Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=[O:2].CN(C)C=O.C(Cl)(=O)C([Cl:48])=O>O1CCCC1>[Cl:48][C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of pivalic acid 6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (54 mg) in tetrahydrofuran (1.5 ml) were sequentially added N,N-dimethylformamide (in catalytic amounts) and oxalyl chloride (0.027 ml) under a nitrogen atmosphere, the solution was stirred for 30 minutes at room temperature, then the solvent was evaporated in vacuo to provide pivalic acid 6-{2-[(4-chlorocarbonylmethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (74 mg). A solution of this compound (37 mg) and dimethylamine (2.0 M solution in tetrahydrofuran) (0.08 ml) in tetrahydrofuran (0.7 ml) was stirred for 30 minutes at room temperature. To a suspension of lithium aluminum hydride (76 mg) in tetrahydrofuran (2 ml) was added aluminum chloride (267 mg) on an ice bath under a nitrogen atmosphere, and the solution was stirred for 1 hour at room temperature. Among the resulting suspension, 0.5 ml was added dropwise thereto followed by stirring for 2 hours at room temperature. Tetrahydrofuran and concentrated aqueous ammonia were sequentially added thereto, the solution was filtered through celite pad, and concentrated under a nitrogen stream. A solution of the resulting residue in N,N-dimethylformamide was purified by LC-MS, and the title compound (7.1 mg) was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([C:29]1[CH:34]=[CH:33][C:32](/[C:35](/[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][CH3:47])[N:40]=2)=[CH:36]\CO)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].O>O1CCCC1>[Br:24][CH2:20]/[CH:36]=[C:35](/[C:39]1[N:40]=[C:41]([O:46][CH3:47])[C:42]([Cl:45])=[CH:43][CH:44]=1)\[C:32]1[CH:31]=[CH:30][C:29]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:34][CH:33]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1nc(/C(=C/CO)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Yield: 118 %

Procedure:
Triphenylphosphine (1.10 g) and carbon tetrabromide (1.81 g) were sequentially added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-ol (912 mg) in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound as a black powder (1.28 g).
Reaction SMILES: C(O)CO.[C:5]([CH:7]([C:12]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1)C(OC)=O)#[N:6].[OH-].[K+]>O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:12]1([CH2:7][C:5]#[N:6])[CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1
Reactant: COC(=O)C(C#N)C1(c2ccccn2)CCOC2(CCCC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: N#CCC1(c2ccccn2)CCOC2(CCCC2)C1
Temperature: 120 °C
Yield: 82.6 %

Procedure:
Ethylene glycol (300 ml) was added to methyl 2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate (15.43 g, 49 mmol) followed by potassium hydroxide (5.5 g, 98 mmol), the resulting mix was heated to 120° C., after 3 h, the reaction mix was cooled and water (300 ml) was added, the product was extracted by Et2O (3×400 ml), washed with water (200 ml), dried (Na2SO4) and concentrated, the residual was purified by flash chromatography (340 g silica gel column, eluted by EtOAc in hexane: 3% 2CV; 3-25%, 12 CV; 25-40% 6CV to give 2-[9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (10.37 g, 82% yield, m/z 257.0 [M+H]+ observed).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[CH:11]=[CH:10][C@@H:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:8][CH2:7]1)[CH:2]=[CH2:3].C(N(C(C)C)C(C)C)C.[C:30](=O)(OC(Cl)(Cl)Cl)[O:31]C(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:4][N:5]1[C:30](=[O:31])[N:8]2[CH2:7][C@H:6]1[CH:11]=[CH:10][C@H:9]2[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCON[C@@H]1C=C[C@@H](CO[Si](C)(C)C(C)(C)C)NC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C=C[C@H]2CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 188.6 %

Procedure:
To a stirred solution of O-allyl-N-((3R,6S)-6-((tert-butyldimethylsilyloxy)methyl)-1,2,3,6-tetrahydropyridin-3-yl)hydroxylamine (Intermediate 128, 2.0 g, 6.70 mmol) in acetonitrile (560 mL), N-ethyl-N-isopropylpropan-2-amine (4.67 ml, 26.80 mmol) was added. Bis(trichloromethyl) carbonate (0.795 g, 2.68 mmol) dissolved in 40 mL CH3CN was added via a syringe pump (at a rate 0.1 ml/min) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. It was then allowed to stir at room temperature overnight. The mixture was then concentrated and diluted with EtOAc (50 mL). The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column (12 g, 0-25% Hex/EA) to give the desired product as a colorless oil (1.64 g).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH2:6])[CH2:3][CH2:2]1.C([O:9][C:10]([C:12]1[S:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]2)=[N:15][N:16]=1)=O)C>>[CH:1]1([CH2:4][CH2:5][NH:6][C:10]([C:12]2[S:13][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22]3)=[N:15][N:16]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: NCCC1CC1
