Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[CH3:30][N:31]1[CH2:36][CH2:35][CH2:34][CH:33]([C:37](O)=[O:38])[CH2:32]1>>[CH3:1][N:2]([C:37]([CH:33]1[CH2:34][CH2:35][CH2:36][N:31]([CH3:30])[CH2:32]1)=[O:38])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN1CCCC(C(=O)O)C1
Reactant: CN[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1
Product: CN1CCCC(C(=O)N(C)[C@@H]2CCN(c3ccc(NC(=O)N4CCC(c5ccc(Cl)cc5)CC4)cc3)C2)C1

Procedure:
(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with 1-methylpiperidine-3-carboxylic acid by method E. This resulted in the product with the molecular weight of 538.14 (C30H40ClN5O2); MS (ESI): 538 (M+H+).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH2:13]([O:15][C:16](=[O:20])[C:17](=O)[CH3:18])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16](=[O:20])[C:17](=[N:12][NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=1)[CH3:18])[CH3:14]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)=NNc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3-Nitro-phenyl)-hydrazine hydrochloride salt (B-4-a) (30.2 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22.3 g, 0.19 mol) was dissolved in ethanol (300 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to give 2-[(3-nitro-phenyl)-hydrazono]-propionic acid ethyl ester, which was used directly in the next step.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: Cc1cccc(CN)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Cc1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-methylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): m/e 316.2 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.42 (br s, 1H); 8.09 (br s, 1H); 7.85 (m, 1H); 7.14 (d, J=7.3 Hz, 1H); 6.84 (d, J=5.5 Hz, 1H); 5.82 (br s, 1H); 4.72 (d, J=5.9 Hz, 2H); 2.38 (s, 3H).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][CH:5]([NH:6][CH2:7]1)[CH2:4][O:3]2.FC(F)(F)S([O-])(=O)=O.[N:17]1([S:22](N2C=C[NH+](C)C2)(=[O:24])=[O:23])[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([S:22]([N:6]2[CH2:7][C@@H:2]3[CH2:8][C@H:5]2[CH2:4][O:3]3)(=[O:24])=[O:23])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Reactant: C1O[C@@H]2CNC1C2
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(N1C[C@@H]2C[C@H]1CO2)n1ccnc1

Procedure:
(1S,4S)-5-(Imidazole-1-sulfonyl)-2-oxa-5-aza-bicyclo[2.2.1]heptane was prepared in accordance with step A of the general method described in example 76 from all-(S)-(+)-2-oxa-5-aza-bicyclo[2.2.1]heptane hydrochloride and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=230.5 (M+H−).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:13].Cl.[SH:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1.Cl.[Cl:26][CH2:27][C:28]1[C:33]([CH3:34])=[C:32]([S:35][CH2:36][C:37]2[O:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=[CH:30][N:29]=1>C(O)(C)C>[ClH:26].[ClH:13].[O:38]1[CH:39]=[CH:40][CH:41]=[C:37]1[CH2:36][S:35][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:27][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[C:33]=1[CH3:34]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(C)O
Product: Cc1c(SCc2ccco2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 90 %

Procedure:
The compound of Example 1 can also be prepared via the corresponding dihydrochloride, by refluxing 2-mercapto-1H-benzimidazole (1.5 g/10 mmol) in 30 ml of isopropanol with 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride (10 mmol) for 5 h, cooling, removing the precipitated solid by filtration and recrystallizing this from isopropanol/water. This gives the title compound (yield 90%) as a colorless solid of m.p. 208° C. (decomp.).
Reaction SMILES: N[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[N:11]([O-:13])=[O:12].[Na+].F[B-](F)(F)F.[Na+]>Cl.O.CCOC(C)=O.[Cu]>[N+:11]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])([O-:13])=[O:12]
Reactant: O=N[O-]
Reactant: COC(=O)c1sccc1N
Agent: [Cu]
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a stirring solution of methyl 3-aminothiophene-2-carboxylate (5 g, 31.8 mmol) in Conc. HCl (4.77 ml) was added aq. solution of sodium nitrite (2.195 g, 31.8 mmol) slowly at 0-5° C. Reaction mixture was stirred at 0-5° C. for 1 h. To this was added aq. solution of sodium tetrafluoroborate (5.24 g, 47.7 mmol) in one lot. After 30 min. precipitated product was filtered. The product was added to the stirring suspension of copper bronze (6.06 g, 95 mmol) and sodium nitrite (26.3 g, 382 mmol) in water (100 ml). Reaction mixture was stirred at 25° C. for 1 h. Reaction mixture was diluted with water and EtOAc and filtered through Hyflow bed. The organic layer was separated and distilled out to get crude product which was column purified using 0-5% EtOAC in hexane to get titled compound as light yellow solid in 63% yield.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](Cl)=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[C:15]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2c(C(N)=O)c3n(c2Cl)CCN(C(=O)NC(C)(C)C)C3)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(-c2cn3c(c2C(N)=O)CN(C(=O)NC(C)(C)C)CC3)cc1
Yield: 58.4 %

