Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:7].[NH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:18].[ClH:18].[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[CH2:17][N:39]2[CH2:44][CH2:43][S:42][CH2:41][CH2:40]2)[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(C/C=C/CCl)C[C@H]1Cc1ccc2ccccc2c1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(C/C=C/CN2CCSCC2)C[C@H]1Cc1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(E)-4-chloro-2-butenyl]-2-(2-naphthylmethyl)piperazine (300 mg), thiomorpholine (0.054 ml) and powdered potassium carbonate (100 mg) in dry acetonitrile (3 ml) was heated at 50° C. for 10 hours. Additional potassium carbonate (100 mg) and thiomorpholine (0.054 ml) were added and then the resulting mixture was further heated at the same temperature. After 2 hours, the reaction mixture was cooled and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (40:1). The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate (0.6 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-((E)-4-thiomorpholino-2-butenyl)piperazine dihydrochloride (190 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].Cl.Cl[C:21]([NH2:23])=[NH:22].COCCOCCOC>O>[NH2:23][C:21]1[N:22]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]=2[CH3:18])[N:1]=1
Reactant: CCCCCCC=Cc1ccc(N)c(C#N)c1C
Reactant: N=C(N)Cl
Agent: Cl
Solvent: COCCOCCOC
Solvent: O
Product: CCCCCCC=Cc1ccc2nc(N)nc(N)c2c1C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 0.64 g of the 2-aminobenzonitrile of Example 4, 0.30 g of chloroformamidine hydrochloride, and 5.0 ml of diglyme was heated at 140°-150° C. for 5 h. The mixture was diluted with 50 ml of water and stirred for 1 h. The precipitated solid was collected by filtration, washed with water and acetone, and dried to leave 0.58 g (78%) of a white solid. (Mixture of cis-trans isomers.) Anal. calc'd for C17H24N4.2/3HCl: C, 66.2; H, 8.05 N, 18.1. Found: C, 66.2, H; 8.05; N, 18.2.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([F:4])[F:3].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: Oc1ccc(SC(F)(F)F)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(SC(F)(F)F)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-trifluoromethylsulfanyl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (70%, clear oil). HPLC-MS m/z=328.0 (M+1), Rt: 5.16 min.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][NH2:15])([CH3:13])([CH3:12])[CH3:11].C(NNC(C)(C)C)(=O)C(C)(C)C>O>[C:1]([NH:15][NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NN
Agent: CC(C)(C)NNC(=O)C(C)(C)C
Solvent: O
Product: CC(C)(C)NNC(=O)c1ccccc1
Yield: 71 %

Procedure:
1-benzoyl-2-tert.-butylhydrazine was prepared in 71% yield by adding benzoyl chloride to a basic solution of t-butylhydrazine in water. The procedure was the same as that for preparing 1-pivaloyl-2-tert.-butylhydrazine in Example XIX A. The product has a melting range of 94°-95° C. and its infra-red spectrum was consistent with that of the proposed structure.
Reaction SMILES: CC1C=CC([C:8]2CC[CH2:11][C:10](=[O:14])[CH:9]=2)=CN=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][N:17]=1.C[O-].[Na+].C(C(C)=O)=C>C1C=CC=CC=1.CO>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH:23]([CH2:8][CH2:9][C:10](=[O:14])[CH3:11])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:29])=[CH:18][N:17]=1
Reactant: CCOC(=O)CC(=O)c1ccc(C)nc1
Reactant: Cc1ccc(C2=CC(=O)CCC2)cn1
Agent: C=CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(=O)C(CCC(C)=O)C(=O)c1ccc(C)nc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
B-2. 3-(2-Methyl-5-pyridinyl)-2-cyclohexen-1-one--To a stirred solution containing 48 g. of ethyl 3-(2-methyl-5-pyridinyl)-3-oxopropanoate in a mixture of 300 ml. of dry benzene and 100 ml. of dry methanol, said solution kept under nitrogen, was added 0.1 g. of sodium methoxide followed by the dropwise addition over a period of about 1 hour of the solution containing 16 g. of freshly distilled methyl vinyl ketone in a mixture of 60 ml. of benzene and 10 ml. of methanol. After the reaction had proceeded slowly at room temperature overnight, an additional 0.1 g. of sodium methoxide plus 4 ml. of additional methyl vinyl ketone were added and the reaction mixture was heated with stirring at 40° C. for 8 hours. The solvent was distilled-off in vacuo; 300 ml. of benzene was added; the benzene solution was washed once with brine, dried over anhydrous sodium