Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]2[N:3]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:4]=[CH:5][C:6]=1[C:7]#[C:8][CH2:9][CH2:10][CH2:11]O.C(N(S(F)(F)[F:26])CC)C>C(Cl)Cl>[F:26][CH2:11][CH2:10][CH2:9][C:8]#[C:7][C:6]1[CH:5]=[CH:4][N:3]2[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=[C:2]2[N:1]=1
Reactant: OCCCC#Cc1ccn2c(n1)nc1ccccc12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCCCC#Cc1ccn2c(n1)nc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.8 %

Procedure:
To 5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pent-4-yn-1-ol (20 mg, 0.08 mmol) in 1 mL dry DCM at 0° C. was added (Diethylamino)sulfur trifluoride (64 mg, 0.4 mmol) dropwise. The reaction was warmed to rt and stirred for 1 h and quenched onto a mixture of ice (10 g) in saturated Na2CO3 (10 mL). The mixture was extracted with EtOAc (2×10 mL) and the organic phase was dried over MgSO4 and concentrated. The residue was purified by silica chromatography (EtOAc in DCM, 5% to 50%) to afford 2-(5-fluoropent-1-yn-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine as a yellow oil (3 mg, 15%). 1H NMR (400 MHz, CDCl3): δ 8.65 (d, J=6.8 Hz, 1H), 8.03 (d, J=8 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.58 (m, 1H), 7.43 (m, 1H), 6.93 (d, J=7.2 Hz, 1H), 4.69 (t, J=5.6 Hz, 1H), 4.57 (t, J=5.6 Hz, 1H), 2.70 (t, J=5.6 Hz, 2H), 2.14-2.00 (m, 2H); MS (ESI) m/z [M+H]+254.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1/[CH:4]=[CH:5]/C(O)=O.[Br:14]Br>ClCCl>[Br:14]/[CH:5]=[CH:4]\[C:3]1[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=1[F:13]
Reactant: BrBr
Reactant: O=C(O)/C=C/c1c(F)cccc1F
Solvent: ClCCl
Product: Fc1cccc(F)c1/C=C\Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of E-2,6-difluorocinnamic acid (2.0 g, 11 mmol) in dichloromethane at 0° C. is added bromine (0.56 mL, 11 mmol) dropwise. The mixture is stirred overnight as it is slowly allowed to reach temperature. Evaporation of the volatiles under reduced pressure affords the crude dibrominated carboxylic acid intermediate that is directly carried to the next step without further purification. To the crude solid is added DMF (20 mL) and a small crystal of BHT. The mixture is cooled to 0° C., and triethylamine (3 mL) is added. The mixture is stirred overnight as it is slowly allowed to reach temperature. Contents are poured in 2N aqueous HCl, extracted with diethyl ether, and the combined organic fractions are washed with saturated aqueous NaCl. Evaporation of the volatiles yields a crude product that is further purified by passing on a SiO2 plug using pentane as an eluent. Evaporation of the solvents under reduced pressure affords bromoalkene 11q as a colorless oil (1.35 g, 57%, ≧20:1 d.r. by 19F-NMR). 1H-NMR (CDCl3, 300 MHz): δ=7.42-7.32 (m, 1H), 7.07 (d, J=7.9 Hz, 1H), 7.05-6.95 (m, 2H), 6.84 (d, J=7.9 Hz, 1H). 13C-NMR (CDCl3, 75 MHz): δ=159.9 (dd, J=250, 7 Hz), 130.0 (t, J=10 Hz), 122.3, 114.8, 130.0 (t, J=20 Hz), 111.5 (dd, J=18, 7 Hz). 19F-NMR (CDCl3, 282 MHz): δ=−108.5. HR-MS (EI): Calcd. for C8H5F2Br [M+]: 217.9543. found 217.9538.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1COCC1>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=1
Reactant: Ic1c[nH]cn1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cnc(I)c1
Reaction time: 0.33 h
Yield: 67.5 %