Procedure:
A mixture of 1.20 g (2.96 mmol) of N2-tert-butyl-6-chloro-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, 6.0 g (95 mmol) of ammonium formate and 0.22 g (0.10 mmol) of 10% palladium-on-charcoal containing 50% water in 80 ml of methanol is refluxed for 6 hours. After cooling, the mixture is filtered through Celite and the Celite is rinsed with methanol and dichloromethane. The filtrate is then concentrated under reduced pressure and the residue is taken up in dichloromethane. The solution is washed with water, dried over sodium sulfate and then concentrated under reduced pressure. The product is then purified by chromatography on a column of 70 g of silica gel, eluting with a mixture of 20 to 50% ethyl acetate in dichloromethane, to give 0.64 g of N2-tert-butyl-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white solid after crystallizing from ethyl acetate and drying.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([C:28]#[CH:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[C:28]([C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1)#[CH:29]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C#C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C#C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 46 %

Procedure:
The title compound II-bb was prepared in 46% yield from 3,3:17,17-bis(ethylendioxy)-6α-ethynylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, cyclohexane/CH2Cl2/acetone 80/10/10). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.69-0.78 (m, 22H), 1.12 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Si]([O:46][CH2:47][CH2:48][N:49]([C:54]1[C:73]([C:74]2[CH:75]=[C:76]([CH:80]=[CH:81][CH:82]=2)[C:77](O)=[O:78])=[CH:72][C:57]2[C:58]([C:68](=[O:71])[NH:69][CH3:70])=[C:59]([C:61]3[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=3)[O:60][C:56]=2[CH:55]=1)[S:50]([CH3:53])(=[O:52])=[O:51])(C(C)(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([NH:5][C:77]([C:76]1[CH:75]=[C:74]([C:73]2[C:54]([N:49]([CH2:48][CH2:47][OH:46])[S:50]([CH3:53])(=[O:51])=[O:52])=[CH:55][C:56]3[O:60][C:59]([C:61]4[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=4)=[C:58]([C:68]([NH:69][CH3:70])=[O:71])[C:57]=3[CH:72]=2)[CH:82]=[CH:81][CH:80]=1)=[O:78])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)c(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(CCO)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)C)c3)cc12
Reaction time: 1 h
Yield: 24.2 %

Procedure:
Tert-butylamine (21 μL, 0.195 mmol) was added to a stirring solution of HATU (45 mg, 0.117 mmol), DIEA (41 μL, 0.234 mmol), and 3-(6-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (50 mg, 0.078 mmol) in DMF (780 μL) at rt. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (11 mg, 23%). 1H NMR (500 MHz, CD3OD) d ppm 8.04 (1 H, br. s.), 7.94-8.02 (2 H, m), 7.77-7.86 (2 H, m), 7.66-7.73 (2 H, m), 7.49-7.59 (2 H, m), 7.24-7.34 (2 H, m), 3.56-3.66 (1 H, m), 3.35-3.43 (2 H, m), 3.27 (3 H, s), 2.94 (3 H, s), 2.78-2.87 (1 H, m), 1.47 (9 H, s). LC-MS retention time: 1.57 min; m/z (MH+): 582. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=10.88 min, purity=97%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=10.27 min, purity=96%.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[N:13]=[C:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:11]=[C:10]([NH:20][S:21]([CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=2)(=[O:23])=[O:22])[C:9]=1[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][CH3:43].[CH3:44]O>>[CH3:6][O:7][C:8]1[N:13]=[C:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:11]=[C:10]([NH:20][S:21]([CH:24]=[CH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([O:34][CH3:44])=[O:33])=[CH:30][CH:31]=2)(=[O:22])=[O:23])[C:9]=1[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][CH3:43]
Reactant: CO
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2ccc(C(=O)O)cc2)nc(-c2ncccn2)nc1OC
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C=CS(=O)(=O)Nc2nc(-c3ncccn3)nc(OC)c2Oc2ccccc2OC)cc1
Reaction time: 8 h

