Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH3:18])=[O:16])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])(F)[F:27])[CH:21]=3)[C:11]3[CH2:30][CH2:31][C:32](=[O:33])[C:10]2=3)=[C:5](F)[CH:4]=1)#[N:2].FC(F)C1C=C(N2C3C[CH2:50][C:51](=[O:52])C=3C(C3C=CC(C#N)=CC=3)NC2=O)C=CC=1.NCCCO>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH2:18][CH2:50][CH2:51][OH:52])=[O:16])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([F:27])[F:29])[CH:21]=3)[C:11]3[CH2:30][CH2:31][C:32](=[O:33])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1F
Agent: NCCCO
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)F)c3)C(=O)N2C(=O)NCCCO)cc1

Procedure:
The title compound is prepared in analogy to 4-(4-cyano-2-fluorophenyl)-N-methyl-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxamide (example 49), using 4-(1-(3-(difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 11, 100 mg, 0.26 mmol) as starting material and replacing methylamine with 3-aminopropanol. Yield: 70 mg; ESI mass spectrum [M+H]+=481; Retention time HPLC: 0.71 min (005_CA01).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[S:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:9]1)C1C=CC=CC=1.Cl>C1COCC1.CO.[Pd]>[C:27]1([S:24]([C:18]2[C:17]3[C:21](=[CH:22][CH:23]=[C:15]([O:14][CH:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[CH:16]=3)[NH:20][N:19]=2)(=[O:25])=[O:26])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCCN(Cc4ccccc4)C3)cc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCCNC3)cc12
Reaction time: 72 h

Procedure:
A mixture of 5-(1-benzylpiperidin-3-yloxy)-3-(1-naphthylsulfonyl)-1H-indazole (0.7 g, 1.4 mmoles), 10% Pd/C and concentrated HCl (1 mL) in THF and methanol was hydrogenated in a Parr hydrogenation bottle at 52 lb/in2 for 72 hours. TLC showed about 30% conversion into desired product. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The concentrate, a mixture of starting material and product, was then separated by reverse phase chromatography on C18 column, using as eluent 10-100% H2O/AcCN, to afford the title compound as an off-white solid, 0.16 g, mp 178-180° C., identified by HNMR and mass spectral analyses, MS (ES) m/z 406.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]C(NCCCl)C#N)=[CH:4][CH:3]=1.[CH2:16]([S:18][C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:20]([CH2:21][CH2:22][C:22]2[C:23]([N+:24]([O-:26])=[O:25])=[C:19]([S:18][CH2:16][CH3:17])[NH:20][CH:21]=2)[CH2:19][C:23]#[N:24])=[CH:4][CH:3]=1
Reactant: N#CC(Cc1ccc(Cl)nc1)NCCCl
Reactant: CCSc1[nH]ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1[nH]cc(CCN(CC#N)Cc2ccc(Cl)nc2)c1[N+](=O)[O-]

Procedure:
This compound was prepared in a manner analogous to that set forth in Step G of Example 1, using 0.17 gram (0.0007 mole) of 2-{[(6-chloro(3-pyridyl)methyl] (2-chloroethylamino}ethanenitrile (prepared in Steps A and B of the present Example), 0.10 gram (0.00064 mole) of 2-ethylthio-3-nitropyrrole and 0.22 gram (0.0016 mole) of potassium carbonate in about 15 mL of DMF. The crude product was purified with column chromatography on silica gel. Elution was accomplished using 50% hexane in diethyl ether and 100% diethyl ether as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.10 gram of Compound I. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]3[N:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[C:13]=3[N:14]=2)[CH2:5][CH2:4]1)=O.Cl>C(O)C>[CH3:20][S:19][C:15]1[C:13]2[N:14]=[C:9]([N:6]3[CH2:5][CH2:4][NH:3][CH2:8][CH2:7]3)[N:10]=[C:11]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:12]=2[N:18]=[CH:17][N:16]=1
Reactant: CSc1ncnc2c(N3CCOCC3)nc(N3CCN(C=O)CC3)nc12
Agent: Cl
Solvent: CCO
Product: CSc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
1.5 gm (0.004 mol) of 2-(N-formyl-piperazino)-8-methylthio-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 205°-207° C.) were dissolved in 200 ml of absolute ethanol. After addition of 10 ml of ethanolic hydrochloric acid, the solution was refluxed for 20 minutes. The solvent was then evaporated in vacuo, and the residue was taken up in about 50 ml of water. The resulting solution of the hydrochloride was adjusted to about pH 10, whereby the free base was obtained as an initially oily precipitate which soon solidified. The precipitate was suction-filtered off, washed well with water and dried.
Reaction SMILES: N1([C:10]([CH:12]2[CH2:20][CH2:19][C:15]3[N:16]=[CH:17][NH:18][C:14]=3[CH2:13]2)=[O:11])C2C(=CC=CC=2)CC1.[OH-:21].[Na+].[ClH:23]>O>[ClH:23].[N:16]1[C:15]2[CH2:19][CH2:20][CH:12]([C:10]([OH:11])=[O:21])[CH2:13][C:14]=2[NH:18][CH:17]=1
Reactant: [OH-]
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCc2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CCc2nc[nH]c2C1

