Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH:15]([NH:17][NH:18][CH:19]=O)=O>>[N:17]1[N:18]=[CH:19][N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[CH:15]=1
Reactant: Nc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: O=CNNC=O
Product: O=C1CCC(c2ccc(-n3cnnc3)cc2)=NN1
Temperature: 220 °C

Procedure:
A mixture of 6-(4-aminophenyl)-3(2H)-pyridazinone (3.78 g, 0.02 mol) and diformylhydrazine (1.76, 0.02 mol) are heated together at 220° C. for six hours. The solid mass is chromatographed and finally crystallized from acetonitrile/methanol to yield the product 4,5-dihydro-6-[4-(4H-1,2,4-triazol-4-yl)phenyl]-3(2H)-pyridazinone, mp 292.5°-293° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:21]3([OH:31])[CH2:30][CH2:29][C:24]4(OCC[O:25]4)[CH2:23][CH2:22]3)[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:21]3([OH:31])[CH2:22][CH2:23][C:24](=[O:25])[CH2:29][CH2:30]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C3(O)CCC(=O)CC3)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To a solution of 8-(5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 33) (756 mg, 1.71 mmol) in tetrahydrofuran (4.3 mL), 6 M hydrochloric acid (8.6 mL) was added, and the obtained solution was stirred at room temperature for 15 hours. The reaction solution was cooled in ice, and 50% aqueous sodium hydroxide solution was added dropwise thereto at 0° C. until it became basic. Thereafter, the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (619 mg, 1.56 mmol, 91%) as an amorphous product.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: CS(=O)(=O)c1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methylsulfonylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methylsulfonylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:4][C:5]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([NH:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[N:6][C:5]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[N:4][C:3]=1[N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Solvent: c1ccncc1
Product: CC(=O)Nc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Yield: 43 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. A solution of 5-amino-2-(4-phenylpiperazin-1-yl)-4,6-dimorpholinopyrimidine (700 mg, 1.64 mmol), acetic anhydride (5 ml), and pyridine (a few drops) was agitated for 1 hour at 60 degrees Celsius. The deposited solid was captured by filtering, washed with ether, and 330 mg of 5-acetylamino-4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained (43% yield). The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 77 are shown below.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([C:13](OC)=[O:14])=[CH:12][C:4]=2[O:3]1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1.C(=O)=O.CC(C)=O>[OH:14][CH2:13][C:11]1[CH:10]=[CH:9][C:5]2[NH:6][C:7](=[O:8])[C:2]([CH3:17])([CH3:1])[O:3][C:4]=2[CH:12]=1
Reactant: COC(=O)c1ccc2c(c1)OC(C)(C)C(=O)N2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC1(C)Oc2cc(CO)ccc2NC1=O
Reaction time: 2.5 h
Yield: 44.2 %

Procedure:
To a solution of methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin -7-carboxylate (1.00 g) in tetrahydrofuran (50 mL) was added dropwise 1M diisobutyl aluminum hydride solution in toluene (13.1 mL) under cooling in dry ice/acetone bath under argon atmosphere, and the mixture was stirred at the same temperature for 2.5 hours. Thereto was further added 1M diisobutyl aluminum hydride solution in toluene (8.5 mL), and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured to an aqueous 2N HCl solution, and the mixture was extracted with diethylether. The organic layer was washed successively with an aqueous saturated sodium hydrogencarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ethyl acetate to give 7-(hydroxymethyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one (389 mg) as a colorless powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CN(C)C=O.C(Cl)(=O)C([Cl:19])=O>ClCCl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([Cl:19])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tetrahydro-2H-pyran-4-ylacetic acid (89 mg), N,N-dimethyl formamide (1 μL), and dichloromethane (1 mL) was added oxalylchloride (54 μL), and the mixture was stirred at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, and then toluene (1 mL) was added thereto, followed by further concentration under reduced pressure, to obtain crude tetrahydro-2H-pyran-4-yl acetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[CH:7]=[C:8]([SH:10])[S:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16]I>>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[CH:7]=[C:8]([S:10][CH3:16])[S:9][C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1cc(S)sc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Product: CSc1cc(=O)c2ccc(F)cc2s1
Yield: 61.9 %