sulfate and heated in vacuo to remove the benzene thereby yielding a quantative yield (63.5 g.) of ethyl 2-(2-methyl-5-pyridinylcarbonyl)-5-oxohexanoate which was added to a mixture containing 95 ml. of concentrated sulfuric acid and 185 ml. of water. The acidic reaction mixture was slowly heated. After about 30 minutes, the temperature reaches 55° C. and the evolution of carbon dioxide became noticeable. The temperature of the reaction mixture was maintained at 65° C. for about 1 hour and then heated to 80° C. and held there for several minutes. By this time the evolution of carbon dioxide appeared to be over. The reaction mixture was cooled and poured into a solution of 305 g. of potassium carbonate in 1 liter of ice water. Chloroform was added; the mixture was shaken well and filtered to remove the precipitated potassium sulfate; and, the layers were separated. The aqueous layer was extracted further with chloroform; the combined chloroform extracts were dried over anhydrous sodium sulfate and filtered; the dried filtrate was heated in vacuo to remove the chloroform to yield, after air-drying, 27.4 g. (80%) of 1-(2-methyl-5-pyridinyl)hexan-1,5-dione, a tan solid melting at 85°-87° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[CH2:10]([O:12][CH:13]([S:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:27]=[CH:28][C:21]=12)[C:14](OCC)=[O:15])[CH3:11].O>C1COCC1.C(Cl)Cl>[CH2:10]([O:12][CH:13]([S:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:27]=[CH:28][C:21]=12)[C:14]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH3:9])[N:8]=1)=[O:15])[CH3:11]
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)C(OCC)Sc1ncnc2c1cnn2-c1ccccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(Sc1ncnc2c1cnn2-c1ccccc1OC)C(=O)Nc1nc(C)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.9 %

Procedure:
Sodium hydride (95%, 3.7 mg, 0.15 mmol) was added to a stirred solution of 2-amino-4-methylthiazol (17.6 mg, 0.154 mmol) in anhydrous THF (4 mL). The reaction mixture was kept at ambient temperature for 5 minutes before ethyl ethoxy{[1-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]thio}acetate (50 mg, 0.129 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h. Water and DCM were added and the two phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with a gradient consisting of 40-100% EtOAc in heptane) to give the title compound as a colourless oil (1.1 mg), 1H NMR (300 MHz, CDCl3) δ 10.03 (br s, 1H), 8.74 (s, 1H), 8.26 (s, 1H), 7.47 (m, 2H), 7.12 (m, 2H), 6.91 (s, 1H), 6.58 (s, 1H), 4.02 (m, 1H), 3.81 (m, 4H), 2.38 (s, 3H), 1.34 (t, 3H), HRMS: calcd for (M+H+) C20H21N6O3S2: 457.1116. Found: 457.1116.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=[CH:31][C:30]=1[N:44]1[CH2:56][CH2:55][N:47]2[C:48]3[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=3[CH:54]=[C:46]2[C:45]1=[O:57])(=[O:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:56][CH2:55][N:47]3[C:48]4[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=4[CH:54]=[C:46]3[C:45]2=[O:57])=[CH:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 130c (250 mg, 0.663 mmol), 2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 114a (338 mg, 0.729 mmol), Pd(PPh3)4 (38.3 mg, 0.033 mmol), Na2CO3 aqueous solution (1.0 N, 2.19 mL, 2.19 mmol), DME (2 mL) were added. The mixture was reacted in microwave at 135° C. for 15 min. CH2Cl2 (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 130d.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18].[CH2:21]([Mg]Br)[CH3:22]>C(OCC)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]([OH:11])[CH2:21][CH3:22])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: COC(=O)c1cc(C=O)c(C(F)(F)F)cc1NC(C)=O
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
A solution of 2-acetylamino-5-formyl-4-trifluoromethyl-benzoic acid methyl ester (840 mg, 2.90 mmol) in dry diethyl ether (29 mL) was cooled to 0° C. and a solution of ethylmagnesium bromide (1M in THF, 5.8 mL, 5.8 mmol) was added dropwise. The mixture was stirred for 1 h at 0° C. and the reaction was quenched by adding aqueous ammonium chloride solution. This mixture was extracted once with EtOAc and the organic phase was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 80:20→70:30) to furnish 2-acetylamino-5-(1-hydroxy-propyl)-4-trifluoromethyl-benzoic acid methyl ester (262 mg, 0.82 mmol, 28%) as a white solid, m.p. 120-122° C., ESI-MS: m/z 320 [M+H]+.