Procedure:
A 24 g portion of the above mentioned (-)-5-(2,3-dihydroindol-1-yl)carbonyl-4,5,6,7-tetrahydrobenzimidazole was dissolved in 120 ml of 6N hydrochloric acid and heated under reflux for 3 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain a residue which was then dissolved in water, made alkaline with an aqueous sodium hydroxide solution, and washed with ethyl ether. Subsequent acidification of the aqueous layer with hydrochloric acid and concentration under reduced pressure yielded a white powder of (+)-4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride containing NaCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[N:5](C(OCC)=O)[N:4]=1.[OH-].[K+]>C(O)C>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: CCOC(=O)n1nc(OC)c2ccc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1n[nH]c2cc(C(=O)O)ccc12
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
1-Ethyl 6-methyl 3-methoxy-1H-indazole-1,6-dicarboxylate (444 mg, 1.60 mmol) was suspended in ethanol (5 mL). An aqueous solution of potassium hydroxide (16 mL, 16 mmol, 1 M) was added and the reaction was heated to 65° C. and stirred for 1.5 hours. The reaction was cooled to room temperature and concentrated. The residue was taken up in water and the solution was acidified with 1 N aqueous hydrochloric acid until a precipitate formed. The solid was collected by filtration, rinsed with water, and dried under vacuum to give the title compound (232 mg, 76%) as an orange solid. +ESI (M+H) 193.2; 1H NMR (400 MHz, DMSO-d6, δ): 12.22 (s, 1H), 7.90-7.94 (m, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.53 (dd, J=8.4, 1.4 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19](OCC)=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1.[BH4-].[Na+].O>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([CH2:19][OH:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1
Reactant: CCOC(=O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Yield: 95.5 %

Procedure:
To a solution of ethyl 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (3 g, 8.73 mmol) and NaBH4 (1.58 g, 43.67 mmol) in CH3OH/dichloromethane (30 mL/10 mL) was stirred at room temperature for 2 hours. The mixture was poured to H2O and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methanol (2.54 g, yield: 95.5%). 1H-NMR (DMSO-d6, 400 MHz) δ 7.60 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.22˜7.28 (m, 1H), 7.08 (s, 1H), 6.94 (dd, J=10.4, 8.4 Hz, 1H), 6.78 (t, J=4.0 Hz, 1H), 5.29 (t, J=6.0 Hz, 1H), 3.71˜3.78 (m, 1H), 3.61˜3.67 (m, 1H). MS (M+H)+: 305.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[F:18].[Li]CCCC.CN([CH:27]=[O:28])C.CCOC(C)=O.CCCCCCC>C1COCC1>[F:18][C:3]1[CH:4]=[C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:6]=[CH:7][C:2]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of (S)-tert-butyl 1-(4-bromo-3-fluorophenyl)ethylcarbamate (318 mg, 1 mmol) in dry THF (5 mL) was cooled to −78° C. BuLi (2.5 M, 840 μL, 2.1 mmol) was added dropwise and the resulting solution was stirred at −78° C. for 1 h. Then DMF (232 μL, 3.00 mmol) was added in one portion. The reaction was stirred for another 30 min at −78° C. then quenched with sat. NH4Cl solution. The reaction was stirred at room temperature for another 30 min then diluted with EtOAc, washed with water and brine. The separated organic was dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 80%) provided (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate as a white solid (70 mg, 26.2% yield).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:3].[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:13]#[CH:14]>>[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[O:3])[CH2:17][CH2:16]1)[C:13]#[CH:14]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Product: C#CCC1CCN(C(=O)Oc2ccc(F)cc2)CC1

Procedure:
4-(fluoro)phenyl chloroformate (5.00 g, 28.6 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.90 g, 21.9 mmol) according to general procedure 1. Yield=5.54 g, 99%. m/z MH+=262.03. HPLC rt=10.6 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[N:37]([CH:38]([O:40][CH2:41][CH3:42])[CH3:39])[N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:5]2=[N:6][C:7]=1[CH:8]([O:11][CH3:12])[O:9][CH3:10]>C1(C)C=CC=CC=1.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>[CH2:16]([C:14]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([CH:38]([O:40][CH2:41][CH3:42])[CH3:39])[N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:5]2=[N:6][C:7]([CH:8]([O:11][CH3:12])[O:9][CH3:10])=[C:2]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][N:6]=3)[CH:3]=[C:4]2[N:15]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nc2cc(Br)c(C(OC)OC)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cc(-c3ccccn3)c(C(OC)OC)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Yield: 111.8 %

