Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][O:17]C(=O)C)[CH2:11]3)[CH2:9][N:8]([C:22]([NH:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][N:29]=3)=[O:23])[C:5]2=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][OH:17])[CH2:11]3)[CH2:9][N:8]([C:22]([NH:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][N:29]=3)=[O:23])[C:5]2=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(CO)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
5-Bromo-N-(5-chlorothiazol-2-yl)-1′-(2-acetoxyacetyl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (64.0 mg, 0.136 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (1 mL). Thereafter, an aqueous solution of sodium hydroxide (2 M, 0.5 mL) was added to the above obtained solution at room temperature, and the obtained mixture was then stirred for 30 minutes. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1→7:1) to obtain the captioned compound (37.8 mg, 65%) in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@:7]([CH2:11][CH2:12][C:13](O)=[O:14])([CH3:10])[C:6]1([CH3:17])[CH3:16])=[O:4].CSC.B>C1COCC1>[OH:14][CH2:13][CH2:12][CH2:11][C@:7]1([CH3:10])[CH2:8][CH2:9][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]1([CH3:17])[CH3:16]
Reactant: COC(=O)[C@H]1CC[C@@](C)(CCC(=O)O)C1(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)[C@H]1CC[C@@](C)(CCCO)C1(C)C
Reaction time: 8 h

Procedure:
To a solution of step 5 intermediate (0.645 g, 2.66 mmol) in dry THF (10 mL) under N2 atmosphere, borane dimethylsulphide (0.328 mL, 3.46 mmol) was added slowly for 30 min through a septum and stirred for overnight. The reaction mixture was quenched with water, oxone then stirred for 30 mins. Then the reaction mixture was extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure to afford the desired product (0.565 g) as colorless liquid. m/z (M+18): 246.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:10]=1.S(=O)(=O)(O)[OH:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]([NH2:20])=[O:24])=[CH:17][CH:16]=2)[N:10]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Product: NC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1

