Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:7][C:8](=[O:22])[CH2:9][N:10]([S:12]([C:15]1[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH3:11])(C)(C)C.[C:23]([OH:27])#[C:24][CH2:25][CH3:26]>O>[CH2:23]([O:27][C:18]1[N:17]=[CH:16][C:15]([S:12]([N:10]([CH2:9][C:8]([OH:7])=[O:22])[CH3:11])(=[O:13])=[O:14])=[CH:20][CH:19]=1)[C:24]#[C:25][CH3:26]
Reactant: CCC#CO
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)CC(=O)O)cn1
Yield: 45 %

Procedure:
To a solution of 0.77 mL (19.3 mmol) of 2-butynl-ol and 0.18 g (4.37 mmol) of sodium hydroxide were heated at 100° C. for one hour. [(6-chloro-pyridine-3-sulfonyl)-methyl-amino]-acetic acid tert-butyl ester (1.0 g, 3.12 mmol) was added to this solution. Additional butynol was added to facilitate stirring, and the reaction was stirred at 100° C. overnight. The reaction was cooled, diluted with water, and washed with ethyl acetate. The aqueous layer was acidified with 2N HCl, and extracted with ethyl acetate (2×). The combined organics were washed with brine, dried over MgSO4, concentrated to solids which were slurried in 1:1:1 dichloromethane:hexane:ethyl acetate to afford 0.41 g (45%) of [(6-but-2-ynyloxy-pyridine-3-sulfonyl)-methyl-amino]-acetic acid as an off-white solid. Electrospray Mass Spec 299.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.Cl([O-])=[O:12].[Na+].S(=O)(=O)(O)N>C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]([OH:12])=[O:9]
Reactant: O=Cc1c(Cl)ccnc1Cl
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A solution of 0.40 g of the aldehyde from Step B was dissolved in 6 mL of THF and then added to a solution of 0.27 g of sodium chlorite and 0.29 g of sulfamic acid in 6 mL of water. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1 N sodium hydroxide (10 mL) and extracted with diethyl ether (1×). The aqueous layer was then acidified with concentrated HCl, extracted with methylene chloride (2×), and the combine methylene chloride extracts were dried over magnesium sulfate. The methylene chloride was removed under vacuum to give 0.22 g of a solid. 1H NMR (CDCl3; 300 MHz) δ 7.38 (d, 1H J is 5.4 Hz), 8.40 (d, 1H, J is 5.5 Hz), 8.60 (bs, 1H).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[OH:28][C@H:29]1[CH2:33][NH:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30]1.CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:32]1[CH2:33][C@H:29]([OH:28])[CH2:30][C@H:31]1[C:34]([O:36][CH3:37])=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 13 h
Yield: 76.8 %

Procedure:
To a suspension of 2.28 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one, which is the compound described in Preparation 1.1 of Brochure No. WO01/55130, and the compound obtained in Step 4-1 (8.15 mmol) in CHCl3 (23 ml) was added dropwise 4.49 g of Et3N over 2 minutes under ice cooling, then, the reaction mixture was stirred at room temperature for 13 hours. An aqueous solution of 5% K2CO3 was added to the reaction solution, and the resulting mixture was stirred for 15 minutes. liquid separation was performed, and the aqueous layer was extracted with CHCl3 extraction. The combined organic layer was washed with saturated brine, then, dried over MgSO4, the drying agent was separated by filtration, then, the solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc) to obtain 2.37 g of a diastereoisomer mixture of the title compound (colorless amorphous).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[N:13](OCCC(C)C)=[O:14].[OH-].[Na+]>O.C1(C)C(C)=CC=CC=1.CO>[OH:14][N:13]=[C:10]([C:11]#[N:12])[C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)CCON=O
Reactant: COc1ccc(CC#N)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1ccc(C(C#N)=NO)cc1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
64.5 g of methanol, 365 g of xylene, 80 g of sodium hydroxyde (2 mol) and 147 g (1 mol) of 4-methoxyphenylacetonitrile are charged to a reactor. Then 125 g (1.07 mol) of isopentyl nitrite are added dropwise at 40° C. over 2 hours. The reaction mixture is stirred initially for 2 hours at this temperature and then for 20 hours at room temperature. Afterwards the reaction mixture is diluted with water to form an emulsion and the pH is adjusted to 14 with aqueous sodium hydroxide and the organic phase is separated. The aqueous phase is acidified with hydrochloric acid and the product is extracted with ether. The ether phase is dried and the ether is stripped off. Recrystallisation from toluene gives 142 g of α-hydroxyimino-4-methoxy-benzylcyanide, corresponding to a yield of 80.6% of theory.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[C:26]([CH:27]=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.C(O)C.O1CCCC1.[BH4-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][OH:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a mixture of 2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarbaldehyde (0.40 g), ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (0.04 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, and dried with air to give crystals (0.35 g, 88%) of [2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 139-140° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:29])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:38](B(O)O)[CH2:39][CH2:40][CH3:41].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1(P([Pd](Cl)(Cl)P(C2CCCCC2)(C2CCCCC2)C2CCCCC2)(C2CCCCC2)C2CCCCC2)CCCCC1.O>[CH2:38]([C:2]1[C:3]([CH3:29])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:20])=[O:21])=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCB(O)O
Reactant: Cc1c(Br)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)O)c1C
Temperature: 100 °C
Reaction time: 36 h