Procedure:
7-Fluoro-2-mercapto-4-oxo-4H-1-benzothiopyran(2.12 g, 10.0 mmol), sodium hydride (567.2 mg, 13.0 mmol) and methyl iodide (0.93 ml, 15.0 mmol) were used to conduct the process simiar to (1) of the Preparation 3, thus obtaining 1.40 g (yield: 62%) of 7-fluoro-2-methylthio-4-oxo-4H-1-benzothiopyran as light yellow powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(OCC)(=O)C>[I:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:5]=1
Reactant: BrCc1ccc(I)cc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: Ic1ccc(CN2CCOCC2)cc1
Temperature: 70 °C

Procedure:
1-Bromomethyl-4-iodobenzene (320 mg, 1.08 mmol) and morpholine (1 mL, 11.47 mmol) were combined. The reaction mixture was heated at 70° C. for 4 hours and then diluted with ethyl acetate. The resulting mixture was filtered and the filtrate was concentrated and dried. The residue was then dissolved in dichloromethane (10 mL), washed with water (4 mL), washed with brine (4 mL), dried over sodium sulfate and concentrated to give the product as an off-white solid ±300 mg, 92%). 1H NMR (300 MHz, CDCl3): δ 7.64 (d, 2H), 7.09 (d, 2H), 3.7 (t, 4H), 3.43 (s, 2H), 2.43 (t, 4H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([C:20](=[O:25])[NH:21][CH2:22][C:23]#[N:24])[CH:17]=[C:16]([Cl:26])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH:17]=[C:16]([Cl:26])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14])[C:20]([NH:21][CH2:22][C:23]#[N:24])=[O:25]
Reactant: N#CCNC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: c1cc2[nH]ccc2cn1
Product: N#CCNC(=O)c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
3,5-Dichloro-N-(cyanomethyl)-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)benzamide (Compound No. 76) was prepared using 1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-[(cyanomethyl)carbamoyl]benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH2:25][OH:26]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:24][CH2:25][OH:26])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: OCCI
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1oc2cccc(OCCO)c2c1C

Procedure:
4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (100 mg), potassium carbonate (500 mg) and 2-iodoethanol (195 μl) were suspended in acetonitrile (10 ml). The mixture was refluxed overnight. Inorganic salt was filtered out and the mother solution was evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography developed by ethyl acetate-hexane to give 4-(2-hydroxy-ethoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (77 mg) as a white powder. FAB-MS: m/z 265 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[N:10]=1.O[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:18][CH:17]=1>>[N:25]1([CH2:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:14][CH2:13][CH2:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[O:7][CH:8]=3)=[CH:17][CH:18]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: OCCCc1coc(-c2cccs2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1csc(-c2nc(CCCOc3ccc(CCCn4ccnc4)cc3)co2)c1
Yield: 72 %

Procedure:
In substantially the same manner as in Working Example 146, 3-[2-(2-thienyl)-4-oxazolyl]propanol was mesylated and then reacted with 1-[3-(4-hydroxyphenyl)propyl]imidazole to obtain 4-[3-[4-[3-(1-imidazolyl)propyl]phenoxy]propyl]-2-(2-thienyl)oxazole. The yield was 72%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 99-100° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=O)[CH:4]=1.S(Cl)([Cl:13])=O>N1C=CC=CC=1>[Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([Cl:13])=[O:10])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(CCl)on1
Solvent: c1ccncc1
Product: O=C(Cl)c1cc(CCl)on1