Procedure:
To a solution of 4-iodoimidazole (1.93 g, 9.95 mmol) in dry THF (50 mL) at 0° C. was added sodium hydride (60% dispersion, 0.43 g, 10.8 mmol) and the mixture was stirred for 20 min. Ethyl bromoacetate (1.1 mL, 1.7 g, 10 mmol) was added by syringe and the cloudy mixture was stirred for 15 min. It was then partitioned between ethyl acetate and water. The organic phase was collected, washed with brine, dried (anhydrous MgSO4), filtered, and concentrated. Silica gel chromatography (50%->75% ethyl acetate/hexanes) of the residue provided 372 (1.88 g, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.57 (d, J=1.4, 1H); 7.32 (d, J=1.4, 1H); 4.93 (s, 2H); 4.13 (q, J=8.0, 2H); 1.20 (t, J=7.2, 3H). LRMS (M+H): 281.0.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[C:23]([C@:25]1([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31])#[CH:24]>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:22])[C:2]([C:24]#[C:23][C@:25]5([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]5=[O:31])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1cc(F)c(Br)cc1-2
Product: CN1CC[C@@](O)(C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2C2CC2)C1=O
Yield: 31 %

Procedure:
10-bromo-3-cyclopropyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 14.2 mg (31%) of 3-cyclopropyl-9-fluoro-10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. M+1=425.0.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:24][O:23][CH:22](OCC)[S:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][P:31]([O:35]CC)[O:32][CH2:33][CH3:34])[CH3:29].P(Cl)(Cl)Cl>ClCCl.[Cl-].[Zn+2].[Cl-]>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][O:23][C@@H:22]([P:31]([O:32][CH2:33][CH3:34])([O:30][CH2:28][CH3:29])=[O:35])[S:21]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOP(OCC)OCC
Reactant: CCOC1OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CCOP(=O)(OCC)[C@@H]1OC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Temperature: 0 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
To a solution of 4-(t-butyldiphenylsilyloxymethyl)-2-ethoxy-1,3-oxathiolane (12.32 g, 30.6 mmol) and triethylphosphite (3.5 mL, 20.4 mmol, 0.66 eq) in dichloromethane (50 mL) were added phosphorus trichloride (890 μL, 10.2 mmol, 0.33 eq) and zinc chloride (catalytic) at 0° C. The solution was stirred at 0° C. for 1 hr and at room temperature for 3 days. The solvent was evaporated and the crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (60:40) to give the pure compound (8.02 g) in 53% yield with a ratio of 2:1 (trans:cis).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:29]=[CH:30][CH:31]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:16][CH2:15]1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O[CH2:42][CH2:43][O:44][CH:45]([CH3:47])[CH3:46])(=O)=O)=CC=1.[OH-].[K+]>CS(C)=O>[CH:45]([O:44][CH2:43][CH2:42][N:8]([C:9]1[CH:10]=[C:11]([CH:29]=[CH:30][CH:31]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:16][CH2:15]1)=[O:13])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)OCCN(C(=O)OC(C)(C)C)c1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1