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Product: O=C(NCCC1CC1)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-cyclopropylethylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.90 g, 83% yield). 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J=7.8 Hz, 1H), 7.64 (dd, J=7.5, 7.5 Hz, 1H), 7.57 (dd, J=7.5, 7.5 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.19 (t, J=5.8 Hz, 1H), 4.04-4.10 (m, 1H), 3.86-3.92 (m, 1H), 3.64-3.75 (m, 2H), 3.49-3.56 (m, 4H), 3.33-3.37 (m, 2H), 1.51 (dt, 2H, J=7.0, 7.0 Hz), 0.68-0.75 (m, 1H), 0.46-0.51 (m, 2H), 0.08-0.12 (m, 2H). MS (ES+) m/z 454.2 (M+1).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[C:12](OC)(=[O:16])[C:13]([CH3:15])=[CH2:14].C(N(CC)O)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>>[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)OC
Reactant: CC(C)CCCCCCCO
Agent: CCN(O)CC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCCCCCCCC(C)C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Four hundred seventy four grams (3.0 moles) of isodecyl alcohol, 750 g (7.5 moles) of methyl methacrylate (MMA), 1.75 g (3.0 millimol) of hafnium actylacetonate, and 50 mg diethylhydroxylamine and 25 mg phenothiazine free radical polymerization inhibitors, are added to a 3 liter flask equipped with an agitator, thermometer, and a 10-plate Oldershaw fractional distillation column. The mixture was heated to reflux at atmospheric pressure while an azeotropic mixture of MMA and methanol was removed from the upper part of the fractionating column. The reaction was continued in this manner for approximately 90 minutes while the temperature at the top of the column was 65°-67° C. and the temperature in the pot was 106°-124° C. Excess MMA was removed under vacuum and the resulting IDMA was isolated (660 grams, 99.0% yield) and analyzed. Gas-liquid chromatographic (GLC) analysis showed >99.9% conversion of isodecanol to IDMA of 99.8% purity.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:14][CH2:13][C@@H:12]2[C@H:7]([O:8][CH2:9][CH2:10][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[N:11]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][O:8][CH:7]2[CH2:6][NH:5][CH2:14][CH2:13][CH:12]12
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]2CN(C(=O)C(F)(F)F)CC[C@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC2CNCCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-tert-butyl 6-(trifluoroacetyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (70 g, 0.20 mol) in MeOH (160 mL) and water (600 mL) was added K2CO3 (34.2 g, 0.24 mol) in one portion at room temperature. The mixture was stirred for 2 h at room temperature, and then extracted with DCM (200 mL×5). The combined organic layers were concentrated to give tert-butyl octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate as a mixture of trans diastereomers. SFC purification afforded the pure S,S diastereomer tert-butyl (4aS,8aS)-octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (peak 1) 1H NMR: (CDCl3) δ 3.88-3.80 (m, 2H), 3.77-3.67 (m, 1H), 3.35-3.34 (m, 2H), 3.29-3.27 (m, 2H), 3.10-3.11 (d, 1H), 2.54-2.42 (m, 3H), 1.76 (s, 1H), 1.70-1.60 (m, 1H), 1.45 (s, 9H) LCMS (M+H)=243 and R,R diastereomer tert-butyl (4aR,8aR)-octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (peak 2)1H NMR: (CDCl3) δ 3.89-3.80 (m, 2H), 3.77-3.67 (m, 1H), 3.35-3.34 (m, 2H), 3.29-3.27 (m, 2H), 3.10-3.11 (d, 1H), 2.54-2.42 (m, 3H), 1.76 (s, 1H), 1.70-1.60 (m, 1H), 1.44 (s, 9H) LCMS (M+H)=243.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH:11](Cl)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH3:30][C@H:31]1[CH2:36][NH:35][C@@H:34]([CH3:37])[CH2:33][NH:32]1.N[C@H](C(N[C@H](C(O)=O)C)=O)C.O=C1NCCNC1=O>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:28][CH3:29])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:32]2[CH2:33][C@H:34]([CH3:37])[NH:35][CH2:36][C@@H:31]2[CH3:30])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: C[C@H]1CN[C@@H](C)CN1
Reactant: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Agent: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Agent: O=C1NCCNC1=O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(O[Si](C)(C)C(C)(C)C)c2)N2C[C@H](C)NC[C@@H]2C)cc1
Yield: 22.1 %

Procedure:
