Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][C:12]1([C:42]([O:44]C)=[O:43])[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@@H:30]4[C:34]4[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=4[F:41])=[CH:25][C:24]=23)=[O:19])[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl>O.C1COCC1.CO>[C:4]([O:8][C:9]([NH:11][C:12]1([C:42]([OH:44])=[O:43])[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@@H:30]4[C:34]4[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=4[F:41])=[CH:25][C:24]=23)=[O:19])[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Reaction time: 6 h
Yield: 87.8 %

Procedure:
LiOH.H2O (43 mg, 1 mmol) in water (2 mL) was added to a stirred solution of (R)-methyl 4-((tert-butoxycarbonyl)amino)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)piperidine-4-carboxylate (120 mg, 0.2 mmol) in THF (6 mL), MeOH (2 mL) and water (2 mL) at 20-35° C. The reaction mixture was stirred for 6 h; thereafter it was concentrated under reduced pressure to afford a crude product. The crude product thus obtained was diluted with cold water, acidified with 2N aqueous HCl solution, extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 100 mg of the title compound as a pale green solid. MS (ESI): m/z 570.2 (M+H).
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:9]1[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:11]=[CH:12][C:13]=1[C:14]([O:16]CC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].CC(C)([O-])C.[Na+].CN(C)C=O.O>C(OCC)(=O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:10]2[C:9]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][NH:1][C:14](=[O:16])[C:13]=3[CH:12]=[CH:11]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(=CN)c1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]c(=O)c2ccn(Cc3ccc(OC)cc3)c12
Reaction time: 0.42 h
Yield: 1711.7 %

Procedure:
A mixture of ethyl 2-{2-amino-1-[(ethyloxy)carbonyl]ethenyl}-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrole-3-carboxylate (0.2 g), sodium tert-butoxide (26 mg) and dimethylformamide (2 ml) was irradiated with microwaves at 160° C. for 8 minutes. The procedure was repeated on a 2 g and 3 g scale, the cooled solutions combined, added slowly to iced water then stirred for 25 minutes. A precipitate formed which was dissolved in ethyl acetate and washed with water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a white solid (3.00 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH2:23](O)[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:23][CH3:24])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of 43 g (200 mmol) of 4-bromophenylacetic acid and 0.2 g of conc. H2SO4 in 470 ml of ethanol was refluxed for 16 hours. The reaction mixture was cooled to ambient temperature, stirred with 6 g of solid K2CO3 for 30 minutes and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (200 ml), washed with 10% aqueous NaHCO3 (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][SH:11].[ClH:12].[C:13]([NH:15][C:16](=[N:19][CH3:20])SC)#[N:14]>N1C=CC=CC=1.O>[ClH:12].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][S:11][C:16](=[N:19][CH3:20])[NH:15][C:13]#[N:14]
Reactant: CN=C(NC#N)SC
Reactant: Cc1[nH]cnc1CSCCS
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CN=C(NC#N)SCCSCc1nc[nH]c1C

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethanethiol (4.0 g) (prepared from the hydrochloride as in Example 1(b) and N-cyano-N', S-dimethylisothiourea (4.0 g) were heated together under nitrogen in pyridine (100 ml) at 100° for 20 hours. After this time the mixture was evaporated to dryness to give the crude title product. This residue taken up in water acidified to pH2 with concentrated hydrochloric acid. After extracting with ethyl acetate the volume of the aqueous fraction was reduced and on cooling gave S-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-N-cyano-N'-methylisothiourea hydrochloride, m.p. 225°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.CN.[C:21]([BH3-])#[N:22].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>C(O)(=O)C.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:22][CH3:21])[CH:12]=2)[CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 58.4 %

