Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:13](=[O:14])[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C(N(CC)CC)C.O.[NH2:34][NH2:35]>O1CCOCC1>[NH:34]([C:2]1[C:3]2[C:13](=[O:14])[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1)[NH2:35]
Reactant: NN
Reactant: CCOC(=O)C1CN(c2ccccc2)c2nc(SC)nc(Cl)c2C1=O
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(c2ccccc2)c2nc(SC)nc(NN)c2C1=O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 96.4 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)-5-oxo-8-phenyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (21 g, 55.57 mmol) in 1,4-dioxane (400 mL) was added triethylamine (8.52 mL, 61.13 mmol) followed by hydrazine hydrate (3.06 g, 61.13 mmol). The reaction mixture was stirred at room temperature for 5-6 h. Upon completion of the reaction, dioxane was removed under reduced pressure and water (250 mL) was added to the reaction mixture. The reaction mixture was then extracted with dichloromethane (200 mL×3). The combined organic layers was washed with water (500 mL) followed by brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude ethyl 4-hydrazinyl-2-(methylthio)-5-oxo-8-phenyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (20 g) which was used in the next step without purification. LCMS [M+H]: 374
Reaction SMILES: Cl.[NH2:2]O.[F:4][C:5]([F:12])([F:11])[C:6](=[O:10])[CH2:7][C:8]#[N:9]>CO>[F:4][C:5]([F:12])([F:11])[C:6]1[O:10][N:9]=[C:8]([NH2:2])[CH:7]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: CO
Product: Nc1cc(C(F)(F)F)on1
Reaction time: 68 h
Yield: 55.5 %

Procedure:
Dry methanol (220 ml) and 96% hydroxylamine hydrochloride (11.52 g, 0.159 mole) were added to trifluoroacetoacetonitrile (16.78 g, 0.122 mole) and the mixture was heated under reflux with stirring for 68 hours. Methanol was then evaporated under reduced pressure and, after addition of water (240 ml), a 48% solution of sodium hydroxide was added to the resulting residue to adjust to pH 11 or higher. The solution was extracted with methylene chloride and, after drying the extract with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (10.30 g, 55.2%) as little colored crystals, m.p. 57°-58° C., b.p. 66°-67° C./0.8 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][O:14][CH3:15].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a cooled mixture of 2-chloro-5-methyl-benzoic acid (1 g, mmol), N,O-dimethylhydroxylamine (860 mg, 8.82 mmol) and Et3N (3.27 mL) in CH2Cl2 (10 mL) was added 1-propane phosphonic acid cyclic anhydride (4.49 mL, 7.05 mmol; 50 wt % solution in EtOAc) dropwise and stirred at room temperature for 3 h. The reaction mixture was filtered, washed with CH2Cl2 (mL), evaporated to dryness and subjected to column chromatography (SiO2, 40% EtOAc-hexanes) to obtain 2-chloro-N-methoxy-5,N-dimethyl-benzamide (1.19 g) as white crystalline solid in 95% yield. ESMS m/z (relative intensity): 214.1 (M+H)+ (100).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=[O:12])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH3:31])[CH:24]=[CH:23][C:22]([S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][C:10](=[O:12])[N:9]2[C:29]([NH:28][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:31])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[O:30])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)N1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)N2C(=O)CN2C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a solution of 1 g of 1-(diphenylmethyl)-1,2-diazetidin-3-one (prepared according to Example 1A.) in 20 mL of methylene chloride, at ambient temperature and under a nitrogen atmosphere, there is added in one portion a solution of one equivalent of p-toluenesulfonylisocyanate in methylene chloride. The reaction mixture is stirred at ambient temperature for 24-72 hours. The solvent is removed under reduced pressure followed by trituration of the residue with ethyl ether to yield 970 mg (53%) of the title compound having a melting point of 115°-123° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]#[C:10][Si](C)(C)C)[CH:6]=[N:5]1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:9]([C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:2]([F:15])([F:16])[F:1])[CH:8]=1)#[CH:10]
Reactant: C[Si](C)(C)C#Cc1cnn(CC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnn(CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.8 %