A mixture of 15.65 g (36 mmol) of N,N-diethyl-4-(3-(t -butyldimethylsilyloxy)-α-chlorobenzyl)benzamide, prepared as described in Example 11, 7.22 g (65 mmol) of (+)-(2S,5S)-2,5-dimethylpiperazine, prepared from L-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) as described by Jung and Rohloff (J. Org. Chem. 50, 4909-13 (1985)), and 3 mL of toluene was heated as in Example 1. The product was purified by chromatography on silica gel (Waters Prep 500 with dichloromethane containing 1% ethanol and 0.1% triethylamine) to give 4.06 g (22%) of N,N-diethyl-4-(3-(tert-butyldimethylsilyloxy)-α-((2S,5S)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide as a beige foam.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:17]=[C:18]=S.[Cl:20][C:21]1[C:22]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:39])([F:38])[F:37])[CH2:31]2)=[CH:23][C:24]([NH:28][CH3:29])=[C:25]([CH:27]=1)[NH2:26].C(Cl)CCl>CC#N>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:17][C:18]1[N:28]([CH3:29])[C:24]2[CH:23]=[C:22]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:38])([F:39])[F:37])[CH2:31]3)[C:21]([Cl:20])=[CH:27][C:25]=2[N:26]=1
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Solvent: ClCCCl
Solvent: CC#N
Product: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate (938 mg, 3.1 mmol) was added to 5-chloro-2-methylamino-4-(3-(trifluoromethyl)piperidin-1-yl)aniline (920 mg, 3.0 mmol) in MeCN (20 mL). The mixture was stirred for 4 h at rt, then EDC (582 μL, 3.3 mmol) was added and it was stirred overnight. The reaction mixture was purified by chromatography to give the sub-title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([CH3:29])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[PH:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28].[CH2:30]([O:32]C(OCC)CBr)[CH3:31].[PH2-].[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1COCC1>[C:11]1([CH3:29])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[P:19]([CH2:31][CH:30]=[O:32])[C:20]1[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26]
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(C)c(Pc2c(C)cc(C)cc2C)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [PH2-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(P(CC=O)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
KHMDS (35 mL of a 0.5 M solution in toluene, 17.5 mmol, Aldrich) 35 was added to a solution of dimesitylphosphine (4.1 g, 15.8 mmol) in THF (50 mL) at −78° C. After stirring for 20 min at −78° C. bromoacetaldehyde diethylacetal (2.85 mL, 19 mmol, Aldrich) was added dropwise to the solution of potassium phosphide. The solution was stirred for 5 min at −78° C., warmed to RT and stirred for 30 min at RT. Assay by 31P-NMR (crude reaction mixture) showed the formation of product (−29.5 ppm). The solvent was evaporated, the residue was flushed through a 6×3.3 cm plug of silica gel and toluene was removed (aspirator) to afford the product as a yellow oil. The product was dissolved in a mixture of degassed acetone (60 mL) and 5% aq. HCl (30 mL) and refluxed under Ar for 2.5 h. A saturated, degassed solution of NaHCO3 (100 mL) was added to the reaction mixture followed by extraction with degassed CH2Cl2 (3×50 mL). The solution was evaporated under Ar followed by filtration through a plug of silica gel (9×3.6 cm; Ar atmosphere), CH2Cl2 eluent, collecting 250 mL. Evaporation afforded product as a very air-sensitive white solid, 4.1 g (83.1%). 31P{1H} NMR (CD2Cl2): −35.6 ppm (s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH2:13][C:14]([OH:16])=O)[C:10](=[O:17])[CH2:9]2)=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([CH2:13][C:14]([N:21]3[CH2:22][CH2:23][NH:18][C:19](=[O:24])[CH2:20]3)=[O:16])[C:10](=[O:17])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1
Reactant: O=C(O)CN1CC(c2ccc(Cl)cc2)CC1=O
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CN(C(=O)CN2CC(c3ccc(Cl)cc3)CC2=O)CCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
82.5 g (325 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid, 32.5 g (325 mmol) of piperazin-2-one (ketopiperazine) and 100.8 g (325 mmol) of freshly distilled triphenyl phosphite are melted at 180°. The whole is allowed to cool to 130° and left to stand for 5 hours. The solidified reaction mass is cooled to room temperature and stirred for 1 hour with 300 ml of dichloromethane. The whole is filtered with suction, washed three times with 150 ml of dichloromethane each time and allowed to dry in the air. 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine having a melting point of 208°-210° is obtained and can be purified further by dissolving in 200 ml of hot acetic acid, adding 800 ml of water and crystallising in an ice bath.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>CC(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:2]([CH3:11])=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: Nc1ccc(Br)cn1
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)nc2ccc(Br)cn12
Yield: 24.5 %

Procedure:
