCCO)nc43)cc2c1
Yield: 16.2 %

Procedure:
A solution of 1-(6-((6-acetyl-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinolin-3-yl)ethanone (74 mg, 0.213 mmol) and 2-aminooxy-ethanol (35 mg, 0.45 mmol) in 5 mL of methanol and 0.1 mL of acetic acid was stirred at 40° C. overnight. The solvent was removed under reduced pressure and the residue was diluted with DCM and methanol. The precipitate was collected, washed with DCM, dried to afford the title compound (16 mg, 15%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.31 (s, 1H), 9.23 (d, 1H), 8.52 (d, 1H), 8.03 (d, 1H), 7.98 (s, 1H), 7.86 (dd, 1H), 6.22 (s, 2H), 4.76 (d, 2H), 4.31 (t, 2H), 4.22 (t, 2H), 3.72-3.69 (m, 4H), 2.32 (s, 3H), 2.29 (s, 3H). LCMS (method E): [MH]+=465, tR=4.85 min.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[F:5][CH:6]([F:14])[C:7]1[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=1.P([O-])(O)(O)=O.[Na+]>O1CCCC1>[F:5][CH:6]([F:14])[C:7]1[O:11][C:10]([CH:12]([OH:13])[C:1]#[CH:2])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(C(F)F)o1
Reactant: C#C[Mg]Br
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(C(F)F)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
43 ml of a 0.5M solution of ethynyl magnesium bromide in tetrahydrofuran were added at 0° C. over one hour to a solution of 2.5 g of the product of Stage A and 30 ml of tetrahydrofuran. The reaction mixture was stirred at 0° C. for 1 hour and then was poured into a saturated aqueous sodium dihydrogenphosphate solution. The 3 g of product were chromatographed on silica by eluting with a 7/3 hexane/ethyl acetate mixture to obtain 2.5 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:47]([CH3:48])=[CH:46][C:39]([O:40][C@@H:41]2[CH2:45][CH2:44][O:43][CH2:42]2)=[CH:38][C:37]=1[CH3:49]>>[CH3:49][C:37]1[CH:38]=[C:39]([O:40][C@@H:41]2[CH2:45][CH2:44][O:43][CH2:42]2)[CH:46]=[C:47]([CH3:48])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O[C@@H]6CCOC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and (R)-3-(4-bromo-3,5-dimethylphenoxy)tetrahydrofuran following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 4): tR=1.89 min; Mass spectrum (ESI+): m/z=555 [M+Na]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH3:15][NH:16][CH2:17][CH2:18][OH:19]>>[CH3:15][N:16]([CH2:17][CH2:18][OH:19])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)OCCCc1ccccc1
Reactant: CNCCO
Product: CN(CCO)CCCc1ccccc1

Procedure:
The title compound was prepared from 3-phenylpropyl methanesulphonate (4.5 g) and 2-(methylamino)ethanol (16.7 ml) by an analogous procedure to that described in preparation 1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f13) and commercially acetyl chloride the title compound is obtained as colorless solid.