Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[C:3]1([CH3:13])[CH:8]=[CH:7][C:6](S(O)(=O)=O)=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[C:3]1([C:13]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH2:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: C=C(c1ccccc1)c1ccccc1
Yield: 36321.4 %

Procedure:
Into a 1-liter reaction flask were introduced 200.23 g of the crude carbinol, 400 ml of toluene, and 1 g of p-toluenesulfonic acid (PTSA). Azeotropic dehydration was conducted for 2 hours with toluene refluxing (94-116° C.). After cooling, this reaction mixture was washed with water, with 2% aqueous soda ash solution, and then with water, dried with magnesium sulfate, and concentrated to obtain 190.09 g of crude 1,1-diphenylethylene (9a; R1 =R2 =H). This crude 1,1-diphenylethylene (9a) was distilled with a Claisen flask equipped with a vigreux, giving 174.06 g of 1,1-diphenylethylene (9a). b.p., 103° C./1 mmHg
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][C:36]([OH:38])=O)[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH:41]([NH2:44])([CH3:43])[CH3:42].C(OCC)(=O)C>CN(C)C=O>[F:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][C:36](=[O:38])[NH:44][CH:41]([CH3:43])[CH3:42])[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1
Reactant: CC(C)N
Reactant: O=C(O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
Under ice cooling, 1,1′-carbonyldimidazole (15 g) was added to a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (30 g) in dimethylformamide (240 ml) and the resultant mixture was stirred for 2 hr. After adding isopropylamine (5.6 g), the mixture was warmed to room temperature and then stirred for additional 2 hr. Next, ice water (240 ml) and ethyl acetate (300 ml) were added to the reaction solution and the layers were separated. The organic layer was washed successively with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in hot ethyl acetate (80 ml). After allowing to cool to room temperature, the resulting crystals were collected by filtration to give the title compound (17.2 g) as a white powder (yield: 52%).
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:17]([O:21][CH2:22][CH:23]1[O:25][CH2:24]1)(=[O:20])[CH:18]=[CH2:19].[C:26]([O:31][CH2:32][CH2:33][OH:34])(=[O:30])[C:27]([CH3:29])=[CH2:28].N([C:44](C)(CC)[C:45]([O-:47])=O)=NC(C)(CC)C([O-])=O>CCCCCCC.C(C(C)=O)C(C)C>[C:1]([O:6][CH:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:17]([O:21][CH2:22][CH:23]1[O:25][CH2:24]1)(=[O:20])[CH:18]=[CH2:19].[C:26]([O:31][CH2:32][CH2:33][OH:34])(=[O:30])[C:27]([CH3:29])=[CH2:28].[CH3:24][O:25][CH2:23][CH2:22][O:21][CH2:17][CH2:18][O:47][CH2:45][CH3:44]
Reactant: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Agent: C=C(C)C(=O)OC(C)OCc1ccccc1
Agent: C=C(C)C(=O)OCCO
Agent: C=CC(=O)OCC1CO1
Solvent: CC(=O)CC(C)C
Solvent: CCCCCCC
Product: CCOCCOCCOC
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 79.3 g (0.36 mol) of 1-benzyloxyethyl methacrylate, 23.1 g (0.18 mol) of glycidyl acrylate, 7.8 g (0.06 mol) of 2-hydroxyethyl methacrylate and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in diethylene glycol ethyl methyl ether, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A-3 (1-benzyloxyethyl methacrylate/glycidyl acrylate/2-hydroxyethyl methacrylate) as a diethylene glycol ethyl methyl ether solution.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5](N)[C:6]2[CH:12]=[N:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[NH:8][C:7]=2[CH:17]=1.[CH3:19][O:20][CH2:21][CH2:22][C@H:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([N:27]3[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:28]3)=[N:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[NH:8][C:7]=2[CH:17]=1
Reactant: Cc1cc(N)c2c(c1)Nc1ccccc1N=C2
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3cc(C)ccc32)CCN1
Temperature: 110 °C
Reaction time: 48 h
Yield: 47.6 %