Procedure:
Concentrated sulfuric acid (0.1 ml) was added to a solution of 150 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-carboxyphenyl)ethenesulfonamide in 10 ml of methanol followed by stirring overnight under a refluxing condition. The reaction mixture was concentrated in vacuo, 1N hydrochloric acid was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the resulting solid was recrystallized form ethyl acetate to give 102 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-methoxycarbonylphenyl)ethenesulfon-amide.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[CH3:15].C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC>O1CCOCC1.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>[CH3:13][C:9]1[N:6]2[C:7](=[O:8])[C:2]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[C:3]([CH:14]([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH3:15])[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc2nc(C(C)N3C(=O)c4ccccc4C3=O)c(Br)c(=O)n12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cccc2nc(C(C)N3C(=O)c4ccccc4C3=O)c(-c3ccccn3)c(=O)n12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2-(1-(3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-ethyl)isoindoline-1,3-dione (0.9386 g, 2.277 mmol), 2-(tributylstannyl)pyridine (1.098 mL, 3.05 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.263 g, 0.228 mmol) in 1,4-dioxane (18.97 mL) was stirred using an overhead stirrer at 110° C. After 20 h, the mixture was cooled to rt and concd under reduced pressure to give a black liquid. The black liquid was purified by column chromatography on a 80 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 25 min and then 100% isocratic of EtOAc for 25 min to give 2-(1-(6-methyl-4-oxo-3-(pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione as a yellow solid: Mass Spectrum (ESI) m/e=411.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:6]([OH:7])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:19][C:2]1([CH3:1])[C:6](=[O:7])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(O)C(C)(C)O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC1(COCc2ccccc2)CC(=O)C(C)(C)O1
Yield: 100 %

Procedure:
The alcohol of Example 3(16 g), methylene chloride (300 ml) and pyridinium chlorochromate (14.5 g) were stirred over two days at room temperature. The solution was filtered through a column of Fluorosil using methylene chloride as eluant. Evaporation of the solvent gave 15.8 g, corresponding a 100% yield, of the desired product, which solidified on cooling.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[N:11]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:10]=2)[C:6]([C:32]#[N:33])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[F:45][C:46]1[C:51]([OH:52])=[C:50]([F:53])[C:49]([F:54])=[C:48]([F:55])[C:47]=1[F:56]>ClCCl>[F:45][C:46]1[C:47]([F:56])=[C:48]([F:55])[C:49]([F:54])=[C:50]([F:53])[C:51]=1[O:52][C:3]1[N:8]=[C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=3)[N:11]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=3)(=[O:24])=[O:23])[CH:10]=2)[C:6]([C:32]#[N:33])=[CH:5][N:4]=1
Reactant: CSc1ncc(C#N)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(C(F)(F)F)cc23)n1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Oc4c(F)c(F)c(F)c(F)c4F)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
2-(Methylthio)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (150 mg, 0.31 mmol) was dissolved in dichloromethane at room temperature. Meta-chloroperbenzoic acid (110 mg, 0.64 mmol) was added in one portion and the reaction was stirred for 5 minutes. Pentafluorophenol (285 mg, 1.55 mmol) was added and the solution was stirred at room temperature for 3 hours. The crude mixture was washed with a diluted solution of sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a solid (60 mg, 31% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=S)[CH3:2].[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:4]([NH:3][CH2:1][CH3:2])=[N:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)#[N:16]
Reactant: N#CN
Reactant: CCNC(=S)NCCNCc1nccs1
Agent: [Pb]
Product: CCNC(=NCCNCc1nccs1)NC#N

