Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=1)C.O>C(O)CCC.Cl>[ClH:1].[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[CH:20][CH:21]=1)[CH:27]=[CH2:28]
Reactant: C=CCOc1ccc(OCC(OCC)OCC)cc1
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: C=CCOc1ccc(OCC2NCCc3cc(O)c(O)cc32)cc1
Yield: 94.8 %

Procedure:
A solution of 3,4-dihydroxyphenethylamine hydrochloride (3.3 g) and (4-allyloxyphenoxy)acetaldehyde diethyl acetal (5.2 g) in a mixture of n-butanol (45 ml), water (12 ml) and concentrated hydrochloric acid (2 drops) was refluxed for 4 hours. After the reaction, the reaction mixture was concentrated to dryness. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixed solvent of 99% ethanol and ether to give 1-(4-allyloxyphenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (6.0 g), mp 114° to 116° C.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[C:9](Cl)=[N:10][C:11]([S:15][CH3:16])=[N:12][C:13]=2[Cl:14])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:27][NH2:28]>C1COCC1>[Cl:14][C:13]1[N:12]=[C:11]([S:15][CH3:16])[N:10]=[C:9]2[NH:27][N:28]=[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]=12
Reactant: NN
Reactant: CSc1nc(Cl)c(C(=O)C2CCCC2)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSc1nc(Cl)c2c(C3CCCC3)n[nH]c2n1
Temperature: 0 °C
Yield: 119.2 %

Procedure:
Cyclopentyl-(4,6-dichloro-2-methylsulfanyl-pyrimidin-5-yl)-methanone (2.0 g, 6.868 mmol) was dissolved in 25 mL dry THF and stirred at 0° C. under nitrogen. N,N-diisopropylethylamine (2.392 mL, 13.763 mmol) was added dropwise, and the reaction mixture was stirred for five minutes. Hydrazine (0.205 mL, 6.525 mmol) was added dropwise, and the reaction was stirred for 16 hours, during which time the reaction mixture was allowed to warm to room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic phase was separated, washed with water, washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to give 2.09 g of 4-Chloro-3-cyclopentyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=270.
Reaction SMILES: Br[C:2]([CH3:16])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1COCC1.C([Li])CCC.Cl[P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:4]1([C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([P:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(Br)=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=C(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Temperature: -70 °C
Reaction time: 13 h
Yield: 57.1 %

Procedure:
Into a reactor were introduced 1.37 g (5.00 mmol) of the 2-bromo-1,1-diphenylpropene and 14 mL of THF under a nitrogen atmosphere. The contents were cooled to −70° C., and 3.4 mL (5.5 mmol; 1.6 M hexane solution) of butyllithium was gradually added dropwise thereto. The resultant mixture was stirred for 30 minutes. Thereafter, 1.1 mL (6.0 mmol) of chlorodiphenylphosphine was added, and this mixture was heated to room temperature and then stirred for 13 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 1.08 g (60%) of the target compound as white crystals.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7][C:6]=2[C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[N:35]([CH:37]=[O:38])C.CO>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7][C:6]=2[C:5]([C:37](=[O:38])[NH2:35])=[CH:4][CH:3]=1
Reactant: CCCN(C(C)C)[C@H]1COc2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCN(C(C)C)[C@H]1COc2c(F)ccc(C(N)=O)c2C1
Temperature: 70 °C
Reaction time: 7.5 h
Yield: 71 %

Procedure:
(R)-8-Fluoro-3-(N-isopropyl-N-n-propylamino)-5-trifluoromethanesulfonyloxy-3,4-dihydro-2H-1-benzopyran (2.4 g, 6.0 mmol), triethylamine (1.3 g, 12.9 mmol), 1,3-bis(diphenylphosphino)propane (95 mg, catalytic amount), palladium(II)acetate (48 mg, catalytic amount) and DMF/MeOH (30 mL, 3:1) were mixed in a 50 mL three necked round bottom flask. The flask was evacuated followed by the inlet of CO (repeated two times). The reaction mixture was stirred at 70° C. for 7.5 hours. The solvent was removed in vacuo and the residue was dissolved in diethyl ether/sat. NaHCO3. The layers were separated and the water phase was extracted once with ether. The combined ether layers were dried (MgSO4) and the solvent was removed in vacuo to give a crude which was purified by flash chromatography (SiO2, hexane/EtOAC, 9:1) to give 1.3 g of the title compound (71% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:4]2[CH2:5][CH2:6][CH:2]([CH3:1])[CH2:3]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC1CCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(C)C2)cc1
Yield: 92.5 %