Procedure:
4-Chloro-2-(3-formyl-phenoxy)-benzonitrile (0.52 g, 2.02 mmol), methylamine (2M in methanol, 1.0 ml, 2.0 mmol) and sodium cyanoborohydride (0.14 g, 2.2 mmol) Were stirred at ambient temperature in a 1% acetic acid/methanol solution (30 ml) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with water, brine and dried over MgSO4. After filtration, fumaric acid (0.23 g, 2.0 mmol) was added to the filtrate and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(3-methylaminomethyl-phenoxy)-benzonitrile fumarate (454 mg, 58%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:19]=[C:20]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])[CH:21]=[CH:22][C:23]=1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:18]([Br:17])[CH:19]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.33 mmol, 1.07 g) in THF at room temperature, NaH (100 mg, 4.5 mmol) was added and stirring continued for 30 min then 4-(3-Bromo-4-cyclohexyloxy-phenyl)-3-butyl-6-chloro-pyridazine (3.50 mmol, 1.5 g) was added. The resulting mixture was stirred at 50° C. for over night, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10-20% ethyl acetate in hexanes to provide 4-[5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=2[N:12]=[C:11]2[N:21](CC=C)[NH:22][C:23]([CH3:24])=[C:10]2[N:9]=1.O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:21][NH:22][C:23]([CH3:24])=[C:10]2[N:9]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(C)c(C)cc3N=C21
Agent: Cl[Ni]Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1=C2N=C(c3ccccc3Cl)c3cc(C)c(C)cc3N=C2NN1
Temperature: 0 °C
Reaction time: 6 h
Yield: 62.2 %

Procedure:
To a solution of 2.7 g (0.00716 mole) of 5-(2-chlorophenyl)-1,2-dihydro-3,7,8-trimethyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVw), 0.155 g (0.00029 mole) of 1,3-bis(diphenylphosphino)propane nickel (II) chloride and 140 mL of anhydrous tetrahydrofuran at −40° C. was added 43 mL of 1M diisobutylaluminum hydride in toluene. The mixture was stirred at 0° C. for 6 hours and then quenched by the careful addition of ice water. The mixture was extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-dichloromethane (1:1) to give 1.5 g of 5-(2-chlorophenyl)-1,2-dihydro-3,7,8-trimethyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVw) as an orange solid. MH+/Z=337.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:13]1[CH:14]=[CH:15][N:16]=[C:17]2[C:22]=1[N:21]=[C:20]([O:23][CH3:24])[CH:19]=[CH:18]2.CC(=O)OCC>CN(C=O)C.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.[Cu]I>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]#[C:11][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[N:21]=2)[N:16]=[CH:15][CH:14]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2nccc(C#CCNC(=O)OC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.3 %

Procedure:
To a solution of N-Boc propargyl amine (3.25 g, 20.9 mmol) and 8-bromo-2-methoxy-[1,5]naphthyridine (5.00 g, 20.9 mmol; prepared as in WO 2006/032466) and TEA (17.5 mL, 6 eq.) in DMF (120 mL) were added Pd(PPh3)2Cl2 (755 mg, 1.08 mmol) and CuI (432 mg, 2.27 mmol). The mixture was degassed with a stream of N2 for 15 min and then stirred at rt for 5 h. The mixture was partitioned between water and EA, the org. layer was washed several times with water and a sat. NH4Cl solution, dried over MgSO4 and concentrated. Chromatography on SiO2 (Hex/EA 1:1, EA) gave the coupling product as a beige solid (2.90 g, 44% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].CN(C)C1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35].Cl>C1(C)C=CC=CC=1>[C:34]([N:5]([CH2:4][C:3]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=1[Cl:1])[C:6]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(C(=O)OC)c(NCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(N(Cc2ccc(Cl)cc2Cl)C(C)=O)c1
Temperature: 50 °C

