Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:25](Cl)(=[O:27])[CH3:26].CCN(CC)CC.C([O-])(O)=O.[Na+]>CC#N>[C:25]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][C:2]([OH:1])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:7]1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(C(O)(CCN2CCCNCC2)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCN(CCC(O)(c2ccccc2)c2cccc(O)c2)CC1
Yield: 18 %

Procedure:
Compound No. 296 (16 mg, 18%) was prepared from 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 78 mg, 0.24 mmol) and acetyl chloride (19 mg, 1.0 equiv). Acetyl chloride and Et3N (121 mg, 1.2 mmol, 5.0 equiv) were added to a solution of 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295) in CH3CN (2.0 mL). The reaction mixture was stirred at room temperature for 30 min. saturated aqueous NaHCO3 (10 mL) was added to the reaction mixture and the mixture was extracted with AcOEt (3×15 mL). The combined extracts were dried over MgSO4. The solvent was removed under reduced pressure to afford an oil which was purified by column chromatography (SiO2, 3-10% CH3OH/CH2Cl2) to give 1-acetyl-4-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 296): 16 mg, 18% yield, colorless oil: RPLC tR=4.75 min (89%), 220 nm (Method B); ESI/MS m/e 369.3 (M++H, C22H29N2O3).
Reaction SMILES: C(O[CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[NH:7][C:6]1=[O:22])(=O)C.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K].[I-].[Na+].CN(C)C=O>O>[C:12]1([C:10]2[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[NH:7][C:6](=[O:22])[CH:5]([N:27]3[C:26](=[O:28])[C:25]4=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]4[C:23]3=[O:33])[N:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C(c2ccccc2)=NC1N1C(=O)c2ccccc2C1=O
Reaction time: 0.75 h
Yield: 54.6 %

Procedure:
A mixture of (3RS)-1,3-dihydro-3-acetoxy-5-phenyl-2H-1,4-benzodiazepine-2-one (11.75 g), potassium phthalimide (11.1 g), sodium iodide (60 g) and N,N-dimethylformamide (80 ml) was stirred for 45 minutes at 90° to 95° C. The reaction mixture was poured into a cold water (1 l). The precipitates were collected by filtration, washed with water and recrystallized from ethanol to give (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepine-2-one (8.32 g).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([S:15][CH3:16])=[O:14].CN([CH:25](N(C)C)[O:26][C:27](C)(C)C)C.Cl.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O.CN(C)C=O>[CH3:1][C:2]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[CH:25][O:26][CH3:27])[C:13]([S:15][CH3:16])=[O:14]
Reactant: CSC(=O)Cc1ccccc1COc1cc(C)ccc1C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC=C(C(=O)SC)c1ccccc1COc1cc(C)ccc1C
Temperature: 60 °C
Yield: 22 %

Procedure:
2 g (0.00665 mol) of S-methyl 2-(2,5-dimethylphenoxymethyl)-phenylthioacetate and 2 g (0.0115 mol) of bis-(dimethylamino)-tert-butoxymethane are heated to 60° C. for 1 hour. The mixture is then admixed with 6 ml of dimethylformamide and 3 ml of concentrated aqueous hydrochloric acid and heated to 60° C. for a further hour. The reaction mixture is admixed with water and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The resulting crude intermediate, S-methyl 2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2-hydroxymethylidene-thio acetate, is dissolved in 10 ml of dimethylformamide, admixed first with 1.6 g (0.0116 mol) of potassium carbonate and then with 0.8 g (0.00634 mol) of dimethyl sulphate and stirred at 20° C. for 24 hours. The mixture is poured into water and extracted with dichloromethane, the organic phase is dried over sodium sulphate, the solvent is distilled off under reduced pressure and the residue is chromatographed over silica gel using diethyl ether/petroleum ether (1:1). 0.5 g (22.9% of theory) of S-methyl 2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2-methoxymethylidene-thioacetate is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](Br)=[CH:17][N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(=O)(O)(O)O.[OH-].[Na+].CCOCC>COCCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2c(Br)cn3Cc2cccc(F)c2)CC1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCN3Cc2cccc(F)c2)CC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4-[3-Bromo-1-(3-fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (273 mg) was dissolved in 3 mL of 2-methoxyethanol and 85% phosphoric acid (575 mL) was added. The dark solution was heated to 140° C. and stirred for 16 h. The next day the mixture was made basic with 1.0 N NaOH and Et2O was added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After filtering and removing solvent the crude material was taken up in 3 mL of THF and di-tert-butyldicarbonate (218 mg) was added. The mixture was stirred for 24 hours at room temperature, after which the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography to provide 115 mg of 4-[1-(3-fluoro-benzyl)-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester, MS: 326 (M−Boc+H)+.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([CH3:29])=[CH:23][N:22]=1>>[CH3:28][O:27][C:25]1[C:24]([CH3:29])=[CH:23][N:22]=[C:21]([CH2:20][S:1][C:2]2[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:26]=1
Reactant: COc1cc(CCl)ncc1C
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Product: COc1cc(CSc2nc3ccccc3c(=O)n2-c2ccccc2)ncc1C
Yield: 22.5 %

