Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN1C(=O)CCC1>[CH2:21]([NH:28][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)[CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: NCc1ccccc1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(NCc3ccccc3)c([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 2,4-dichloro-5-nitro-pyridine E-2.1″ (5.000 g; 25.908 mmol) in NMP are added DIPEA (8.372 ml, 51.817 mmol) and benzylamine (3.054 ml, 28.499 mmol). The mixture is stirred for 1 h at RT. 1-Methylpiperazine (3.172 ml; 28.499 mmol) is then added and the mixture is stirred at 50° C. overnight. The residue is loaded onto isolute, split into 5 portions and purified using the basic preparatory reversed phase chromatography (method: prep. HPLC1). Product containing fractions are combined and freeze-dried (yield: 66%, 5.619 g; 17.163 mmol)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[C:59]([N:66]1[CH2:71][CH2:70][CH:69]([NH2:72])[CH2:68][CH2:67]1)([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]>CN(C=O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([NH:72][CH:69]6[CH2:68][CH2:67][N:66]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:71][CH2:70]6)=[O:27])=[CH:28][CH:29]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)cc2)CC1
Reaction time: 0.08 h
Yield: 42.3 %

Procedure:
To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml), HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and triethylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min, 1-Boc-4-aminopiperidine (0.210 g, 1.04 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.125 g. 42%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.40 (d, J=7.8 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.20 (d, J=8.7 Hz, 1H), 8.03-7.99 (m, 4H), 7.84 (dd, J=8.7, 1.8 Hz, 1H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.22 (s, 2H). 3.99 (m, 3H), 2.87 (m, 2H), (d, J=9.9 Hz, 2H), 1.45-1.37 (m, 1H).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH2:22]>>[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[NH:22][C:13](=[O:15])[CH2:12][N:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH3:11]
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Agent: Cl
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1

Procedure:
N-(Toluene4-sulfonyl)sarcosine was coupled to Nε-Boc-L-lysine methyl ester hydrochloride using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-Nε-Boc-L-lysine methyl ester. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C([N:15](CC)CC)C.[C:20]([S:24](Cl)=[O:25])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([S:24]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]([NH2:15])[CH2:3]1)=[O:25])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)S(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(S(=O)C(C)(C)C)CC1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
Ethyl 4-amino-1-piperidinecarboxylate (300 mg) and triethylamine (258 mg) were dissolved in 5 ml of dichloromethane. To the mixture, 2 ml of solution of t-butylsulfinyl chloride (222 mg) in dichloromethane was added and the mixture was stirred at room temperature for 4 hours. The solution was partitioned into an aqueous solution of potassium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 378 mg of 4-t-butylsulfinyl amino-1-ethoxycarbonyl piperidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[F:13][C:14]1[CH:19]=[C:18]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:12])[CH2:6][CH2:7][O:8]3)=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C1CCOc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCOc2cc(-c3cccc(F)c3)ccc21
Temperature: 100 °C
Yield: 87.6 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-2H-chromen-4-one (1.5 g, 6.6 mmol), 3-fluorophenylboronic acid (1.39 g, 9.9 mmol) and sodium carbonate (2.1 g, 19.8 mmol) in dioxane (20 mL) and water (1 mL) was added Pd(PPh3)4 (382 mg, 0.3 mmol) at rt. The solution was heated at 100° C. overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE/EtOAc/DCM=10:1:2) to give 1.4 g (88%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 2.86 (2H, t, J=6.6 Hz), 4.60 (2H, t, J=6.6 Hz), 7.11-7.14 (1H, m), 7.18 (1H, d, J=1.5 Hz), 7.23-7.29 (2H, m), 7.32-7.45 (2H, m), 7.98 (1H, d, J=8.1 Hz).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O.C1COCC1>CCOCC>[CH2:7]([CH:15]([CH2:16][OH:17])[CH2:21][OH:22])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC(CO)CO
Yield: 65 %

