Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@H:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([NH:23][CH3:24])=[O:22].CO>CCCCCCC>[CH3:24][NH:23][C:21]([CH:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CNC(=O)[C@H](N)c1ccccc1
Agent: Cl
Solvent: CCCCCCC
Solvent: CO
Product: CNC(=O)C(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and (αR)-α-amino-N-methyl-benzeneacetamide hydrochloride (1:1) (CAN 97549-10-5) as starting materials. Racemization occurred during the synthesis and the product was isolated by chiral chromatography on Chiralpak AD using heptane/20% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 380.1968 (M+H)+, αD20 (MeOH)=−6.0°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:4][CH:3]=1>COCCOC.[Pd].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1C=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccccc1CCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
2-[2-(4-Fluorophenyl)ethenyl]benzonitrile (8.10 g, 36.3 mmol) was dissolved in ethylene glycol dimethyl ether (200 mL). Palladium on charcoal (10% Pd; 0.81 g) in H2O (1.0 mL) was added, and the reaction mixture was shaken under 60 psig H2 for 1 h. The reaction mixture was then filtered through Celite®, and the filtrate was rotary evaporated (75° C.). This provided 8.03 g (98.3%) of the product as an orange oil which crystallized on standing.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:15]1)=[O:11])=O)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[CH2:17][CH2:18][CH:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH2:8])[CH2:15]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100.7 %

Procedure:
To a solution of 3-[{N-(tert-butoxycarbonyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (804 mg, 2.11 mmol) in methanol (10 mL) was added 4 N HCl in dioxane (5 mL). The solution was stirred at room temperature for 3.5 h. The reaction mixture was concentrated and 1 N NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (20 mL×3), and the combined extracts were dried over sodiumsulfate and concentrated to give desired 1-(4-chlorobenzyl)-3-{(glycylamino)methyl}pyrrolidine (599 mg, 100%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 282.2 (M++H, C14H20(ClN3O).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)(=[O:13])[CH3:12].[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1COCC1>[C:11]([O:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([O:18][Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])[CH:16]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Oc1cccc(O)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (73 ml, 73 ml, 1M solution in THF) was added dropwise to a solution of resorcinol monoacetate (10 g, 65.7 mmol) in THF (100 ml) at 78° C. under argon. The solution was stirred for 10 minutes and then triisopropylsilyl chloride (15.5 ml, 73 mmol) was added via syringe. After stirring at room temperature overnight, the mixture was partitioned between water and ethyl acetate. The organic layer was dried, filtered and evaporated under vacuum to yield 13 g of crude 3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenyl acetate which was used in the next step without further purification. NMR 1H Cl3CD δ: 7.19 (t, 1H, J=8 Hz), 6.75 (m, 1H), 6.68 (m, 1H), 6.63 (t, 1H, J=4 Hz), 2.29 (s, 3H), 1.25 (m, 3H), 1.11 (d, 18H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH:3]=1.[F:19][C:20]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C([O-])(O)=O.[Na+]>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>[NH2:8][C:6]1[N:7]=[C:2]([C:26]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([F:19])[CH:27]=2)[CH:3]=[C:4]([NH:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(NC2CCc3ccccc32)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(NC3CCc4ccccc43)nc(N)n2)cc1F