Procedure:
The title compound was prepared in a yield of 22.5%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 2- mercapto-6-methyl-3-phenyl-4(3H)-quinazolinone and 2-chloromethyl-4-methoxy-5-methylpyridine in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:27]3=[CH:28][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]4[O:38][C:15]([NH:16][C@@H:17]([CH:35]([CH3:37])[CH3:36])[C:18](=[O:34])[N:19]5[CH2:29][C@H:22]([O:23][C:24]3=[N:25][CH:26]=1)[CH2:21][C@H:20]5[C:30]([O:32]C)=[O:31])=[N:14][N:13]=4)=[CH:5][CH:4]=2.[Li+].[OH-].Cl>C1COCC1.O>[I:1][C:2]1[C:3]2[C:27]3=[CH:28][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]4[O:38][C:15]([NH:16][C@@H:17]([CH:35]([CH3:36])[CH3:37])[C:18](=[O:34])[N:19]5[CH2:29][C@H:22]([O:23][C:24]3=[N:25][CH:26]=1)[CH2:21][C@H:20]5[C:30]([OH:32])=[O:31])=[N:14][N:13]=4)=[CH:5][CH:4]=2
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)C)Nc1nnc(o1)CCCCCc1ccc3c(I)cnc(c3c1)O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H]1Nc2nnc(o2)CCCCCc2ccc3c(I)cnc(c3c2)O[C@@H]2C[C@@H](C(=O)O)N(C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (3R,5S,8S)-23-iodo-8-isopropyl-7-oxo-2,28-dioxa-6,9,11,12,25-pentaazapentacyclo[17.6.2.13,6.110,13.022,26]noncosa-1(25),10,12,19,21,23,26-heptaene-5-carboxylate (from Step 2) in THF/H2O (1/1 v/v) was added LiOH (4 eq). The resulting reaction mixture was stirred at RT for 2 h and then treated with 1N aq. HCl until pH=2 was reached. Aqueous phase extracted with EtOAc and organic layer dried over Na2SO4 to get a white solid. MS (ES+) C26H30IN5O5 requires: 619. Found: 620 (M+H+).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]2[N:7]([C:8]([CH3:14])([CH3:13])[CH2:9][CH2:10]2)[C:6](=[O:15])[CH:5]=1)=[N+]=[N-]>CCO.[Pd]>[NH2:1][CH:4]1[CH2:12][CH:11]2[N:7]([C:8]([CH3:13])([CH3:14])[CH2:9][CH2:10]2)[C:6](=[O:15])[CH2:5]1
Reactant: CC1(C)CCc2cc(N=[N+]=[N-])cc(=O)n21
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCC2CC(N)CC(=O)N21
Yield: 89 %