Procedure:
6 g of 1-[3-(N-tert-butyloxycarbonylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine and 4.18 g of 2-isopropyloxyethyl p-toluenesulfonate are reacted in DMSO in the presence of 1.01 g of finely powdered KOH. The oily 1-{3-[N-(2-isopropyloxyethyl)-N-tert-butoxycarbonylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine so obtained is reacted further directly.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19](Br)[C:18]([C:22]#[N:23])=[C:17]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]([NH:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:18]([C:22]#[N:23])=[C:17]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(Br)c2C#N)C1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(NCc3ccccc3)c2C#N)C1
Temperature: 70 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a stirred solution of tert-butyl 3-{6-[2-(benzyloxy)phenyl]-2-bromo-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (0.300 g, 0.547 mmol) in DMSO were added triethylamine (0.229 mL, 1.341 mmol) and benzylamine (0.147 g, 1.367 mmol). The mixture was stirred at 70° C. for 12 hrs. After cooled to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtrated, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-2/1) to give tert-butyl 3-{6-[2-(benzyloxy)phenyl]-2-benzylamino-3-cyano-4-pyridinyl}-1-piperidinecarboxylate as a yellow amorphous. (0.290 g, yield; 92%)
Reaction SMILES: Cl.[C:2]1([C:8]2[C:12]3=[C:13]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]=[N:15][CH:16]=[C:11]3[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([C:32]2[CH:36]=[C:35]([CH:37]=O)[O:34][N:33]=2)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([C:32]2[CH:36]=[C:35]([CH2:37][N:22]3[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:13]4[N:14]=[N:15][CH:16]=[C:11]5[O:10][N:9]=[C:8]([C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[C:12]=45)[CH2:20][CH2:21]3)[O:34][N:33]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(-c2noc3cnnc(NCC4CCNCC4)c23)cc1
Reactant: O=Cc1cc(-c2cccc(Cl)c2)no1
Agent: Cl
Product: Clc1cccc(-c2cc(CN3CCC(CNc4nncc5onc(-c6ccccc6)c45)CC3)on2)c1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 84 instead of the compound obtained in Example 11 and 3-(3-chlorophenyl)isoxazole-5-carbaldehyde instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: C(O[C:4](=[NH:15])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]([NH:27][NH2:28])=[O:26]>C(Cl)(Cl)Cl>[NH2:15][C:4](=[N:28][NH:27][C:25]([C:17]1[O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=1)=[O:26])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Reactant: NNC(=O)c1cc2ccccc2o1
Solvent: ClC(Cl)Cl
Product: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1cc2ccccc2o1
Yield: 59.8 %

Procedure:
3.4 g (0.0125 Mol) of 2-(phenylsulfonyl)-ethanimidic acid ethyl ester was stirred together with 2.2 g (0.015 mol) benzofuran-2-carboxylic acid hydrazide in 80 ml chloroform for 24 hours at 50° C. The resulting precipitate was filtered off and dried. 2.67 g of benzofuran-2-carboxylic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as off-white crystals. Mp.: 205-220° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([Br:21])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Na+].Cl>CO>[Br:21][C:15]1[CH:16]=[C:17]([N+:18]([O-:20])=[O:19])[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:22])=[O:3])[CH2:11][CH2:10]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)CC1CCN(c2ncc(Br)cc2[N+](=O)[O-])CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCN(c2ncc(Br)cc2[N+](=O)[O-])CC1
Temperature: 60 °C
Yield: 75.6 %

Procedure:
To a suspension of 1.00 g (2.69 mmol) of (5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in a 1:1 mixture of water:methanol (50 mL) is added 2.0 mL (5.0 mmol) of sodium hydroxide as a 10% aqueous solution. The mixture is heated at 60° C. for 1 hour then cooled to room temperature and the pH of the mixture is adjusted to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid. The mixture is extracted with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.700 g (75.7%) of (5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid as an orange oil. No further purification is performed.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][S:14]([C:17]1[N:22]=[C:21]2[N:23]([CH3:33])[N:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=3)[C:20]2=[CH:19][N:18]=1)(=[O:16])=[O:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]2[C:20]3[C:21](=[N:22][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[N:18][CH:19]=3)[N:23]([CH3:33])[N:24]=2)=[CH:31][CH:30]=1)(=[O:11])=[O:10]
Reactant: Cn1nc(-c2ccc(N)cc2)c2cnc(S(C)(=O)=O)nc21
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)c2cnc(S(C)(=O)=O)nc21
Reaction time: 2 h

