Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[C:24](Br)[CH:25]=1)#[N:19].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:20]1[CH:25]=[C:24]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)[CH:23]=[N:22][CH:21]=1)#[N:19]
Reactant: N#Cc1cncc(Br)c1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1cncc(N2C[C@H]3CN(C(=O)OCc4ccccc4)C[C@H]32)c1
Temperature: 80 °C
Yield: 46.6 %

Procedure:
The product of Example 52D (0.800 g, 3.40 mmol) in toluene (34 mL) was treated with 3-cyano-5-bromopyridine (0.690 g, 3.8 mmol), Pd2(dba)3 (0.0.64 g, 0.10 mmol), BINAP (0.086 g, 0.010 mmol) and Cs2CO3 (0.221 g, 6.80 mmol) and the reaction was heated at 80° C. for 12 hours. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 5% MeOH/CH2Cl2) to provide the title compound as a yellow oil (47%, 0.530 g). MS (DCI/NH3) m/z 335 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[NH:5][C:6]1[C:10]2[CH:11]=[N:12][C:13]([NH:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[O:17])=[CH:14][C:9]=2[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:7]=1)[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:46])[NH:5][C:6]1[C:10]2[CH:11]=[N:12][C:13]([NH:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[O:17])=[CH:14][C:9]=2[NH:8][N:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
(R)-ethyl(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (0.037 mmol) was taken up in TFA (1 ml) and the reaction mixture stirred at room temperature for 1 h. Triethylsilane (0.006 ml, 0.037 mmol) was added drop wise, and the reaction mixture stirred for an additional 5 minutes. The mixture was concentrated, re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered preparative HPLC to afford (R)-ethyl(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (5.7 mg, 0.015 mmol, 41.7% yield) as a white solid. MS ESI calc'd. For C18H21N6O3 [M+H]+ 369. found 369. 1H NMR (ppm, 600 MHz, DMSO): δ 8.95 (s, 1H); 7.78 (s, 1H); 7.42 (s, 1H); 7.30-7.31 (m, 4H); 7.19-7.22 (m, 1H); 4.85 (t, J=7.2 Hz, 1H); 4.14 (q, J=7.1 Hz, 2H); 1.39 (d, J=7.0 Hz, 3H); 1.22 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1)(OC(C)(C)C)=O.[ClH:17]>>[ClH:17].[NH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](O)CC1
Agent: Cl
Product: NC[C@H]1CC[C@H](O)CC1

Procedure:
trans-4-Aminomethyl-cyclohexanol hydrochloride (342 mg) was prepared by following General Procedure L using trans-N-Boc-4-aminomethyl-cyclohexanol (500 mg) and hydrogen chloride (5.45 mL, 4.0 M solution in 1,4-dioxane).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].Cl.[Cl-].[Na+]>>[F:1][C:2]([F:21])([F:22])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)C(C(=O)O)c1cccc(OC(F)(F)F)c1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
Diethyl 3-trifluoromethoxyphenylmalonate (3.00 g, 9.38 mmol) was stirred in an aqueous sodium hydroxide solution (15 g, 20% by weight) at 65° C. for 10 min. The reaction mixture was then cooled in an ice bath, and ice (7 g) was added to the reaction mixture, followed by 6 N hydrochloric acid to adjust the pH to about 2. The aqueous mixture was saturated with sodium chloride and extracted with ethyl acetate three times. The combined organic phases were dried (MgSO4) and concentrated to give a solid, which was triturated with a mixture of 33% diethyl ether/hexane to give the title compound as a white solid (2.24 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]4=[O:25])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: Oc1ccccn1
Reactant: CSc1nc(CNC(=O)c2ccc(Cl)s2)cn1-c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: CSc1nc(CNC(=O)c2ccc(Cl)s2)cn1-c1ccc(-n2ccccc2=O)cc1
Temperature: 130 °C
Yield: 43.8 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (56 mg, 0.11 mmol), 2-hydroxypyridine (30 mg, 0.32 mmol), 8-hydroxyquinoline (8 mg, 0.055 mmol) and K2CO3 (100 mg, 0.72 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the titled compound (22 mg). MS 457.0 and 459.0 (M+H, Cl pattern).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23])(=[O:15])=[O:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)Cc1ccccc1N
Product: CS(=O)(=O)Cc1ccccc1Nc1cccn2nc(Cl)nc12