Procedure:
7-Azido-3,3-dimethylindolizin-5 (1H)-one (0.3 g, 1.5 mmol) is dissolved in EtOH (20 ml). The clear solution is transferred to a Parr hydrogenation flask and placed under nitrogen. 10% Pd—C (0.25 g) was added to the Parr flask under nitrogen. The mixture was then transferred to a Pan hydrogenation apparatus, evacuated and filled with hydrogen (×3). The mixture was hydrogenated at 30 psi (optionally topping-up hydrogen) until LC/MS and TLC indicated complete reaction to the amine. After complete reaction, the mixture was placed under nitrogen and filtered through a small pad of Celite. The filter cake was washed with MeOH (×3) and the filtrate was concentrated under vacuum to leave the 7-amino-hexahydro-3,3-dimethylindolizin-5-(1H)-one in 89% yield (0.25 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][C:8]([C:10]3[O:11][C:12]4[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]5[N:23]=[C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[S:25][CH:26]=5)[C:13]=4[CH:14]=3)=[CH:9][N:4]2[N:3]=1.[CH3:33][OH:34].C[O-].[Na+]>ClCCl>[F:19][C:17]1[CH:16]=[C:15]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:25][CH:26]=2)[C:13]2[CH:14]=[C:10]([C:8]3[N:7]=[C:5]4[N:4]([CH:9]=3)[N:3]=[C:2]([O:34][CH3:33])[S:6]4)[O:11][C:12]=2[CH:18]=1
Reactant: Fc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1nn2cc(-c3cc4c(OCc5csc(-c6ccccc6)n5)cc(F)cc4o3)nc2s1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 64 %

Procedure:
2-Bromo-6-(6-fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (17 mgs, 0.032 mmol) was dissolved in dichloromethane (1.3 mL) (some heat and sonication were required). Methanol was then added (0.3 mL) followed by sodium methoxide (14.74 μL, 0.064 mmol) in one shot. The reaction was stirred at r.t. for 25 min., then quenched with HCl 1.0 N and stirred until the reaction color changes to yellow. Sat. NaHCO3 was then added and this was extracted with dichloromethane (4×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (BIOTAGE® 12 g column using 100% dichloromethane to 5% ethyl acetate in dichloromethane (increment of 1%) to give the title material (10 mgs, 64%) as a yellowish solid. LC (Method A): 2.488 min. HRMS (ESI) calcd for C23H15FN4O3S2 [M+H]+ m/z 479.0570. found 479.0661. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.94-8.03 (m, 2H), 7.89 (s, 1H), 7.43-7.53 (m, 3H), 7.39 (s, 1H), 7.19 (s, 1H), 6.85-6.94 (m, 1H), 6.59-6.68 (m, 1H), 5.40 (s, 2H), 4.23 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[C:18]([O:19]C)=[CH:17][C:6]2[C:7](=[O:16])[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[C:18]([OH:19])=[CH:17][C:6]2[C:7](=[O:16])[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(=O)Cc1ccccc1O2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C1Cc2ccccc2Oc2cc(O)c(O)cc21
Temperature: 190 °C
Yield: 66.9 %

Procedure:
A mixture of 7,8-dimethoxy-10,11-dihydrodibenzo[b,f]oxepin-10-one (5 mg) and pyridine hydrochloride (20 mg) was heated at 190° C. for two hours. Water was added to the reaction mixture followed by extracting with ethyl acetate. This was washed with water and dried over magnesium sulfate and the solvent was evaporated to give the title compound (Compound 13) (3 mg, 60%) as brown plates.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]([CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])[CH:12]=[CH:13][CH:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>O.C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]4[CH2:15][CH2:16][N:17]=[C:18]([CH3:19])[C:12]4=[CH:13][CH:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)NCCn1cccc1-c1ccc2c(c1)OCO2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC1=NCCn2c1ccc2-c1ccc2c(c1)OCO2
Reaction time: 0.75 h
Yield: 66 %

