Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:30])[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]2[CH2:16][C:15]([CH2:28][OH:29])([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][C:13]1=2.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][C:18]1([CH3:22])[CH2:19][CH2:20][C:12]([CH3:11])([CH3:30])[C:13]2[CH2:14][C:15]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH:28]=[O:29])[CH2:16][C:17]1=2
Reactant: CCCCCC1(CO)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCC1(C=O)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
2 ml of oxalyl chloride were dissolved in 100 ml of methylene chloride and treated at −70° C. dropwise with 2.8 g of dimethylsulfoxide. The reaction mixture was warmed for 5 minutes to −35° C., cooled again to −60° C. and treated dropwise with a solution of 2.9 g of (4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-methanol in 20 ml of methylene chloride. After 15 minutes of stirring at −50° C., 5 ml of triethylamine were added dropwise. The reaction mixture was stirred at room temperature for 3 hours, then poured onto ice/water, extracted with methylene chloride, dried (Na2SO4) and the solvent was evaporated. The yellow, oily residue was purified with flash chromatography (silica gel, hexane/ethyl acetate=20:1) to yield 2.8 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbaldehyde as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14]>N1CCCC1.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.[Cu]I>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][CH2:11][OH:15])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(Cl)ccc1Br
Reactant: C#CCCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: COc1cc(Cl)ccc1C#CCCO
Temperature: 80 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a stirred solution of 2-bromo-5-chloroanisole (2 g, 9 mmol), Pd(PPh3)4 (520 mg, 0.45 mmol), and CuI (400 mg) in pyrrolidine (20 mL) was added a solution of 3-butyn-1-ol (1.26 g, 18 mmol) in pyrrolidine (30 mL). The reaction mixture was stirred at 80° C. for 6 h, and then concentrated in vacuo. The resulting residue was extracted with ethyl acetate and the organic phase was washed with 1N hydrochloric acid, followed by water, then brine, and dried over sodium sulfate. Upon removal of the solvent under reduced pressure, the crude product was subjected to column chromatography on silica gel (gradient elution with 0%-40% EtOAc/hexane) to give 4-(4-chloro-2-methoxy-phenyl)-but-3-yn-1-ol as a colorless oil (1.46 g, 76.7%). 1H NMR (300 MHz, CDCl3) δ ppm 7.29 (d, J=8.2 Hz, 1H), 6.88 (dd, J=8.2, 1.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 3.87 (s, 3H), 3.82 (t, J=6.2 Hz, 2H), 2.73 (t, J=6.2 Hz, 2H), 1.92 (br. s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12.[Na].[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12)[CH3:25]
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Reactant: CCO
Agent: [Na]
Product: CCOc1c2c(nc3c1cnn3CC)C(=O)c1ccccc1CC2

Procedure:
6.2 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]-cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.02 mol.), from example 1(e), are added to a solution of 0.5 g. of sodium (0.022 mol.) in 150 ml. of absolute ethanol. The mixture is heated at 120° (bath temperature) in an autoclave for four hours. After cooling, the crystallized 4-ethoxy-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-(1H)-one is filtered off and washed with water; yield: 3.5 g. An additional crop of 2.1 g. is obtained by work up of the mother liquor, total yield: 5.6 g. (87.5%); m.p. 150°-152° (ethanol; refrigerator).
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([CH3:25])[C:7]([O:14][Si](C(C)C)(C(C)C)C(C)C)=[C:8]([CH3:13])[CH:9]=2)[O:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[CH3:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH3:25])[C:7]=1[OH:14])[O:4][CH2:3][C@@H:2]([N:36]1[CH2:35][CH2:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)([OH:39])[CH2:38][CH2:37]1)[C@H:11]2[OH:12]
Reactant: Cc1cc2c(=O)c(Br)coc2c(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc2c(c(C)c1O)OC[C@@H](N1CCC(O)(c3ccc(F)cc3)CC1)[C@H]2O
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-6,8-dimethyl-7-triisopropylsilyloxychromen-4-one (the compound of Example 19, 0.23 g, 0.54 mmol), 4-(4-fluorophenyl)-4-hydroxypiperidine (0.22 g, 1.12 mmol) and triethylamine (0.3 mL, 2.15 mmol) in acetonitrile (15 mL) was stirred over the weekend at ambient temperature. The precipitate which formed was collected and rinsed with water and ether. This solid was flash chromatographed on silica gel (1×4 inches packed in hexane) with elution proceeding as follows: 10% ethyl acetate/hexane (100 mL), nil; 25% ethyl acetate/hexane (200 mL), 0.065 g (22%) 6,8-dimethyl-7-triisopropylsilyloxy-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chromen-4-one which had: mp 226.5-227° C. Analysis calculated for C31H42FNO4Si: C, 68.98; H, 7.84; N, 2.59. Found: C, 69.00; H, 7.94; N, 2.37. This product was identical to the product isolated in the first step of example 19 and was converted to the title product following the procedure of example 19.
Reaction SMILES: Br[C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[NH2:13][CH:14]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>CCOCC>[CH2:18]([O:17][C:15]([CH:14]([NH:13][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11])[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:16])[CH3:19]
Reactant: CC1(Br)C(=O)Nc2ccccc21
Reactant: CCOC(=O)C(N)CCc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCc1ccccc1)NC1(C)C(=O)Nc2ccccc21