Procedure:
250 ml of ether and 19.0 of lithium aluminum hydride were put in a 1-liter four-necked flask, and a solution obtained by dissolving 72.1 g of the thus prepared diethyl octylmalonate in 50 ml of ether was put therein dropwise at such a rate that ether is gently refluxed. After the dropwise addition, the mixture was refluxed with heating for 3 hours, and after allowing it to cool, a mixture of water-THF was added to decompose excess lithium aluminum hydride. The resultant solid was removed by filtration, and the filtrate was washed with saturated saline and dried over anhydrous sodium sulfate. The crude crystal obtained by distilling away the solvents was recrystallized from isooctane to give 32.4 g of colorless crystals. Yield 65%.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH2:8][OH:9])[O:6][CH:7]=1.[OH2:11].[C:12]1(C)C=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1>C(Cl)Cl>[OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH2:8][O:9][CH:16]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1
Reactant: O
Reactant: O=c1cc(CO)occ1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=c1cc(COC2CCCCO2)occ1O
Reaction time: 1.5 h
Yield: 14083.9 %

Procedure:
To a solution of 56.8 g of 5-hydroxy-2-hydroxymethyl-4-pyrone (kojic acid) in 2 L of methylene chloride, 0.4 g of p-toluenesulfonic acid monohydrate was added and the mixture was stirred for 1.5 h. The reaction mixture was extracted with 3% sodium hydroxide solution twice and then the combined aqueous phase was neutralized to pH 8 with 0.5M sodium dihydrogen phosphate. An extractive work-up (methylene chloride) followed by recrystallization afforded 67 g (75%) of the title compound (mp 94° C.), NMR (CDCl3) 60 MHz: 4.32 (d, J=14, 1H, right hand of AB pattern), 4.61 (d, J=14, left half of AB pattern), 4.73 (broad S, 1H, acetal H), 6.60 (S, 1H, H-3), 7.86 (S, 1H, H-5) ppm; IR (CHCl3): 3430, 1640, 1600 cm-1 /UV (MeOH): 270 nm (Σ7,400).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH3:15])[C:12]2[CH:16]=[CH:17][C:18]([N:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH3:21])=[CH:19][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[ClH:28].[CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH3:15])[C:12]2[CH:16]=[CH:17][C:18]([N:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:38][C:37]4[CH:39]=[CH:40][C:34]([CH2:33][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:35][CH:36]=4)[N:23]=3)[CH3:21])=[CH:19][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: CCn1c(NCc2ccccc2)nc2cc(N(C)c3ccnc(Cl)n3)ccc21
Product: CCn1c(NCc2ccccc2)nc2cc(N(C)c3ccnc(Nc4ccc(CS(C)(=O)=O)cc4)n3)ccc21
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N2-Benzyl-N5-(2-chloro-pyrimidin-4-yl)-1-ethyl-N5-methyl-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) as a white solid (65 mg, 45%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.53 (s, 1H), 7.75 (m, 3H), 7.19-7.40 (M, 9H), 7.10 (s, 1H), 6.87 (m, 1H), 5.66 (m, 1H), 4.60 (m, 2H), 4.32 (s, 2H), 4.11 (m, 2H), 6.41 (s, 3H), 2.83 (s, 3H), 1.24 (M, 3H).
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].[H-].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:27]([O:37][C@H:38]3[C@H:42]4[O:43][CH2:44][C@@H:45]([OH:46])[C@H:41]4[O:40][CH2:39]3)=[N:26][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.CCOC(C)=O.CCCCCC>CN(C=O)C>[CH2:1]([O:46][C@@H:45]1[CH2:44][O:43][C@@H:42]2[C@H:38]([O:37][C:27]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:10]4[C:11]([N:26]=3)=[N:12][C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:18][CH:19]=3)=[C:8]([Cl:7])[CH:9]=4)[CH2:39][O:40][C@H:41]12)[CH:2]=[CH2:3]
Reactant: C=CCI
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Allyl iodide (130 μl, 1.422 mmol) and sodium hydride (16.0 mg, 0.400 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydro-furo[3,2-b]furan-3-ol (82.8 mg, 0.143 mmol) in DMF (1.4 ml). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc (75 ml), water (20 ml), and 2 N HCl (10 ml). The organic layer was washed with water (2×30 ml, brine was added to each wash to break an emulsion) and brine (1×20 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give an amber residue. Flash chromatography of the residue utilizing a 4 g silica RediSep Rf® column and employing a 0-40% EtOAc/hexane gradient followed by 40% EtOAc/hexane afforded the title compound as a pale yellow solid. LC-MS: calculated for C33H38ClN3O5Si 619.23 observed m/e: 620.32 (M+H)+ (Rt 1.43/2 min).
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[NH:6]1[CH2:16][CH2:15][CH:9]([C:10]([O:12]CC)=[O:11])[CH2:8][CH2:7]1>>[CH:1]1([CH2:4][N:6]2[CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[CH2:15][CH2:16]2)[CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: CCOC(=O)C1CCNCC1
Product: O=C(O)C1CCN(CC2CC2)CC1

