Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C[O:4][CH2:3]C1.[C:6]([Si:10]([O:13][C:14]1[CH:19]=[C:18]([CH2:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].C([Li])(CC)C.[Cl-].[NH4+]>C(OCC)C.CN(C=O)C>[Si:10]([O:13][C:14]1[C:15]([F:22])=[C:16]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[CH:3]=[O:4])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: C1CCOC1
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
A 250 ml THF solution containing 12.7 g of t-butyl-(5-ethyl-2-fluorophenoxy)dimethylsilane and 7.5 g of N,N,N′N′-tetramethylethylenediamine was cooled to −75° C. under a nitrogen atmosphere, and then 55.6 ml of s-butyllithium (0.99 M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After then adding 7.74 ml of DMF, the mixture was stirred at −75° C. for 1 hour and the temperature was raised to room temperature. Next, 500 ml of diethyl ether and 500 ml of a 5% aqueous ammonium chloride solution were added to the reaction mixture, the organic layer was washed twice with 500 ml of water and once with 500 ml of saturated aqueous sodium chloride in that order, and the aqueous layer was extracted with 100 ml of diethyl ether. The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane system) to obtain the target compound (12.6 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[C:25](=[O:26])[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:23](=[O:35])[C:22]([CH3:36])=[N:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:23](=[O:35])[C:22]([CH3:36])=[N:21]3)[CH2:12][CH2:13]2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: Cc1nn(CCCCl)c(=O)n(COCC[Si](C)(C)C)c1=O
Reactant: COc1cc(F)ccc1N1CCNCC1
Product: COc1cc(F)ccc1N1CCN(CCCn2nc(C)c(=O)n(COCC[Si](C)(C)C)c2=O)CC1

Procedure:
substituting 1-(4-fluoro-2-methoxyphenyl)piperazine and 2-(3-chloropropyl)-6-methyl-4-[2-(trimethylsilyl)ethoxymethyl]-1,2,4-triazine-3,5(2H,4H)-dione gave 2-{3-[4-(4-fluoro-2-methoxyphenyl)piperazin-1-yl]propyl}-6-methyl-4-[2-(trimethylsilyl)ethoxymethyl]-1,2,4-triazine-3,5(2H,4H)-dione;
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: COC(=O)/C=C/c1cnccc1N=C=Nc1cccc(C(F)(F)F)c1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COC(=O)CC1c2cnccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 107 mg (0.31 mmol) of the carbodiimide from Example 15A and 56 mg (0.31 mmol) of 4-fluorophenylpiperazine, general procedure [C] and purification by preparative HPLC result in 50 mg (28% of theory) of product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[C@@H:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH3:26])[C:19]=3[CH3:27])[CH2:15][CH2:16][CH2:17][C@H:10]2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2]>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:14]2[N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[CH2:17][CH2:16][CH2:15]2)=[C:19]([CH3:27])[C:20]=1[CH3:26]
Reactant: COc1ccc([C@H]2CCC[C@H]3CN(Cc4ccccc4)CCN32)c(C)c1C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Product: COc1ccc([C@H]2CCC[C@H]3CNCCN32)c(C)c1C

Procedure:
A solution containing the compound obtained in step 3 (2.66 g, 7.30 mmol) and ammonium formate (6.90 g, 109.50 mmol, 15 eq) is treated with 665 mg of 20% palladium hydroxide on carbon, and heated at reflux under a nitrogen balloon for 2 h. The mixture is filtered through a CELITE pad. The pad is washed with 200 mL of chloroform and the solution is concentrated in vacuo. The residue is taken up in 200 mL dichloromethane and washed with 1N NaOH, water and brine (75 mL each) to remove any residual ammonium formate. The organic solution is concentrated in vacuo to afford (6R,9aS)-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazine as an amber colored oil which is used in the next step with no further purification. LC/MS: 275 (M+1). 1H NMR (400 MHz, CDCl3): 7.36 (1H, dd), 6.74 (1H, dd), 4.50 (1H, dd), 3.80 (3H, s), 3.28 (1H, d), 2.86 (1H, dd), 2.78 (2H, m), 2.67-2.55 (3H, m), 2.22 (3H, s), 2.17 (3H, s), 1.78-1.67 (4H, bm), 1.56-1.31 (4H, bm).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:13]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]#[N:25])[CH:18]=[C:19]([CH3:21])[CH:20]=2)=[O:14])=[N:5][C:6]([O:11]C)=[N:7][C:8]=1[O:9]C)[CH3:2].C(Cl)(=O)C(Cl)=O>C1COCC1>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6](=[O:11])[NH:5][C:4]=1[C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]#[N:25])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[O:14])[CH3:2]