Procedure:
A solution of 2.5 g 3-bromo-3-methyloxindole, 2 g ethyl 2-amino-4-phenylbutyrate and 1.6 ml triethylamine in 150 ml ether was refluxed for 48 hours. The resulting crude product was partitioned between 50% potassium carbonate solution and ethyl acetate. The organic phase was dried (MgSO4) and concentrated. Chromatography at the residue (silica, ether) afforded 3-(1-ethoxycarbonyl-3-phenylpropyl)amino-3-methyl-1,2-dihydro-2-oxo-3H-indole as a mixture of diastereomers.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C1C=CN=CC=1)C.O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: Cc1cccc(-c2nc(C)c(C)cc2O)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3cccc(C)n3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,6′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (157 mg), cesium carbonate (229 mg), and 4-(N,N-dimethylamino)-pyridine (86 mg), and the mixture was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (17 mg, yield 18%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][C:5]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:6]=1[CH2:7][N:8]=[C:9]=[O:10].CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:9]([NH:8][CH2:7][C:6]1[CH:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:5]=1[CH3:4])=[O:10])[NH2:3]
Reactant: CNN
Reactant: Cc1ccc(-c2ccccc2)cc1CN=C=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2)cc1CNC(=O)N(C)N
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
254 mg (5.52 mmol) of methylhydrazine was dissolved in 10 ml of anhydrous toluene, and the mixture was cooled to 0° C. Tot this solution was slowly dropped while stirring a solution prepared by dissolving 1.12 g (5.02 mmol) of 2-methyl-5-phenylbenzyl isocyanate in 20 ml of anhydrous toluene. In this operation, the temperature of the reaction solution was controlled in the range from 0 to 5° C. After completion of dropping, the solution was stirred at 0° C. for 1 hour, further, stirring was continued for 2 hours at room temperature. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=1/1, then, 1/2 (v/v), then only ethyl acetate), to obtain 1.28 g (4.75 mmol) of 2-methyl-4-(2-methyl-5-phenylbenzyl) semicarbazide having a melting point of 91.6° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[NH2:37][C:38]([CH2:43][OH:44])([CH2:41][OH:42])[CH2:39][OH:40].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:40][CH2:39][C:38]([NH:37][C:24]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:34])([F:35])[F:36])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:25])([CH2:43][OH:44])[CH2:41][OH:42]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: NC(CO)(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NC(CO)(CO)CO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol) and 2-amino-2-hydroxymethyl-1,3-propanediol (0.15 g, 1.24 mmol) in N,N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (0.15 g, 1.11 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.22 g, 1.15 mmol) followed by N,N-diisopropylethyl amine (0.27 mL, 1.55 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography using a solvent system of 5% methanol in chloroform provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.19 g).
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:8]=[CH:7][CH:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(=O)C2C=CC=CC=2)[CH:13]=[C:12]3[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[CH2:5][CH2:4]1>CO>[NH3:14].[O:3]1[CH:4]=[CH:5][CH:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH2:26][CH2:27][N:28]([CH3:29])[CH3:30])[CH2:7][CH2:8]1
Reactant: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(C3C=COCC3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCc1c[nH]c2ccc(C3C=COCC3)cc12
Product: N
Temperature: 25 °C
Reaction time: 16 h
Yield: 10 %
Yield: 141.5 %

