Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:13][C:14](ON1C(=O)CCC1=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[CH2:6]([O:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NCCCN
Solvent: ClC(Cl)Cl
Product: NCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
1,3-Diaminopropane (35.5 g, 0.48 mol) was dissolved in 300 mL CHCl3, and the solution was cooled to 0° C. A solution of N-(benzyloxycarbonyloxy)succinimide (4.5 g, 0.018 mol) in 150 mL CHCl3 was added dropwise over 6 h, with the internal temperature maintained below 10° C. After addition was complete, the reaction solution was stirred at room temperature overnight. The solution was washed with water, dried (Na2SO4), filtered and concentrated in vacuo to provide 3.0 g (80%) of the title compound as a low melting solid: 1H NMR (CDCl3) δ 1.25 (bs, 2 H), 1.63 (quintet, 2 H), 2.77 (t, 2 H), 3.2-3.34 (bm, 2 H), 5.09 (s, 2 H), 5.37 (bm, 1 H), 7.28-7.40 (m, 5 H); MS, m/e 209 ((M+H)+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1(=[O:18])=[O:17].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O>CN(C=O)C>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[S:10](=[O:12])(=[O:11])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7]2(=[O:18])=[O:17])[CH2:27][CH2:26]1
Reactant: O=S1(=O)c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)c2ccccc2S(=O)(=O)N1CCCCN1CCN(c2ncccn2)CC1
Temperature: 0 °C

Procedure:
0.028 mol of 2-(4-bromobutyl)-1,3,2-benzodithiazole 1,1,3,3-tetroxide and 0.056 mol of 1-(2-pyrimidinyl)piperazine in 125 ml of absolute DMF are stirred at 250° C. for 6 hours. The mixture is then cooled to 0° C., 150 ml of water are added dropwise with stirring, and the substance which has crystallised out is filtered off with suction. The product is purified by chromatography on silic gel; the eluting agent is ethyl acetate.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C(O)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1csc(C(C)C)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)c1nc(C=O)cs1
Temperature: -78 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
A solution containing the product from Example 56B (18 g, 90.5 mmol) in dichloromethane (100 mL) was treated with DIBAL (150 mL, 1 M in dichloromethane) dropwise at −78° C. over 2 hours, stirred at −78° C. for 2 hours, treated with acetic acid (10 mL), warmed to 25° C., treated with 10% solution of aqueous sodium potassium tartrate, stirred vigorously for 1 hour, and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting 0-5% ethyl acetate in dichloromethane to give the title compound (5.24 g, 40% yield).
Reaction SMILES: CN(C)C=O.[CH2:6]([NH:13][C@H:14]1[C@H:18]([OH:19])[CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[CH2:6]([N:13]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:14]1[C@H:18]([OH:19])[CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Yield: 107.3 %

Procedure:
To an N,N-dimethylformamide solution (2.5 mL) of tert-butyl (3R,4R)-3-(benzylamino)-4-hydroxypyrrolidine-1-carboxylate (500 mg, 1.70 mmol), benzyl bromide (203 μL, 1.70 mmol) was added at room temperature and the resultant solution was stirred for 1 day. To the reaction solution, tetrabutylammonium iodide (188 mg, 0.51 mmol) and potassium carbonate (470 mg, 3.40 mmol) were added and the resultant mixture was stirred for 1 day. After completion of the reaction, water was added to the reaction solution and extraction with ethyl acetate from the resultant mixture was performed. The organic layer was washed with brine and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0→1/1 (v/v)) to obtain the title compound (698 mg, quantitative).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])[CH3:4].[Cl-].[Na+].Cl>C(O)C>[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)N1CCC(=O)C(c2ccccc2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)N1CC[C@H](O)[C@H](c2ccccc2)C1