Procedure:
164 a) A suspension of o-Nitrobenzylbromide (5.71 g, 26.4 mmol) and sodium methanesulfinate (4.0 g, 40.0 mmol) in ethanol (70 mL) was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure. To the residue was added water (50 mL) and stirred for 30 minutes. The suspension was filtered, rinsed with water and air dried. 1-Methanesulfonylmethyl-2-nitro-benzene was isolated as a yellow solid (5.36 g, 94%). MP=115-117° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=8.1 Hz, 1H), 7.74-7.65 (m, 2H), 7.62-7.58 (m, 1H), 4.80 (s, 2H), 2.91 (s, 3H). 164 b) 2-Methanesulfonylmethyl-phenylamine was prepared from 1-methanesulfonylmethyl-2-nitro-benzene (1.0 g, 4.6 mmol) in a manner analogous to Example 111a. Product isolated as an off-white solid (0.84 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.20 (t, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.86-6.76 (m, 2H), 4.30 (s, 2H), 4.28 (br s, 2H), 2.87 (s, 3H). MS=186 (MH)+. 164 c) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 2-methanesulfonylmethyl-phenylamine (440.0 mg, 2.375 mmol) in a manner analogous to Example 2d. Product isolated as a tan solid (0.62 g, 51%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=5.9 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.47-7.41 (m, 3H), 6.89-6.81 (m, 2H), 4.41 (s, 2H), 2.93 (s, 3H). MS=337, 339 (MH)+. 164 d) N(8)-(2-Methanesulfonylmethyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepare from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.013 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.8 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.43-7.37 (m, 2H), 7.18 (t, J=7.4 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.83 (d, J=7.8 Hz, 1H), 6.70 (s, 1H), 6.67 (t, J=7.1 Hz, 1H), 4.45 (s, 2H), 3.18-3.13 (m, 4H), 2.94 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:32])([O:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:33])[N:17]=2)[CH2:9]1.[OH:35][C:36]1([C:43]2[CH:44]=[N:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1>>[OH:35][C:36]1([C:43]2[CH:44]=[N:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[CH2:37][CH2:38][CH:39]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:32])([O:30][CH3:31])[C:26]([F:29])([F:27])[F:28])[CH:23]=4)[N:18]([CH3:33])[N:17]=3)[CH2:11]2)[CH2:40][CH2:41]1
Reactant: COC(F)(c1ccc2c(c1)c(NCC(=O)NC1CNC1)nn2C)C(F)(F)F
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(OC)C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt and 4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[NH2:1][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: [N-]=[N+]=N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
To a solution of (3R)-3-azido-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (4.48 g, 15.4 mmol) (obtained as described in Reference Example 53(4)) in acetonitrile (134 ml) was added triphenylphosphine (4.22 g, 16.1 mmol), and the mixture was stirred in an oil bath (70° C.) for 1.5 hours. After checking the disappearance of the raw materials, sodium sulfate decahydrate (5.19 g, 16.1 mmol) was added thereto and then the reaction mixture was stirred for 5 hours. After checking the completion of the reaction, the reaction mixture was filtered and partitioned between methylene chloride and 0.1M aqueous hydrogen chloride solution. To the obtained aqueous layer were added methylene chloride and sodium hydrogencarbonate, and the aqueous layer was extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried under reduced pressure to give (3R)-3-amino-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (3.53 g, yield 86%) as pale yellow crystals.
Reaction SMILES: [CH3:1][NH:2][CH:3]=[N:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH3:12].[CH2:13]([O:15][C:16](=[O:24])[C:17](=[CH:20]OCC)[C:18]#[N:19])[CH3:14]>CCOCC>[CH2:13]([O:15][C:16]([C:17]([C:18]#[N:19])=[CH:20][N:2]([CH3:1])[CH:3]=[N:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH3:12])=[O:24])[CH3:14]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CNC=Nc1ccc(C)cc1C
Solvent: CCOCC
Product: CCOC(=O)C(C#N)=CN(C)C=Nc1ccc(C)cc1C

Procedure:
48.6 g of N1 -methyl-N2 -(2,4-dimethylphenyl)-formamidine are dissolved in 100 cc of ether and a solution of 51 g of ethoxymethylene-cyanoacetic acid ethyl ester in 100 cc of ether is added at about 20° C. while stirring. The precipitated product is filtered off with suction after 5 hours. It is very pure. If desired it can be recrystallized from chloroform/petroleum ether (40°-80° C.). Yield 68 g, b.p. 140°-142° C. ##STR5##
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][CH2:22][CH:23](OC)[O:24]C)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>O1CCOCC1.[Cl-].[Na+].O>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][CH2:22][CH:23]=[O:24])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(CNC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NCC=O
Reaction time: 7 h
Yield: 94 %