Procedure:
An aqueous solution of sodium hydroxide (2M, 1 mL, 2 mmol) was added to 5-(3,4-dihydropyran-4-yl)-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (30 mg, 0.08 mmol) in methanol (2 mL) and the resulting solution was stirred at room temperature for 16 h. The reaction mixture was partitioned between water and ethyl acetate, washed with brine, dried over sodium sulfate and the solvent was removed in vacuo. Preparative thin layer chromatography (silica gel, 10% 2M methanolic ammonia in dichloromethane) yielded 5-(3,4-dihydropyran-4-yl)-3-[2-(N,N-dimethylamino)ethyl]-1H-indole (15.3 mg, 70%); HRMS-FAB+ for C17H22N2O: calculated MH+ :271.18103; found MH+ :271.18177.
Reaction SMILES: C[O-].[Na+].[N:4](OCCC(C)C)=[O:5].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1>CO.O1CCCC1>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:24])[C:21](=[N:4][OH:5])[CH2:22][CH3:23])=[CH:16][CH:15]=1
Reactant: CC(C)CCON=O
Reactant: CCCC(=O)c1ccc(SC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=NO)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
11.0 g (0.206 mol) of sodium methoxide is suspended in 130 ml of methanol. Then isoamyl nitrite (27 ml, 0.206 mol) and 25 g (0.129 mol) of 1-(4-Methylsulfanyl-phenyl)-butan-1-one dissolved in 70 ml of tetrahydrofuran (THF) are added and the reaction solution is stirred at room temperature for 1.5 days. After concentrating, water and acetic acid are added to neutralise. The crude product is extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (15:85) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 1.14 (t, 3H), 2.52 (s, 3H), 2.72 (q, 2H), 7.25 (d, 2H), 7.89 (d, 2H), 8.01 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([CH:29]=1)[C:26]([Cl:28])=[O:27]>>[ClH:28].[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([CH:29]=1)[C:26]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:27]
Reactant: Cc1cc(N2CC[C@@H](N3CCC[C@H]3C)C2)ccc1N
Reactant: Cc1ccc(F)cc1C(=O)Cl
Product: Cc1cc(N2CC[C@@H](N3CCC[C@H]3C)C2)ccc1NC(=O)c1cc(F)ccc1C
Product: Cl

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-(R)-methyl-[1,3′(R)]bipyrrolidinyl-1′-yl)-phenylamine with 5-fluoro-2-methyl-benzoyl chloride (from Alfa Aesar).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.Cl[CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([S:48]([CH:47]=[CH2:46])(=[O:50])=[O:49])[CH2:33][CH2:34]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:11]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCC(Nc2ncc3c(n2)-c2c(c(C(=O)Nc4c(CC)cccc4CC)nn2C)CC3)CC1
Temperature: -78 °C
Yield: 55.5 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (300 mg, 0.606 mmol) under nitrogen, in dry dichloromethane (15 mL), DIPEA (0.527 mL, 3.03 mmol) and 300 mg of molecular sieves were added, and the mixture was cooled at −78° C. 2-chloroethanesulfonyl chloride (0.063 mL, 0.606 mmol) was added. Temperature was allow to rise to room temperature then the solvent was evaporated to dryness and the crude was purified by flash chromatography on silica gel (eluant: ethyl acetate/dichloromethane: 2/8) to give 185 mg of the title compound (56% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:34][C:35](O)=[O:36])[N:30]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:65]([O:72][C:73](=[O:79])[C@@H:74]1[CH2:78][CH2:77][CH2:76][NH:75]1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C=O)C.C(Cl)CCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:34][C:35]([N:75]3[CH2:76][CH2:77][CH2:78][C@H:74]3[C:73]([O:72][CH2:65][C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)=[O:79])=[O:36])[N:30]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 2.50 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 30 ml DMF were added 621 mg HOBt, 1.3 ml DIPEA, 778 mg EDC and 981 mg L-proline benzyl ester hydrochloride. After stirring for 12 h the solvent was evaporated, the residue dissolved in ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: [Cl-:1].C([NH:5][C:6]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N+:12]1[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[NH:28]C(=O)C)[CH:13]=1)(=[O:4])C>O>[OH2:4].[ClH:1].[ClH:1].[ClH:1].[ClH:1].[Cl-:1].[NH2:5][C:6]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N+:12]1[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[NH2:28])[CH:13]=1
Reactant: CC(=O)Nc1ccc(N)cc1OCCCn1cc[n+](CCCOc2cc(N)ccc2NC(C)=O)c1
Agent: [Cl-]
Solvent: O
Product: Cl
Product: Nc1ccc(N)c(OCCCn2cc[n+](CCCOc3cc(N)ccc3N)c2)c1