Procedure:
To a solution of 7.34 g of sodium borohydride in 315 ml of denatured ethanol is added, dropwise with stirring under nitrogen over a 30-minute period, a solution of 48.0 g of 1-ethoxycarbonyl-3-phenyl-4-piperidone in 485 ml of denatured ethanol, keeping the temperature below 10° C. during the addition. After stirring overnight at room temperature, 1200 ml of saturated sodium chloride is added. After stirring for one hour 500 ml of 2 N hydrochloric acid is cautiously added. The mixture is extracted with ether (3×600 ml). The solvent is removed in vacuo from the organic extracts and the residue is partitioned between ether (1200 ml) and saturated sodium chloride solution (600 ml). After drying the ether phase overnight over anhydrous sodium sulfate, filtration and concentration of the filtrate affords an orange gum. Separation of the isomeric mixture by preparative high pressure liquid chromatography using 40% ethyl acetate/hexane as solvent affords the cis-isomer as a clear yellow gum in which crystals eventually formed upon standing. The gum is triturated with a mixture of petroleum ether containing a little ether. The colorless solid is filtered, washed and dried to afford the cis-isomer mp 54.5°-57.5° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:22][CH2:21][CH2:20][CH:19]4[CH3:23])[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Temperature: 100 °C
Yield: 41.1 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.05 g, 0.152 mmol), 3-methoxyphenylboronic acid (0.025 g, 0.167 mmol), Pd2(dba)3 (0.017 g, 0.03 mmol), X-phos (0.029 g, 0.06 mmol) and Na2CO3 (0.048 g, 0.456 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:10) to afford 6-(3-methoxyphenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (25 mg, 41%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.76 (s, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 7.47-7.32 (m, 4 h), 7.03-6.99 (m, 1H), 6.23 (d, 1H, J=7.5 Hz), 6.03 (d, 1H, J=8.4 Hz), 4.25-4.21 (m, 1H), 3.86 (s, 3H), 3.62-3.56 (m, 1H), 3.44-3.35 (m, 1H), 2.17-1.99 (m, 3H), 1.74-1.71 (m, 1H), 1.17 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 401, tR=1.961 min, HPLC: 95.06% at 214 nm, 98.71% at 254 nm, tR=7.643 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]2[C:4]=1[C:5]1[CH:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:7][CH2:8][CH2:9][C:10]=1[NH:11]2.[H-].[Na+].[I-].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:26]([N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[C:4]2[C:12]1=[C:13]([CH3:16])[CH:14]=[CH:15][C:3]=2[O:2][CH3:1])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CCCc2[nH]c3c(C)ccc(OC)c3c21
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCc2c1c1c(OC)ccc(C)c1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A solution of 1.58 g of ethyl 5-methoxy-8-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxylate in 5 ml of dimethylformamide was added to 0.24 g of sodium hydride (60% in mineral oil) in 5 ml of dimethylformamide and stirred for 30 minutes at room temperature. Potassium iodide (90 mg) and 0.75 ml of benzyl bromide were then added and the reaction was stirred overnight. The reaction mixture was poured into 75 ml of saturated ammonium chloride solution and then extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using hexane/ethyl acetate mixtures to afford 1.09 g (53%) of the subtitle compound. ESIMS m/e 378 (M++1) NMR (300 MHz, CDCl3): δ 7.28-7.19 (m, 3H); 6.84 (d, J=7.4, 2H); 6.67 (d, J=7.8, 1H); 6.33 (d, J=7.9, 1H); 5.55 and 5.39 (ABq, J=7.8, 2H); 4.17 (q+m, J=6.9, 3H); 3.80 (s, 3H); 2.64 (dt, J=16.1, 5.3, 1H); 2.48 (dt, J=16.6, 6.9,1H); 2.41 (s, 3H); 2.05 (m, 2H); 1.95 (m, 1H); 1.83 (m, 1H); 1.25 (t, J=7.3, 3H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([OH:14])=O.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:12](=[O:14])[CH2:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(O)CC1CCc2ccccc2C1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)CC1CCc2ccccc2C1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a solution of 3.4 g of 1,2,3,4-tetrahydronaphthalen-2-ylacetic acid in 50 ml of methylene chloride was added 14.1 g of WSC.HCl with stirring at room temperature. Then, 3.6 g of L-proline methyl ester hydrochloride and 2.2 g of triethylamine were added to the solution. The mixture was stirred for 17 hours at room temperature. The reaction mixture was washed with water, diluted hydrochloric acid, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.6 g of 1-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-proline methyl ester as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:53][C@H:54]1[O:59][C@@H:58]([CH3:60])[CH2:57][N:56]([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][C:70](OS(C(F)(F)F)(=O)=O)=[CH:69][CH:68]=3)=[CH:63][CH:62]=2)[CH2:55]1.[N:81]1([C:87]2[CH:97]=[CH:96][C:90]([C:91]([O:93][CH2:94][CH3:95])=[O:92])=[CH:89][CH:88]=2)[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:94]([O:93][C:91](=[O:92])[C:90]1[CH:89]=[CH:88][C:87]([N:81]2[CH2:82][CH2:83][N:84]([C:70]3[CH:71]=[CH:72][C:67]([C:64]4[CH:65]=[CH:66][C:61]([N:56]5[CH2:57][C@H:58]([CH3:60])[O:59][C@H:54]([CH3:53])[CH2:55]5)=[CH:62][CH:63]=4)=[CH:68][CH:69]=3)[CH2:85][CH2:86]2)=[CH:97][CH:96]=1)[CH3:95]
Reactant: C[C@@H]1CN(c2ccc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3)cc2)C[C@H](C)O1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(-c4ccc(N5C[C@@H](C)O[C@@H](C)C5)cc4)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 74.8 %