Procedure:
A mixture of Example 225A (123 mg, 0.26 mmol), potassium phosphate (192 mg, 0.9 mmol), butylboronic acid (34 mg, 0.33 mmol), bis(tricyclohexylphosphino)palladium dichloride (19 mg, 0.03 mmol), toluene (4 mL), and water (0.2 mL) was purged with argon and shaken at 100° C. for 36 hours in a sealed container. The mixture was diluted with ethyl acetate (10 mL), washed with water (2×10 mL) and brine, dried (Na2SO4), filtered, concentrated and passed through a silica gel cartridge (20 g) with 15% ethyl acetate/hexanes. The isolated solid was substituted for Example 108C in Example 108D and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide the desired-product. MS (ESI(+)) m/e 383 (M+NH4)+; (ESI(−)) m/e 364 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.09 (br s, 1H), 9.74 (br s, 1H), 7.78 (m, 2H), 7.39 (m, 2H), 7.08 (d, 1H), 6.71 (d, 1H), 2.55 (q, 2H), 2.18 (s, 3H), 1.44 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][CH2:20][CH2:21][CH2:22][OH:23])([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:44]1[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]2[C:45]1=[O:54]>C1COCC1>[C:15]([O:19][CH2:20][CH2:21][CH2:22][O:23][N:44]1[C:48](=[O:49])[C:47]2[C:46](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:45]1=[O:54])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OCCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Diisopropyl azodicarboxylate (13.4 mL, 68 mmol) was added dropwise at 0° C. to a stirred suspension of 3-tert-butoxy-propan-1-ol (9.0 g, 68 mmol), triphenylphosphine (17.8 g, 68 mmol), and N-hydroxyphthalimide (11.1 g, 68 mmol) in THF (150 mL), and the reaction stirred for 16 h at room temperature. The solution was concentrated in vacuo and purified by silica gel chromatography (20% Et2O/hexanes) to give 15.5 g (82%) of 2-(3-tert-Butoxy-propoxy)-isoindole-1,3-dione as a faintly yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.72-7.84 (m, 4H), 4.30 (t, 2H, J=4.8 Hz), 3.58 (t, 2H, J=4.8 Hz), 1.94-2.00 (m, 2H), 1.20 (s, 9H). MS (ES) [m+H] calc'd for C15H19NO4, 278; found 278.
Reaction SMILES: Cl.C([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])C.[CH2:10]([C:12]1[CH:21]=[C:20]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[C:31]([CH3:33])[C:30]([CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:29][N:28]=3)[O:24][N:23]=2)[CH:19]=[C:18]([CH3:38])[C:13]=1[O:14][CH2:15][CH2:16]N)[CH3:11].C(N(CC)CC)C>C(O)C>[CH2:10]([C:12]1[CH:21]=[C:20]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[C:31]([CH3:33])[C:30]([CH2:34][CH:35]([CH3:36])[CH3:37])=[CH:29][N:28]=3)[O:24][N:23]=2)[CH:19]=[C:18]([CH3:38])[C:13]=1[O:14][CH2:15][CH2:16][NH:8][CH2:7][CH2:6][C:5]([OH:4])=[O:9])[CH3:11]
Reactant: CCOC(=O)CCN
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCNCCC(=O)O
Temperature: 80 °C
Reaction time: 18 h
Yield: 27.1 %