Procedure:
Reacting N-(2-thiazolylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3(b) and then chromatographing gives N-ethyl-N' -[2-(2-thiazolylmethylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-cyano-N' -ethyl-N"-[2-(2-thiazolylmethylamino)ethyl]guanidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)[C:8]([OH:10])=[O:9])=[O:4]>[Pd].CO>[NH2:14][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)cc(C(=O)O)c1
Reaction time: 3 h
Yield: 82 %

Procedure:
A suspension of 3-(methoxycarbonyl)-5-nitrobenzoic acid (11.25 g, 50 mmol) and palladium on carbon (10 wt %, 1.0 g) in MeOH (10 mL) was shaken in hydrogenator under hydrogen at 50 psi for 3 h. The mixture was filtered and concentrated in vacuo to give the title compound (8.0 g, 82% yield): 1H NMR (CD3OD, 500 MHz) δ ppm 3.91 (3H, s), 7.53 (1H, m), 7.55 (1H, m), 7.92 (1H, m). HPLC retention time: 0.922 min (method A). MS (ESI) (M+H)+ 196.12.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:12])[CH:3]=1.C[O-].[Na+].CO.S(OC)(O[CH3:22])(=O)=O>CO.O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:22])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)cc1O
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of 4-amino-5-chloro-2-hydroxybenzoic acid (1.88 g, 0.010 mole) in absolute methanol (20 ml) was treated with 25% sodium methoxide/methanol (2.16 g, 0.010 mole), stirred for 30 minutes, and concentrated in vacuo. The solid residue was taken up in anhydrous acetone (30 ml), treated with dimethyl sulfate (1.64 g, 0.013 mole) and refluxed for 2 hours. The resultant solution was diluted with water (100 ml), and the precipitate was filtered, washed with water, and dried exhaustively in vacuo to afford 1.75 g (87%) of the title compound as fine colorless needles. The material was recrystallized from ethyl acetate/hexane; mp 138°-139° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:14]3[N:15]=[C:16]([CH3:21])[C:17]([C:18]([OH:20])=O)=[C:13]3[CH:12]=[C:11]([CH3:22])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:31][NH2:32])([CH3:26])([CH3:25])[CH3:24]>S(Cl)(Cl)=O.ClCCl>[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:31][NH:32][C:18]([C:17]1[C:16]([CH3:21])=[N:15][N:14]2[C:9]([O:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:10][C:11]([CH3:22])=[CH:12][C:13]=12)=[O:20])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc(OCC2CCCCC2)n2nc(C)c(C(=O)O)c2c1
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCC3CCCCC3)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 110 mg (0.364 mmol) of 7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 120A in 1 ml of thionyl chloride was stirred at 100° C. for 1 h. After the reaction had ended, the solvent was drawn off under reduced pressure and the residue was suspended in 3 ml of dichloromethane and then added to a solution of 102.3 mg (0.473 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A in 2 ml of dry dichloromethane. The resulting solution was stirred at room temperature overnight. The solvent was drawn off under reduced pressure and the residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 40 mg (13% of theory, 59% pure) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:17]([CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])=[N:18][N:19]=[C:20]2[CH2:20][N:16]([CH2:17][CH3:21])[CH2:5][CH3:4])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN(CC)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 13, 5-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is reacted with the above suspension, then neutralized with sodium bicarbonate to give 5-chloro-2-[3-[(diethylamino)-methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10]>ClCCl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CO)ccc1Br
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.2 %

Procedure:
3.7 g (43 mmol, 10 eq) of manganese dioxide are added to a solution of 900 mg (4.3 mmol, 1 eq) of (4-bromo-3-methylphenyl)methanol in 8 mL of dichloromethane. The reaction mixture is stirred for 12 hours at room temperature. The solid is filtered off and the solvent is evaporated off. 900 mg of 4-bromo-3-methylbenzaldehyde are obtained in oil form and used in the following reaction without further purification.