Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)[N:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[CH3:20][CH:19]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[NH2:27])[CH2:18][N:15]1[CH2:14][CH2:13][N:12]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]3)[CH2:17][CH2:16]1
Reactant: Cc1ccc2c(N3CCN(CC(C)c4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(N3CCN(CC(C)c4cccc(N)c4)CC3)cccc2n1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 2-methyl-5-{4-[2-(3-nitrophenyl)propyl]-1-piperazinyl}quinoline (70 mg) in methanol (1 mL) was added dropwise to a stirred suspension of iron powder (3.0 equiv., 30 mg) and ammonium chloride (5.0 equiv., 48 mg) in water (1 mL). The reactants were heated at reflux for 18 hours. The reaction mixture was cooled to room temperature then filtered using a Millipore filter. The filtrate was concentrated under reduced pressure and purified using chromatography (SiO2, SPE) eluting with DCM-methanol (95:5) to afford the title compound (40 mg, 60% yield).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[C:7]([C:11](OC)=[O:12])[CH:8]=[N:9][CH:10]=1)([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[OH:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[O:12])[CH:8]=[N:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)c1cncc(C(C)(C)O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cncc(C=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of the title compound from Step B (0.50 g, 2.6 mmol) in toluene (15 mL) and dichloromethane (15 mL) was added a solution of diisobutyl aluminum hydride in toluene (1.0 M, 6.0 mL, 6.0 mmol). After 10 min, the reaction was quenched with water (5 mL), allowed to warm to room temperature and dried with magnesium sulfate. Concentration of the filtrate under reduced pressure provided the title compound: 1H NMR (500 MHz, CDCl3) δ 10.10 (s, 1 H), 8.99 (d, J=2.3 Hz, 1 H), 8.93 (s, 1 H), 8.30 (s, 1 H), 2.22 (br s, 1 H), 1.67 (s, 6 H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:40][C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:30][CH:29]=5)=[N:21][N:22]([CH2:24][CH2:25][NH:26][CH3:27])[CH:23]=4)=[C:13]3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].[OH-].[Na+].[CH2:43]=O.O>CO.[OH-].[OH-].[Pd+2]>[CH3:27][N:26]([CH3:43])[CH2:25][CH2:24][N:22]1[CH:23]=[C:19]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:40][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:6]=4)=[CH:12][C:13]=23)[C:20]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:32][CH:33]=2)=[N:21]1
Reactant: C=O
Reactant: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
To N′-(4-{4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(methylamino)ethyl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea.3TFA (300 mg, 0.34 mMol) in MeOH (10 mL) was added with stirring at RT aq. 1 N NaOH (1.1 mL, 1.1 mMol), 37 wt. % CH2O in water (50 uL, 0.67 mMol) and 20% Pd(OH)2/C (Pearlman's catalyst) (˜10 mg). A balloon of H2 was attached and the reaction stirred at RT for 3 days. The reaction was evaporated to dryness under vacuum, taken up in (9:1) CHCl3/iPrOH (15 mL) and treated with excess methyl isatoic anhydride polystyrene resin (˜500 mg, >1.8 mMol/g). After stirring at RT for 4 h the reaction was filtered, rinsed with (9:1) CHCl3/iPrOH, and the filtrate concentrated to dryness under vacuum. Purification by Gilson HPLC provided the title compound (56.6 mg, 30%) as a white solid. ESMS [M+H]+: 551.6
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[F:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: Oc1cccc(F)c1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2cccc(F)c2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
5-Nitrothiophene-2-carbonitrile (2 g, 13 mmol), 3-fluorophenol (1.75 g, 15.6 mmol) and potassium carbonate (3.6 g, 26 mmol) were suspended in dimethylsulfoxide (15 mL), and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added for partitioning, silica gel was added to the organic layer, and the solvent was evaporated in vacuo for adsorption. Purification was carried out by silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (670 mg, 3.1 mmol, 23.5%) was obtained as an oil.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2([CH3:37])[CH2:28][CH2:27][C:26]3[C:29]([CH3:36])=[C:30]([OH:35])[C:31]([CH3:34])=[C:32]([CH3:33])[C:25]=3[O:24]2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C.C(O)(=O)C>CO>[OH:6][C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2([CH3:37])[CH2:28][CH2:27][C:26]3[C:29]([CH3:36])=[C:30]([OH:35])[C:31]([CH3:34])=[C:32]([CH3:33])[C:25]=3[O:24]2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Oc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(OCc3ccccc3)c(O)c1)O2