Procedure:
A solution of β-alanine ethyl ester hydrochloride (88 mg, 570 μmol) in ethanol (2 mL) is filtered over PL-HCO3 MP SPE ion exchange. The methanesulfonic acid ester intermediate of Example 48 (90 mg, 190 μmol) and triethylamine (77 mg, 760 μmol) is added to the filtrate and the mixture is stirred in a sealed vial at 80° C. for 18 h. The mixture is cooled to rt and the solvent is evaporated. The crude 3-(2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-ethylamino)-propionic acid ethyl ester is dissolved in ethanol (2 mL) and 1 N aq. NaOH (2 mL) and the mixture is stirred at rt for 3 h. The mixture is neutralised by adding 1 N aq. HCl, the solvent is removed in vacuo and the residue is separated by prep. HPLC to give the title compound (24 mg) as a white solid; LC-MS: tR=0.90 min, [M+H]+=466.79; 1H NMR (CDCl3): δ1.00 (d, J=6.5 Hz, 6H), 1.30 (t, J=7.3 Hz, 3H), 1.90-1.99 (m, 1H), 2.38 (s, 3H), 2.46 (s, 3H), 2.60-2.68 (m, 4H), 2.73 (q, J=7.5 Hz, 2H), 3.20-3.27 (m, 2H), 3.27-3.33 (m, 2H), 4.07-4.15 (m, 2H), 7.92 (s, 1H), 7.94 (s, 1H), 8.08 (s, 1H), 8.54 (s, 1H).
Reaction SMILES: [CH3:1][O-].[Na+:3].CCO[C:7]([CH3:9])=[O:8].C(OC)=O.[C:14]([CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[S:18])#[N:15]>CO.CCO>[C:14]([C:16]1[CH:1]=[CH:9][C:7](=[O:8])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]=1[S-:18])#[N:15].[Na+:3]
Reactant: CCOC(C)=O
Reactant: C[O-]
Reactant: N#CCC(=S)Nc1ccccc1
Agent: [Na+]
Solvent: COC=O
Solvent: CCO
Solvent: CO
Product: N#Cc1ccc(=O)n(-c2ccccc2)c1[S-]
Reaction time: 8 h
Yield: 100 %

Procedure:
Sodium methoxide (2.88 g) was added to EtOAc (8.7 mL), cooled to +14° C. To the resulting suspension was added methyl formate (2.2 mL) slowly over 4.3 h whilst maintaining the reaction temperature at +14° C. After this time, the temperature was adjusted to +25° C. and the reaction was allowed to stir out at this temperature overnight. Absolute EtOH (25 mL) and a solution of sodium methoxide in MeOH (30 wt %, 6.7 mL) were then added followed by 2-cyano-N-phenylthioacetamide (5 g) and the resulting mixture was heated at reflux for 24 h. The reaction was cooled to +5° C. when the product was recovered by filtration. The filter cake was washed with cold (+5° C.) absolute EtOH (20 ml) and then dried to constant weight under vacuum at 45° C. to give the title compound as a pale pink solid (2.77 g; equivalent to 2.63 g at 100%). δH (DMSO-d6) 7.32 (2H, m), 7.27-7.18 (1H, m), 7.16 (1H, d, J 9.1 Hz), 6.92 (2H, m), 5.63 (1H, d, J 9.1 Hz). LCMS (ES+) RT 2.43 minutes, 229 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:19][C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:18][CH:17]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)cn2)cc1
Temperature: 170 °C

Procedure:
2,5-dichloropyridine (1.48 g; 10 mmol), 4-methylsulfonylphenol (1.89 g; 11 mmol) and Cs2CO3 (4.24 g; 13 mmol) was slurried in 75 mL of NMP. The slurry was heated to approx 170° C. over night. After cooling the Cs2CO3 was filtered off and the solvent was extracted between H2O and EtOAc. The organic phase was dried over Na2SO4 and evaporated. Heptane:EtOAc 2:1 was added to the residue and the crystalls was filtered off 1.42 g (50%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([Cl:14])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Product: CCc1[nH]c(C(=O)Cl)nc1Cl
Temperature: 75 °C
Reaction time: 0.83 h

Procedure:
4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (55 mg, 0.29 mmol) was dissolved in thionyl chloride (1.5 mL), and the mixture was stirred at 75° C. for 50 minutes. The reaction solution was concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([C:15](=O)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:19][O:20][C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)=[O:22]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:30][NH:29][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:32][CH:31]=3)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C)c(C)c2)c1O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C)cc1

Procedure:
From 1-(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 4-methoxycarbonylbenzhydrazide, 53.0 mg of the desired product was obtained in the same manner as in Synthetic Example 4 as a pale yellow solid (yield 64%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:12][N:11]=1)(=[O:25])=[O:24]
Reactant: Nc1ccc(COCC2CC2)cn1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1ccc(COCC2CC2)cn1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.06 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.096 g) as an off-white solid (0.069 g). MS (ESI−): 399.1 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1([CH2:20][OH:21])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.CC(C)([O-])C.[Li+].Br[CH2:29][C:30]#[N:31].O>C1COCC1>[NH2:1][C:2]1([CH2:20][O:21][CH2:29][C:30]#[N:31])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2
Reactant: N#CCBr
Reactant: COc1cc(F)c2c(c1)C(N)(CO)c1cc(Br)ccc1O2
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)C(N)(COCC#N)c1cc(Br)ccc1O2