Reaction SMILES: [Br-].[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][CH:32]=2)[CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:3]1.[H-].[Na+].C(OCC)C.[Cl:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=O>CN(C)C=O>[Cl:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:10]/[C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][S:2][CH:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc([P+](Cc2cccc(-c3ccsc3)c2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CCCCCCl
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: ClCCCC/C=C/c1cccc(-c2ccsc2)c1
Reaction time: 0.25 h

Procedure:
400 mg of 3-(3-thienyl)benzyl(triphenyl)phosphonium bromide was dissolved in 2 ml of dimethylformamide, and under ice cooling, 37 mg of 60% oily sodium hydride was added. The mixture was stirred for 15 minutes, and to this solution was added an ethyl ether solution (0.6 ml) of the foregoing aldehyde compound. The mixture was stirred overnight at room temperature, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [hexane/ethyl acetate=19/1] to give 123 mg of the captioned compound (a mixture of E:Z=1:1) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:19](=O)(O)[O-:20].[Na+].C(Cl)(Cl)=O.[C:28]([C:32]1[CH:33]=[C:34]([C:41](=[O:44])[NH:42][CH3:43])[C:35]([O:39][CH3:40])=[C:36]([CH:38]=1)[NH2:37])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([C:32]1[CH:33]=[C:34]([C:41](=[O:44])[NH:42][CH3:43])[C:35]([O:39][CH3:40])=[C:36]([NH:37][C:19]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[O:20])[CH:38]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: Nc1ccc(Oc2ccncc2)c2ccccc12
Reactant: O=C([O-])O
Reactant: CNC(=O)c1cc(C(C)(C)C)cc(N)c1OC
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccncc3)c3ccccc23)c1OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-Amino-4-(4-pyridinyloxy)naphthalene (Example 6) (1.0 mmol) is dissolved in dichloromethane (15 mL). An equal volume of sat. aqueous sodium bicarbonate is added, and the biphasic solution is cooled to 0° C. During the addition of phosgene (1.93 M in toluene, 1.0 mL), stirring is stopped. Immediately afterward, stirring is resumed for 15 min with the reaction mixture at 0° C. The layers are separated, the organics dried over solid magnesium sulfate and concentrated to approximately 5 mL of solution. 5-tert-Butyl-3-methylcarbamoyl-2-methoxyaniline (Example 3) (0.9 mmol) in dichloromethane (5 mL) is added, and the reaction mixture is stirred overnight at ambient temperature. The solvent is removed by rotary evaporation and the resulting product purified by flash chromatography over silica gel with a suitable elutant such as CH2Cl2:MeOH (95:5) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[NH:24]=[C:25]1[CH2:29][N:28]([CH3:30])[C:27](=[O:31])[N:26]1C(C1C=CC=CC=1)=O.[CH3:40]C(C)([O-])C.[K+].[Cl-].[NH4+]>C(O)C>[F:22][C:2]([F:23])([F:1])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:29]2/[C:25]([NH:24][CH3:40])=[N:26][C:27](=[O:31])[N:28]/2[CH3:30])[CH2:10][CH2:11]1
Reactant: CN1CC(=N)N(C(=O)c2ccccc2)C1=O
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCO
Product: CNC1=NC(=O)N(C)/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 3.2 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (26.0 g) in ethanol (100 mL) were added 4-imino-1-methyl-3-(phenylcarbonyl)imidazolidin-2-one (16.7 g) and potassium tert-butoxide (8.60 g) under ice-cooling. The reaction mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution at room temperature, and ethanol was evaporated under reduced pressure. Water and ethyl acetate were added to the residue, and the insoluble material was collected by filtration, recrystallized from ethanol/water, and further recrystallized from acetone/water. To a solution of the obtained solid (2.03 g) in toluene (10 mL) was added a solution (4.8 mL) of methylamine in 40% methanol at room temperature. The reaction mixture was stirred at 70° C. overnight, 40% methanol solution (4.8 mL) was added at room temperature, and the mixture was stirred at 70° C. overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) and recrystallized from ethyl acetate/heptane to give the title compound (1.10 g).