Procedure:
A solution of 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile (1.0 g, 0.003 mol) in conc. sulphuric acid (10 mL) was heated to 70° C. for 15 h. The reaction mixture was quenched in ice water. The reaction mass was basified till pH ˜6-6.5 with dilute NaOH. The obtained solid was filtered off, washed with water and suck dried to afford 0.300 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.36 (br s, 1H), 7.84 (t, 1H), 7.57 (d, 1H), 7.67 (d, 1H), 7.98 (m, 5H), 12.70 (br s, 1H); MS (m/z): 333.11 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[CH2:12]([N:19]1[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]1[CH:25]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[NH:35][C:36]([CH2:38]O)=[CH:37][C:30]=12>O1CCCC1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:25][C:20]1[N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:23]([CH3:24])=[CH:22][CH:21]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[NH:35][C:36]([CH3:38])=[CH:37][C:30]=12
Reactant: COc1ccnc2[nH]c(CO)cc12
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: Cc1ccc(C=O)n1Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(C)n1Cc1ccccc1
Product: COc1ccnc2[nH]c(C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1-Benzyl-5-methyl-1H-pyrrol-2-yl)-acrylic acid methyl ester, 5: Sodium (14.45 g, 628 mmol) was added in portions to a dry methanol (420 mL). To the fresh formed sodium methoxide solution was added dropwise the solution of trimethyl phosphonoacetate (50 mL, 302 mmol) in tetrahydrofuran (105 mL) at room temperature. After addition the mixture was stirred for additional 60 min at room temperature. Then to the reaction mixture was added dropwise the solution of 1-benzyl-5-methyl-1H-pyrrole-2-carbaldehyde, 4 (30.8 g, 154 mmol) in tetrahydrofuran (630 mL) at room temperature. The reaction mixture was stirred for 2 h at room temperature. The mixture was concentrated and redissolved in ethyl acetate (1 L). The mixture was washed with 1 M HCl solution, then saturated NaHCO3, H2O. The organic solution were dried over MgSO4 and then filtered, concentrated to afford the crude product, 3-(1-benzyl-5-methyl-1H-pyrrol-2-yl)-acrylic acid methyl ester, 5 as a light yellow solid. Yield: 40 g
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[NH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][CH:54]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60]3[C:55]2=[CH:56][CH:57]=[CH:58][CH:59]=3)=[O:51])[CH2:46][CH2:45]1>CN(C)C=O>[CH:65]1[C:66]2[CH:54]([CH2:53][O:52][C:50]([N:47]3[CH2:48][CH2:49][CH:44]([NH:43][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][C:22]([NH:21][C:19]5[N:18]=[CH:17][C:8]6[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]7[CH2:5][CH2:4][CH2:3][CH2:2]7)[C:7]=6[N:20]=5)=[C:23]([O:31][CH3:32])[CH:24]=4)[CH2:45][CH2:46]3)=[O:51])[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:61]=2[CH:62]=[CH:63][CH:64]=1
Reactant: NC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a mixture of 0.15 g (0.34 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.24 mL (1.3 mmole) of ethyldiisopropyl amine and 0.13 g (0.37 mmole) of 4-amino-1-Fmoc-piperidine hydrochloride in 5.0 mL of dimethylformamide was added 0.16 g (0.37 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum to give 0.25 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (I-70) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5](=[O:17])[N:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]([CH3:10])[C:8]=2[CH3:9])[CH2:3][CH2:2]1.[Br:18]Br>O1CCOCC1.O.CCOC(C)=O>[Br:18][CH2:9][C:8]1[N:7]([CH3:10])[N:6]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5](=[O:17])[C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)c(=O)n(-c2ccccc2)n1C
Reactant: BrBr
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(CBr)c(C2CC2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 4-cyclopropyl-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.081 g) in a round bottom flask under argon in dioxane (1.5 mL) was added bromine (0.057 g). The reaction was stirred at ambient temperature for 2 days. The reaction was diluted with water and EtOAc and the phases were separated. The aqueous phase was extracted with more EtOAc and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was purified via ISCO combiflash chromatography (EtOAc/heptane) to afford the desired 5-Bromomethyl-4-cyclopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one as a light brown solid. MS (ESI+): 307.1 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1O.[H-].[Na+].COS([O:20][CH3:21])(=O)=O.O.[CH3:23]N(C=O)C>CCOCC>[CH3:23][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: CN(C)C=O
Reactant: Oc1ccc2ccccc2c1O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2ccccc2c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To the solution of 1,2-dihydroxynaphthalene (5 g, 31.2 mmol) in DMF (140 mL) was added NaH (3.0 g, 75.0 mmol). After stirred at room temperature for 1 h, dimethylsulfate (7.09 mL, 75.0 mmol) was added. After stirring at room temperature for 22 h, water and Et2O was added, the organic layer was washed with brine, water, dried (MgSO4), filtered and concentrated. Column chromatography yielded the title compound as a colorless oil (3.83 g, 65%). 1H NMR (CDCl3) δ 8.12 (d, 1H), 7.79 (d, 1H), 7.59 (d, 1H), 7.47 (m, 1H), 7.35 (m, 1H), 7.29 (d, 1H), 3.99 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[NH:6][N:5]=1)=[O:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20].O>N1C=CC=CC=1>[CH3:17][N:18]([CH3:22])[C:19]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=2)[C:4]([NH:3][CH:1]=[O:2])=[N:5]1)=[O:20]
Reactant: CN(C)C(=O)Cl
Reactant: O=CNc1n[nH]c2ccc(C(F)(F)F)cc12
Solvent: O
Solvent: c1ccncc1
Product: CN(C)C(=O)n1nc(NC=O)c2cc(C(F)(F)F)ccc21
Yield: 57 %

Procedure:
0.2 mol of 3-formylamino-5-trifluoromethylindazole and 0.05 mol of dimethylcarbamic acid chloride in 20 ml of pyridine are heated for 4 hours to 50° C. After cooling, 150 ml of water are allowed to run in and the reaction product which has crystallized out is isolated by filtration. Recrystallization from ethanol gives 3formylamino-5-trifluoromethylindazole-1-carboxylic acid dimethylamide (melting point: 198°-200° C; 57% of theory).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[C:15]1[N:24]=[C:23]([NH2:25])[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1>>[NH2:25][C:23]1[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=[C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([CH:1]3[CH2:2][CH:3]=[CH:4][CH2:5]3)=[O:7])[CH2:13][CH2:12]2)[N:24]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CC=CC1)N1CCNCC1
Product: COc1cc2nc(N3CCN(C(=O)C4CC=CC4)CC3)nc(N)c2cc1OC

Procedure:
N-(3-cyclopentenylcarbonyl)piperazine (2.7 g., 0.015 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (3.6 g., 0.015 mole) are reacted according to the procedure of Example 1(a). The crude product crystallized from methanol affords analytically pure 4-amino-2-[4-(3-cyclopentenylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 215.5°-217.5° C. (corr.).
Reaction SMILES: C(Cl)Cl.Br[C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.CCN(CC)CC.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][BH:28][O:27]1>C1(C)C=CC=CC=1.Cl[Pd]Cl>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([B:28]3[O:29][C:30]([CH3:32])([CH3:31])[C:26]([CH3:33])([CH3:25])[O:27]3)[CH:6]=2)[CH2:12][CH2:13]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: Cl[Pd]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1