Procedure:
Combine 3-methyl-5H-dibenzo[b,e][1,4]diazepin-1-ylamine hydrochloride (400.0 mg, 1.54 mmol), (S)-2-(2-methoxy-ethyl)-piperazine (444.2 mg, 3.08 mmol), N,N-diisopropylethylamine (199.0 mg, 1.54 mmol), DMSO (0.7 ml), and toluene (2.8 ml) and stir and heat the mixture at 110° C. After 48 hours, cool the mixture to ambient temperature and dilute with ethyl acetate. Wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 257.1 mg (48%) of a yellow foam: mp=64° C. dec; mass spectrum (ion spray): m/z =433.1 (M+1).
Reaction SMILES: [CH3:1]I.C([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[CH2:13][CH2:14][SH:15])C.[Na]>C(O)C>[CH3:1][S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:5])=[O:17])=[O:16]
Reactant: CI
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)CCS
Agent: [Na]
Solvent: CCO
Product: CSCCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (71 g) is added to a solution of 1-(3-mercaptopropanoyl)-L-proline ethyl ester (115 g) and sodium (11.5 g) in ethanol (400 ml). The reaction is allowed to proceed overnight, the ethanol is removed in vacuo and the residue is dissolved in a mixture of ethyl acetate and water. The organic layer is dried and concentrated to dryness in vacuo. The resulting 1-(3-methylthiopropanoyl)-L-proline ethyl ester (98 g) is suspended in a mixture of methanol (200 ml) and 5 N sodium hydroxide (200 ml) and stirred at room temperature for five hours. The methanol is removed in vacuo, and the aqueous phase is extracted with ethyl acetate, acidified and reextracted with ethyl acetate. This last organic phase is washed with water, dried and concentrated to dryness to yield 1-(3-methylthiopropanoyl)-L-proline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][OH:26])[CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:21]2[CH:20]=[C:19]([CH3:18])[CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1ccnc(CO)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccnc(COc2nc(N)nc(-c3ccco3)c2C#N)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (4-methyl-pyridin-2-yl)methanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[OH-].[K+:23]>O1CCCC1>[K+:23].[Br:9][C:6]1[CH:5]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])[CH:3]=[C:2]([Br:1])[C:7]=1[O-:8]
Reactant: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ccncc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(c1cc(Br)c([O-])c(Br)c1)N1CCOc2ccncc21
Temperature: 25 °C

Procedure:
In a 100 ml flask, (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (500 mg, 1.20 mmol) was suspended in tetrahydrofuran (40 ml) and the mixture was dissolved under heating. After cooling to room temperature, 10N potassium hydroxide solution was added thereto dropwise. The solvent was evaporated under reduced pressure, and the residue was dissolved in a solvent of acetonitrile and water (1:1 ratio, 80 ml), and freeze-dried to obtain the target compound 73 as white non-crystalline form (480 mg, 92%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:13]([NH:14][C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)=S)=[CH:12][CH:11]=[CH:10][N:9]=1.[S]>[Hg]=O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[N:14]=[C:15]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2cccnc2NCc2ccco2)CC1
Agent: O=[Hg]
Agent: [S]
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3cccnc3n2Cc2ccco2)CC1
Yield: 79 %

Procedure:
A mixture of 74 parts of ethyl 4-[[[2-[(2-furanylmethyl)amino]-3-pyridinyl]aminothioxomethyl]amino]-1-piperidinecarboxylate, 96 parts of mercury (II) oxide, 0.1 parts of sulfur and 800 parts of ethanol was stirred and refluxed for 3 hours. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 52.5 parts (79%) of ethyl 4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate; mp. 149.2° C. (intermediate 32).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:13][NH2:14]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:14][CH3:13])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: CN
Product: CNC(=O)Cc1ccc(O)c(F)c1

Procedure:
was prepared from 3-fluoro-4-hydroxyphenylactic acid and methyl amine following Method A. S1H NMR (300 MHz, CD3OD) δ 7.89 (s, 1H), 6.90 (d, 1H, J=13.37 Hz), 6.82–6.71 (m, 1H), 3.29 (s, 2H), 2.62 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 184, found 184.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:10][C:8](=[O:9])[NH:7][C:5]1=[O:6].[C:11]([N:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]([CH2:26][C:27]([NH:29][C@@H:30]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31](OC2C=CC([N+]([O-])=O)=CC=2)=[O:32])=[O:28])[C:16](=[O:50])[CH:15]1[CH:51]([CH3:53])[CH3:52])(=[O:13])[CH3:12].[Cl-].[NH4+]>O1CCCC1>[C:11]([N:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:17]([CH2:26][C:27]([NH:29][C@@H:30]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31]([N:7]2[C:8](=[O:9])[CH2:10][N:4]([CH3:3])[C:5]2=[O:6])=[O:32])=[O:28])[C:16](=[O:50])[CH:15]1[CH:51]([CH3:53])[CH3:52])(=[O:13])[CH3:12]
Reactant: CN1CC(=O)NC1=O
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)C1C(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)N2C(=O)CN(C)C2=O)C(=O)C1C(C)C
Reaction time: 0.33 h

