Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[N:10]=[CH:9][C:8]1=[O:19])=[O:5])[CH3:2].[OH:20]O.O>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9](=[O:20])[C:8]1=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)cnc2cc(Cl)cc(Cl)c21
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)cc(Cl)c21
Yield: 48 %

Procedure:
The above ester, (70 mg, 0.23 mmol) was reacted with 30% H2O2 (0.345 ml) in glacial acetic acid (0.92 ml) at 55° C. for 4.5 h. The mixture was cooled in an icebath and H2O (0.40 ml) was added. The precipitate was filtered off, washed with water and dried to give 35 mg (48%) of the title compound. 1H-NMR (DMSO-d6):δ1.23 (t, 3H), 4.20 (q, 2H), 5.02 (s, 2H), 7.21 (d, 1H), 7.42 (d, 1H), 12.3 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([CH2:14]O)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Cl:43])C(=O)C1>C(Cl)Cl>[Cl:43][CH2:14][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([N:2]([CH3:16])[CH3:1])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(CO)cc(N(C)C)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(CCl)cc(N(C)C)c1
Reaction time: 1.5 h
Yield: 96 %

Procedure:
To a solution of Compound 2 (3.45 g, 15.452 mmol) and PPh3 (6.14 g, 23.17 mmol) in 70 mL of DCM was added NCS (3.19 g, 23.178 mmol) at 0° C. The reaction mixture was stirred for 1.5 hours. After removal of solvent under reduced pressure, the residue was dissolved in Et2O. The solution was washed with brine and dried with MgSO4. The solution was filtered and concentrated. The residue was subjected to chromatography over silica gel (Hexanes/EtOAc=9.5/0.5) to give Compound 3 (3.585 g, 96%). 1H-NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 7.35 (s, 1H), 6.89 (s, 1H), 4.57 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.00 (s, 6H), 1.39 (t, J=7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ 166.73, 150.63, 138.35, 131.59, 117.31, 116.20, 113.22, 60.95, 46.40, 40.43, 14.31; ESI-MS: m/z (MH+): 242.0942 (calc'd), 242.0944 (found).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:16]=1)=[O:10].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[O:10])(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(N2CCOCC2)nc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(N3CCOCC3)nc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 158 mg of (2-Amino-5-chloro-phenyl)-(6-morpholin-4-yl-pyridin-3-yl)-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.22 (s, 3H), 3.76 (t, 4H, J=4.6 Hz), 3.857 (t, 4H, J=4.6 H), 8.78 (d,1H, J=9.2 Hz), 7.30 (m, 2H), 7.34 (m, 1H), 7.46 (m, 1H), 7.54-7.56 (m, 3H), 7.99 (d, 1H, J=9.2 Hz), 8.16 (v, 1H), 9.29 (s, 1H). MS: m/z 515.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.CC[N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])C.CN(C(ON1N=NC2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:21]=[C:22]([C:26]([N:32]5[CH2:33][C:35]6([CH2:7][CH2:29][CH2:3][CH2:4]6)[C:50]6[C:38](=[CH:48][CH:53]=[CH:52][CH:51]=6)[CH:36]5[CH3:37])=[O:28])[N:23]=[CH:24][N:25]=4)[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC5(CCCC5)c5ccccc5C4C)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
42 mg (0.11 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]pyrimidine-4-carboxylic acid and 25 mg (0.11 mmol) 1′-methyl-2′,3′-dihydro-1′H-spiro[cyclopentan-1,4′-isoquinoline hydrochloride in 63 μL (0.36 mmol) DIPEA and 1.0 mL DMF were combined with 39 mg (0.12 mmol) TBTU and the mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and partially evaporated down. The precipitate formed was suction filtered and dried. The filtrate was freeze-dried. The residue remaining was identical to the precipitate.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[N:12]1([C:18](=[O:38])[CH2:19][CH2:20][CH2:21][N:22]2[C:34]3[C:33]4[N:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N:27]=[CH:26][C:25]=3[N:24]=[C:23]2[CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[OH-].[NH4+:40].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[N:12]1([C:18](=[O:38])[CH2:19][CH2:20][CH2:21][N:22]2[C:34]3[C:33]4[N:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N:27]=[C:26]([NH2:40])[C:25]=3[N:24]=[C:23]2[CH2:35][CH2:36][CH3:37])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
mCPBA (1.18 g, 6.86 mmol) was added to a solution of 1-(4-morpholin-4-yl-4-oxobutyl)-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridine (1.80 g, 4.90 mmol) in chloroform (25 mL); the reaction was stirred for two hours at ambient temperature. Ammonium hydroxide (10 mL) was added followed by p-toluenesulfonyl chloride (1.03 g, 5.39 mmol). The reaction was stirred for one hour and partitioned between saturated aqueous sodium bicarbonate (75 mL) and dichloromethane (70 mL). The aqueous layer was extracted with dichloromethane (2×25 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown solid was triturated twice with acetonitrile and then purified by column chromatography using a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc.; Charlottesville, Va., USA) using a FLASH 40+M cartridge (also available from Biotage, Inc.). The polar component of the eluent was chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The purification was carried out eluting with chloroform:CMA in a gradient from 100:0 to 75:25. The resulting solid was dried under high vacuum at 80° C. to provide 0.583 g of 1-(4-morpholin-4-yl-4-oxobutyl)-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as an off-white powder, mp 196-197° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:8]=1[CH:9]=O)C.[BH4-].[Na+]>C1COCC1.CCO>[CH3:18][O:17][C:12]1[CH:13]=[C:14]([O:15][CH3:16])[C:7]2[O:6][C:5]([CH2:4][OH:3])=[CH:9][C:8]=2[CH:11]=1
Reactant: CCOC(COc1c(C=O)cc(OC)cc1OC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(OC)c2oc(CO)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Compound 39 (460 mg, 2.23 mmol) was dissolved in THF (5 mL) and EtOH (1 mL). NaBH4 (102 mg, 2.68 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1 h. Solvents were evaporated off in-vacuo. The crude residue was taken up in EtOAc and washed with water, brine and dried (MgSO4). The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (1:1) to give 41 (388 mg, 82%) as a white solid. m/z=209.08 (M+H). 1H NMR (500 MHz, CDCl3): δ: 6.62 (1H, s, H-3), 6.60 (1H, s, H-6), 6.46 (1H, s, H-4), 4.76 (2H, s, 2-CH2), 3.99 (3H, s, OMe), 3.85 (3H, s, OMe). 13C NMR (500 MHz, CDCl3): δ: 157.23 (C-5), 156.72 (C-1), 145.36 (C-7), 139.50 (C1a), 129.38 (C4a), 104.62 (C-3), 96.96 (C-6), 94.58 (C-4), 57.98 (2-CH2), 55.95 (OMe), 55.83 (OMe).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1O.P(Cl)(Cl)(Cl)=O>>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[O:4][C:3](=[O:5])[CH2:2][C:1]([O:7][C:10]1[C:9]([Cl:8])=[CH:14][C:13]([Cl:15])=[CH:12][C:11]=1[Cl:16])=[O:6]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Temperature: 70 °C
Yield: 100.6 %