Reactant: CCc1c(OC)nc(OC)nc1C(=O)c1cc(C)cc(C=CC#N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CCc1c(C(=O)c2cc(C)cc(C=CC#N)c2)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 21.8 %

Procedure:
A mixture of 3-[3-(5-ethyl-2,6-dimethoxy-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (2.3 g, 6.82 mmol) and oxalyl chloride (10 ml) in anhydrous THF (30 ml) was refluxed for 4 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:1)) to afford 460 mg (22%) of a white solid. m.p. 305-306° C.; 1H NMR (200 MHz, DMSO-d6) δ 0.83 (3H, t, J=7.4 Hz), 1.94 (2H, q, J=7.4 Hz), 2.42 (3H, s), 6.65 (1H, d, J=16.8 Hz), 7.72 (1H, d, J=16.8 Hz), 7.80 (1H, s), 7.87 (1H, s), 8.01 (1H, s), 11.08 (1H, s), 11.29 (1H, s); m/z (LC/Mass, EI) 310 (M+H+).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].S(Cl)([Cl:27])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([Cl:27])=[O:24])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: O=S(Cl)Cl
Reactant: C=CCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: C=CCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
A mixture of 1.3 g of 4-(7-octenyloxy)biphenyl4'-carboxylic acid and an excessive amount of thionyl chloride was refluxed for 6 hours, and then unaltered thionyl chloride was evaporated to leave 4-(7-octenyloxy)-biphenyl-4'-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][CH:5]=4)=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1nocc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
A dry flask was charged with 3-Methyl-isoxazole-4-carboxylic acid (0.500 g, 3.9339 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (39 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.992 g, 3.932 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF (5 mL) and collected to afford the 3-Methyl-isoxazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.938 g, 2.60 mmol, 66%).
Reaction SMILES: [CH:1]1([N:6]2[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)N[Si](C)(C)C.[Li].C([C:32]([O:34][CH3:35])=[O:33])#N.[NH4+].[Cl-]>O1CCCC1>[CH:1]1([N:6]2[CH:10]=[C:9]([CH:11]([C:32]([O:34][CH3:35])=[O:33])[C:12]([O:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[O:13])[N:8]=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)C#N
Reactant: O=C(Cc1cn(C2CCCC2)cn1)OC1CCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC1CCCC1)c1cn(C2CCCC2)cn1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
Cyclopentyl (1-cyclopentyl-1H-imidazol-4-yl)acetate (2.00 g; 7.60 mmol) was dissolved in tetrahydrofuran (THF; 45 ml). The reaction solution was cooled to 0° C. and then lithium hexamethyldisilazane (20% in THF; 6.33 ml; 7.60 mmol) was added dropwise. The mixture was stirred at 0° C. for a further hour. Then methyl cyanoformate (0.66 ml; 8.36 mmol) was added. The mixture was stirred at 0° C. for 10 min and then at RT for 7 h. The reaction solution was then added to saturated NH4Cl solution. It was extracted with EA, and the organic phase was washed with H2O and dried over Na2SO4. The solvent was removed under reduced pressure. Purification of the crude product by column chromatography (120 g of silica gel; EtOAc/n-heptane—2/1) resulted in 0.46 g of cyclopentyl methyl 2-(1-cyclopentyl-1H-imidazol-4-yl)malonate.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(N(C)C)=C(C)C.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(OCC)(=O)C>ClCCl>[CH:1]1([CH2:6][O:7][C:8]2[N:13]=[C:12]([C:14]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:16])[CH:11]=[N:10][C:9]=2[N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cnc(N2CCCC2)c(OCC2CCCC2)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cnc(N2CCCC2)c(OCC2CCCC2)n1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