Procedure:
120 g (743 mmol) of 5-chloromethylisoxazole-3-carboxylic acid were refluxed together with 500 ml of thionyl chloride and 2 drops of pyridine for 10 h, then concentrated under reduced pressure and subsequently distilled under 20 torr. The product distilled at 125-133° C. to result in 78 g (58% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1F.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>CN1C(=O)CCC1>[CH2:13]([O:20][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)Cc1ccc(Cl)c(OCc2ccccc2)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 4-chloro-3-fluorophenylacetic acid (5 g, 26.5 mmol) and benzyl alcohol (5.5 mL, 53.0 mmol) in NMP (50 mL) at 0° C. was added sodium hydride (60% in mineral oil; 2.3 g, 58.3 mmol), and the reaction was then heated to 120° C. and stirred overnight. The mixture was acidified to pH 4 and extracted with EtOAc to give (3-benzyloxy-4-chloro-phenyl)-acetic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]([C:16](OCCC)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]([CH2:16][OH:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCCOC(=O)c1cc(CCCOC)nc2ccccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: COCCCc1cc(CO)c2ccccc2n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of propyl 2-(3-methoxypropyl]quinoline-4-carboxylate from the previous step (1 eq.) in toluene (0.1 M) was added at −78° C. DIBAL (1.5 M toluene solution, 2 eq.) dropwise over 10 min. The reaction mixture was stirred at −78° C. for 30 min and then at 0° C. for 2 h. The reaction mixture was quenched with sat. aq. Rochelle's salt and extracted with EtOAc. The combined organic extracts were washed sequentially with water, sat. aq. NaHCO3 and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a milky oil. Purification by way of column chromatography (SiO2, 10:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:22])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][O:21][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:15][CH2:14]2)[CH3:11])=[O:22])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@H](CCO)CC1)C(=O)Oc1ccc(Cl)cc1
Product: CN(C[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 2-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexyl)-ethyl ester as colorless viscous oil, MS: 404 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](S(C1C=CC(C)=CC=1)(=O)=O)[CH:13]=[C:12]2[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30]([N:36]2[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]2)[N:29]=1.[OH-].[Na+]>O1CCOCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30]([N:36]2[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]2)[N:29]=1
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4c(F)cccc4F)cc23)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(-c2c[nH]c3ccc(-c4c(F)cccc4F)cc23)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Yield: 53.7 %

Procedure:
To a solution of tert-butyl (1-(4-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamate (60 mg, 0.087 mmol) in dioxane (0.8 mL) was added 7M aq.NaOH (1 mL) and the mixture was heated at 90° C. for 6 h. The reaction was quenched with water and the suspension was filtered. The resulting solid was washed with water and dried. The crude was purified with basic alumina chromatography to give tert-butyl (1-(4-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamate (25 mg, 54%). 1H-NMR (300 MHz, DMSO-d6): δ 11.80 (brs, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.40-7.55 (m, 2H), 7.18-7.26 (m, 4H), 6.85 (d, J=7.5 Hz, 1H) 6.49 (s, 1H), 4.66 (d, J=11.7 Hz, 2H), 3.84 (s, 3H), 3.52 (brs, 2H), 2.97-3.05 (m, 2H), 1.7 (brs, 2H), 1.38 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24](O)=[O:25].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH2:36][NH:35][CH2:34][CH2:33]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[N:6]=[C:5]2[C:24]([N:35]1[CH2:34][CH2:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([O:29][CH3:28])[CH:31]=2)[CH2:36]1)=[O:25]
Reactant: COc1ccc2c(c1)CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1ccc2c(c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccc(F)cc13)C2
Yield: 53.8 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 105 (53.8% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.84 and 2.90 (2t, 2H), 3.60 and 4.06 (2t, 2H), 3.76-3.3.81 (m, 6H), 3.85 and 3.92 (2s, 6H), 4.55 and 4.98 (2s, 2H), 6.50-7.27 (m, 3H), 7.62-7.86 (m, 3H), 7.98-8.07 (m, 1H), 8.23-8.28 (m, 1H); MS (ESI) m/z 504 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[C:12]([NH:15][NH2:16])(=O)[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]2[O:8][C:12]([CH3:13])=[N:15][N:16]=2)=[CH:9][CH:10]=1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Reactant: CC(=O)NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: N#CC(Cl)(Cl)Cl
Product: Cc1nnc(-c2ccc(Cl)nc2C)o1
Temperature: 150 °C

Procedure:
6-Chloro-2-methylnicotinic acid (200 mg, 1.2 mmol), acetohydrazide (95 mg, 1.3 mmol), solid supported triphenylphosphine on polystyrene (1.88 mmol/g loading, 1.94 g, 3.5 mmol) were placed in a microwave vial. Dry acetonitrile (16.7 ml) followed by trichloroacetonitrile (0.23 ml, 2.33 mmol) were added and the vial was heated in a microwave at 150° C. for 20 minutes. It was allowed to cool to room temperature, filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(C(F)(F)F)=O.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:2]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:6][CH:5]=[CH:4][C:3]=23)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COc2ccc(Oc3ccnc4[nH]ccc34)cc2)cc1
Temperature: 140 °C