Procedure:
N-[2-[2-(1,3-Benzodioxol-5-yl)-pyrrol-1-yl]-ethyl]acetamide (1.7 g) was treated with 10 ml of phosphorus oxychloride under argon and boiled for 45 minutes while stirring. The reaction mixture was hydrolyzed at 0° C. with 50 ml of 2N sodium hydroxide solution and 50 ml of 28% sodium hydroxide solution, diluted with 600 ml of water and extracted with methylene chloride (1×100 ml, 2×60 ml). The organic extracts were combined, dried with MgSO4 and freed from solvent. 1.4 g of crude product was dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 1.5 g (66%) of 6-(1,3-benzodioxol-5-yl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 191°-193° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH:3]([NH:15][C:16]([CH:18]1[CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:27]1[O:29][CH2:28]1>>[CH3:1][CH:2]([CH3:26])[CH:3]([NH:15][C:16]([CH:18]1[CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][N:19]1[CH2:27][CH2:28][OH:29])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCCC1CNC1C(=O)NC(C(C)C)C1OC(SC)C(O)C(O)C1O
Reactant: C1CO1
Product: CCCCC1CN(CCO)C1C(=O)NC(C(C)C)C1OC(SC)C(O)C(O)C1O

Procedure:
A sample of 3-Butyl-azetidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide prepared in example 70 was alkylated with ethyleneoxide as depicted in scheme 12 (R6=2-hydroxyethyl) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([CH:28]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH3:31][NH:32][C:33](=[O:38])C(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([CH:28]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([S:21]([NH:22][C:33]([NH:32][CH3:31])=[O:38])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)c1cc(Cl)ccc1OC)CCO2
Reactant: CNC(=O)C(Cl)(Cl)Cl
Product: CCOc1cc2c(cc1S(=O)(=O)NC(=O)NC)C(CNC(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7-ethoxychroman ##STR39## 4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7ethoxychroman is prepared as described in Example 1 from 4-(5-Chloro-2-methoxybenzamidomethyl)6-sulfamoyl-7-ethoxy-chroman and N-methyltrichloroacetamide. Melting point: 207°-208° C.
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH:15]1([C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][C:24]=2F)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[NH4+].[Cl-]>C1COCC1>[CH:15]1([C:21]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][C:28]=2[S:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: SCc1ccccc1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1F)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1ccc(OCc2ccccc2)cc1SCc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
A solution of phenylmethanethiol (2.35 ml, 20 mmoles) in THF (10 ml) was slowly added to a mixture of potassium tert-butoxide (2.24 g, 20 mmoles) in THF (80 ml) under N2 at room temperature. The mixture was stirred for 15 min at room temperature and cyclohexyl (4-benzyloxy-2-fluorophenyl)methanone (6.5 g, 20 mmoles) in THF (10 ml) was slowly added. The mixture was heated for 2 h at 50° C. and poured into an aqueous solution of NH4Cl, extracted with ethyl acetate, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography (Heptane/AcOEt 90/10 with 0.1% TEA) to give cyclohexyl (4-benzyloxy-2-benzylthiophenyl)methanone (8.3 g, 100%).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:16]>C(#N)C>[Br:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([Cl:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(Br)ccc2c(O)ccnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1c(Br)ccc2c(Cl)ccnc12
Temperature: 90 °C

Procedure:
To a flask charged with 7-bromo-8-methylquinolin-4-ol (1.00 g, 4.20 mmol) was added Acetonitrile (21.00 ml) and POCl3 (0.411 ml, 4.41 mmol) and the resulting suspension heated to 90° C. for 1.5 hrs affording a brown solution and near complete conversion to desired product. The mixture was added to a cooled solution of sat. aq. NaHCO3 affording a tan precipitate which was collected via vacuum filtration and washed with water and dried under high vacuum affording product as a tan solid. m/z (ESI) 258.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:22]([NH:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=1)=[O:23])[CH:8]=[CH:7][CH:6]=2
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc2c(N)cccc2cn1
Product: Cc1cc2c(NC(=O)NCc3ccc(OC(F)(F)F)cc3)cccc2cn1