Procedure:
60% Sodium hydride (200 mg) is added to a solution of 1-methylhydantoin (571 mg) in anhydrous tetrahydrofuran (20 ml), and the mixture is stirred for 20 minutes. Then, 4-nitrophenyl (2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionate (1.17 g, Compound No. 14-1) is added to the mixture, and the whole is stirred for three days. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (116 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.CC1(C)C(C)(C)OB([C:25]2[C:26]([C:30]([F:33])([F:32])[F:31])=[N:27][NH:28][CH:29]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:25]4[C:26]([C:30]([F:33])([F:32])[F:31])=[N:27][NH:28][CH:29]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Reactant: CC1(C)OB(c2c[nH]nc2C(F)(F)F)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1n[nH]cc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 80 °C
Yield: 2.6 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (750 mg, 1.91 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-1H-pyrazole (550 mg, 2.10 mmol), PdCl2dppf.DCM (156 mg, 0.19 mmol) and Cs2CO3 (1.55 g, 4.77 mmol) in dioxane (12 mL) and H2O (3 mL) was purged with argon and heated at 80° C. for 18 h. Further 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-1H-pyrazole (225 mg, 1.05 mmol) and PdCl2dppf.DCM (78 mg, 0.09 mmol) were added and the mixture heated at 85° C. for a further 24 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-5% MeOH in DCM) affording 9-Bromo-2-(3-trifluoromethyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a white solid (20 mg, 3%). LCMS: RT 4.42 min [M+H]+ 399.0 and 401.0. 1H NMR (CDCl3, 400 MHz): δ 13.65 (1H, s), 8.57 (1H, d, J=2.61 Hz), 8.30 (1H, s), 7.43-7.42 (2H, m), 7.00 (1H, d, J=8.71 Hz), 4.52-4.45 (4H, m)
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:32][C:33](O)=[O:34]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[CH2:32][C@H:28]5[CH2:29][CH2:30][CH2:31][O:27]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C[C@H]1CCCO1
Agent: Cl
Product: O=C(C[C@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (72 mg, 65%), MS (ISP) m/z=441.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (R)-2-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH2:21]([NH2:24])[CH2:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[CH:7]=[C:2]([NH:24][CH2:21][CH2:22][CH3:23])[C:3]4[CH:19]=[N:18][N:17]([CH3:20])[C:4]=4[N:5]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CCCN
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CCCNc1cc(-c2cccc3[nH]ncc23)nc2c1cnn2C
Temperature: 190 °C
Yield: 11.7 %

Procedure:
A solution of 4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.04 g, 0.14 mmol) in acetonitrile (2 mL) was treated with propylamine (0.041 g, 0.7 mmol) in the presence of p-toluenesulfonic acid monohydrate (0.03 g, 0.14 mmol). The reaction mixture was heated at 190° C. in microwave for 2 h. Solvent were removed and the crude material was purified by mass directed purification to obtain 5 mg of 103 as a white solid. 1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 8.11 (d, J=1.2, 1H), 7.63 (t, J=7.4, 2H), 7.50 (t, J=7.2, 1H), 6.72 (s, 1H), 4.04 (t, J=22.1, 3H), 3.40 (dd, J=20.2, 13.0, 2H), 1.79 (dd, J=14.5, 7.1, 2H), 1.07 (t, J=7.4, 3H). MS (ESI) m/z 307.2 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[CH2:12](O)[CH3:13].OS(O)(=O)=O>>[CH2:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:13]
Reactant: CCO
Reactant: COc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(OC)c1

Procedure:
3-Methoxy-benzoic acid ethyl ester is prepared from 3-methoxy-benzoic acid using a standard protocol with ethanol/H2SO4 according to L.-F. Tietze & T. Eicher, Reactions and Syntheses in the Organic Chemistry Laboratory; University Science Books, Mill Valley, Calif., 1989). Title compound: b.p. 151° C. (25 mm Hg); single peak at tR=6.51 min (System 1).
Reaction SMILES: [N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:41][C@@H:42]([C:60]([NH:62][C@H:63]([C:68]([NH:70][C@H:71]([C:76]([NH2:78])=[O:77])[CH2:72][CH2:73][S:74][CH3:75])=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66])=[O:61])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:59])[NH:48][S:49]([C:52]1[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=1)(=[O:51])=[O:50].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:41][C@@H:42]([C:60]([NH:62][C@H:63]([C:68]([NH:70][C@H:71]([C:76]([NH2:78])=[O:77])[CH2:72][CH2:73][S:74][CH3:75])=[O:69])[CH2:64][CH:65]([CH3:66])[CH3:67])=[O:61])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:59])[NH:48][S:49]([C:52]1[CH:53]=[CH:54][C:55]([CH3:56])=[CH:57][CH:58]=1)(=[O:50])=[O:51])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 46 %