Temperature: 120 °C
Yield: 53.8 %

Procedure:
A mixture of 6-chloro-N4-(2,3-dihydro-1H-inden-1-yl)-2,4-pyrimidinediamine (700 mg, 2.69 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (797 mg, 3.23 mmol) in 1,4-dioxane (150 mL) and a solution of NaHCO3 (903 mg, 10.76 mmol) in water (50 mL) was protected with nitrogen. Pd(Ph3P)4 (31 mg, 0.0269 mmol) was added, and the reaction mixture was heated at 120° C. for 16 hours. The mixture was decanted to remove the solids, and the solution was concentrated to dryness. The crude material was purified by SiO2 chromatography eluting with 1:1 THF:petroleum ether to afford the title compound (500 mg) as a yellow solid. LC-MS (ES) m/z=246 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([CH:19]([CH3:21])[CH3:20])[C:14]4[CH2:22][CH:23]5[NH:27][CH:26]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>ClCCl.C(OCC)C>[ClH:35].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]([CH3:21])[CH3:20])[C:14]2[CH2:22][CH:23]4[NH:27][CH:26]([C:13]3=2)[CH2:25][CH2:24]4)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)n1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)n1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the product of step B (100 mg, 0.06 mmol) in dichloromethane was added 2M HCl in diethylether (2 mL). After stirring at ambient temperature for 5 h the reaction mixture was concentrated in vacuo, triturated with ethyl acetate and lyophilized from water to give 2-phenylsulfonyl-5-isopropyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (50 mg, 57%, AUC HPLC >99%) as a white solid: mp 260-265° C., 1H NMR (CD3OD, 300 MHz) δ 8.26 (d, J=1.5 Hz, 1H), 7.93-7.97 (m, 2H), 7.67-7.76 (m, 2H), 7.51-7.59 (m, 3H), 5.28-5.30 (m, 1H), 4.69-4.75 (m, 1H), 4.52 (br s, 1H), 3.55 (dd, J=17.2, 5.1 Hz, 1H), 3.11 (d, J=17.4 Hz, 1H), 2.28-2.43 (m, 3H), 1.93-2.02 (m, 1H), 1.59 (d, J=7.2 Hz, 3H), 1.56 (d, J=6.9 Hz, 3H); ESI, m/z 381 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][C:7]=3[O:11][CH3:12])[N:1]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: COc1cccc(N)c1C(N)=O
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cccc2nc(-c3cc(C)c(OCCO)c(C)c3)[nH]c(=O)c12
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-6-methoxy-benzamide (1.00 g, 6.01 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.28 g, 6.59 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was heated at 115° C. for 20 hours, and cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 h, filtered, and dried under vacuum to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.1 g (55%).
Reaction SMILES: C[SiH](C)C1C=CC=CC=1[SiH](C)C.[CH3:13][N:14]([CH3:25])[C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:25][N:14]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:13]
Reactant: COc1ccc(C(=O)N(C)C)cc1
Agent: C[SiH](C)c1ccccc1[SiH](C)C
Solvent: Cc1ccccc1
Product: COc1ccc(CN(C)C)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A 20-mL eggplant flask equipped with a three-way cock and a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with argon atmosphere. Into the flask, iron complex A (1.0 mg, 0.002 mmol) was admitted as catalyst and dissolved in toluene (0.5 mL). To the solution, 1,2-bis(dimethylsilyl)benzene (475 μL) was added through a syringe, and N,N-dimethyl-4-methoxybenzamide (179 mg, 1.0 mmol) was added. The solution was stirred at 100° C. for 30 minutes. Toluene was distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (10/1) as developing solvent, obtaining N,N-dimethyl-4-methoxybenzylamine (159 mg, 0.96 mmol, 96%). The results are shown as Entry 1 in Table 5. The resulting amine was identified for geometry by 1H and 13C-NMR spectroscopy and IR spectroscopy.