Procedure:
2,3-Dichlorobenzenesulfonyl chloride (342 mg, 1.5 equiv.) was added to a mixture of 4-(6-Methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl amine (283 mg., 0.93 mmol) and DIEA (325 μl, 2 equiv.) in CH2Cl2 (10 ml) at room temperature. After 2 hrs, the mixture was diluted by CH2Cl2 (10 ml) and washed by 10% NaHCO3, brine, drying and concentration left 420 mg as a golden yellow solid; LC/MS(m/e)=512.0 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[NH4+].[Ni]>[C:1]([C:5]1[CH:6]=[C:7]([CH2:8][NH2:9])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(C#N)c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cccc(CN)c1
Reaction time: 2 h

Procedure:
To 3-tert-butylbenzonitrile (400 mg) in MeOH (5 mL), aqueous ammonium hydroxide (1 mL) and Raney Nickel (catalytic) were added and the reaction mixture was hydrogenated at 50 psi for 2 h. Then the reaction mixture was filtered and solvent evaporated. (3-tert-butylphenyl)methanamine was used without any purification.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:47]1([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(O)C.C1(C)C=CC=CC=1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:58])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCCC4)CC3)ncn2)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h
Yield: 8.4 %

Procedure:
After dissolving 4-[2-(pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (49 mg) in ethanol (2 ml) under a nitrogen atmosphere, D-10-camphorsulfonic acid (53 mg) was added and the mixture was stirred for 5 minutes. A 0.25 M solution of 2-phenylacetyl isothiocyanate in toluene (0.684 ml) was added to the reaction mixture and stirring was carried out for 1 hour. The reaction mixture was partitioned between ethyl acetate (50 ml) and saturated aqueous sodium hydrogencarbonate (30 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate (30 ml), water (30 ml) and brine (30 ml) in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:8). Fractions containing the target compound were concentrated under reduced pressure, and then diethyl ether (1.0 ml) and hexane (1.5 ml) were added to the resultant residue to produce a suspension of the solid. After filtering the solid, it was subjected to aeration drying to provide the title compound (5.8 mg, 8.4%) as white powder.
Reaction SMILES: [C:1]([C:4]1[CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][C:8]=2[CH:9]=1)(=O)[CH3:2].Cl.[NH2:22][OH:23]>CCO.N1C=CC=CC=1>[C:1](=[N:22][OH:23])([C:4]1[CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][C:8]=2[CH:9]=1)[CH3:2]
Reactant: CC(=O)C1=Cc2cc(Oc3ccccc3)ccc2OC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)C1=Cc2cc(Oc3ccccc3)ccc2OC1
Reaction time: 48 h

Procedure:
The ketone (2.53 g, 9.5 mmol) is dissolved in 90 ml of an EtOH/pyridine mixture (1:1), and treated with hydroxylamine hydrochloride (0.99 g, 14.3 mmol). The mixture is stirred for 2 days. The reaction mixture is partitioned between ether and water, and the aqueous layer is extracted twice with ether. The combined organic layer is then washed twice with 2N HCl and water, dried (MgSO4), and evaporated. The residue is purified by flash chromatography (10% EtOAc/hexane) to give 3-acetyl-6-phenoxy-2H-1-benzopyran oxime as a crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[I:13])[NH:4][C:3]1=O.[CH:15]1([C:18]2[O:22][N:21]=[C:20]([CH2:23][N+:24]#[C-:25])[N:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[O:22][N:21]=[C:20]([C:23]3[N:24]=[CH:25][N:4]4[C:5]5[C:10](=[C:9]([I:13])[CH:8]=[CH:7][CH:6]=5)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=34)[N:19]=2)[CH2:17][CH2:16]1
Reactant: Cn1c(=O)[nH]c2cccc(I)c2c1=O
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Product: Cn1c(=O)c2c(I)cccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
M.p. 217°-220° C. by reaction between 3-methyl-5-iodo-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: [Li+:1].[CH3:2][CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[SH:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>C1COCC1>[Li+:1].[CH3:2][CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[F:15][C:16]([F:23])([F:22])[C:17]([C:12]1[S:11][C:10]([SH:9])=[N:14][CH:13]=1)=[O:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Sc1nccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.38 h