Procedure:
A solution of (9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methanol (9.83 g, 27.8 mmol) in THF (46.3 mL) was sequentially treated with lithium t-butoxide (1 M in THF) (30.5 mL, 30.5 mmol) and 2-bromoacetonitrile (2.90 mL, 41.6 mmol) at RT. After 2.5 hours reaction time, additional 0.5 equivalent lithium t-butoxide and 2-bromoacetonitrile (1.5 mL) were added. After 4 hours reaction time, an additional 0.25 equivalent lithium t-butoxide and bromoacetonitrile (0.75 mL) were added. After 5 hours reaction time another 0.25 equivalent of lithium t-butoxide and bromoacetonitrile (0.75 mL) were added to the mixture. Water (100 ml) was added and solvents were removed under reduced pressure. The aqueous residue was filtered, the solid was washed twice with water, dried under reduced pressure and re-suspended in ethanol. The solid was filtered off, washed with ethanol and dried under reduced pressure to afford 2-((9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methoxy)acetonitrile.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:37]=2[CH:38]=[N:39][NH:40]3)O1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(O)C>[NH:40]1[C:41]2[C:37](=[C:36]([C:2]3[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 130 °C

Procedure:
A mixture of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine 31 from Example 4 (2.00 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole 7 (2.26 g), toluene (24 mL), ethanol (12 mL), water (6 mL), sodium carbonate (1.72 g) and PdCl2(PPh3)2 (325 mg) was heated to 130° C. in the microwave for 90 minutes (US 2008/0076768; WO 2006/046031, incorporated by reference herein).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])=[C:4](C)[CH:3]=1.[Li+].CC([N-]C(C)C)C.[F:24][C:25]([F:33])([F:32])[C:26](N(OC)C)=[O:27]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[O:7])=[C:13]([C:26](=[O:27])[C:25]([F:24])([F:32])[F:33])[CH:14]=1
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1C
Reactant: CON(C)C(=O)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(Br)cc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromo-N,N-diethyl-2-methylbenzamide (500 mg, 1.851 mmol) in Tetrahydrofuran (4.63 ml) was cooled to −78 C and treated with LDA (2.313 ml, 4.63 mmol) for 15 minutes before 2,2,2-trifluoro-N-methoxy-N-methylacetamide (320 mg, 2.036 mmol) in Tetrahydrofuran (4.63 ml) was added to the reaction mixture and allowed to warm to room temperature. The reaction was stirred overnight and then partitioned between 1N HCl (100 mL) and EtOAc (100 mL). The aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (150 mL), dried over magnesium sulfate, filtered and concentrated. Purification using MPLC (0-20% EtOAc/Hex) affords 4-bromo-N,N-diethyl-2-(trifluoroacetyl)benzamide. LC-MS (IE, m/z): 366 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18].O>CN(C=O)C>[C:17]([C:10]1[C:11]2[NH:12][C:13]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:14]=3)[C:6]=2[CH:7]=[CH:8][N:9]=1)(=[O:19])[CH3:18]
Reactant: Clc1ccc2c(c1)[nH]c1cnccc12
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1nccc2c1[nH]c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product from example 12 (104 mg, 0.50 mmol) in DMF (2.0 ml) at 3° C. to 5° C. was added NaH (95%, 15 mg, 0.625 mmol). The resulting mixture was stirred for 15 min before adding acetic anhydride (0.083 ml, 0.875 mmol). The reaction was allowed to warm to RT and stirred for 3 h before pouring into with water (25 ml). The slurry was stirred for 12 h, and the product collected to give after chromatography (1:3 hexane-ethyl acetate) on silica gel 82 mg of 1-acetyl-7-chloro-β-carboline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[I-:14].[Na+].CNC1CCCCC1NC>[Cu]I.O1CCOCC1>[I:14][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: [I-]
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
3-bromo-1,1′-biphenyl (5.00 g, 21.5 mmol), sodium iodide (6.43 g, 42.9 mmol), copper(I) iodide (1.226 g, 6.43 mmol), and dioxane (214 ml) were added into a 500 mL 3-necked flask. N1,N2-dimethylcyclohexane-1,2-diamine (1.691 ml, 10.72 mmol) was then added. The solution was heated and refluxed overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of celite and washed several times with dichloromethane. The solvents are evaporated under vacuum and the crude material was purified via column chromatography using hexane/DCM (90/10). The target 3-iodo-1,1′-biphenyl (5.5 g, 19.64 mmol, 92% yield) was afforded as a colorless oil.