Procedure:
A mixture of dimethyl 2-(2,4-dichlorobenzyl)aminoterephthalate (12.00 g), N,N-dimethylaniline (7.92 g) and acetyl chloride (5.5 ml) in toluene (140 ml) was heated at 50° C. for 15 hr. After cooling, ice and concentrated hydrochloric acid were added to acidify the reaction mixture and the toluene layer was separated. The toluene layer was washed successively with water and a saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulfate and concentrated. The residue was crystallized from 2-propanol to give the objective compound (8.40 g) as white crystals.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@@H:8]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[N:9]1[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:21]=3[N:27]=2)[C:10]1=[O:28])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([C@@H:8]([N:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:21]=4[N:27]=3)[C:10]2=[O:28])[CH2:7][C:6]([OH:37])=[O:5])=[CH:34][CH:33]=1
Reactant: COc1ccc([C@H](CC(=O)OC(C)(C)C)n2ccn(CCCc3ccc4c(n3)NCCCC4)c2=O)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@H](CC(=O)O)n2ccn(CCCc3ccc4c(n3)NCCCC4)c2=O)cn1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a solution of 3-7 (0.85 g, 1.67 mmol) in dichloromethane (10 mL) was added anhydrous TFA (5 mL). After 4 hours, the mixture was concentrated, diluted with toluene, and re-concentrated. The residue was chromatographed on silica gel (15:10:1:1 to 15:10:1:1 EtOAc/EtOH(NH4OH/H2O) to give 600 mg of 3-8 as a white solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][C:29]([CH3:34])=[CH:28]4)=[N:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:35][CH3:36].[CH2:37]([S:39]([CH2:42][CH2:43][CH2:44]O)(=[O:41])=[O:40])[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:37]([S:39]([CH2:42][CH2:43][CH2:44][O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][C:29]([CH3:34])=[CH:28]4)=[N:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:35][CH3:36])(=[O:41])=[O:40])[CH3:38]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: CCS(=O)(=O)CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)CCCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
Diethyl azodicarboxylate (117 mg, 0.67 mmol) was added in portions to a solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (120 mg, 0.37 mmol), (prepared as described in Example 49), and 3-(ethylsulphonyl)-1-propanol (74 mg, 0.48 mmol) in methylene chloride (3.5 ml) and triphenylphosphine (176 mg, 0.67 mmol). After stirring for 2 hours at ambient temperature, the residue was poured onto a column of silica and eluted with ethyl acetate/methylene chloride (1/1) followed by methylene chloride/methanol (97/3 followed by 95/5). After removal of the solvent under vacuum, the residue was triturated with ether, filtered and dried under vacuum to give 7-(3-(ethylsulphonyl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (93 mg, 55%).
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](O)=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)C.ClCCl.O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]([CH2:11][C:12]([OH:16])=[O:13])=[N:3][O:4][C:14]=2[CH:15]=1
Reactant: O=c1cc(O)c2ccc(Br)cc2o1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)Cc1noc2cc(Br)ccc12
Yield: 76.8 %

Procedure:
Sodium metal (0.36 g) was dissolved in dry ethanol (30 ml) then treated with hydroxylamine hydrochloride (1.12 g). A solution of 7-bromo-4-hydroxy-2H-chromen-2-one (Intermediate 31) (1.3 g) in dry ethanol (30 ml) was added and the mixture was stirred at reflux under nitrogen for 3.5 h. On cooling the mixture was added to 2M aqueous sodium bicarbonate (100 ml). Water (100 ml) and dichloromethane (100 ml) were added, the phases were separated and the aqueous layer was washed with more dichloromethane (75 ml). The aqueous layer was acidified by the cautious addition of 2N hydrochloric acid to yield a precipitate which was collected by filtration and dried to give the title compound as a white solid (1.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.N1C=CC(C2C=CN=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.C([O-])(=O)C.[Cu+]>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH:12]3[CH2:14][CH2:13]3)[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OB(O)C1CC1
Reactant: O=c1nc(Cl)cc2n1CCN2
Agent: [Cu+]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Product: O=c1nc(Cl)cc2n1CCN2C1CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
A mixture of 7-chloro-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (300 mg, 1.75 mmol), cyclopropylboronic acid (300 mg, 3.50 mmol), 4,4′-bipyridine (273 mg, 1.75 mmol), copper (I) acetate (214 mg, 1.75 mmol) and Na2CO3 (371 mg, 3.50 mmol) in 1,2-dichloroethane (DCE) (20 mL) was stirred at 70° C. for 3 h and concentrated to remove solvent under vacuo. Purification via Biotage system with inverse phase column (water and acetonitrile as eluent) afforded the title product (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [Mn+4]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1-(4′-Fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (60.5 kg) produced in Example 17 was added to toluene (520.9 kg) and manganese dioxide (544.8 kg, type HMH, manufactured by Toso) divided in three portions was added at 10–30° C. over 3 hr. The mixture was stirred at 23–27° C. for 1 hr, and the starting material was confirmed by HPLC to be 0.03%. Thereto were added Hyflo Super-Cel® (18.2 kg, Celite Co.) and anhydrous magnesium sulfate (30.2 kg). The mixture was cooled to about 100° C. over 2 hr and stirred at 2–10° C. for 40 min. The mixture was filtrated and the residue (waste manganese) was washed with toluene (284 kg). As a result of the analysis, 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (60 kg, yield about 100%) was contained in the solution (917 kg). The crystals obtained by partial concentration of the solution showed the same physical properties as in Example 18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13](O)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][OH:14]
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2[nH]cc(CCO)c2c1