Procedure:
To a N2 purged round bottom flask was added 4-chloro-7-azaindole (15.8 g, 104 mmol, 1.0 eq.) followed by 4-benzyloxyphenol (41.5 g, 207 mmol, 2.0 eq), 20 ml of TFA/Et3N (1/1, 107 mmol, 1.0 eq.) and DMAP (13 g, 106 mmol, 1.0 eq.). The reaction was heated to 140° C. for 48 h. The mixture was cooled to RT and diluted with CH2Cl2 (100 mL) Silica gel was added and the mixture was evaporated to dryness onto the silica. The crude mixture was purified by column chromatography (20-100% EtOAc/Hexane) to give 4-(4-benzyloxy-phenoxy)-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[N:9]2)=[N:6][CH:7]=1>CN(C)C=O.[C].[Pd]>[CH3:13][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][N:6]=2)[N:9]=[CH:10][C:11]=1[C:14]([OH:16])=[O:15]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Br)cn1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)O)cnn1-c1ccccn1
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (30 mg) described in Reference Example 24 in N,N-dimethylformamide (1 ml) was added 10% palladium carbon (containing about 50% water) (10 mg) at room temperature, and stirred at the same temperature for 30 minutes under hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, then the solvent was evaporated in vacuo, azeotropically concentrated together with toluene to give the titled compound (23 mg) as a white solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1>O1CCCC1.C(OCC)C.[Cl-].[NH4+]>[CH2:3]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)[CH:2]=[CH2:1]
Reactant: C=CCBr
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCc1ccc(F)cc1
Reaction time: 16 h

Procedure:
Allyl bromide (4.33 mL, 50 mmol) was added dropwise to a solution of 4-fluorophenyl magnesium bromide (50 mmol) in tetrahydrofuran (25 mL) and diethyl ether (25 mL). After 16 hours, the reaction suspension was diluted with diethyl ether (100 mL) and saturated aqueous ammonium chloride (50 mL). The layers were separated, and the organic layer was washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13](Br)[CH:14]=1.[C-]#N.[Na+].CN([CH:23]=[O:24])C>O>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13]([O:24][CH3:23])[CH:14]=1
Reactant: CN(C)C=O
Reactant: CN1CCC[C@H]1COc1cc(Br)c[n+]([O-])c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1cc(OC[C@@H]2CCCN2C)c[n+]([O-])c1

Procedure:
A sample of 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5bromo-pyridine-N-oxide, from Example 98a above, is reacted with sodium cyanide in DMF and water according to standard procedures. The solvents are removed, and the product is extracted, then purified by chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]=[CH2:17])=[C:10]([Cl:18])[CH:9]=1.[H][H]>C(O)C.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([Cl:18])[CH:9]=1
Reactant: [H][H]
Reactant: C=CCOc1ccc(CC(=O)NCC(=O)OC)cc1Cl
Agent: O=[Pt]=O
Solvent: CCO
Product: CCCOc1ccc(CC(=O)NCC(=O)OC)cc1Cl
Reaction time: 5 h
Yield: 19.9 %

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-glycine methyl ester (see Example 6; 3.0 g) was dissolved in absolute ethanol (100 ml) and Adams catalyst (20 mg) was added. Hydrogenation was carried out in an atmospheric pressure hydrogenator for 5 hrs. until hydrogen (310 ml) had been taken up. The catalyst was removed from the reaction mixture by filtration, the solvent was evaporated at reduced pressure, and light petroleum (b.p. 40°-60° C.) was added to the residue; a solid product (600 mg) of m.p. 76°-80° C. was obtained. After recrystallisation from chloroform/light petroleum (b.p. 40°-60° C.), the abovenamed product (200 mg), m.p. 79°-82° C., was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:22]1[CH:23]=[CH:24][S:20][CH:21]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccsc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-thiophene boronic acid to give (6-methoxy-1-thiophen-3-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 323(MH+).