Procedure:
To a mixture of cesium carbonate (1.43 g), palladium(II) acetate (35 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (146 mg) in dioxane (6 ml) was successively added trifluoromethanesulfonic acid 4′-(cis-2,6-dimethylmorpholin-4-yl)-1,1′-biphenyl-4-yl ester (1.30 g) and ethyl 4-piperazinylbenzoate (0.88 g) in a stream of nitrogen. The mixture was stirred at ambient temperature for 30 minutes and at 100° C. for further 6.5 hours. After cooling to room temperature, water was added to the reaction mixture. The resulting precipitates were filtered, washed with water and dried. The residue was pulverized with acetone and collected by filtration to give 4-[4-[4′-(cis-2,6-dimethylmorpholin-4-yl)-1,1′-biphenyl-4-yl]piperazinyl]benzoic acid ethyl ester (1.17 g).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([CH2:12][C:13]1([N:32]2[CH:36]=[C:35]([C:37]3[C:38]4[CH:45]=[CH:44][N:43](COCC[Si](C)(C)C)[C:39]=4[N:40]=[CH:41][N:42]=3)[CH:34]=[N:33]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11].[OH-].[NH4+].C([O-])(O)=O.[Na+]>C(#N)C.O>[C:10]([CH2:12][C:13]1([N:32]2[CH:36]=[C:35]([C:37]3[C:38]4[CH:45]=[CH:44][NH:43][C:39]=4[N:40]=[CH:41][N:42]=3)[CH:34]=[N:33]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C@@H:26]([CH3:31])[C:27]([F:28])([F:29])[F:30])=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11]
Reactant: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C(F)(F)F
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
Boron trifluoride etherate (0.078 mL, 0.62 mmol) was added to a solution of 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide in acetonitrile (4.0 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature for 3 h. (LCMS (M+H)+: m/z=527.2). The mixture was cooled to 0° C., water (1.6 mL) was added. After 30 min., 5.0 M ammonium hydroxide in water (0.38 mL, 1.9 mmol) was added slowly at 0° C. in 5 min. Then the reaction mixture was stirred at room temperature overnight. The mixture was worked up with saturated aqueous NaHCO3, extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-5%) to afford the desired product (52 mg, 51%). LCMS (M+H)+: m/z=497.1. 1H NMR (400 MHz, DMSO-d6): δ 12.60 (br, 1H), 9.09 (s, 1H), 8.84 (d, J=8.8 Hz, 1H), 8.83 (s, 1H), 8.69 (d, J=1.4 Hz, 1H), 8.56 (s, 1H), 8.02 (d, J=1.4 Hz, 1H), 7.77 (br, 1H), 7.23 (br, 1H), 4.84 (d, J=9.9 Hz, 2H), 4.80 (m, 1H), 4.57 (d, J=9.9 Hz, 2H), 3.80 (s, 2H), 1.36 (d, J=7.1 Hz, 3H).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+:6].[Na+].[Si:8]([O-])([O-:11])([O-:10])[O-:9].[Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[Al+3:27].[K+]>O>[O-:10][Si:8]([O-:11])=[O:9].[O-:10][Si:8]([O-:11])=[O:9].[Na+:6].[Al+3:27]
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [K+]
Solvent: O
Product: O=[Si]([O-])[O-]
Temperature: 55 °C

Procedure:
The sodium aluminosilicate of Example 44 was prepared as follows. Approximately 300 L of hot process water and 12.4 kg of anhydrous sodium sulfate were added to a 1200-L reactor. While mixing, the reactor contents were heated to 55° C., and 5.9 L of sodium silicate were added to the reactor and mixed. A 25-min simultaneous addition step with alum and silicate solution followed, using a sodium silicate addition rate of 19.9 L/min and an alum addition rate of 7.26 L/min. After the simultaneous addition step, a reduced alum flow rate (1-2 L/min) was used to bring the batch pH to about 5.3. After digesting the batch for 10 min, the product slurry was washed and filtered using a press filter. The filtered cake was collected. A portion of filtered cake was spray dried and hammer milled to an average 5-6 micron particle size.
Reaction SMILES: C(N1C2C(=CC=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15](C)[CH2:14]3)C=2)C=C1)(C)C.Br[C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][N:27]2[CH:30]([CH3:32])[CH3:31])=[CH:23][CH:22]=1.CC1CNCCN1.CC([O-])(C)C.[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C(C)=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:30]([N:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([CH:14]3[CH2:15][NH:16][CH2:17][CH2:18][N:13]3[CH3:10])[CH:29]=2)[CH:25]=[CH:26]1)([CH3:32])[CH3:31]
Reactant: CC1CN(c2ccc3ccn(C(C)C)c3c2)CCN1
Reactant: CC(C)n1ccc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: CC(C)n1ccc2ccc(C3CNCCN3C)cc21