Procedure:
3-Methylcyclopentanol (5.0 g, 49.9 mmol) was reacted with p-toluenesulfonyl chloride in pyridine (50 ml) in the same procedure as in Reference Example 7 to obtain 3-methylcyclopentyl p-toluenesulfonate (11.7 g, 46.2 mmol, 92.5% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][CH2:22][NH:23][OH:24])[CH:16]=3)[C:11]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][N:27]=[C:28]=[O:29]>O1CCOCC1.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][CH2:22][N:23]([C:28]([NH:27][CH3:26])=[O:29])[OH:24])[CH:16]=3)[C:11]2=[O:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccc(OCCNO)cc2CCN1CCCc1ccccc1
Reactant: CN=C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O
Reaction time: 12 h

Procedure:
2-(3-Phenylpropyl)-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (498 mg, 1.5 mmol) is dissolved in dioxane (15 mL) and methyl isocyanate (0.22 mL, 3.7 mmol) is added. After 12 hours, the reaction mixture is diluted with EtOAc (150 mL) and the organic phase washed with 2N HCl (2×200 mL), H2O (4×200 mL), saturated NaHCO3 solution (2×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The resulting material is triturated with hexanes and recrystallized from CH2Cl2 /hexanes to give 2-(3-phenyipropyl)-6-{2-[N-(methylaminocarbonyl)-N-hydroxyamino]-ethoxy}-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 138°-139°.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH:13]1([NH:16][CH2:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH2:15][CH2:14]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:13]1([NH:16][CH2:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:9]([C:5]2[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=2[CH3:8])=[O:11])[CH2:15][CH2:14]1
Reactant: C1CN[C@H](CNC2CC2)C1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (270 mg, 1.61 mmol), cyclopropyl-(S)-1-pyrrolidin-2-ylmethyl-amine (220 mg, 1.57 mmol), HOBt (199 mg, 1.47 mmol), EDAC (344 mg, 1.8 mmol) and TEA (0.5 mL) in DMF (7 mL) was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was dried, concentrated and filtered through silica gel to give 4-((S)-2-cyclopropylaminomethyl-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([C:26](=[O:31])N(OC)C)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([C:26]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=2)=[O:31])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Brc1ccc(Br)nc1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Br)cn2)C1
Temperature: -80 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
Add dropwise n-BuLi (3.2 mL, 5.1 mmol) to an suspension of 2,5-dibromopyridine (1.0 g, 4.2 mmol) in dry toluene (50 mL) at −80° C. under nitrogen. Allow the mixture to stir at −80° C. for 2 h. Slowly add a solution of 3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.4 g, 5.5 mmol) in dry toluene (10 mL). Allow the reaction mixture to stir for 1 h at −78° C., then warm to −10° C. Quench the mixture with saturated NH4Cl (1 mL) and warm to RT. Separate the organic layer and concentrate. Purify the crude material by flash chromatography, eluting with 10-20% ethylacetate/hexane to give 0.61 g (43%) of the title compound. LC-MS/ES m/z (79Br) 299 [M-tert-Bu+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH3:19])=[O:17]>C1(C)C=CC=CC=1>[CH3:19][O:18][C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:17]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: COC(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Yield: 42.1 %

Procedure:
6.0 g (31.7 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone and 3.3 g (34.9 millimoles) of methyl chloroformate in 100 ml of absolute toluene are kept for 6 hours at 80° C. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from dimethylformamide/water. 3.3 g (42% of theory) of 4,5-dihydro-6-(p-methoxycarbonylaminophenyl)-3(2H)-pyridazinone are obtained as beige crystals, of melting point 246°-247° C. (with decomposition).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:38])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([CH:35]=[CH:36][CH:37]=1)[CH2:20][N:21]([CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)C(=O)OC(C)(C)C)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:38])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:37]=[CH:36][CH:35]=[C:19]([CH2:20][NH:21][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(CNC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
To a solution of tert-butyl 3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (450 mg, crude) in DCM (6 mL) was added TFA (6 mL). The mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated, and the residue was purified by prep-HPLC to give the title product (200 mg, 54.9%). 1H NMR (CD3OD, 400 MHz): δ 8.08 (s, 1H), 8.00-7.89 (m, 1H), 7.81-7.68 (m, 1H), 7.58 (s, 1H), 7.39-7.15 (m, 4H), 4.75-4.47 (m, 2H), 4.46-4.39 (m, 1H), 4.34 (s, 2H), 4.05 (dd, J=11.6, 3.6 Hz, 2H), 3.98-3.70 (brs, 1H), 3.62-3.55 (m, 2H), 3.55-3.45 (m, 4H), 3.45-3.32 (m, 2H), 3.32-3.06 (m, 2H), 2.22-2.07 (m, 2H), 1.89-1.72 (m, 2H). LCMS (m/z): 424.2 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=O.Cl.Cl.[NH2:20][CH:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1>>[N:23]12[CH2:28][CH2:27][CH:26]([CH2:25][CH2:24]1)[CH:21]([NH:20][C:15]([C:2]1[CH:3]=[CH:4][C:5]3[C:14](=[N:13][C:12]4[C:7]([N:6]=3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=1)=[O:17])[CH2:22]2
Reactant: O=C(O)c1ccc2nc3ccccc3nc2c1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1ccc2nc3ccccc3nc2c1
Yield: 25.2 %