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[F:35].[CH2:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH2:37][CH3:38]>C1(C)C=CC=CC=1.C(O)C>[CH2:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH2:37][CH3:38].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:48]([NH:47][C:45](=[O:46])[C:42]2[CH:43]=[CH:44][C:39]([CH2:36][CH2:37][CH3:38])=[CH:40][CH:41]=2)=[S:49])=[CH:30][C:29]=1[F:35]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CCCc1ccc(C(=O)Cl)cc1
Agent: CCCc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
4-Propyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-propyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-propyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 86%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[O:10][CH2:13][CH2:14][OH:15]
Reactant: OCCBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCO)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A solution of 4-nitro-m-cresol (1.4 g, 9.4 mmol), 2-bromoethanol (1.0 mL, 0.014 mol) and potassium carbonate (3.3 g, 0.024 mol) in N,N-dimethylformamide (10 mL) was stirred with heating at 70° C. for 12 h. Cooled to ambient temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 2-(3-methyl-4-nitrophenoxy)ethanol as solid (1.3 g, y. 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[CH2:10](I)[CH3:11].C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:10][CH3:11])[C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(Br)cc(=O)[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1c(C)cc(Br)cc1=O

Procedure:
4-bromo-1-ethyl-6-methylpyridin-2(1H)-one was prepared by alkylation of 4-bromo-6-methylpyridin-2(1H)-one with ethyl iodide using K2CO3 following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@@H:29]([CH3:34])[C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH3:35]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@@H:29]([CH3:34])[C:30]([NH2:35])=[O:32])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: N
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(N)=O
Yield: 84 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with ammonia to give the title compound as a pale solid (210 mg, 84%); NMR Spectrum 1.67 (d, 3H), 5.14 (q, 1H), 5.77 (s, 2H), 6.94 (d, 1H), 7.02 (d, 1H), 7.30 (m, 1H), 7.36 (d, 1H), 7.55 (br s, 1H), 7.76-7.67 (m, 4H), 7.90 (br s, 1H), 8.15 (s, 1H), 8.52 (m, 3H), 10.80 (br s, 1H); Mass spectrum MH+ 440.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10](=[O:23])[C:11]3[C:15]=2[C:14](=[O:16])[NH:13][C:12]=3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:28][N:13]1[C:14](=[O:16])[C:15]2=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][C:10](=[O:23])[C:11]2=[C:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NC(c2ccccc2)=C2C(=O)OC(c3ccc(Br)cc3)=C12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C2=C(c3ccc(Br)cc3)OC(=O)C2=C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of furopyrrole 6 (1.5 g, 4.08 mmol), methyl tosylate (1.14 g, 6.12 mmol), potassium carbonate (1.13 g, 8.16 mmol) and dimethylformamide was stirred at room temperature overnight. Water was then added, and the organic component extracted with DCM. The solvent was removed, and washing with water then methanol gave the methylated compound 7 as a red solid (0.831 g, 53%), m.p. 215-216° C. δH (CDCl3) 8.19 and 7.61 (each 2H, AA′BB′, p-C6H4Br), 7.78-7.73 (2H, m, o-Ph), 7.54-7.50 (3H, m, m/p-Ph) and 3.38 (3H, s, NCH3). λmax (abs) (DCM)/nm 454 (ε 15,878)
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:24])([CH3:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC(C)C)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)NS(=O)(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 28.5 %

Procedure:
To a stirred solution of methyl 2-(3-(N-isopropylsulfamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (120 mg, 0.288 mmol) in methanol/tetrahydrofuran (4 mL/4 mL) was added 1N sodium hydroxide (4.32 mL). The resultant mixture was heated to reflux for 1.5 h. Organic solvent was removed and the residue was dissolved in water. The aqueous layer was acidified to pH=4. The precipitates were filtered, and redissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate. anhydrous magnesium sulfate was removed, and after evaporation, the residue was treated with dichloromethane to afford 33 mg of 2-(3-(N-isopropylsulfamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (Yield: 28%). MS(ESI+APCI) M+1=403.1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[C:3]=1[C:4]#[N:5].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>CC(N(C)C)=O.CCOC(C)=O>[NH2:5][C:4]1[C:3]2[C:6]([O:10][CH2:11][C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:7][CH:8]=[CH:9][C:2]=2[NH:1][S:23](=[O:26])(=[O:25])[N:24]=1