Procedure:
Prepared from 3-methylisoquinolin-5-amine (Description 45) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 376 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=2)[N:4]([CH3:13])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)O1>O1CCOCC1.O.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>[CH3:13][N:4]1[C:5]2=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=[C:10]2[C:2]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)=[N:3]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CSc1ncc2c(Br)nn(C)c2n1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc2c(-c3ccc(N)cc3)nn(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 3-bromo-1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (2.6 g, 10 mmol) in dioxane (40 mL) and H2O (20 mL) was added anhydrous potassium carbonate (4.14 g, 30 mmol, 3 eq), followed by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.28 g, 15 mmol, 1.5 eq). The reaction mixture was degassed and tetrakis(triphenylphosphine)palladium (58 mg, 0.5 mmol, 0.05 eq) was added. The system was then heated under reflux for 24 hours and cooled to room temperature. The mixture was treated with water (150 mL) and cooled to 0° C. and allowed to sit for three hours. The resulting mixture was then filtered. The filtrate was dried in a vacuum oven overnight to afford 1.66 g (61% yield) of 4-(1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenylamine; 1H-NMR (CDCl3): • 2.69 (s, 3H), 3.90 (br s, 2H), 4.08 (s, 3H), 6.82 (d, 2H), 7.77 (d, 2H), 9.11 (s, 1H); LC/MS (m/e)=272.4 (MH+). Rt=1.57 min.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:24]2[CH2:29][NH:28][C:27](=[O:30])[NH:26][CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1([CH2:56][CH2:57][CH2:58][CH2:59]O)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O1CCCC1.C(OCC)(=O)C>[C:50]1([CH2:56][CH2:57][CH2:58][CH2:59][O:15][C:16]2[CH:17]=[C:18]([CH:24]3[CH2:25][NH:26][C:27](=[O:30])[NH:28][CH2:29]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: COc1ccc(C2CNC(=O)NC2)cc1O
Reactant: OCCCCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CNC(=O)NC2)cc1OCCCCc1ccccc1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
Diisopropylazodicarboxylate (1.1 ml, 5.70 mmol, 1.2 eq) was added to a mixture of (1.06 g, 4.75 mmol, 1.0 eq) tetrahydro-5-(3-hydroxy-4-methoxyphenyl)-2(1H)-pyrimidinone, (1.37 g, 5.23 mmol, 1.1 eq) triphenylphosphine, and (714 mg, 4.75 mmol, 1.0 eq) 4-phenyl-1-butanol in 20 ml of anhydrous tetrahydrofuran. After heating to reflux for 18 hours, the reaction mixture was cooled to room temperature, diluted with 350 ml ethyl acetate, washed twice with 1N NaOH, once with H2O, once with brine, dried over Na2SO4, and concentrated to yield an orange solid. Silica gel chromatography eluting with 4% CH3OH--CH2Cl2 yielded 527 mg of a white solid, which was recrystallized from ethyl acetate to afford 480 mg, 29%, of white needles. M.P.: 142°-143° C. Elemental Analysis Calc'd for C21 H26N2O3 : Calc'd: C, 71.17; H, 7.40; N, 7.90. Found: C, 71.12; H, 7.32; N, 7.75.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[O:21])=[CH:13][CH:14]=3)[N:9](COCC[Si](C)(C)C)[N:8]=2)=[O:5])[CH2:3][CH2:2]1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>C(Cl)Cl>[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].[CH:1]1([C:4]([NH:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=4)=[O:21])=[CH:13][CH:14]=3)[NH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Nc1ccc2c(NC(=O)C3CC3)nn(COCC[Si](C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Nc1ccc2c(NC(=O)C3CC3)n[nH]c2c1
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 3-(3-(cyclopropanecarboxamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ylamino)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (25 mg) in CH2Cl2 (1 mL) was added TFA (0.25 mL) at room temperature. The reaction mixture was stirred for 2 hours and the organic solvent was concentrated under reduced pressure. To a solution of the resulting mixture in THF (0.5 mL) and MeOH (0.5 mL) was added LiOH aqueous solution (1.0 M, 1.0 mL). The resulting mixture was stirred for another 2 hours at room temperature. The organic solvent was removed under reduced pressure and the aqueous layer was extracted with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by Prep HPLC and acetonitrile was removed under reduced pressure. The remained water was freeze-dried to afford TFA salt of title compound (16 mg, 66%), MS (ESI) m/z 494 (M+H)+.