Procedure:
Prepared in analogy to the method for Example 1 starting from 236 mg of phenazine-2-carboxylic acid and 200 mg of 3-aminoquinuclidine dihydrochloride. 84 mg (25% yield) of the free base were obtained after chromatographic separation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>>[S:17]([CH2:20][CH2:14][CH2:15][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:9][CH2:10]1)([OH:19])(=[O:18])=[O:16]
Reactant: O=S1(=O)CCCO1
Reactant: Clc1ccccc1N1CCNCC1
Product: O=S(=O)(O)CCCN1CCN(c2ccccc2Cl)CC1

Procedure:
The reaction is conducted in the same manner as in Example 4 except that 4.2 g (21.4 mmols) of 1-(o-chlorophenyl)piperazine and 3.2 g (26.2 mmols) of 1,3-propanesultone are used. The resulting product is recrystallized from water.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[C:9](Br)[CH:8]=[C:7]([Br:12])[CH:6]=1>CN(C=O)C>[Br:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[CH:8]=[C:7]([Br:12])[CH:6]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(Br)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
Sodium methoxide (25 g; WAKO) was added to a DMF (250 mL) solution of 1,3,5-tribromobenzene (75 g; TCI) and the resulting mixture was stirred at 90° C. for 15 minutes. The reaction mixture was concentrated, aqueous ammonium chloride (400 mL) and ethyl acetate (400 mL) were added to extract the reaction mixture, the organic layer was washed with saturated brine (200 mL×2), and the organic layer was dried. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (n-hexane) to give the title compound (39.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[N:7]([CH3:10])[CH:8]=[N:9][C:5]=2[CH:4]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].COCCO.[ClH:33]>C(O)(C)C>[ClH:33].[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[N:7]([CH3:10])[C:8]([N:25]3[CH2:26][CH2:27][N:22]([C:20]([C:16]4[O:15][CH:19]=[CH:18][CH:17]=4)=[O:21])[CH2:23][CH2:24]3)=[N:9][C:5]=2[CH:4]=1
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: COc1cc2ncn(C)c2cc1OC
Agent: Cl
Solvent: COCCO
Solvent: CC(C)O
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)n(C)c2cc1OC

Procedure:
3.50 g. 2-chloro. 5,6-dimethoxy-1-methyl benzimidazole [(J. Org. Chem. USSR 1 1466), (1965)] 7.00 g N-(2-furoyl) piperazine, and 25 ml 2-methoxyethanol were reacted as described in Example I. The product was converted to its hydrochloride by dissolving in isopropyl alcohol and acidifying with a solution of HCl gas in isopropyl alcohol. Yield: 3.99 g product, mp 212°-215° C decomp.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[C:5]21[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2.O.[NH2:21][CH2:22][C@H:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]3[CH:3]=[CH:2][N:21]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:12]=32)=[CH:7][CH:8]=1
Reactant: C[C@@H](O)CN
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C21CCCCC1
Reaction time: 0.75 h
Yield: 83 %