Procedure:
A mixture of malonic acid (20 g, 192 mmol), 2,4,6-trichlorophenol (72 g, 365 mmol), and phosphorus oxychloride (38 mL, 403.2 mmol) was stirred at reflux for 12 hours. The reaction mixture was cooled to 70° C. and poured into ice water. The solid was collected by filtration, washed with water, and air dried to give malonic acid bis-(2,4,6-trichloro-phenyl) ester (85 g, 95%). A solution of malonic acid bis-(2,4,6-trichloro-phenyl) ester (85 g, 183.6 mmol) and ethyl 3-aminocrotonate (26.1 g, 202 mmol) in bromobenzene (100 mL) was stirred at reflux for 50 min. The reaction mixture was cooled to 50° C. and diluted with EtOAc (260 mL). The solid was collected by filtration, washed with water, and air dried to give 4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 86%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])(C)(C)C.[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24].[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32](C(O)=O)=[C:31]([O:39][CH3:40])[CH:30]=1>>[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:26]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])[CH2:11]2)=[O:7])=[C:31]([O:39][CH3:40])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CCCCN=C=O
Product: CCCCNC(=O)NCCCCCN1CC[C@H](CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
5-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentylamine (2.00 g) as starting compound was reacted and treated in the same manner as in Example 34 using n-butyl isocyanate (0.79 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.54 g) to give 4-amino-N-((3R)-1-(5-(3-n-butylureido)pentyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:11]([O:19][CH3:20])=[CH:10][C:4]=1[O:5][CH2:6][C:7]([NH2:9])=[O:8])=O.[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:7]([CH2:6][O:5][C:4]1[CH:10]=[C:11]([O:19][CH3:20])[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:13][C:3]=1/[CH:1]=[CH:22]/[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[O:23])(=[O:8])[NH2:9]
Reactant: COc1cc(OCC(N)=O)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OCC(N)=O)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 70 %