Procedure:
1-Isopropyl-6-(3-methylpiperazinyl)-indole; from 6-Bromo-1-isopropylindole (23.8 mg, 0.1 mmol), 2-methylpiperazine (60 mg, 0.6 mmol), NaOtBu (14.1 mg, 0.15 mmol), tBu3P(1 mg) and Pd(OAc)2 (1 mg) in xylene (1 ml), heating overnight. Yield 6.7 mg (26%).
Reaction SMILES: O[CH2:2][C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@H:25]([CH2:42][C:43]3[CH:52]=[C:51]([CH3:53])[C:46]4[NH:47][C:48](=[O:50])[O:49][C:45]=4[CH:44]=3)[C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[C:39]([OH:41])=[O:40])[CH2:30][CH2:29]3)=[O:27])=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:54]=[CH:55][CH:56]=[CH:57][C:11]=2[NH:10]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:42][C:43]3[CH:52]=[C:51]([CH3:53])[C:46]4[NH:47][C:48](=[O:50])[O:49][C:45]=4[CH:44]=3)[C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[C:39]([O:41][CH2:2][C:3](=[O:4])[N:5]([CH3:7])[CH3:6])=[O:40])[CH2:32][CH2:33]3)=[O:27])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:54]=[CH:55][CH:56]=[CH:57][C:11]=2[NH:10]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc2oc(=O)[nH]c12
Reactant: CN(C)C(=O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)OCC(=O)N(C)C)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 mg (0.06 mmol) 2-hydroxy-N,N-dimethyl-acetamide were added to a solution of 34 mg (0.05 mmol) (R)-2-[4-((S)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 18 mg (0.06 mmol) TBTU and 8 μL triethylamine in 2 mL DMF and the reaction mixture was shaken overnight at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:26])[C:10](=[O:11])[O:9][C:8]2[CH:12]=[CH:13][C:14]3[C:19]([C:7]1=2)=[CH:18][C:17]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[CH:16][CH:15]=3.C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:5][C:6]1([CH3:26])[C:10](=[O:11])[O:9][C:8]2[CH:12]=[CH:13][C:14]3[C:19]([C:7]1=2)=[CH:18][C:17]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[C:16]([N+:1]([O-:4])=[O:2])[CH:15]=3
Reactant: O=[N+]([O-])O
Reactant: CC1(C)C(=O)Oc2ccc3ccc(Cn4cncn4)cc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)Oc2ccc3cc([N+](=O)[O-])c(Cn4cncn4)cc3c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Nitric acid (72% by weight, 0.045 ml) was added dropwise to a stirred, ice-cooled mixture of 1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone (0.44 g) and acetic anhydride (6 ml). The mixture was stirred at room temperature for 18 h, then added to a stirred mixture of aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phase was separated, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography. Elution with ethyl acetate:pentane, 3:1 v/v, gave 1,1-dimethyl-7-nitro-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone, m.p. 183°-185° after recrystallisation from ethyl acetate. (Example 13).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Product: COc1ccc(/C(C#N)=C/c2ccc(F)c([N+](=O)[O-])c2)cc1OC
Yield: 49.3 %

Procedure:
4-Fluoro-3-nitrobenzaldehyde (507 mg) and 3,4-dimethoxybenzyl cyanide (532 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (485 mg, yield: 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[CH:8]([C:18](OCC)=[O:19])[CH:7]2[OH:23].Cl.[NH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(C(C)C)C(C)C)C>O1CCOCC1.O.CCOC(C)=O>[C:30]([O:29][C:27](=[O:28])[CH2:26][NH:25][C:18]([C:8]1[C:7](=[O:23])[C:6]2[C:16](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:10]2([CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:9]=1[OH:17])=[O:19])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)C1C(=O)C2(CCOCC2)c2c(Cl)cccc2C1O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C2(CCOCC2)c2c(Cl)cccc2C1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 38.5 %

Procedure:
A mixture of ethyl 8-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.27 g, 0.80 mmol), and tert-butyl 2-aminoacetate hydrochloride (0.20 g, 1.2 mmol) in 1 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.26 g, 2.0 mmol). The mixture was warmed to 100° C. and stirred for 2.5 hours. The mixture was then cooled to room temperature, diluted with 20 mL H2O and 100 mL EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (10-20% EtOAc/hexane) to give 0.13 g off-white solid. MS m/e: (M+H)+ 422.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: C1COCCN1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCOCC2)s1

Procedure:
2-Morpholin-4-yl-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate F and morpholine. MS calcd. for C24H21ClN4O3S [(M+H)+] 481.1, obsd. 481.