Procedure:
A solution of 2.56 g of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 2:3). 2.45 g (83%) of (R)-1-[7'-methyl-1',4'-dihydro-spiro[cyclohexane-1,4'-indeno[1,2-b]pyrrole]-1'-yl]-propan-2-ol were obtained as a brown oil.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[OH:22][C:7]1[C:8]2[S:14][C:13]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(Nc3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(Nc3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A mixture of 7-hydroxy-2-phenylamino-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (39 mg, 0.12 mmol) and glycine (186 mg, 2.48 mmol) in 0.5 M sodium methoxide/methanol (4.7 mL) was refluxed for 22 h before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (20 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.5 mL). The suspension was extracted with ethyl acetate (2×30 mL) and chloroform/isopropanol (3:1, 40 mL). The organic layer was combined and dried in vacuo to give the title compound as a brown solid (35 mg): 1H NMR (DMSO-d6, 200 MHz): δ=12.99 (br s, 1H), 11.00 (s, 1H), 9.25 (t, 1H), 8.47 (s, 1H), 7.77 (m, 2H), 7.39 (t, 2H), 7.09 (t, 1H), 4.00 (d, J=6.3 Hz, 2H); MS: (+) m/z 345.07 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18]2)[N:3]=1.[C:24]([O-:27])(O)=[O:25].[Na+]>C1COCC1.O>[C:8]1([CH2:6][O:27][C:24](=[O:25])[NH:23][C@@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([C:4]3[CH:5]=[C:6]([C:8]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=4)[N:7]=[C:2]([NH2:1])[N:3]=3)[CH2:18]2)[CH:15]=[CH:14][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@@H](N)C3)nc(N)n2)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCC[C@@H](NC(=O)OCc4ccccc4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-{2-amino-6-[(3R)-3-amino-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (125 mg, 0.324 mmol) in THF (4 mL) and saturated NaHCO3 (2 mL) was added phenylmethyl chloridocarbonate (0.055 mL, 0.389 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with water (10 mL), then extracted with EtOAc (3×10 mL). The organic was combined, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated to afford the crude title compound (155 mg) as a yellow oil. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: S(Cl)(Cl)(=O)=O.CS[S:8][CH3:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:16]=[C:15]2[CH2:28][C:29]([NH2:31])=[O:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([S:8][CH3:9])=[C:15]2[CH2:28][C:29]([NH2:31])=[O:30]
Reactant: COc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Reactant: CSSC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(N)=O)c(SC)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
Sulfuryl chloride (0.8 mL, 10 mmol) was added to an ice-bath cooled solution of 1.0 mL of dimethyldisulfide in 25 mL of methylene chloride, the cooling bath removed, and the mixture allowed to warm to room temperature. Three mL of this solution (containing methanesulfenyl chloride) was added to 320 mg (1.1 mmol) of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (Example 3) in 100 mL of methylene chloride, stirred 0.33 hours, saturated NaHCO3 solution added, stirred well, and the methylene chloride solution separated, washed with saturated NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue chromatographed on silica was eluted with 40% EtOAc/hexane→100% EtOAc to give 115 mg (31% yield) of 5-methoxy-2-(methylthio)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 195-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]1([C:29]2[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)[O:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:32]2[O:31][N:30]=[C:29]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:33]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1cc(-c2ccccc2)no1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(-c5ccccc5)no4)c3)c2cc1OC
Yield: 44 %

Procedure:
The title compound was prepared according to the procedure described in Example 113C, by using compound 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol) and compound phenyl 3-phenylisoxazol-5-ylcarbamate from the previous step (126 mg, 0.45 mmol) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-phenylisoxazol-5-yl)urea as a white solid (63.34 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 10.4 (s, 1H), 9.14 (s, 1H), 8.5 (s, 1H), 7.83 (d, 2H), 7.83-7.48 (m, 7H), 7.42 (d, 1H), 7.00 (d, 1H), 6.56 (s, 1H), 4.00 (s, 6H); LC-MS (ESI) m/z 484 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]1(C)C=CC(S(O)(=O)=O)=C[CH:12]=1.C(OCC)(OCC)(OCC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]=[C:11]([CH3:12])[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1
Product: Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 8 h

Procedure:
A mixture of 4,5-dichloro-1,2-phenylenediamine (25 g, 0.14 mol) and a catalytic amount of p-toluenesulfonic acid suspended in toluene (200 mL) is heated to reflux in a 500 mL three-necked flask fitted with a reflux condenser and addition funnel. Triethyl orthoacetate (23 g, 0.14 mol) is added dropwise over the course of 2 hours. The reflux condenser is then replaced with a distillation head and approximately 50 mL of solvent (mixture of ethanol and toluene) is collected. The remaining reaction mixture is allowed to stand at room temperature overnight. The resulting solid is collected by suction filtration and dried under vacuum for 24 hrs. The product is used without further purification.