Reactant: NS(=O)(=O)Cl
Reactant: CCCC(=O)N1CCCC[C@@H]1COc1cccc(N)c1C#N
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCC(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a solution of (R)-2-amino-6-((1-butyrylpiperidin-2-yl)methoxy)benzonitrile (Example 16a, 1.0 g, 3.32 mmol) in DMA (15.0 mL) was added sulfamoyl chloride (2.68 g, 23.21 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen for 2 hrs and the solution was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%). The intermediate was dissolved in EtOH (25.0 mL) and aq.NaOH (2.0 N, 5.0 mL) was added at room temperature. The reaction mixture was then refluxed overnight then cooled to 0° C. and neutralized carefully with 1 N HCl. The precipitate was collected by filtration and was recrystallized with 20% water/EtOH to provide the title compound as a white solid (730 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6, room temperature) δ 0.86 (t, J=7.6 Hz, 3H), 1.35-1.76 (m, 8H), 2.28-2.32 (m, 2H), 3.14 (t, J=13.6 Hz, 1H), 3.74 (d, J=14 Hz, 1H), 4.07-4.11 (m, 1H), 4.25-4.38 (m, isomer), 4.50 (t, J=10 Hz, 1H), 5.16 (t, J=4.4 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.68 (s, isomer), 7.77 (s, 1H), 8.23 (s, 1H), 8.36 (s, isomer), 10.89 (s, 1H). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 0.88 (t, J=7.6 Hz, 3H), 1.35-1.40 (m, 1H), 1.49-1.67 (m, 7H), 1.77 (d, J=11.6 Hz, 1H), 2.27-2.32 (m, 2H), 3.85-3.90 (m, 1H), 4.18-4.20 (m, 1H), 4.07-4.11 (m, 1H), 4.46 (t, J=10 Hz, 1H), 5.00-5.03 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.81 (s, 2H), 10.64 (s, 1H). MS 381 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Cu][C:22]#[N:23].CN1CCCC1=O.O>C(OCC)(=O)C>[C:22]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)#[N:23]
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3I)nc2c1
Reactant: N#C[Cu]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 80 °C
Yield: 38 %

Procedure:
A mixture of 0.39 g of 2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of copper (I) cyanide and 2 ml of 1-methyl-2-pyrrolidinone was stirred while heating at 80° C. for 2 hours. Water and ethyl acetate were poured into the reaction mixture, which was filtered through Celite™. The resultant filtrate was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.11 g of 2-(3-cyanopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 31”).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.[C:20]([O:24][C:25](=[O:34])[NH:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)([CH3:23])([CH3:22])[CH3:21].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[N:14]([C:30]4[CH:29]=[CH:28][C:27]([NH:26][C:25](=[O:34])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:32][CH:31]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2ccc(NC(=O)OC(C)(C)C)cc2)c(=O)c1N1CCc2nc(N)ncc2C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (250 mg, 0.97 mmol), tert-butyl(4-iodophenyl)carbamate (200 mg, 0.97 mmol), N1,N2-dimethylethane-1,2-diamine (50 mg, 0.49 mmol), copper iodide (40 mg, 0.20 mmol), and potassium phosphate (410 mg, 1.94 mmol) in 2 mL of N-methylpyrrolidone was heated to 70° C. and stirred overnight (17 h). The reaction was complete and allowed to cool to room temperature. The reaction was extracted with EtOAc (3×˜5 mL) and with NaHCO3 (2×˜10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and the concentrated in vacuo. The crude mixture was then purified using the ISCO flash chromatography system using an 0-100% EtOAc/100-0% Hexane gradient mixture. Following concentration of the appropriate fractions the desired product was collected as an off white solid (115 mg, 27%). 1H NMR (DMSO) δ: 9.52 (s, 1H), 7.92 (s, 1H), 7.45-7.52 (m, 2H), 7.41 (d, J=6.7 Hz, 1H), 7.24-7.31 (m, 2H), 6.28 (s, 2H), 6.17 (d, J=7.0 Hz, 1H), 3.96 (br. S, H), 3.29 (s, 2H), 2.66(t, j=5.3 Hz, 2H), 2.18 (s, 3H), 1.39 (s, 9H)