To a solution of 0.0874 g (0.0003 mol) 6-cyclopentylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid in 1.0 mL dichloromethane was added 0.047 g (0.00035 mol)(1-chloro-N,N,2-trimethyl-1-propenylamine and the mixture was stirred at room temperature for 45 min. To the resulting solution was added 0.0683 g (0.0008 mol) piperidine and the mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between 10% citric acid and dichloromethane. The phases were separated and the organic phase was washed with water and brine, dried over sodium sulfate, evaporated and the residue was purified by chromatography on silica gel with dichloromethane:ethyl acetate=1:1 to yield 0.064 g (0.00018 mol) of the title compound as beige crystals melting at 61-62° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1>CC(C)=O>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][CH2:5][C:4]([CH3:17])([CH3:16])[C:3](=[O:18])[CH2:2][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(CCOc1ccc(Cl)cc1Cl)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CCOc1ccc(Cl)cc1Cl)C(=O)Cn1cncn1
Reaction time: 3 h
Yield: 94.7 %

Procedure:
30.9 g (0.1 mol) of 1-chloro-5-(2,4-dichlorophenoxy)-3,3-dimethyl-2-pentanone, dissolved in 80 ml of acetone, are added dropwise, with stirring, to a mixture of 13.8 g (0.1 mol) of potassium carbonate and 13.8 g (0.2 mol) of 1,2,4-triazole in 200 ml of boiling acetone. The mixture is boiled for a further 3 hours, cooled down to 0° to 10° C., the salt is filtered off and the filtrate is evaporated in vacuo. After trituration of the oily residue with a little petroleum ether, 32.4 g (94.6% of theory) of 5-(2,4-dichlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-pentanone are obtained as colorless crystals of melting point 62° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH2:9]([NH:11][C:12](=[O:32])[NH:13][C:14]1[S:15][C:16]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:21][C:20](B(O)O)=[CH:19][C:17]=2[N:18]=1)[CH3:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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.Cl[Pd]Cl>[Br:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:20]2[CH:21]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:16]3[S:15][C:14]([NH:13][C:12]([NH:11][CH2:9][CH3:10])=[O:32])=[N:18][C:17]=3[CH:19]=2)[CH:7]=1
Reactant: Brc1cnnc(Br)c1
Reactant: CCNC(=O)Nc1nc2cc(B(O)O)cc(-c3ccccn3)c2s1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnnc(Br)c3)cc(-c3ccccn3)c2s1
Temperature: 80 °C
Yield: 85.2 %

Procedure:
To a solution of 3,5-dibromopyridazine (0.32 g, 1.34 mmol) in DMF (5 mL) was added 2-(3-ethylureido)-7-(pyridin-2-yl)benzothiazol-5-ylboronic acid (0.46 g, 1.34 mmol) and aqueous solution of K3PO4 (0.43 g, 2.01 mmol). The reaction was degassed by purging N2 for 15 min followed by addition of bis(triphenylphosphine)palladium (II) chloride (0.11 g, 0.13 mmol). The reaction mixture was again degassed for 10-15 min then heated up to 80° C. for 2-3 h. After reaction completion (by TLC), the mixture was poured onto crushed ice and extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 3% MeOH-DCM to obtain the desired product as off-white solid (0.52 g, 85%). 1H NMR (DMSO-d6): δ 10.71 (s, 1H), 9.94 (m, 2H), 8.82 (m, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.46 (m, 1H), 7.17 (br s, 1H), 3.22 (q, J=7.20 Hz, 2H), and 1.11 (t, J=7.20 Hz, 3H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])[CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O)(=O)C.Br>CCOCC>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])[CH3:11])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 1 h

Procedure:
To 2.10 g of Z-Leu-Ala-Gln-OH was added 20 ml of acetic acid solution containing 25% of hydrogen bromide, then the mixture was allowed to stand at a room temperature for 1 hour. After the completion of the reaction, dried ether was added to the reaction mixture to obtain H-Leu-Ala-Gln-OH.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].O>C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1[O:1][CH2:2][CH2:3][CH2:4][CH:5]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1=COCCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCCO1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3,4-dihydro-2H-pyran (500 mg, 5.94 mmol) in THF (10 mL) was brought to −78° C. followed by the addition of tert-butyllithium (12.2 mL, 20.8 mmol, 1.7 M in pentane). The resulting yellow solution was brought to 0° C. and stirred for 15 min. The reaction was then cooled to −78° C. and tributyltin chloride (4.8 mL, 17.8 mmol) was slowly added. The reaction was monitored by TLC. Upon completion by TLC, water was added (20 mL) to the reaction. The organic phase was separated, washed with water, dried over MgSO4, concentrated and chromatographed on silica gel using hexanes (500 ml hexanes and 0.5 mL triethylamine). The title compound was obtained as a colorless oil. MS m/z: 375 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:17])=[O:16]
Reactant: COCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a stirred solution of 3-methoxy-propan-1-ol (300 g, 3.3 mol) in anhydrous CH2Cl2 (3 L) was added triethylamine (790 mL, 5.7 mol). The mixture was cooled to 0° C. and methanesulfonyl chloride (376 mL, 4.8 mol) in anhydrous CH2Cl2 (1 L) added dropwise. After stirring for 2 h at rt, the mixture was washed with water and brine, dried and evaporated to give the crude product as an oil (540 g, yield 96%) that was used in the next step without purification. 1H NMR (400 MHz, CDCl3): δ 3.40-3.37 (t, J=6.0 Hz, 2H), 2.55-2.52 (t, J=6.0 Hz, 2H), 2.40 (s, 3H), 2.06 (s, 3H), 1.08-1.02 (m, 2H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[Cl:6][C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=1.ClC1C=CC2SC3C(=CC=CC=3)N([Li])C=2C=1.C(Br)C#C>CCOCC>[Cl:6][C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:3][C:2]#[CH:1])[C:9]=2[CH:8]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Reactant: [Li]CCCC
Agent: C#CCBr
Agent: [Li]N1c2ccccc2Sc2ccc(Cl)cc21
Solvent: CCOCC
Product: C#CCN1c2ccccc2Sc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
To a solution containing 0.2 mole of butyllithium in 350 ml. of absolute ether (prepared in situ under nitrogen) were added 46.5 g. (0.2 mole) of 2-chlorophenothiazine while the mixture was maintained at -10° C. The reaction mixture was then allowed to stir for forty-five minutes at 0° C. To the resulting solution of 2-chloro-10-phenothiazinyllithium were added 30 g. (0.25 mole) of propargyl bromide in 30 ml. of absolute ether. This reaction mixture was allowed to stir at room temperature overnight. After quenching with dilute hydrochloric acid, the ethereal phase of the reaction mixture was washed with water and dried over anhydrous calcium sulfate. Upon removal of the solvent a semi-solid mass of crude 2-chloro-10-propargylphenothiazine remained. Recrystallized from methanol and from ether-hexane, pure 2-chloro-10-propargylphenothiazine melted at 112.0°-115.0° C. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [O:1]=[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH:10]([NH:14]C(=O)OC(C)(C)C)[CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3]1>Cl.CO>[NH2:14][CH:10]1[CH2:9][C:8]2[C:13]3=[C:4]([NH:3][C:2](=[O:1])[N:12]3[CH2:11]1)[CH:5]=[CH:6][CH:7]=2
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc3[nH]c(=O)n(c23)C1
Agent: Cl
Solvent: CO
Product: NC1Cc2cccc3[nH]c(=O)n(c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
t-Butyl (1,2,5,6-tetrahydro-2-oxo-4H-imidazo(4,5,1-ij)quinolin-5-yl)carbamate (1.65 g, 0.057 mol) was dissolved in methanol HCl (85 mL) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give 1.29 g of crude product. An analytical sample was recrystallized from methanol and ether to give a pink solid, mp >300° C. Anal. Calcd. for C10H11N3O.HCl.1/2H2O: C, 51.58; H, 5.58; Cl, 15.11; N, 17.90. Found: C, 51.04; H, 5.47; Cl, 15.10; N, 17.86.