Reaction time: 1.5 h

Procedure:
Sodium hydroxide, 0.12 g (3 mmol), was added to a solution of 0.47 g (1 mmol) of rac-2-{[3-acetyloxy-4-(phenylmethoxy)phenyl]ethynyl}-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol in 10 ml of methanol. The mixture was stirred under argon for 1.5 hours and was then acidified with glacial acetic acid and partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The methylene chloride layer was separated, dried and passed over a pad of silica gel. The filtrate was evaporated and the residue was crystallized from ether/hexane to give colorless crystals with m.p. 103°-106°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCc1cc(C(=O)OC)cc(C#N)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
Methyl 3-cyano-5-ethyl-4-methoxybenzoate (480 mg) was dissolved in tetrahydrofuran (6 mL) and water (2 mL), and lithium hydroxide monohydrate (370 mg) was added to the solution, and then the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (403 mg) as a colorless crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=3)=[CH:27][CH:26]=2)[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CCO
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[F:31][C:32]1[CH:40]=[C:39]2[C:35]([C:36]([CH2:41][CH2:42][NH2:43])=[CH:37][NH:38]2)=[CH:34][CH:33]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:43][CH2:42][CH2:41][C:36]3[C:35]4[C:39](=[CH:40][C:32]([F:31])=[CH:33][CH:34]=4)[NH:38][CH:37]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1c[nH]c2cc(F)ccc12
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3c[nH]c4cc(F)ccc34)n2)c1

Procedure:
Intermediate 4 was coupled with 2-(6-Fluoro-1H-indol-3-yl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 497. 1H NMR (Varian 300 MHz, CDCl3-CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 7.8 (d, 1H) 7.5 (m, 4H) 7.3 (m, 1H) 6.8 (m, 2H) 4.4 (d, 2H) 3.9 (m, 1H) 3.6 (m, 2H) 3.3 (m, 2H) 3.1 (m, 1H) 2.8 (m, 5H) 1.7 (m, 2H).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH2:18]([NH2:21])[C:19]#[CH:20]>CO>[C:1]([NH:3][C:4]([NH:21][CH2:18][C:19]#[CH:20])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)#[N:2]
Reactant: CSC(=NCCSCc1ccccn1)NC#N
Reactant: C#CCN
Solvent: CO
Product: C#CCNC(=NCCSCc1ccccn1)NC#N

Procedure:
A mixture of the product of Step A (4.0 g; 15.0 mmoles) and propargylamine (6.88 g; 125 mmoles) in methanol (20 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 20 hours. The reaction mixture was evaporated under reduced pressure and the product recrystallized from acetonitrile to give the title compound; mp 124.5°-130.5° C. (remelted at 128°-131.5° C.).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[Cl-].[Na+]>CN(C)C=O.O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc(Cl)nc(N3CCN(C(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4.62 g (17.8 mmol) of commercially available 2,4-dichloro-6,7-dimethoxyquinazoline in 50 ml of dimethylformamide were added 12.4 ml (89.1 mmol) of triethylamine and 3.65 g (19.6 mmol) of N-tert-butoxycarbonylpiperazine, followed by overnight stirring in an atmosphere of argon at room temperature. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried to give 7.15 g (98%) of the desired compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20].C(OCC)(=O)C>CN1CCCC1=O>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:5][CH:6]=1