Procedure:
0.7 g (1.1 mmole) of the compound obtained in step 9 was dissolved in 5 ml of toluene and to the resulting solution were added 486 mg (1.32 mmole) of 2-(tributyltin)-pyridine and 25 mg (0.022 mmole) of Pd(PPh3)4. The resultant was heated to reflux for 16 hours under argon gas, cooled and extracted with a mixture of ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate) to obtain 389 mg of the title compound (yield 56%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH3:7].C([Li])CCC.[S:23](Cl)([Cl:26])(=[O:25])=[O:24]>C1COCC1>[C:11]([O:10][C:8]([N:5]([CH2:6][CH3:7])[C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([S:23]([Cl:26])(=[O:25])=[O:24])[CH:3]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)c1cccc(S(=O)(=O)Cl)c1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 93.8 %

Procedure:
3-Bromo-N-tert-butoxycarbonyl-N-ethylaniline (3.0 mmol) was dissolved in freshly distilled THF (25 ml) under a N2 atmosphere. The solution was chilled to −78° C. and butyl lithium (1.8 ml, 2.0 M solution in cyclohexane, 3.6 mmol) was added. After 35 minutes, sulfuryl chloride (0.30 ml, 3.6 mmol) was added over ˜2 minutes. The reaction was stirred for 5 minutes at −78° C. then was allowed to warm to room temperature. After 30 minutes at room temperature the reaction was cooled to −78° C. and quenched with a saturated ammonium chloride solution. The THF was removed by evaporation and the resulting residue was and partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O and brine before being dried with Na2SO4. The solvent was removed in vacuo to give 900 mg of crude product. HPLC showed the material to be ˜80% pure and it was used as is. LC/MS (ES): 320.1 (M+1).
Reaction SMILES: [N:1]1O[C:3]([O-])=[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][N+:5]=12.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#C)=[CH:14][CH:13]=1>C1(C)C=C(C)C=C(C)C=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:3]=[C:4]3[CH2:9][CH2:8][CH2:7][CH2:6][N:5]3[N:1]=2)=[CH:14][CH:13]=1
Reactant: [O-]c1on[n+]2c1CCCC2
Reactant: C#Cc1ccc(F)cc1
Solvent: Cc1cc(C)cc(C)c1
Product: Fc1ccc(-c2cc3n(n2)CCCC3)cc1
Temperature: 165 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
A mixture of 2.44 g (16.5 mmol) of 4,5,6,7-tetrahydro[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium 3-olate and 2.15 g (16.5 mmol) of 4-fluorophenylacetylene in 80 ml of mesitylene is stirred under argon at 165° C. for 16 h. After cooling, the reaction mixture is concentrated under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 888 mg (27%) of the desired product; log P(HCOOH): 2.76; 1H-NMR (MeCN-d3): 7.76 (dd, 2H), 7.11 (dd, 2H), 6.29 (s, 1H), 4.09 (dd, 2H), 2.79 (dd, 2H), 2.02 (m, 2H), 1.84 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=3)[O:16][C:10]=2[N:11]=[C:12]([S:14][CH3:15])[N:13]=1.Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C)C=O>[Cl:7][C:8]1[C:9]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:21]([CH3:27])[CH:20]=3)[O:16][C:10]=2[N:11]=[C:12]([S:14][CH3:15])[N:13]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CSc1nc(Cl)c2nc(-c3cc(C)c(O)c(C)c3)oc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2nc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)oc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
7.46 g of potassium carbonate were added to a solution of 4.34 g of 4-(7-chloro-5-methylsulfanyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenol in 45 ml of dimethylformamide, and 2.90 g of tert-butyl bromoacetate were then added. The mixture was stirred at 60° C. for 1 h. The cooled reaction mixture was then added to ice water, and the precipitated solid was filtered off with suction and washed with water. The solid was taken up in dichloromethane and dried over sodium sulfate, activated carbon was added and the mixture was filtered and concentrated under reduced pressure. This gave 4.20 g (71%) of the title compound, which was reacted further without any further purification.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[CH3:24])C.[NH2:26][NH2:27]>CCO.O>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:6]([CH2:5][C:4]([NH:26][NH2:27])=[O:3])=[C:7]([CH3:24])[N:8]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NN
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2)c2cccc(OC)c12
Solvent: O
Solvent: CCO
Product: COc1cccc2c1c(CC(=O)NN)c(C)n2Cc1ccccc1
Yield: 75 %