Procedure:
The title compound was prepared from cyclopropanecarboxaldehyde and ethyl isonipecotate using similar procedures to those described for Example E15.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.OS(O)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
201 g tert-Butyl 4-hydroxypiperidine-1-carboxylate, 160 ml triethylamine and 6.0 g 4-dimethylaminopyridine are dissolved in 750 ml DCM. 191 g 4-toluenesulfonylchloride is added and the mixture is refluxed for 7 h. The mixture is cooled in ice and acidified with 100 ml of 1M H2SO4; the organic layer is washed with 300 ml of water (twice), 250 ml of 1 M Na2CO3 solution (twice), dried over MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[N:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[N:17][CH:16]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Clc1cnnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2cnnc3ccccc23)c2ccccc12
Temperature: 80 °C
Reaction time: 60 h

Procedure:
1 mmol (175 mg) of 1H-indole-3-carboxylic acid methyl ester, 1.1 mmol (181 mg) of 4-chloro-cinnoline and 1.2 mmol (390 mg) of Cs2CO3 are suspended in 3 ml of dry DMF. The mixture is stirred for 60 h at 80° C. under argon, allowed to cool to room temperature, and diluted with water (20 ml). Part of the product precipitates and is filtered off, the filtrate is extracted twice with ethyl acetate (20 ml portions). The combined extracts are dried over anhydrous Na2SO4 and evaporated. The residue is combined with the precipitate and purified by prep. HPLC to yield 1-(cinnolin-4-yl)-1H-indole-3-carboxylic acid methyl ester (MS molpeak 304 (M+H, electrospray ionization)) as an off-white foam after freeze-drying.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[O:10])[CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:19][O:18][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:7][C:6]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N)cc1NC(=O)Nc1cnccn1
Solvent: c1ccncc1
Product: COc1ccc(NS(C)(=O)=O)cc1NC(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
A solution of 1-(5-amino-2-methoxyphenyl)-3-pyrazin-2-yl-urea (Compound 14, Example 4) (260 mg, 1 mmol) in dry pyridine (15 mL) was treated with methanesulfonyl chloride (0.08 mL, 1 mmol) and stirred 16 h at room temperature. The reaction mixture was concentrated in vacuo and the solid residue was triturated with ethanol, collected by filtration, and dried in vacuo to afford the product (205 mg, 61%). 1H NMR (300 Mhz, d6-DMSO) δ: 10.16 (s, 1H), 10.07 (s, 1H), 9.40 (s, 1H), 8.92 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.91 (dd, J=8.7, 2.4 Hz, 1H), 3.91 (s, 3H), 2.91 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1)=[O:12])C1C=CC=CC=1.[CH:28]1([CH2:31][O:32][CH2:33][CH2:34][C:35]2[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]3[O:43][CH2:42]3)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50]>C(O)CC>[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50].[OH:43][CH:41]([CH:40]([CH2:46][C:47]1[CH:11]=[CH:10][CH:9]=[CH:49][CH:48]=1)[O:39][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][CH2:33][O:32][CH2:31][CH:28]2[CH2:29][CH2:30]2)=[CH:45][CH:44]=1)[CH2:1][NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:18][CH:19]=1)=[O:12].[OH:43][CH:41]([CH:40]([CH2:46][C:47]1[CH:19]=[CH:14][CH:15]=[CH:49][CH:48]=1)[O:39][C:38]1[CH:44]=[CH:45][C:35]([CH2:34][CH2:33][O:32][CH2:31][CH:28]2[CH2:30][CH2:29]2)=[CH:36][CH:37]=1)[CH2:42][NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:18][CH:19]=1)=[O:12]
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCc2ccccc2)cc1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCCO
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCC(O)C(Cc2ccccc2)Oc2ccc(CCOCC3CC3)cc2)cc1
Yield: 116.1 %