Reactant: NCCc1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)NCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12.4 Gram of 4-(2-aminoethyl)phenol and 9.15 g of triethylamine were dissolved in 100 mL of N-methylpyrrolidone, and the solution was cooled to 0° C. in a nitrogen stream. Thereto, 9.45 g of methacryloyl chloride was added dropwise over 0.2 hours, and the obtained reaction solution was stirred at 0° C. for 1 hour and further stirred at room temperature for 4 hours. After adding 500 mL of ethyl acetate, the organic layer was washed, in sequence, twice with an aqueous saturated sodium hydrogencarbonate solution and twice with water and dried over sodium sulfate. The solvent was concentrated to obtain 12.2 g of N-(4-hydroxyphenethyl)methacrylamide as a brown oil. Thereafter, 7.49 g of the oil and 11.5 g of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride were dissolved in 100 mL of THF, and the resulting solution was cooled to 0° C. Thereto, 4.43 g of triethylamine was added dropwise over 0.3 hours, and the obtained reaction solution was stirred at 0° C. for 1 hour and further stirred at room temperature for 3 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with an aqueous saturated sodium hydrogencarbonate solution and twice with water and dried over sodium sulfate. The solvent was concentrated, and the brown oil as residue was dissolved in 100 ml of methanol. Thereto, 10 g of sodium hydrogencarbonate as solid was added, and the mixture was stirred at 50° C. for 6 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with saturated brine and twice with water and dried over sodium sulfate to obtain 15.7 g of 3-((4-(2-methacrylamido)ethyl)phenoxy)sulfonyl)-1,1,2,2,3,3-hexafluoropropane-1-sulfonylfluoride as a brown oil. Thereafter, 7.29 g of this brown oil was dissolved in 100 mL of methanol, and 4.81 g of triphenylsulfonium bromide was added thereto, followed by stirring at room temperature for 3 hours. After adding 200 mL of chloroform, the organic layer was washed with water, and the solvent was concentrated, as a result, 10.1 g of a brown transparent oily compound was obtained. 1H-NMR (300 MHz, CDCl3) δ 1.91 (s, 3H), 2.87 (t, 2H), 3.50 (quartet, 2H), 5.27 (s, 1H), 5.66 (s, 1H), 6.39 (bs, 1H), 7.14 (d, 2H), 7.23 (d, 2H), 7.67-7.76 (m, 15H), 19F-NMR (300 MHz, CDCl3) δ −107.4 (m, 2F), −114.0 (m, 2F), −118.1 (m, 2F).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][N:3]=1.[CH3:11][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])([CH3:11])[CH3:9])=[CH:4][N:3]=1
Reactant: CC(=O)c1cnc(Cl)nc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1cnc(Cl)nc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
To a solution of 1-(2-chloropyrimidin-5-yl)ethanone (268 mg, 1.7 mmol) in THF (20 mL) was added MeMgBr (2.68 mL, 8.04 mmol) at −78° C. under nitrogen. The solution was stirred at −78° C. for 20 min, quenched with satd aq NH4Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give an oil, which was purified by prep TLC (PE:EA 3:1) to give 2-(2-chloropyrimidin-5-yl)propan-2-ol (150 mg, yield 51%).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]#[N:15])[N:13]=2)[CH2:3]1.CN(C=O)C.[Br:21]N1C(=O)CCC1=O.[OH-].[Na+]>O>[Br:21][C:11]1[S:10][C:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]2)=[N:13][C:12]=1[C:14]#[N:15]
Reactant: C[C@@H]1CN(c2nc(C#N)cs2)C[C@H](C)O1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2nc(C#N)c(Br)s2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
A flask charged with Intermediate 2 (25.61 g, 114.69 mmol) and DMF (250 mL) was cooled in an ice/water bath. N-bromosuccinimide (24.49 g, 137.63 mmol) was added portionwise (slightly exothermic reaction). The reaction mixture was stirred at room temperature for 10 min. Water (400 mL) was then added dropwise leading to a yellow precipitate, followed by sodium hydroxide 1 M (115 mL). The precipitate was filtered, washed with water (50 mL) and DIPE (10 mL). This solid was recrystallised from acetonitrile. Filtration and overnight drying in a vacuum oven at 50° C. yielded 25.5 g (73%) of Intermediate 3 as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]3[O:23][C:24]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][C:26](=[O:28])[CH:27]=3)[CH2:11][C:10]=2[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:19]([S:18][C:17]3[C:16]([C:22]4[O:23][C:24]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:25][C:26](=[O:28])[CH:27]=4)=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [5-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl]-carbamic acid tert-butyl ester (19)(1.08 g, 2.19 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (2 ml) and left under stirring at room temperature overnight. The solvent was dried in vacuo revealing a viscous dark brown liquid. Saturated sodium bicarbonate solution (20 ml) was added to the residue, which was left to stir for 20 mins. The brown precipitate was filtered, washing with water and left to dry in the vacuum oven overnight (0.77 g, 90%). 1HNMR (300 MHz, DMSO-d6): δH=3.40 (4H, t), 3.70 (4H, t), 3.77 (2H, s), 5.23 (2H, bs), 5.50 (1H, d), 6.17 (1H, d), 6.44 (1H, dd), 6.65 (1H, d), 7.09 (1H, d), 7.35 (1H, t), 7.47–7.59 (2H, m); m/z (LC-MS, ESP), RT=3.51 minutes, (M++1)=392.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1)=[N:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:42][O:43][CH2:44][CH2:45]Br.O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:45][CH2:44][O:43][CH3:42])=[N:15][CH:14]=[CH:13]2)(=[O:8])=[O:9]