Procedure:
The title compound was prepared by condensing 2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-acetamide (Ex-71A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 70% yield, mp 235° C. (dec.). 1H-NMR (300 MHz, DMSO-d6) δ 8.26–8.30 (m, 3H), 8.08–8.11 (m, 4H), 7.67 (d, 1H, J=2.7 Hz), 7.65 (brs, 1H), 7.53 (d, 1H, J=4.0 Hz), 7.49 (brs, 1H), 7.13 (m, 1H), 6.77 (s, 1H), 4.75 (s, 2H), 3.97 (s, 3H). MS (EI) m/z=437 ([M]+, 100%). HRMS (EI) Calcd. for C23H19NO6S: 437.0933. Found: 437.0924.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:9]([O:17][CH3:18])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:9]([O:17][CH3:18])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCCCCl
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1cc(C#N)c(N)cc1OCCCCl
Temperature: 25 °C
Yield: 65.3 %

Procedure:
A mixture of 2-nitro-4-chloropropoxy-5-methoxy-benzonitrile (0.563 g, 2.24 mmol), Pd/C (0.035 g) and anhydrous ethanol (25.0 mL) were added into a round bottom flask. The solution was stirred and heated under reflux. Cyclohexene (1.15 mL) was added and refluxed until the disappearance of the starting materials as monitored by TLC. After cooling, the resulting mixture was filtered and washed with ethanol. The filtrate was concentrated to yield a solid product. The crude product was suspended in anhydrous ethanol (4 ml), stirred at 40° C. to react for 30 min, then cooled to room temperature, filtered and air-dried to yield light yellow solid product (0.352 g) with a recovery rate of 71%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6]C=C[C:3]=1[F:8].[CH2:9]([Li])[CH2:10][CH2:11]C.[CH3:14][C:15]([CH3:18])([O-])[CH3:16].[K+].[K].C(Br)CCCC.CN1CCCN(C)C1=O>O1CCCC1>[F:8][CH:3]([CH:2]([F:1])[CH2:7][CH3:6])[CH2:14][C:15]1[CH:18]=[CH:11][CH:10]=[CH:9][CH:16]=1
Reactant: CC(C)(C)[O-]
Reactant: [Li]CCCC
Reactant: Fc1ccccc1F
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Solvent: CCCCCBr
Solvent: CN1CCCN(C)C1=O
Product: CCC(F)C(F)Cc1ccccc1

Procedure:
2,3-Difluoro-4-pentylbenzoic acid is obtained by reacting o-difluorobenzene with butyllithium in the presence of potassium tertiary-butoxide at -90° to -100° in tetrahydrofuran, alkylating the potassium compound formed using pentyl bromide/1,3-dimethyltetrahydro-2-(1H)-pyrimidinone (DMPU), isolating the 2,3-difluoropentylbenzene, re-metallating by means of butyllithium and subsequently reacting with solid carbon dioxide. Esterification of this acid using trans-4-pentylcyclohexanol gives trans-4-pentylcyclohexyl 2,3-difluoro-4-pentylbenzoate.
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:10]=[N:11][NH:12][CH:13]=1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]([CH3:24])[CH3:23]>O>[CH3:21][CH:22]([CH3:24])[CH2:23][N:11]1[CH:10]=[C:9]([N+:6]([O-:8])=[O:7])[CH:13]=[N:12]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1cc([N+](=O)[O-])cn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 276 %

Procedure:
To a DMF solution (30 ml) of 4-nitro-1H-pyrazole (1.00 g) were added potassium carbonate (3.67 g) and 1-bromo-2-methylpropane (1.82 g), and the mixture was stirred at 70° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (4.13 g, containing DMF).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([CH3:9])[CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[NH2:1][C@H:4]1[C@@H:8]([CH3:9])[CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To solution of (+/−)-(cis)-benzyl 3-azido-4-methylpyrrolidine-1-carboxylat (2.00 g, 7.68 mmol) in acetonitrile (30 mL) and water (3 mL) was added triphenylphosphine (2.42 g, 9.22 mmol) in one portion as solid and the resulting mixture was stirred at rt for 30 min then heated to 60° C. overnight. The resulting mixture was concentrated and taken up in diethyl ether (300 mL), extracted with aq 2N HCl (30 mL×4). The combined aqueous washes were washed with diethyl ether, then the aqueous portion was cooled with ice-bath and was made basic by slowly adding 2N aq NaOH to pH>10. The aqueous mixture was extracted with ether (80 mL×4) and the combined ether extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness to afford the title compound as a tan oil (1.67 g, 7.13 mmol, 93%). HPLC (method B) retention time=1.51 min. LCMS (m+1)=235.2. 1H NMR (400 MHz, METHANOL-d4) δ 7.42-7.32 (m, 4H), 5.14 (s, 2H), 3.65-3′50 (m, 2H), 3.43 (td, J=5.2, 3.4 Hz, 1H), 3.32-3.28 (m, 1H), 3.25-3.14 (m, 1H), 2.33 (dsxt, J=13.7, 7.0 Hz, 1H), 1.07 (dd, J=6.8, 3.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:12][CH3:13])[N:6]=[CH:7]2.[I-].CS[C:17]1[S:18][CH2:19][CH:20]2[CH2:28][C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]=12>>[CH2:12]([C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:1]=[C:17]1[N:21]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH2:28][CH:20]3[CH2:19][S:18]1)[CH:11]=[CH:10][CH:9]=2)[CH3:13]
Reactant: CCc1cc2c(N)cccc2cn1
Reactant: CSC1=[N+]2c3ccccc3CC2CS1
Agent: [I-]
Product: CCc1cc2c(N=C3SCC4Cc5ccccc5N34)cccc2cn1
Yield: 70.6 %