In a 100 ml round-bottomed flask, 865 mg of 2-amino-5-bromopyridine are dissolved in 25 ml of acetone, then 1.06 g of 2-bromo-1-phenyl-1-propanone are added and the mixture is heated at the reflux of the solvent for 57 hours. The reaction mixture is allowed to cool and then the precipitate is recovered by filtration, washed with diethyl ether and dried under reduced pressure. 350 mg of compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N(C[CH2:34][N:35]([CH3:37])[CH3:36])N>>[CH3:34][N:35]([CH3:37])[CH2:36][CH2:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1
Reactant: CN(C)CCNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CN(C)CCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (2-hydrazino-ethyl)-dimethyl-amine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=4.6, 1.7, Hz, 2H), 8.18 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.71 (m 2H), 7.55 (t, J=7.1 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.15 (d, J=6.2 Hz, 2H) 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 4.25 (t, J=6.6 Hz, 2H), 2.82 (t, J=6.6 Hz, 2H), 2.28 (s, 6H); MS: (M+H m/z=450.4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][C:13](Cl)=[O:14])=[CH:6]2.C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH:13]=[O:14])=[CH:6]2
Reactant: COc1ccc2[nH]c(CC(=O)Cl)cc2c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(CC=O)cc2c1

Procedure:
A solution of 5-methoxy-2-indolylacetyl chloride (0.1 mol.) in dry tetrahydrofuran is treated with 0.25 mole of lithium aluminum tri-t-butoxy hydride with ice-cooling and stirring. After the initial reaction, the mixture is stirred at room temperature for 4 hours and poured into ice. Excess of acetic acid is added, and the product is extracted with ether. The ethereal solution is washed with sodium bicarbonate, dried over sodium sulfate, and evaporated to a syrup. Chromatography of the residue on a column of silica gel, using ether-petroleum ether (v./v.) 10-30% as eluent, gives 5-methoxy-2-indolyl acetaldehyde.
Reaction SMILES: [OH:1][CH:2](/[CH:16]=[CH:17]/[CH3:18])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30]>O1CCCC1.CN(C)C=O>[C:29]([O:33][C:34](=[O:37])[CH2:35][N:4]([CH2:3][CH:2]([OH:1])[CH:16]=[CH:17][CH3:18])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C/C=C/C(O)CNS(=O)(=O)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC=CC(O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (+)-(E)-N-(2-hydroxy-pent-3-enyl)-4-methoxybenzenesulfonamide (1.2 grams, 4.42 mmol) in tetrahydrofuran-dimethylformamide (10 mL, ca. 3:1) at 0° C. is added sodium bis(trimethylsilyl)amide (4.9 mL, 1.0M solution in tetrahydrofuran). After 10 minutes, t-butylbromoacetate (786 mL, 4.83 mmol) is added. The mixture is warmed to room temperature, stirred for 1 hour and quenched with saturated ammonium chloride solution. The mixture is extracted with ethyl acetate and the combined extracts are dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with 1:1 ethyl acetate-hexanes) to provide [(2-hydroxy-pent-3-enyl)-(4-methoxybenzenesulfonyl)-amino]-acetic acid t-butyl ester.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: N=C(N)c1ccccc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2ccccc2)ns1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a solution of benzamidine hydrochloride (5.00 g, 31.9 mmol) and perchloromethyl mercaptan (3.43 ml, 39.2 mmol) in dichloromethane (32 ml) was added dropwise a solution of sodium hydroxide (6.38 g, 160 mmol) in water (13 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.90 g (46.2%) of the desired product as a solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].Cl.[CH2:9]([N:11]1[C:15]2[N:16]=[CH:17][C:18]([C:27]3[O:31][N:30]=[C:29]([CH2:32][CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[N:28]=3)=[C:19]([NH:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:14]=2[CH:13]=[N:12]1)[CH3:10].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:9]([N:11]1[C:15]2[N:16]=[CH:17][C:18]([C:27]3[O:31][N:30]=[C:29]([CH2:32][CH:33]4[CH2:38][CH2:37][N:36]([C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:35][CH2:34]4)[N:28]=3)=[C:19]([NH:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:14]=2[CH:13]=[N:12]1)[CH3:10]
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCNCC4)no3)cnc21
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCN(C(=O)CC(C)C)CC4)no3)cnc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Isovaleryl chloride (0.04 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and diisopropylethylamine (0.1 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 1.5 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 1 g) and the cartridge was eluted sequentially with chloroform, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartridge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Example 176. LCMS showed MH+=496, TRET=3.17 min.