Reactant: COCCBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4)nccc3c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCN1CCCC1c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3nccs3)ccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
N-(2,4-dimethoxybenzyl)-1-(pyrrolidin-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.050 g, 0.080 mmol) and potassium carbonate (0.055 g, 0.400 mmol) were dissolved in DMF (0.800 ml). 2-Bromoethyl methyl ether (9.03 μl, 0.096 mmol) was added and the reaction was stirred for three hours at 70° C. Water was added followed by ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 20% MeOH:EtOAc with 5% triethylamine modifier) to afford N-(2,4-dimethoxybenzyl)-1-(1-(2-methoxyethyl)pyrrolidin-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as an off white solid. m/z (ESI) 569.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([C:31](=[O:37])[NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: CCOC(=O)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (52 mg, 0.13 mmol) and ethyl 2-chloro-2-oxoacetate (0.030 mL, 0.27 mmol). Yield 53 mg (81%).
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8]S[N:10]=[C:6]2[C:5]([S:11]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1>CC(O)=O.O.[Zn]>[NH2:10][C:6]1[C:7]([NH2:8])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[S:11]([NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)(=[O:12])=[O:13]
Reactant: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc(F)c3nsnc23)cc1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc(F)c(N)c2N)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the compound 39D (382 mg, 1.0 mmol) in AcOH/H2O (8 mL/3 mL) at 70° C. was added zinc powder (975 mg, 15 mmol) and the resulting suspension was stirred at 70° C. for 1 h. The solid was filtered off and washed with EtOAc. The filtrate was partitioned between satd. NaHCO3 and EtOAc. The organic layer was separated and washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give crude product 39E, which was confirmed by LCMS, and used in the next reaction without further purification. LC-MS: m/z 354.4 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:4]=2[O:3]1.C(Cl)(=O)OCC.[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH2:31]>CN(C)C=O.CC(C)=O.C(N(CC)CC)C>[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH:31][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=1)=[O:13]
Reactant: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)O)c2O1
Reactant: CN1CCCC1CN
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)NCC3CCCN3C)c2O1
Reaction time: 15 h

Procedure:
2-Methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid, 5.0 g, is dissolved in a mixed solvent of 50 ml of dimethylformamide and 50 ml of acetone, 6.5 ml of triethylamine is added and the solution is stirred. Under cooling at 15°-18° C., 2.2 g of ethyl chlorocarbonate is added dropwise for 10 minutes, and the solution is stirred at room temperature for one hour. Thereafter, 2.7 g of 1-methyl-2-aminomethylpyrrolidine is added and the whole is stirred at room temperature for 3 hours and allowed to stand for 15 hours. Excess triethylamine and acetone are distilled off under reduced pressure and the resulting residue is poured into 300-400 ml of water. The aqueous layer is extracted via with chloroform three times and the extract layer is washed with aqueous sodium bicarbonate solution, water and sodium chloride saturated water in this sequence. After drying, the chloroform is distilled off under reduced pressure and the residue obtained is recrystallized from ethyl acetate to give crystals of N-(1-methyl-2-pyrrolidinyl-methyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 187°-189° C.