Procedure:
To a solution of PdCl2 (dppf). DCM (10 mg, 0.012 mmol) in anhydrous toluene (4 ml) in an argon filled sealed microwave tube was added the 1-(3-Bromo-phenyl)-4-methyl-piperazine (100 mg, 0.39 mmol), Et3N (0.11 ml, 2 equiv.), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.09 ml, 1.5 equiv). The microwave tube was evacuated and backfilled with Argon before being irradiated in a CEM Microwave reactor at 100° C. for 1 hr using an initial power of 200 W. The reaction mixture was partitioned between more toluene (6 ml) and water (10 ml), the organic layer separated, washed with water (1×10 ml), dried over MgSO4 and then evaporated in vacuo to leave a purple/brown residue which was used for suzuki coupling without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[CH:12]12[O:17][CH:16]1[CH2:15][CH:14]=[CH:13]2>CS(C)=O.O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:13]2[CH2:12][C@H:16]([OH:17])[CH:15]=[CH:14]2)=[C:4]([Cl:11])[N:3]=1
Reactant: C1=CC2OC2C1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a stirred solution of 2-amino-6-chloro-9H-purine (4.0 g, 23.7 mmol) in dry dimethylsulfoxide (40 mL) at room temperature under N2 is added tetrakis(triphenylphosphine)palladium(O) (0.27 g, 0.23 mmol) and the mixture is stirred for 2 minutes. The solution is cooled to 0° C. and a solution of 6-oxa-bicyclo[3.1.0]hex-2-ene (2.1 g, 25.6 mmol) in dry tetrahydrofuran (20 mL) is added over 15 minutes. The resulting yellow solution is allowed to warm to ambient temperature (about 15°-30° C.) over 3 hours and stirred overnight (about 16 h). The clear, yellow solution is evaporated to a viscous oil which is taken up in dichloromethane (50 mL) and filtered through a small pad of Celite (trademark of Manville Products Corp. for infusorial earth filter aid). The solvent is evaporated and the residue is purified by silica gel chromatography using i) ethyl acetate followed by ii) 10:1 ethyl acetate:methanol as eluent to give cis-(±)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclo-penten-1-ol as a white solid, 5.14 g (86%). M.pt. 160°-162° C. 1H nmr: δ7.83 (s, 1H), 6.34 (dt, J1 =5.5 Hz, J2 =2 Hz, 1H), 5.85 (dd, J1 =5.5 Hz, 1H), 5.34 (d, J=10 Hz, 1H), 5.26 (dq, J1 =9 Hz, J2 =2 Hz, 1H), 5.12 (br s, 2H), 4.85 (br t, J=9 Hz, 1H), 2.97 (ddd, J1 =15 Hz, J2 =9 Hz, J3 =7 Hz, 1H), 2.13 (br d, J=15 Hz, 1H).
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[NH3:20]>>[S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](=[O:13])[NH2:20])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7]
Reactant: N
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Product: CC(C)OC(=O)C(C(N)=O)=C1SCS1

Procedure:
A solution of isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate (10 g) in methanolic ammonia (60 ml) was stirred at room temperature for 4 hrs. The mixture was concentrated and purified with n-hexane and ethyl ether to give the titled compound as a white solid. (5.2 g, 68%)
Reaction SMILES: [C-:1]#[N:2].[K+].[NH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[O:9]1[C:13]2([CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.C(OCC)(=O)C>C(O)C.O>[N:4]1([CH:19]([CH:16]2[CH2:15][CH2:14][C:13]3([O:9][CH2:10][CH2:11][O:12]3)[CH2:18][CH2:17]2)[C:1]#[N:2])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: C1CCNC1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC(C1CCC2(CC1)OCCO2)N1CCCC1
Reaction time: 72 h

Procedure:
KCN (0.17 mol) and pyrrolidine (12.07 g, 0.17 mol) were added to a solution of 1,4-dioxa-spiro[4.5]decane-8-carboxaldehyde (0.141 mol) in a mixture of ethanol (141 ml) and water (70 ml), and stirring was carried out for 72 h at 25° C. After addition of ethyl acetate (700 ml), the organic phase was separated off and washed in succession with water (4×150 ml) and aqueous FeSO4 solution (4×150 ml). The organic phase was separated off and dried over Na2SO4 and then filtered off. The solvent was removed in vacuo, and the product was used in the next stage without being purified further.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](=[O:31])[CH:10]([CH2:18][CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:3][CH:2]=1.C1COCC1.[BH4-].[Na+]>CO>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([OH:31])[CH:10]([CH2:18][CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:28]2[OH:29])[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C(CCN1C(=O)c2ccccc2C1=O)C(=O)CCc1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)C(CCN1C(=O)c2ccccc2C1O)C(O)CCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of the compound (165 mg) prepared from Step 1 above, in dry methanol and THF (1:1, 8 ml) at −20° C. was added sodium borohydride (38 mg) and the reaction mixture was stirred at rt for 3 h and then at 45° C. for 1 hour. The reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The solvents were evaporated in vacuo and the residue taken into water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude title compound (165 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[C:9]([F:16])([F:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1.Cl>C(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([F:15])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 73.4 %