Procedure:
To a solution of 200 mg of 8-(cyclohexylmethoxy)-N-(2,2-dimethoxyethyl)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide in 2 mL of dioxane was added 6 M hydrochloric acid, followed by stirring for 7 hours. To the reaction mixture were added saturated brine and ethyl acetate to carry out a layer separation operation. To the obtained aqueous layer was added a 1 M aqueous sodium hydroxide solution, and the resulting solid was collected by filtration and dried to obtain 165 mg of 8-(cyclohexylmethoxy)-2-methyl-N-(2-oxoethyl)imidazolo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH:20](O)=[O:21].C(OC(=O)C)(=O)C>O>[NH:1]([CH:20]=[O:21])[C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=CO
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CN[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
444.7 g (1.67 mole) of commercially available H—Orn(Z)—OH was dissolved in 3.5 L (93 moles) of formic acid. The solution was cooled in an ice bath, and 1.17 L (12 moles) of acetic anhydride was subsequently added in dropwise fashion over two hours while the temperature of the reaction mixture was maintained between about 5° and 15° C. The resultant reaction mixture was stirred at room temperature for about two hours after the addition was completed, and the reaction vessel was refrigerated overnight. 1.5 L of cold water was then added, and the solution was concentrated to dryness under reduced pressure. The residual, light yellow syrup was taken up into EtOAc, washed with water and then with saturated NaCl, and then dried overnight over sodium sulfate. After filtration and evaporation to dryness, the residual syrup was dissolved in 5 L of ethyl ether. The solution was cooled in a dry ice bath and seeded. The resulting crystalline product was filtered, washed with ethyl ether, air dried for two hours and finally dried in a lyophilizer. 431.6 g (1.47 mole, 88%) of For—Orn(Z)—OH was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26](O)=O)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:13]([O:12][C:10]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]1[NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[N:9]=1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: Nc1ccc(I)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(I)ccc2[nH]1
Temperature: 0 °C
Yield: 47 %

Procedure:
To a mixture of 4-iodo-benzene-1,2-diamine (1.5 g, 6.4 mmol) and (S)-N-Cbz-2-piperidine-carboxylic acid (available commercially at Aldrich) (1.7 g, 6.4 mmol) in DMF (20 mL) at 0° C. is added DIPEA (3.3 mL, 19.2 mmol) followed by HATU (3.0 g, 7.69 mmol). The reaction mixture is stirred at 0° C., brought to room temperature and stirred overnight. The reaction mixture is than concentrated in vacuum and the residue is dissolved in AcOH (15 mL) and stirred at 60° C. for 4 hours. The mixture is concentrated in vacuum and the residue is dissolved in EtOAc and washed with water, 1N HCl and brine, dried over sodium sulfate and concentrated in vacuum. The residue is purified by flash column chromatography on silica gel (MeOH/DCM 0% to 20%) to give the title compound (1.4 g, 47%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])([O-:10])=[O:9]
Reactant: N#Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of 2-fluoro nitrobenzene (1.41 g, 10 mmol, 1.0 equiv) and 3-hydroxybenzonitrile (1.19 g, 1.0 equiv) in 10 mL of DMF was added K2CO3 (2.76 g, 2 equiv). After stirring at 60° C. for 3 h, the mixture was diluted with EtOAc and washed with H2O. The organic layer was dried over MgSO4, filtered and evaporated to give 3-(2-nitrophenoxy)benzonitrile (2.38 g, 99%). MS found for C13H9N2O3 (M+H)+: 241.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:38]([C:36]5[O:35][N:34]=[C:33]([O:32][CH3:31])[CH:37]=5)=[O:39])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)no1
Reactant: COc1cc(C(=O)O)on1
Product: COc1cc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)cnc43)CC2)on1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 37) has been coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light grey solid. MS: 553.1 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:21])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)(=[O:11])=[O:10].O.O.[Sn](Cl)Cl>CO.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:21])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)(=[O:11])=[O:10]
Reactant: CN(c1ccccc1Cl)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CN(c1ccccc1Cl)S(=O)(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(2-chlorophenyl)-N-methyl-(3-nitrophenyl)sulfonamide (2.6 mmol, 848 mg) and tin (II) chloride dihydrate (10.4 mmol, 2.35 g) were heated for 4 hr at reflux in 15 mL of methanol. The reaction mixture was cooled to room temperature and diluted with 20 mL of ethyl acetate and 10 mL of a saturated solution of aqueous sodium carbonate. Heavy gas evolution was observed upon addition of aqueous sodium carbonate to the reaction mixture. The reaction mixture was stirred 1 hr and then filtered through a plug of Celite®. The layers were separated and the organic layer was extracted once with a saturated solution of aqueous sodium carbonate, once with brine, and then dried with sodium sulfate. The crude product was purified using flash chromatography (0-5% ethyl acetate/methylene chloride) to give N-(2-chlorophenyl)-N-methyl-(3-aminophenyl)sulfonamide as an off white foam. 1H NMR (300 MHz) 3.13 (s, 3H), 3.80 (br s, 2H), 6.80-6.87 (m, 1H), 7.02-7.25 (m, 6H), 7.30-7.38 (m, 1H). MS (ESI): m/e 297.2, 299.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1C(OC)=O.[OH-].[Na+].Cl.[C:14]([OH:19])(=[O:18])[C:15]([OH:17])=[O:16]>CCOCC>[C:14]([OH:19])(=[O:18])[C:15]([OH:17])=[O:16].[NH2:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1
Reactant: COC(=O)c1sccc1N
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CCOCC
Product: Nc1ccsc1
Temperature: 115 °C