Reaction SMILES: [Si]([O:8][C@H:9]([C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH2:42][OH:43])[CH:36]=1)[CH2:10][NH:11][C@H:12]([CH3:34])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:23])[CH:15]=1)(C(C)(C)C)(C)C.CO.O.ClCCl>CO>[NH3:11].[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][N:24]1[C:22](=[O:23])[CH2:21][CH2:20][C:16]1[CH:15]=[C:14]([CH2:13][C@H:12]([NH:11][CH2:10][C@@H:9]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH2:42][OH:43])[CH:36]=2)[OH:8])[CH3:34])[CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](Cc1cccc(CCC(=O)N2CCc3ccccc3C2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C[C@H](Cc1cccc(CCC(=O)N2CCc3ccccc3C2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Product: N

Procedure:
Prepared from 4-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[((1R)-2-{3-[3-(3,4-dihydroisoquinolin-2-(1H)-yl)-3-oxopropyl]phenyl}-1-methylethyl)amino]ethyl}-2-(hydroxymethyl)phenol (Preparation 50) according to the method for example 1 using methanol:water (2.4:1 v/v) instead of acetic acid as solvent and using dichloromethane:methanol: 880 ammonia (95:5:0.5 by volume) as the column eluent to give the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:19](=O)[C:18](=O)[N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.C(O)(=O)C>O1CCCC1.B#B>[CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1
Reactant: CN1CC2c3cccn3Cc3ccccc3N2C(=O)C1=O
Agent: B#B
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
To the suspension of 12.8 g of 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine in 460 ml of tetrahydrofuran, 200 ml of 1-molar diborane in tetrahydrofuran are added while stirring and cooling with ice. The mixture is refluxed for one hour, again cooled and combined with 25 ml of acetic acid. It is evaporated, the residue taken up in 50 ml of 30% aqueous sodium hydroxide and the mixture extracted with methylene chloride. The extract is dried, evaporated, the residue dissolved in diethyl ether, the solution filtered and the filtrate evaporated, to yield the 2-methyl-1,3,4,14b-tetrahydro-10H--pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].O=[C:26]([CH3:37])[CH2:27][C:28]([O:30][C@@H:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[O:29]>C1COCC1>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:27]([C:28]([O:30][C@@H:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[O:29])=[C:26]([CH3:37])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=3)[C:10](=[O:11])[NH:12]2)=[CH:19][CH:18]=1)#[N:16]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COC(=O)[C@H](C)OC(=O)CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)OC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
200 mg (0.98 mmol) N-[3-(trifluoromethyl)phenyl]urea, 129 mg (0.98 mmol) 4-cyanobenzaldehyde, 92 mg (0.49 mmol) (1S)-2-methoxy-1-methyl-2-oxoethyl 3-oxobutanoate, and 295 mg polyphosphoric acid ethyl ester are suspended in 3 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate as eluent. A mixture of diastereoisomers is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Mg].II.CN([CH:15]=[O:16])C>C1COCC1>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][CH:15]=[O:16]
Reactant: BrCCC1OCCO1
Reactant: CN(C)C=O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=CCCC1OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To the solution of 2-(2-bromoethyl)-1,3-dioxolane (10 g, 55.2 mmol) in THF (50 mL) was added magnesium (1.6 g, 66.3 mmol) and trace amount of I2 as initiator. The reaction mixture was stirred at rt for 2 hrs. After cooling to −78° C., the mixture was quenched with dry DMF (1.39 g, 66.3 mmol) and kept at −78° C. for 2 hrs. After dilution with H2O the reaction mixture was extracted with CH2Cl2 (2×), followed by distillation (45-55° C. @ 8 mmHg) to afford 2 g (28%) of the title compound. MS (DCI/NH4+) m/z 131 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([NH2:23])=[S:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(O)C>[CH2:35]([O:34][C:32]([C:31]1[N:23]=[C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:13]3[CH2:14][C:15](=[O:17])[NH:16][C:10]4[CH:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH:28]=[CH:27][C:11]=4[N:12]=3)[CH:19]=2)[S:22][CH:30]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamide (Example 149) (39 mg, 0.1 mmol) and ethyl bromopyruvate (29 mg, 0.15 mmol) in ethanol (0.5 mL) was heated at reflux for 7 h. The solution was cooled to 0° C., stirred for 0.5 h, and the title compound was isolated by filtration as light yellow solid (29 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].[H-].[Na+].Cl[C:23]1[N:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[N:24]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([C:23]3[N:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[N:24]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1cc2ccn(-c3nc(C)cc(C)n3)c2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (10 mg, 0.04 mmol) in DMF (0.5 mL) is added NaH (95%, 3 mg). The reaction mixture is stirred at room temperature for 30 minutes, and then 2-chloro-4,6-dimethyl-pyrimidine (17 mg, 0.12 mmol)) is added. The mixture is heated at 60° C. overnight and cooled. Water (1 mL) and EtOAc (2 mL) are added to the mixture. The organic layer is separated, washed with water once and concentrated under reduced pressure. The residue is purified by PTLC (Hexane/EtOAc 4:1) to give the titled compound. 1H NMR: (CDCl3) 10.21 (s, 1H), 8.48 (d, 1H), 7.47 (s, 1H), 7.28 (t, 1H), 7.15 (d, 2H), 6.87 (s, 1H), 6.68 (d, 1H), 2.55 (s, 6H), 2.36 (m, 4H), 1.03 (t, 6H).