Procedure:
A mixture of 0.20 g (0.6 mmole) 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138) and 0.12 g (0.91 mmole) of 4-aminobenzoic acid in a 1:4 mixture of 10 mL of ethanol and 1M hydrochloric acid was heated at 100 degrees for 18 hours. After cooling, the precipitate was collected by filtration, washed with water and dried to give 0.19 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-138).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.OS(O)(=O)=O.CCCCCC.C(OCC)(=O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]2[C:4]=1[C:14]([CH3:15])=[CH:13][C:12](=[O:17])[NH:11]2
Reactant: COc1cc(NC(=O)CC(C)=O)cc(OC)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(C)cc(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Compound 9 (13.9 g, 58.6 mmol) was taken in a 100 mL round bottom flask and cooled to 0° C. Conc. H2SO4 (35 mL, 657 mmol) was added dropwise for 10 min at 0° C. and allowed the reaction mixture to reach room temperature over a period of 30 min. After completion of the reaction (TLC hexane : ethyl acetate 1:1, Rf=0.3) it was poured into water (200 mL) and solid separated was filtered, the solid was washed with water till neutral to pH and dried under vacuum to give product 5,7-dimethoxy4-methyl-1,2-dihydro-2-quinolinone (11, 12.5 g) in 97.6% yield as a solid. M.P. 239-240° C.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:19])=[C:12]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)[CH:13]=2)OC1.Br[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1>>[F:19][C:11]1[CH:10]=[CH:9][C:8]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:13][C:12]=1[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-n3cccn3)c2)OC1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-n1cccn1

Procedure:
1-[5-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]-1H-pyrazole (300 mg, 1.0 mmol) was coupled to 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (266 mg, 1.0 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then recrystallisation from toluene/isohexane, gave 3-[4-fluoro-3-(pyrazol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 6.55 (1H, dd, J 3 and 2), 7.28 (1H, d, J 7), 7.44-7.47 (2H, m), 7.77 (1H, d, J 2), 8.13-8.15 (2H, m), 8.21-8.24 (1H, m), 8.85 (1H, d, J 7); m/z (ES+) 348 (M++H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:35]=[CH:36][CH:37]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1cccc(OCCCCCCl)c1
Agent: Cl
Product: COc1cccc(OCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-(3-methoxyphenoxy)pentyl chloride were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(5-(3-methoxyphenoxy)pentyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[F:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]([CH2:17]C(OCC)=O)=O)=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]2[N:1]=[C:2]3[CH:6]=[CH:5][S:4][C:3]3=[C:7]([OH:9])[CH:17]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccsc1C(=O)O
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1cc(-c2ccc(F)cc2)nc2ccsc12
Temperature: 25 °C
Yield: 16.6 %

Procedure:
A mixture of 3-amino-2-thiophenecarboxylic acid (8 g, 49 mmol), ethyl 4-fluorobenzoylacetate (9.6 g, 49 mmol), and p-toluenesulfonic acid monohydrate (0.2 g, 1 mmol) in toluene (100 mL) is refluxed for 20 hours with a Dean-Stark water trap to remove produced water. After cooling to room temperature, the precipitate is filtered and washed with diethyl ether. The solid is dissolved in diphenyl ether (80 mL) and heated at 220° C. for 2 hours. The reaction solution is then cooled to room temperature, diethyl ether is added, and the precipitate is filtered and washed with diethyl ether to give 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (2 g, 17% yield) as brown crystalline needles, m.p. 316-318°C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>>[CH3:14][C:5]1([CH3:15])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]2[C:10]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:11][CH:2]=[CH:3][C:4]1=2
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Product: CC1(C)CCC(C)(C)c2c(C#C[Si](C)(C)C)cccc21
Yield: 66.1 %

Procedure:
Following the basic procedure of Example 1(a), by reacting 26.7 g (0.1 mol) of 2-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene with 20 g (0.204 mol) of trimethylsilylacetylene, 18.8 g (66%) of the expected compound were obtained in the form of a colorless oil.