Procedure:
Methyl 3-aminothiophene-2-carboxylate (1.52 g, 9.68 mmol) is dissolved in 2M NaOH (10 mL, 20 mmol) and heated to reflux in a 115° C. oil bath for 30 min. The mixture is cooled to rt, placed in an ice bath, and carefully acidified with concentrated HCl. The slurry is filtered and rinsed with H2O (25 mL). The cake is then dissolved in acetone (50 mL), dried over MgSO4, filtered, and concentrated to a thick paste. The crude material is dissolved in 1-propanol (25 mL), and oxalic acid (0.90 g, 10.0 mmol) is added portionwise. The mixture is heated at 38° C. for 45 min, cooled to rt, and diluted with ether. The precipitate is isolated via filtration, and washed with ether, affording 3-amino-thiophene oxalate (C135) as a fluffy white solid (70% yield). HRMS (FAB) calculated for C4H5NS+H: 100.0221, found 100.0229 (M+H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[S:37])[NH:16][NH:17][C:18](=O)[C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28][CH2:29][O:30][CH3:31])=[CH:21][C:20]=3[O:32][CH2:33][O:34][CH3:35])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>[OH-].[Na+]>[CH:25]([C:23]1[C:22]([O:28][CH2:29][O:30][CH3:31])=[CH:21][C:20]([O:32][CH2:33][O:34][CH3:35])=[C:19]([C:18]2[N:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[C:15](=[S:37])[NH:16][N:17]=2)[CH:24]=1)([CH3:27])[CH3:26]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)NNC(=S)Nc1ccc(CN2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1-c1ccc(CN2CCOCC2)cc1
Yield: 41.6 %

Procedure:
Crude crystals of 4-[4-(morpholin-4-ylmethyl)-phenyl]-1-(5-isopropyl-2,4-bismethoxymethoxy-benzoyl)thiosemicarbazide (IM5-S-a02) and 5% aqueous sodium hydroxide (30 mL) were placed in a 100 mL eggplant shaped flask and refluxed for 2 hours. After completing the reaction, the reaction mixture was extracted with methylene chloride, and the organic layer was combined, dried over anhydrous sodium sulfate. After filtration and evaporation, the residue thus obtained was purified by silica gel column chromatography to obtain the title compound (IM6-S-a02: 1.43 g, 41.6%).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:3]1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:3]1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)CC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ethyl 1-methyl-5-oxoprolinate (0.27 g, 1.58 mmol) was dissolved in ethanol (5 ml) and cooled to 0° C. in an ice bath. To this was added 2M aqueous sodium hydroxide solution (3 ml) and the mixture was stirred for ˜4 hours at 0° C. The ethanol was evaporated under vacuum and the aqueous residue was acidified with 2N aqueous hydrogen chloride to pH1. The volume of the aqueous phase was reduced to ˜3 ml under vacuum and then extracted with a 3:1 mixture of chloroform and isopropanol using a phase separator. The combined organic layers were concentrated to give 1-methyl-5-oxoproline which was used without further purification.