Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:28]\[O:29][CH3:30])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH3:30][O:29]/[N:28]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]\1[CH2:19][C:20](=[O:51])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CO/N=C1\C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: CO/N=C1\C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 70 %

Procedure:
The title compound II-au was prepared in 70% yield from 3,3:17,17-bis(ethylendioxy)-6(E)-methoxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.78 (s, 3H), 3.37 (dd, 1H), 2.68-1.14 (m, 19H), 1.01 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:6]=1)=[O:4].[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:2]([C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:6]=1)=[O:4])[CH3:16])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(Br)C(=O)c1ccc(NS(C)(=O)=O)cc1
Solvent: CC#N
Product: C[C@@H](C(=O)c1ccc(NS(C)(=O)=O)cc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Reaction of 4'-(2-bromopropionyl)methanesulfonanilide with 2 molar equivalents of dibenzylamine in acetonitrile provides 4'-(N,N-DIBENZYLALANYL)METHANESULFONANILIDE purified as the hydrochloride, m.p. 216.0°-218.0°C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([CH3:33])(=[O:32])=[O:31])=[N:17][C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([CH3:33])(=[O:32])=[O:31])=[N:17][C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:35]([F:38])([F:36])[F:37]
Reactant: COCN(c1cc(Cl)c(C)nc1C(=O)c1ccccc1S(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C(=O)c2ccccc2S(C)(=O)=O)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture 4-chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-6-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (40 mg, 0.07 mmol) in 4 M HCl in dioxane (2 mL), and water (1 mL) was heated at 100° C. for 4 h and then it was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and it was treated with aqueous NaHCO3 to adjust pH to 5-6 and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide the desired product. 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1 H), 8.21 (s, 1 H), 8.15 (s, 1 H), 7.98-7.96 (m, 2 H), 7.70-7.62 (m, 3 H), 7.33-7.31 (m, 1H); Mass spectrum m/z: 567.4.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C@@H:4]([OH:6])[CH3:5].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C@@H:4]([O:6][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH3:5]
Reactant: C[C@H](O)c1ccccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1Br
Reaction time: 8 h
Yield: 82 %

Procedure:
To a 25 mL flask containing (S)-(−)-2-bromo-alpha-methylbenzyl alcohol (200 mg, 1.0 mmol), tert-butyldimethylsilyl chloride (165 mg, 1.1 mmol), and imidazole (203 mg, 3.0 mmol) flushed with nitrogen was added 5 mL of dimethylformamide. After stirring overnight, the mixture was quenched with saturated sodium bicarbonate, diluted with ethyl acetate, washed with NaH2PO4, saturated aqueous sodium bicarbonate, water, brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (10 g SiO2, linear gradient 0-10% ethyl acetate/Hexanes, 30 mL/minute, over 30 minutes) gave about 260 mg (0.82 mmol, 82%) of (5)-[1-(2-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane as a colorless oil. GC/MS (EI): 315 (M). The (5)-[1-(2-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane was coupled to piperazine in a manner similar to Preparation 1A. LRMS (ESI+): 321.5 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:27]2[CH2:28][NH:29][CH2:30][CH2:31][CH:32]=2)=[N:24][C:25]=1[CH3:26].O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:29]1[CH2:30][CH2:31][CH:32]=[C:27]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[C:25]([CH3:26])[N:24]=2)[CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: Cc1ccc(C2=CCCNC2)nc1C
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C2=CCCN([C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)C2)nc1C