Procedure:
1-(2,2,2-Trifluoroethyl)-4-((trimethylsilyl)ethynyl)-1H-pyrazole (Preparation 147, 1.19 g) was dissolved in methanol (7 ml) and potassium carbonate (30 mg) was added. The reaction was stirred at room temperature for 3.5 hours. The methanol was evaporated and the residue taken up in dichloromethane (20 ml) and filtered through a plug of silica eluting with DCM to afford the title compound (326 mg, 53%). 1H-NMR (CDCl3, 500 MHz): δ 3.06 (s, 1H), 4.70 (q, J=8.20 Hz, 2H), 7.69 (s, 1H), 7.70 (s, 1H). 19F-NMR (CDCl3, 470.385 MHz): −71.69
Reaction SMILES: O[C:2]1([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:10]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[N:28][OH:29])[CH2:23][CH2:22]4)[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.C(OCC)(=O)C.O>[N:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:12][C:8]([C:2]3[CH2:7][CH2:6][NH:5][CH2:4][CH:3]=3)=[CH:9][C:10]=2[C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[N:28][OH:29])[CH2:23][CH2:22]3)=[CH:14][CH:15]=1
Reactant: ON=C1CCc2cc(-c3cc(C4(O)CCNCC4)oc3-c3ccncc3)ccc21
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: ON=C1CCc2cc(-c3cc(C4=CCNCC4)oc3-c3ccncc3)ccc21
Yield: 60.6 %

Procedure:
A solution of the product of Example 29, Step 1 (1.06 g, 2.0 mmol) in THF (25 ml) at 0° C. was treated with (methoxycarbonylsulfamoyl)-triethylammonium hydroxide inner salt (Burgess reagent, 952 mg, 4 mmol). After 18 hours at room temperature the mixture was diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried and concentrated in vacuo. Purification of the residue by silica gel chromatography gave the title compound (450 mg, 46%); MS(ES+) m/e 486 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1.Br[CH2:17][C:18]1[CH:37]=[CH:36][C:21]2/[C:22](=[C:32](/[CH3:35])\[C:33]#[N:34])/[C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[O:25][CH2:26][C:20]=2[CH:19]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:23]2=[C:24]([CH:27]=1)[O:25][CH2:26][C:20]1[CH:19]=[C:18]([CH2:17][N:11]3[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[N:8]=[C:7]3[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:37]=[CH:36][C:21]=1/[C:22]/2=[C:32](/[CH3:35])\[C:33]#[N:34]
Reactant: c1ccc(-c2nc3ccccc3[nH]2)nc1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(-c4ccccn4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 77.7 %

Procedure:
Using commercially available 2-(pyridin-2-yl)-1H-benzo[d]imidazole (50 mg, 0.34 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (123 mg, 86%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1CCOCC1.[CH3:21][C:22]([CH3:28])([CH3:27])[CH2:23][C:24](Cl)=[O:25]>ClCCl>[CH3:21][C:22]([CH3:28])([CH3:27])[CH2:23][C:24]([NH:11][NH:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:25]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A suspension of 4-nitrobenzohydrazide (0.500 g, 2.76 mmol), and 4-methylmorpholine (0.455 ml, 4.14 mmol) were stirred in dichloromethane (20 ml). 3,3-Dimethylbutanoyl chloride (0.422 ml, 3.04 mmol) was added and the reaction mixture was stirred for 2 hours. Normal phase chromatography of the crude reaction mixture gave the title compound.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:23][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CCc1cccc(C(=O)O)c1
Reactant: NCCc1ccccc1
Product: CC(C)CCc1cccc(C(=O)NCCc2ccccc2)c1
Yield: 74.5 %