Procedure:
Following the procedure of Example 1 but starting with 5-amino-3-ethylisoquinoline (3.3 g) and (RS)-3-methylthio-9,9a-dihydrothiazolo[3,4-a]indolium iodide (6.3 g), (RS)-3-[(3-ethylisoquinol-5-yl)imino]-9,9a-dihydrothiazolo[3,4-a]indole (4.4 g) is obtained, after recrystallisation from ethanol (40 cc), in the form of white crystals melting at 142° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:17][CH:18]=1.C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Br:32][C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][CH:18]=2)=[N:10][N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1ccccc1-n1cnnc1-c1ccc(-c2ccccc2)nc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1ccccc1-n1c(Br)nnc1-c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 69 %

Procedure:
5-[4-(2-Bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine prepared in the Production Example 2 was dissolved in a mixture solvent of carbon tetrachloride (100 ml) and acetic acid (100 ml), followed by addition of n-bromosuccinimide (5.90 g), and refluxed under heating for 3 hours. After the reaction solution was cooled to ambient temperature, the solution was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and extracted with chloroform. Subsequently, the organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1), to afford the entitled compound as yellow solid (6.96 g, 69%). The physico-chemical values are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([NH2:26])([C:20]1[S:24][N:23]=[C:22]([CH3:25])[N:21]=1)[CH3:19]>>[CH3:17][C:18]([NH:26][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[S:24][N:23]=[C:22]([CH3:25])[N:21]=1)[CH3:19]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: Cc1nsc(C(C)(C)N)n1
Product: Cc1nsc(C(C)(C)NC(=O)c2cccc(-c3cccc(Cl)c3)n2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-ethylamine as starting materials, MS (LC/MS): 373.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]([Br:21])=[CH:4][N:3]=1
Reactant: [Br-]
Reactant: Nc1nccnc1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1ncc(Br)nc1Cc1ccccc1
Yield: 89 %

Procedure:
To a solution of 3-benzyl-2-aminopyrazine 12 (1.38 g, 7.40 mmol) in chloroform (40 mL), pyridine (1.80 mL, 22.00 mmol) and tetrabutylamoniumtribromide TBATB (3.57 g, 7.40 mmol) were added at room temperature. After 1 h the reaction mixture was washed with 20% aqueous solution of NaCl, the organic layer was then dried over Na2SO4, filtered and the solvent removed under reduced pressure. The crude was purified by flash chromatography (EtOAc-dichloromethane, 80:20) to get 1.75 g (89% yield) of the title compound 13 as a pale brown solid and subsequent recrystallization (n-exane/diethyl ether) gave colorless crystals suitable for crystallographic studies. 1H-NMR (CDCl3): 3.97 (s, 2H), 4.74 (br s, 2H), 7.10-7.24 (m, 5H), 7.89 (s, 1H). MS (ESI): m/z 265 (M+H). The crystallography of compound 13 is shown in FIG. 3, demonstrating its purity.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[CH3:33][N:34]1[CH2:38][CH2:37][NH:36][C:35]1=[O:39]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[CH2:37][CH2:38][N:34]([CH3:33])[C:35]5=[O:39])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Reactant: CN1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cc2N2CCCS2(=O)=O)CC1
Yield: 65.4 %

Procedure:
Using [4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (205 mg) described in Preparation Example 240 and 1-methylimidazolidin-2-one (59 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (139 mg) was obtained.
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[S:33]([CH2:36][CH2:37][CH2:38][C:39]([O:41]C)=[O:40])(=[O:35])=[O:34])=[CH:7][CH:6]=1)#[N:4]>O.O1CCOCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[C:13](=[O:32])[N:12]2[S:33]([CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])(=[O:34])=[O:35])=[CH:7][CH:6]=1)#[N:4]
Reactant: COC(=O)CCCS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2S(=O)(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium hydroxide (2 mg, 84 μmol) in water (200 mL) is added to a solution of methyl 4-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-ylsulfonyl)butanoate (example 44.10, 19 mg, 33 μmol) in 1,4-dioxane (1 mL). The mixture is stirred at room temperature for 2 h and purified by it) preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 6 mg; ESI mass spectrum [M+H]+=562; Retention time HPLC: 0.91 min (Z018_S04).