Reaction SMILES: O.C(OC(N[C@H](C(O)=O)CC(C)C)=O)(C)(C)C.C(N1CCNCC1)C.[C:26]1([CH:32](C2C=CC=CC=2)[N:33]2[CH2:38][CH2:37][N:36]([C:39]([C@@H:41]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH2:34]2)C=CC=CC=1>>[CH2:32]([N:33]1[CH2:34][CH2:35][N:36]([C:39]([C@@H:41]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:37][CH2:38]1)[CH3:26]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN1CCNCC1
Solvent: O
Product: CCN1CCN(C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC1
Yield: 65 %

Procedure:
Tert-butoxycarbonyl-L-leucine monohydrate (7.47 g) and 1-ethylpiperazine (3.42 g) were condensed in the same manner as employed in the preparation of tert-butyl (s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate to yield 6.4 g of tert-butyl (s)-1-(4-ethylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate as a colorless viscous liquid (yield: 65%).
Reaction SMILES: O.[CH:2]1[N:6]=[CH:5][N:4]2[C@H:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=3[F:18])[CH2:8][CH2:9][C:3]=12.C([O:23]O)(C)(C)C>[Fe](Cl)(Cl)Cl.N1C=CC=CC=1>[F:18][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[C@H:7]1[N:4]2[CH:5]=[N:6][CH:2]=[C:3]2[C:9](=[O:23])[CH2:8]1)[C:14]#[N:15]
Reactant: N#Cc1ccc([C@@H]2CCc3cncn32)c(F)c1
Reactant: CC(C)(C)OO
Agent: Cl[Fe](Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc([C@@H]2CC(=O)c3cncn32)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.6 %

Procedure:
To a 500 mL round-bottomed flask equipped with a water condensor is added (S)-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile (6.0 g, 26.3 mmol) and pyridine (32.6 mL). To the solution is added iron(III) chloride (0.21 g, 1.32 mmol and tert-butyl hydroperoxide (10.9 mL, 79 mmol). The reaction is heated to reflux and stirred for 5 hours. The reaction is allowed to cool to room temperature and is then filtered through celite. The collect filtrate is concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (XBridge, C8 H2O (0.1% NH4OH)/CH3CN) to give 1.5 g of the entitled product. MS (m+1)=242.1; LCMS condition B, retention time=0.97 min; 1H NMR (400 MHz, CDCl3) δ ppm 3.12 (dd, 1H), 3.80 (dd, 1H), 6.04 (dd, 1H), 7.14 (t, 1H), 7.48-7.57 (m, 2H), 7.61 s, 1H, 7.72 s, 1H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)=[O:25].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CC(=O)c3ccc4ccccc4c3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and α-bromo-2'-acetonaphthone as described for compound 8. Purified by chromatography [ethyl acetate: petroleum ether (60°-80° C.)/1:3]. Crystallized from methanol at -20° C. M.p. 89°-90° C.