Procedure:
Condensation of BocPro-DTrp-PheOH (Example 33, 658 mg.) and HDArg(Tos)-Leu-MetNH2 (630 mg.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 in 46% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 (524 mg.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 in 78% yield. De-p-toluenesulfonylation of HPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 (420 mg.) using liquid hydrogen fluoride with anisole gave HPro-DTrp-Phe-DArg-Leu-MetNH2, which was isolated as the amorphous off-white solid dihydrochloride acetate (2:1) salt hydrate (2:5) in 61% yield.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=2)[NH:5][N:4]=1)#[N:2].[OH-].[Li+]>CO>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1)#[N:2]
Reactant: COC(=O)c1ccc2[nH]nc(C#N)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
Methyl 3-cyano-1H-indazole-5-carboxylate (500 mg, 2.5 mmol) was dissolved in methanol (12 mL) and 2 N aqueous lithium hydroxide (3.7 mL, 7 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated to remove the methanol and the residue was acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting yellow precipitate was collected by filtration, washed with water, and dried in a vacuum oven to provide the title compound (445 mg, 96%). −ESI (M−H) 186.4; 1H NMR (400 MHz, DMSO-d6, δ): 13.17 (br. s., 1H), 8.42 (s, 1H), 8.05 (dd, J=8.8, 1.6 Hz, 1H), 7.83 (d, 1H).
Reaction SMILES: C(C1C=C([NH:17][C:18](=[O:40])[C:19]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=[O:20])N(C2C=CC(C)=CC=2)N=1)(C)(C)C.COC(=O)C(C1C2C(=CC=CC=2)C(OCCN2CCOCC2)=CC=1)=O.N[C:67]1[C:68]([O:82][CH3:83])=[C:69]([NH:77][S:78]([CH3:81])(=[O:80])=[O:79])[CH:70]=[C:71]([C:73]([CH3:76])([CH3:75])[CH3:74])[CH:72]=1>>[C:73]([C:71]1[CH:70]=[C:69]([NH:77][S:78]([CH3:81])(=[O:80])=[O:79])[C:68]([O:82][CH3:83])=[C:67]([NH:17][C:18](=[O:40])[C:19]([C:21]2[C:30]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=[O:20])[CH:72]=1)([CH3:76])([CH3:74])[CH3:75]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Agent: COC(=O)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Product: COc1c(NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
The title compound was prepared by the same method described for compound 13 starting from compound 12 and compound 14. Calculated mass=583. Observed mass=584.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36]Br)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.O>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][C:14]([CH3:16])([CH3:15])[C:13]([OH:18])=[O:17])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C(=O)O
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(C)(CCCOc1ccc(OCc2ccccc2)cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 15 g of diisopropylamine in 75 ml of dry tetrahydrofuran was dropwise added 100 ml of n-butyl lithium (15 w/w, n-hexane solution) at -5 to 0° C. After stirring at the same temperature for 30 minutes, 6.7 g of isobutyric acid was added dropwise to the mixture. After stirring was continued at the same temperature for 1 hour, a solution of 20 g of p-(3-bromopropoxy)phenyl benzyl ether in 60 ml of dry tetrahydrofuran was dropwise added to the solution. Thirty minutes after, the mixture was stirred at room temperature for 16 hours. The mixture was cooled and 250 ml of water was added thereto. After the aqueous layer was washed with ether, the aqueous layer was acidified with 6N hydrochloric acid and extracted twice with 70 ml of methylene chloride. The extract was washed with an aqueous saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure and the residue was recrystallized from ethyl acetate to give the desired product, 5-(p-benzyloxyphenoxy)-2,2-dimethylpentanoic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9]P(=O)(OCC)OCC)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.Cl.[NH2:19]CP(=O)(OCC)OCC>>[N:9]1[CH:5]=[CH:6][C:1]([CH2:2][CH2:3][NH2:19])=[CH:7][CH:8]=1
Reactant: CCOP(=O)(CN)OCC
Reactant: CCOP(=O)(NCCc1ccccc1)OCC
Agent: Cl
Product: NCCc1ccncc1
Yield: 47.5 %

Procedure:
Treatment of the phosphoramidate obtained in stage (d) with an aqueous solution of hydrochloric acid, under the conditions described in Example 1, gives, after rendering the mixture basic, 5.6 g. (yield: 47.5%, referred to the diethyl aminomethylphosphonate) of the desired amine in the form of a yellow oil which turns brown in air.