Procedure:
Starting with 23.5 g (0.0454 mol) of 1,3-bis [3-(2-acetylamino-5-aminophenoxy)propyl]-3H-imidazol-1-ium chloride synthesized above in the previous step, 15.0 g of white crystals melting with decomposition at 210-215° C. (Kofler) were obtained, the 1H NMR of which was in accordance and the elemental analysis of which, calculated for C21H33N6O2Cl5.H2O, was:
Reaction SMILES: C([N:3](CC)CC)C.FC(F)(F)S(O[C@H:14]([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=O)=O>ClCCl>[NH2:3][C@H:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:22]
Reactant: C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-nitrophenylalanine, ethylester, hydrochloride (2.3 g) in dichloromethane (10 ml), add triethylamine (2.55 ml) and then t-butyl 2(R)-(trifluoromethanesulfonyloxy)propionate (2.80 g) (see Preparation 4) in dichloromethane (10 ml). Stir the resulting solution at room temperature for 20 hours. Concentrate the reaction mixture, add diethyl ether and extract with salt solution. Dry over magnesium sulfate and concentrate the ether solution in vacuo to give an oil. Place the oil on a column of silica gel (100 ml, 60-200 mesh) and elute with diethyl ether:hexane 60:40 to give N-[1(S)-ethoxycarbonyl)-2-(4-nitrophenyl)ethyl]-(S)-alanine, t-butyl ester.
Reaction SMILES: [OH-].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].CO.[C:9]1([O:16][CH3:17])[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11]>CO>[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[CH3:17][O:16][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[O-:11].[CH:10]([OH:11])([CH3:12])[CH3:9]
Reactant: COc1ccccc1O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CO
Product: CC(C)O
Product: COc1ccccc1[O-]
Yield: 200 %

Procedure:
To 5.20 ml of a commercially available 10% tetramethylammonium hydroxide-methanol solution (manufactured by TOKYO KASEI; 5.05 mmole equivalents) was added 0.6264 g of guaiacol (5.05 mmoles), and methanol was removed under reduced pressure. To the residue was added 10 ml of isopropanol, and the alcohol was removed under reduced pressure again. Finally 5 ml of isopropanol was added to obtain about 7 ml of a tetramethylammonium-2-methoxyphenolate-isopropanol solution (containing 5.05 mmoles of guaiacol).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:27])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[N:36]=[CH:37][C:30]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([O:27][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:44])[N:36]=[CH:37][C:30]=23)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: Cc1ccc(NC(=O)[C@@H](O)CN2CC(O[Si](C)(C)C(C)(C)C)C2)nc1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 115.8 %

Procedure:
Sodium hydride (132 mg, 3.30 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AD8) (482 mg, 1.32 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (385 mg, 1.45 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was neutralised with 1M citric acid and diluted with water and EtOAc. The organic layer was separated and washed with saturated brine, dried (MgSO4) and evaporated to afford the product (908 mg) which was used without further purification. m/z (ES+) (M+H)+=594.52; HPLC tR=1.87 min.