Procedure:
A solution of 15 g of (5-methoxyindol-3-yl)acetic acid (0.073 mol) in 100 ml of tetrahydrofuran is added to a suspension of 2.1 g (0.219 mol) of lithium aluminum hydride in 100 ml of ethyl ether and the reaction mixture is brought to reflux for 6 hours. The reaction mixture is then hydrolyzed with 80 ml of a saturated aqueous magnesium sulfate solution. The whole mixture is filtered through celite and the solvents are evaporated under vacuum. The residue is taken up in a small amount of water and extracted a number of times with dichloromethane. The product is obtained after evaporation of the solvant.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:23])=[C:10]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[C:16]([NH:21][CH3:22])[N:15]=[CH:14]4)[C:5]=2[S:4][N:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:27]=[C:28](N)[CH:29]=[CH:30][CH:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:22][NH:21][C:16]1[N:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:10]3[C:5]4[S:4][N:3]=[C:2]([NH:1][C:30]5[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[CH:31]=5)[C:6]=4[CH:7]=[CH:8][C:9]=3[CH3:23])[CH:12]=2)[N:17]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(N)nsc34)ccc2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(C(F)(F)F)c5)nsc34)ccc2n1
Temperature: 150 °C

Procedure:
6-(3-Amino-6-methylbenzo[d]isothiazol-7-yl)-N-methylquinazolin-2-amine (0.100 g, 0.31 mmol), 3-(trifluoromethyl)benzenamine (0.060 g, 0.37 mmol),tris(dibenzylideneacetone)dipalladium (o) (0.0085 g, 0.0093 mmol), X-phos (0.0089 g, 0.019 mmol) and sodium t-butoxide (0.042 g, 0.44 mmol) were all placed in a clear microwave vial along with 4 ml of toluene. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 150° C. for 10 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 40-80% EtOAc in hexanes to give N-methyl-6-(6-methyl-3-(3-(trifluoromethyl)phenylamino)benzo[d]isothiazol-7-yl)quinazolin-2-amine as yellow solid. MS(M+H)+ 466.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[Cl:25][C:26]1[N:27]=[N:28][C:29]([Cl:33])=[CH:30][C:31]=1Cl.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[Cl:25][C:26]1[N:27]=[N:28][C:29]([Cl:33])=[CH:30][C:31]=1[N:23]1[CH:24]=[C:20]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:12])=[O:13])[CH:7]=2)[CH:21]=[N:22]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: Clc1cc(Cl)c(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3cc(Cl)nnc3Cl)c2)c2ccc(F)cc21
Temperature: 85 °C
Reaction time: 24 h
Yield: 38.7 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 200 mg; 0.59 mmol) in MeCN (10 mL) was added 3,4,6-trichloropyridazine (97 mg; 0.529 mmol) and K2CO3 (146 mg; 1.06 mmol) under nitrogen. The mixture was stirred at 85° C. for 24 hours, diluted with EtOAc (100 mL), washed with water (50 mL×3), brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by reversed phase flash chromatography to afford 100 mg (39%) of the title compound a the yellow solid.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[N+:17]([O-:19])=[O:18])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(=O)O)n[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 80.3 %

Procedure:
5-Isopropyl-1H-pyrazol-3-carboxylic acid (5 g, 32.5 mmol) was added portionwise to concentrated sulfuric acid (25 ml) at room temperature with stirring. The reaction mixture was then heated to 60° C. and concentrated nitric acid (70%, 6 ml, 90 mmol) was added dropwise, keeping the temperature at 60° C. The reaction was then stirred at 60° C. for 3 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. After 15 minutes the white precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-isopropyl-4-nitro-1H-pyrazol-3-carboxylic acid (5.2 g) as a white solid. 1H NMR (400 MHz, DMSO-D6): δ=13.86-13.93 (1H, brs), 13.50-13.80 (1H, brs), 3.39-3.52 (1H, m), 1.18-1.30 (6H, d) ppm. LRMS (electrospray): m/z [M−H]+ 198.