Procedure:
In a manner similar to that of Example 1 (iii), 6-[4-(3-benzylaminopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (21.8 g) and 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane (19.4 g) in n-propanol (200 ml) were stirred under reflux for 41/2 hours. The mixture was cooled and a solution of fumaric acid (6.96 g) in hot n-propanol (150 ml) added with stirring. Cooling (and seeding) and stirring overnight afforded 6-[4-[3-[2-hydroxy-3-[4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-N-benzylpropylamino]propionamido]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone hemifumarate (31.05 g), m.p. 125°-8° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH3:23])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH:24]2[CH2:25][CH2:26][CH2:27]2)[CH3:23])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCCNCc1ccccc1
Reactant: CN(c1cnc(C=O)c(Cl)n1)C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1)C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
Sodium triacetoxyborohydride (0.71 g) was added to a solution of 3-chloro-5-[cyclobutyl(methyl)amino]pyrazine-2-carbaldehyde (0.50 g), N-benzylethanolamine (0.40 g) and acetic acid (0.38 mL) in acetonitrile (8 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→60% ethyl acetate/hexane) to give the title compound (0.74 g, 92%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)([CH3:15])[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)([CH3:15])[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(CCO)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 740 mg (1.84 mmol) of the compound from Example 104A in 20 ml of tetrahydrofuran was added dropwise to 5.5 ml (5.5 mmol) of a 1N solution of diisobutylaluminum hydride in dichloromethane in 20 ml of tetrahydrofuran at RT under argon. The mixture was stirred at RT for 2 h and then water and dichloromethane were added, and the phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 437 mg (66% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:8]=1[CH:9]=[O:10].[CH3:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.CC1C=C(C=[C:34]([CH3:37])[C:35]=1O)C=O>>[CH3:15][C:14]1[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:22]([CH2:35][CH2:34][CH3:37])[CH2:21][CH2:20][CH3:26])=[C:8](/[CH:9]=[CH:17]/[C:18]2[S:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:11]=[C:12]([CH3:16])[CH:13]=1.[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: Cc1nc2ccccc2s1
Agent: Cc1cc(C)c(OCCCCCl)c(C=O)c1
Product: CCCN(CCC)CCCCOc1c(C)cc(C)cc1/C=C/c1nc2ccccc2s1

Procedure:
The title compound was prepared according to the procedure of Example 5 above using 4-chlorobutoxy-3, 5-dimethylbenzaldehyde in place of 4-chlorobutoxybenzaldehyde and using 2-methylbenzothiazole in place of 2-methylbenzoxazole. 4-Chlorobutoxy-3, 5-dimethylbenzaldehyde was prepared from 3,5-dimethyl-4-hydroxybenzaldehyde according to the procedure Example 1 above.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:18]>CO>[NH2:18][C:9]1[C:8](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:12][C:11](=[O:13])[C:10]=1[N:14]=[O:15]
Reactant: N
Reactant: COC1=C(N=O)C(=O)NC1=Cc1ccccc1
Solvent: CO
Product: NC1=C(N=O)C(=O)NC1=Cc1ccccc1
Yield: 45 %

Procedure:
A solution of 0.11 g (0.5 mmol) 5-benzylidene-4-methoxy-3-nitroso-1,5-dihydropyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in methanol was boiled under reflux with 0.25 ml (0.25 mmol) of an aqueous ammonia solution for two minutes. The compound 4-amino-5-benzylidene-3-nitroso-1,5-dihydropyrrol-2-one was obtained in a yield of 45% after recrystallization from methanol. The compound decomposes at 260° C.