Yield: 35.7 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5,6-dimethyl-1′,2′,5′,6′-tetrahydro-2,3′-bipyridine (3.96 g, 21.0 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.35 g of the intended substance (yield 35.7%).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])=[O:6])C.[OH-].[K+]>C(O)C.O>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[NH:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[C:5](=[O:6])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(=O)c1sccc1Nc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)c1sccc1Nc1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
3.44 g (10 mmoles) of 3-(2,6-dichloroanilino)-2-thiophenglyoxylic acid ethyl ester are dissolved in 10 ml of ethanol with 1 g of potassium hydroxide until a homogeneous solution has formed--after 10 minutes. The solution is diluted with 50 ml of water, acidified and extracted with ethyl acetate; the organic phase is dried and concentrated. Recrystallization from cyclohexane with a little toluene yields 3-(2,6-dichloroanilino)-2-thiophenglyoxylic acid.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10])[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>C1COCC1.O>[C:23]([O:22][C:20]([NH:2][CH:3]([CH2:7][CH2:8][C:9]([F:10])([F:11])[F:12])[C:4]([OH:6])=[O:5])=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: NC(CCC(F)(F)F)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCC(F)(F)F)C(=O)O
Reaction time: 0.17 h
Yield: 122.4 %

Procedure:
To a stirred solution of 2-amino-5,5,5-trifluoropentanoic acid hydrochloride (400 mg, 1.503 mmol) in THF (8 mL) and water (8 mL) was added K2CO3 (831 mg, 6.01 mmol) at rt and the solution was stirred for 10 min. To this mixture was added BOC2O (656 mg, 3.01 mmol). The reaction mixture was stirred for 8 h at rt. The reaction mixture was concentrated under reduced pressure. The aq. layer was washed with ethyl acetate (3×5 mL). The aqueous layer was acidified with saturated citric acid solution (5 mL) and then extracted with ethyl acetate (3×8 mL). The combined organic layers were washed with water (3×5 mL) followed by brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2-((tert-butoxycarbonyl)amino)-5,5,5-trifluoropentanoic acid (500 mg, 1.84 mmol) quantitatively as a colorless oil. The crude material was taken as such to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 5.04 (s, 1H), 4.38 (s, 1H), 2.15-2.28 (m, 2H), 1.91-1.95 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: Nc1ccccc1B(O)O
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccccc2N)cc1
Yield: 65 %

Procedure:
Prepared in a similar manner to example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 2-aminophenylboronic acid. Yield: 65%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 2H), 6.65-6.75 (m, 1H), 6.9 (m, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.4 (d, 2H), 7.55 (d, 2H). MS (M+H, 311).
Reaction SMILES: [O:1]=[C:2]1[CH:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[CH2:5][CH2:4][CH:3]1[CH2:17][C:18]([O:20]C)=O.O[Li].O.Cl.[NH2:26][C@H:27]([C:31]([NH:33][C@H:34]([C:38]([O:40][CH3:41])=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])[CH:28]([CH3:30])[CH3:29].OC1C2N=NNC=2C=CC=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(N(CC)CC)C.O.O1CCOCC1>[CH3:41][O:40][C:38](=[O:39])[C@H:34]([CH:35]([CH3:37])[CH3:36])[NH:33][C:31](=[O:32])[C@H:27]([CH:28]([CH3:29])[CH3:30])[NH:26][C:18](=[O:20])[CH2:17][CH:3]1[CH2:4][CH2:5][C:6]([CH3:16])=[CH:7][CH:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:2]1=[O:1]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C
Reactant: COC(=O)CC1CCC(C)=CC(Cc2ccccc2)C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC1CCC(C)=CC(Cc2ccccc2)C1=O)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the above keto ester (23) (0.51 g) in 4:1 dioxane, water (10 mL) was added LiOH.H2O (82 mg). The reaction was stirred overnight at room temperature, evaporated, taken up in ethyl acetate washed with aqueous 1N HCl, saturated NaCl, dried over MgSO4 and evaporated to give the crude keto acid. The acid was dissolved in DMF (10 mL) to which was added HCl.Val-Val-OMe (0.51 g), triethylamine (1.5 mL), hydroxybenzotriazole (0.48 g) followed by Bop reagent (1.57 g). The reaction was stirred overnight at room temperature and evaporated to dryness. The product (24) was obtained as a mixture