Procedure:
A solution of LDA (95.4 mmol) in THF was prepared at −10° C. and cooled to −78° C. To the LDA was added a solution of 2-mercaptothiazole (10.00 g, 85.3 mmol) in 25 mL of THF. After 15-30 min of stirring, ethyl trifluoroacetate (13.2 mL, 110.9 mmol) in 15 mL of THF was added. The solution was brought to −10° C. and quenched with NH4Cl followed by HCl (10%) and diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4. The solvent was evaporated and the residue chromatographed on silica gel (toluene/acetone; 8:2 with 1% methanol) to give the title compound.
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH:6]([CH:8]=O)[CH2:5][CH:4]1[O:10][C:11](=[O:13])[CH3:12])=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:14]([N:21]1[CH2:1][CH:3]2[CH2:7][CH:6]([CH2:5][CH:4]2[O:10][C:11](=[O:13])[CH3:12])[CH2:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)OC1CC(C=O)CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC1CC2CC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the above solution of acetic acid 2,4-diformyl-cyclopentyl ester was added at room temperature benzyl amine (5.8 mmol) and acetic acid (5.8 mmol) under nitrogen. After 2 h at room temperature sodium triacetoxy borohydride (25 mmol) was added and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (100 mL) and the phases were separated. The aqueous layer was extracted with dichloromethane (3×100 mL). The solvents were removed via rotary evaporation and the residue was purified by silica gel chromatography to afford a yellow oil (3.6 mmol). 1H NMR (CDCl3, 400 MHz): δ 7.37 (m, 2H), 7.23 (m, 3H), 5.15–4.95 (m, 1H), 3.63–3.35 (m, 2H), 2.84–2.55 (m, 2H), 2.25–2.15 (m, 4H), 2.08 (s, 3H), 1.80–1.70 (m, 2H), 1.62–1.25 (m, 2H); APCl MS m/z 260.2 (M+H)+.
Reaction SMILES: C(S[C:9]1[C:10]([Cl:22])=[C:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C:16]2=[O:21])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[S:23]([Cl:27])(Cl)(=[O:25])=[O:24]>>[Cl:22][C:10]1[C:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C:16]2=[O:21])=[CH:12][CH:13]=[CH:14][C:9]=1[S:23]([Cl:27])(=[O:25])=[O:24]
Reactant: O=C1COCCN1c1cccc(SCc2ccccc2)c1Cl
Reactant: O=S(=O)(Cl)Cl
Product: O=C1COCCN1c1cccc(S(=O)(=O)Cl)c1Cl

Procedure:
Intermediate 17 (1 g, 3.05 mmol) was converted to the title sulfonyl chloride using the procedure described in 1.7). The crude material was used without further purification in the next step.
Reaction SMILES: [N+:1]([C:4]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)O1)([O-])=O.[NH3:19]>>[C:13]1([C:4]2[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:19][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])C1(c2ccccc2)OC1c1ccccc1
Reactant: N
Product: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)nc2-c2ccccc2)cc1

Procedure:
12 parts of 2-nitro-2,3-diphenyl-oxirane melting at from 109° to 110° C and 100 parts by volume of liquid ammonia are shaken for 6 hours in an autoclave at 100° and 65 atmospheres. After evaporation of the ammonia, the solid residue is treated with water and the constituent left undissolved is filtered off and recrystallized from glacial acetic acid. 5.2 parts of 2,3,5,6-tetraphenylpyrazine (54% of theory) melting at from 253° to 254° C are obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]1[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:32][O:33][C:34]=1[CH3:35]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[C:31]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[N:32][O:33][C:34]=5[CH3:35])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: Cc1onc(-c2ccccc2)c1CBr
Agent: [H-]
Agent: [Na+]
Product: Cc1onc(-c2ccccc2)c1CN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 71 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 4-(bromomethyl)-5-methyl-3-phenylisoxazole, to give the desired product as a brown oil (71%).