Procedure:
4-Methoxy-2-methyl-l(phenylmethyl)-1H-indole-3-acetic acid hydrazide. A solution of 2.8 g (8.3 mmol) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester and 10 mL of hydrazine in 40 mL of EtOH was heated to maintain reflux for 16 hours, diluted with water and extracted with EtOAc. The EtOAc solution was washed with NaCl solution, dried (MgSO4), and concentrated at reduced pressure. The residue was crystallized from MeOH to give 2.0 g (75% yield) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide, mp, 145-147° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1)=O.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:35]=[CH:34][C:32]([NH:33][CH2:1][C:3]3[CH:12]=[C:11]4[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]4)=[CH:5][CH:4]=3)=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: N#Cc1ccc2ccc(C=O)cc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
7-Formyl-2-naphthalenecarbonitrile obtained in Reference Example 1 (849 mg) and 1,370 mg of 4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]aniline were dissolved in 10 ml of dichloromethane and 2.7 ml of acetic acid, 1,290 mg of sodium triacetoxyborohydride was added to the solution, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was washed with 2M potassium carbonate, water and 10% citric acid aqueous solution in that order, dried over sodium sulfate, and then evaporated. By recrystallizing the resulting residue from methanol, 1,698 mg of 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(OCC)C>C(O)CCC.N1CCCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: N#CCC#N
Reactant: O=Cc1ccc(Cl)cc1Cl
Solvent: CCCCO
Solvent: CCOCC
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon, 2,4-dichlorobenzaldehyde (30.00 g, 171 mmol) and malononitrile (13.59 g, 206 mmol) were suspended in 1-butanol (350 ml). After stirring for 15 min, 8 drops of piperidine were added at room temperature. After stirring for an additional 3 h, diethyl ether was added. The precipitate was filtered and washed with diethyl ether and hexane to give the title compound, MS: m/e=222.8 (M+), as a colorless solid (35.34 g, 92%).
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[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]1([CH3:51])[CH:28]=[CH:27][C:26]([N:29]2[C:33]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)=[CH:32][C:31]([C:44]3([C:47]([F:50])([F:49])[F:48])[CH2:46][CH2:45]3)=[N:30]2)=[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[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:33]2[N:29]([C:26]3[CH:25]=[CH:24][C:23]([CH3:51])=[CH:28][CH:27]=3)[N:30]=[C:31]([C:44]3([C:47]([F:50])([F:49])[F:48])[CH2:45][CH2:46]3)[CH:32]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2NC(=O)Oc2ccccc2)cc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C5(C(F)(F)F)CC5)nn4-c4ccc(C)cc4)c3)c2cc1OC
Yield: 83.3 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol) and the carbamate from Example 346A (120 mg, 0.3 mmol) using the procedure in Example 115C to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea (152 mg, 0.25 mmol, 82%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 7.79 (s, 1H), 7.51-7.32 (m, 8H), 7.25 (d, 1H), 6.54 (s, 1H), 3.99 (s, 6H), 2.38 (s, 3H), 1.38-1.27 (m, 4H); LC-MS (ESI) m/z 621 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][N:12]([C@H:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:24][CH:25]=[CH2:26])[C:13](=[O:22])[C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B.[OH:35]O.[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][N:12]([C@H:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:24][CH2:25][CH2:26][OH:35])[C:13](=[O:22])[C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: C=CC[C@H](N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)N(NC(=O)OCc2ccccc2)[C@@H](CCCO)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a solution of (S)—N′-(1-tert-butyl-but-3-enyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester (200 mg, 0.49 mmol) in THF (3 mL), was added borane dimethyl sulfide (2 M in THF, 125 μL, 0.25 mmol) at 0° C. The mixture was stirred at room temperature for 16 h. Excess borane and THF was removed in vacuo, and additional THF (3 mL), followed by H2O2 (61 microliters, 0.54 mmol) and 3N NaOH (90 microliters, 0.27 mmol) were added. After stirring at 50-55° C. for 1 h, more water was added, the mixture was extracted with ether, and the ether layer was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography to give (S)—N′-(1-tert-butyl-4-hydroxy-butyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester as a white solid (128 mg, yield 61%). Rf=0.30 (1:1 EtOAc:n-hexane). 1H NMR (400 MHz, DMSO-d6) δ 9.71+9.63 (2s, 1H), 7.44-6.88 (m, 8H), 5.06 (dd, J=3.6, 12.8 Hz, 1H), 4.79 (dd, J=12.4, 25.2 Hz, 1H), 4.43 (d, J=10.8 Hz, 1H), 4.28 (t, J=5.2 Hz, 1H), 3.47 (m, 2H), 2.27 (s, 6H), 1.86-1.21 (m, 4H), 1.01 (s, 9H); HRMS (ESI) m/z calcd for C25H35N2O4 [M+H]+ 427.2597. found 427.2587, calcd for C25H34N2NaO4 [M+Na]+ 449.2416. found 449.2407.