of diastereomers by flash chromatography on silica gel eluted with 50% ethyl acetate in n-hexane. (0.44 g, 51%) (24); TLC Rf 0.24 and 0.26 (40% ethyl acetate, n-hexane); 1H NMR (CDCl3) δ0.8-1.0(12H, m) Val γ(CH3)2's, 1.7(3H, s) allylic CH3, 3.7(3H, s) CO2CH3, 3.8 (1H, br s) allylic CH, 4.55 (2H, dd), 5.15 (1H, m) vinylic CH, 7.25 (5H, s) phenyl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][C:20]([NH:22][NH2:23])=O)[CH:15]=3)[N:10]=[CH:9]2)=[CH:5][CH:4]=1.Cl[C:27]1[N:28]=[N:29][C:30]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:31][CH:32]=1>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][C:20]4[N:22]5[N:23]=[C:30]([C:33]6[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=6)[CH:31]=[CH:32][C:27]5=[N:28][N:29]=4)[CH:15]=3)[N:10]=[CH:9]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: COc1ccc(Cn2cnc3ccc(CC(=O)NN)cc3c2=O)cc1
Solvent: CCCCO
Product: COc1ccc(Cn2cnc3ccc(Cc4nnc5ccc(-c6cccnc6)nn45)cc3c2=O)cc1
Yield: 53.4 %

Procedure:
[3-(4-Methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetic acid hydrazide (0.024 g, 0.071 mmol) and 3-chloro-6-pyridin-3-yl-pyridazine (0.012 g, 0.063 mmol) were heated to 130° C. in butanol (0.5 mL) for several hours. The compound was purified via reverse phase HPLC on a C18 column eluting with acetonitrile in water (0.1% TFA) to give 0.016 g (53%) of 3-(4-methoxy-benzyl)-6-(6-pyridin-3-yl [1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3H quinazolin-4-one. 1H NMR (400 MHz, CDCl3) δ 9.08 (m, 1H), 8.71 (dd, 1H, J=4.8, 1.6 Hz), 8.39 (m, 1H), 8.25 (m, 1H, 8.13 (d, 1H, J=9.6 Hz), 7.99 (s, 1H), 7.77 (dd, 1H, J=8.4, 2.0 Hz), 7.58 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=9.6 Hz), 7.41 (m, 1H), 7.21 (d, 2H, J=8.4 Hz), 6.77 (d, 2H, J=8.8 Hz), 5.05 (s, 2H), 5.05 (s, 2H), 4.71 (s, 2H), 3.70 (s, 3H). Mass spectrum (LCMS, ESI pos.): Calcd for C27H21N7O2; found: 476.1, 477.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])#[N:2].[CH3:12][Li]>C1COCC1>[F:11][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:10][C:7]=1[CH:8]([OH:9])[CH3:12]
Reactant: [Li]C
Reactant: N#Cc1ccc(F)c(C=O)c1
Solvent: C1CCOC1
Product: CC(O)c1cc(C#N)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyano-2-fluorobenzaldehyde (1.50 g, 10.06 mmol) in THF (15 mL) cooled to 0° C. was added methyllithium (7.90 mL, 11.06 mmol). The mixture was stirred at room temperature for 2 h and quenched by the addition of saturated NH4Cl (10 mL). The mixture was partitioned between ethyl acetate (50 mL) and water (20 mL), the organic was washed with water (20 mL), dried over magnesium sulfate and concentrated in vacuo to provide a residue. Purification via flash column chromatography (30×150 mm column; elution with EtOAc: Hex, 1:2) afforded pure compound:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 25.9 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol), 3-(trifluoromethyl)phenylboronic acid (165 mg, 869 μmol; 4 eq.), copper(II) acetate (158 mg, 869 μmol; 4 eq.) and 4 Å molecular sieve (500 mg) were initially charged in dichloromethane (5 ml), pyridine (281 μl; 16 eq.) and triethylamine (121 μl; 4 eq.) were added and the mixture was subsequently stirred at RT for 20 h. The reaction mixture was then filtered through kieselguhr which was then washed repeatedly with methanol, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Gromsil, C-18 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (34 mg, 26% of theory).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])=[N:9][C:10]1=[O:14]
Reactant: Cc1nc(C)c(-c2cc[nH]c(=O)n2)s1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C)c(-c2ccn(CCCCCl)c(=O)n2)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a solution of 4-(2,4-Dimethyl-thiazol-5-yl)-1H-pyrimidin-2-one (120 mg, 0.58 mmol) in dry DMF (21 ml), 60% NaH (24 mg, 0.75 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (86 μl, 0.75 mmol) was added at room temperature and the mixture was stirred overnight then was heated at 69° C. for 2 hours. Water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate was washed with brine, dried (Na2SO4) and evaporated to give 80 mg of the title compound as a solid (48% yield).
Reaction SMILES: COC[O:4][C:5]1[C:6]([CH2:22][CH2:23][CH3:24])=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:18]([F:21])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[O:9][CH2:8]2.Cl.C(O)C>>[CH2:22]([C:6]1[C:5]([OH:4])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][O:9][C:10]2([C:18]([F:21])([F:19])[F:20])[C:14]([F:15])([F:16])[F:17])[CH2:23][CH3:24]
Reactant: CCCc1c(OCOC)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCCc1c(O)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-(methoxymethoxy)-4-propyl-1,1-bis(trifluoromethyl)-1,3-dihydroisobenzofuran (1.12 g, 3.13 mmol), hydrochloric acid-ethanol (2 mol/L, 5 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate) and of the title compound (952.6 mg, 96%) was obtained as colorless crystalline powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1.[OH-].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: c1cc[nH]c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Cn2cccc2)cc1
Yield: 79.2 %

Procedure:
To a stirred solution of pyrrole (10.0 mL, 9.67 g, 144.13 mmol) in dichloromethane (200 mL) were added tetrabutylammonium bromide (46.5 g, 144.13 mmol), 4-fluorobenzyl bromide (17.7 mL, 158.54 mmol) and 50% NaOH aqueous solution (120 mL) with cooling in an ice-water bath. The resulting mixture was heated to reflux for 5 hr. After cooling down, it was quenched with saturated aqueous NH4Cl solution (200 mL), and extracted with dichloromethane (300 mL). The organic extract was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography. Elution with dichloromethane:ethyl acetate:hexanes (1:1:5) provided the title compound (20 g, 79% yield). 1H NMR (CDCl3) δ ppm 6.96-7.09 (m, 4H), 6.67 (d, 2H, J=2.0 Hz), 6.19 (t, 2H, J=2.0 Hz), 5.03 (s, 2H). LCMS (APCI, M+H+): 176.1.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:17]=[CH:16][C:9]2[CH2:10][CH2:11][CH:12]=[CH:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4]>C1C=CC=CC=1.C(O)C>[N+:3]([C:6]1[CH:17]=[CH:16][C:9]2[CH2:10][CH2:11][CH:12]([NH:2][CH3:1])[CH2:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4]
Reactant: CN
Reactant: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Solvent: CCO
Solvent: c1ccccc1
Product: CNC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 101.5 g of extemporaneously prepared monomethylamine in 700 ml of benzene was added at 20° C. with stirring to a mixture of 101.6 g of the product of Step B in 1 liter of ethanol and the mixture was stirred for 2 1/2 hours at room temperature and was allowed to stand for 12 hours. The mixture was evaporated to dryness under reduced pressure to obtain 125 g of 3-nitro-7-methylamino-6,7,8,9-tetrahydro [5H] benzocycloheptene-5-one in the form of a brown oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[O:21])[CH:14]=2)[C:9]2[N:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)([OH:3])=O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCOCC1.C(OCC)(=O)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[NH:19][C:15]1[CH:14]=[C:13]([N:10]2[C:11](=[O:12])[C:6]([CH2:5][CH2:4][C:1]([N:60]3[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]3)=[O:3])=[N:7][C:8]3[CH:34]=[CH:33][CH:32]=[N:31][C:9]2=3)[CH:18]=[CH:17][CH:16]=1
Reactant: CN1CCNCC1
Reactant: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)O)nc3cccnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)N3CCN(C)CC3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 2-(2-carboxyethyl)-3-oxo-4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (115 mg) and 1-hydroxybenzotriazole (40 mg) in dry dioxane (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (47 mg) and N-methylpiperazine (30 mg). The mixture was stirred at room temperature for 4 hours, diluted with ethyl acetate, washed with water. After evaporation of the solvents, crude residue was crystallized from ethanol to give 4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-2-[2-(4-methylpiperazin-1-yl)carbonylethyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine.
Reaction SMILES: [N:1]1[C:2]([C:10](OCC)=[O:11])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6][C:5]=12.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[N:1]1[C:2]([CH:10]=[O:11])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6][C:5]=12
Reactant: CCOC(=O)c1cn2c(n1)SCCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cn2c(n1)SCCC2
Temperature: -70 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
Ethyl 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine-2-carboxylate (2.12 g, 10 mmol) was dissolved in dry dichloromethane (40 ml) under argon and cooled to -70°. Diisobutylaluminium hydride (1.5M in toluene, 12 ml, 18 mmol) was added below -68° C. and the reaction mixture stirred at -70° C. for 1 h. Water was added carefully and the cooling removed. The reaction mixture was stirred vigorously at ambient temperature for 15 minutes and Celite (2 g) added. The mixture was filtered through Celite, the filter bed washed with dichloromethane and water, the filtrate and the washings combined and evaporated to dryness under reduced pressure. The residue was evaporated from ethanol (2×) to give the title compound as a white solid (1.31 g, 78%); νmax (CH2Cl2) 1685, 1543 and 1453 cm-1 ; δH (250 MHz; CDCl3) 2.34-2.43 (2H, m), 3.20 (2H, t, J 6 Hz), 4.17 (2H, t, J 6 Hz), 7.58 (1H, s), 9.75 (1H, s).