Procedure:
Using preparation method 1, 96B (288 mg, 1.5 mmol) was reacted with phenethyl amine (276 μL, 266 mg, 2.2 mmol). Purification by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100% afforded white crystals (330 mg, 74%). NMR 1H (ppm, CDCl3): 7.52 (s, 1H), 7.44-7.41 (m, 1H), 7.34-7.22 (m, 7H), 6.09 (br. s, 1H), 3.74-3.67 (m, 2H), 2.92 (t, J3=6.9 Hz, 2H), 2.64-2.59 (m, 2H), 1.63-1.40 (m, 3H), 0.92 (d, J3=6.3 Hz, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1)[NH2:29]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:29]=[C:28]([C:30]4[CH:35]=[N:34][CH:33]=[CH:32][N:31]=4)[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1cnccn1
Product: CCc1ccc(C2CC(c3nc(-c4cnccn4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxypyrazine-2-carboximidamide were reacted according to the General Method 1. Yield: 45 mg (50% of theory)
Reaction SMILES: C(OC([N:8]([CH2:35][C:36]1[CH:37]=[C:38]([CH:52]=[CH:53][CH:54]=1)[C:39]([O:41][CH2:42][O:43]/[N:44]=[N+:45](\[O-:51])/[N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])=[O:40])[S:9]([C:12]1[CH:17]=[C:16]([C:18]([NH:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[CH:27][CH:28]=3)[CH2:23][CH:22]2[CH3:33])=[O:19])[CH:15]=[CH:14][C:13]=1[Cl:34])(=[O:11])=[O:10])=O)(C)(C)C.Cl.O>O1CCOCC1>[Cl:34][C:13]1[CH:14]=[CH:15][C:16]([C:18](=[O:19])[NH:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[CH:27][CH:28]=3)[CH2:23][CH:22]2[CH3:33])=[CH:17][C:12]=1[S:9]([NH:8][CH2:35][C:36]1[CH:37]=[C:38]([CH:52]=[CH:53][CH:54]=1)[C:39]([O:41][CH2:42][O:43]/[N:44]=[N+:45](\[O-:51])/[N:46]([CH2:47][CH3:48])[CH2:49][CH3:50])=[O:40])(=[O:10])=[O:11]
Reactant: CCN(CC)/[N+]([O-])=N/OCOC(=O)c1cccc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2cc(C(=O)NN3c4ccc([N+](=O)[O-])cc4CC3C)ccc2Cl)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)/[N+]([O-])=N/OCOC(=O)c1cccc(CNS(=O)(=O)c2cc(C(=O)NN3c4ccc([N+](=O)[O-])cc4CC3C)ccc2Cl)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Dissolve the compound obtained in Step D (4.38×10−4 mol) in dioxane (25 ml). Place under stirring and then add 37% hydrochloric acid (3.5 ml) and heat at 70° C. After 2 hours, the reaction mixture is poured into water (50 ml). Extract 3 times with ethyl acetate (20 ml). The organic phase is washed with water and then with brine, dried over magnesium sulphate, filtered and concentrated using a rotary evaporator. The oily orange-coloured crude product obtained is chromatographed on a silica column using as eluant a 60/40 n-heptane/ethyl acetate mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH:5]=[N:6][OH:7].[Cl:12]Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([Cl:12])=[N:6][OH:7]
Reactant: ON=Cc1ccc(Cl)c(Cl)c1
Reactant: ClCl
Solvent: ClC(Cl)Cl
Product: ON=C(Cl)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
A cold solution of 18.9 g of 3,4-dichlorobenzaldoxime in 150 ml of chloroform was treated with chlorine gas until no more chlorine was absorbed. The green mixture was stirred for 1 hour at 5°, then heated under reflux for 30 minutes, when the solid went into solution and the clear green solution changed to yellow. The solution was evaporated under reduced pressure to give a white solid, m.p. 104°-106°, which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([C@H:24]4[CH2:29][CH2:28][C@H:27]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH2:26][CH2:25]4)[C:20]3=[O:41])=[C:13]([Cl:42])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4]>CO.[OH-].[Na+]>[Cl:17][C:15]1[CH:16]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH:12]=[C:13]([Cl:42])[C:14]=1[CH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C@H:24]2[CH2:25][CH2:26][C@H:27]([O:30][Si:31]([CH:32]([CH3:33])[CH3:34])([CH:35]([CH3:36])[CH3:37])[CH:38]([CH3:40])[CH3:39])[CH2:28][CH2:29]2)[C:20]1=[O:41]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reaction time: 3 h

Procedure:
Place 3′,5′-Dichloro-4′-[(R)-2-oxo-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid methyl ester (Preparation 20) (1.32 g, 2.09 mmol) in MeOH (10 mL) and 1N NaOH solution (10 mL). Stir for 3 hours at reflux. Strip most of the solvent and quench with 1N HCl. Filter white precipitate and rinse with water on the filter. After drying receive 0.95 g (74%) of the title compound: Mass spectrum (apci) m/z=617 (M+H).
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11](=[O:13])[CH3:12])[CH:6]=1.CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([C:7]1[CH:6]=[C:5]([CH2:4][O:3][S:21]([CH3:24])(=[O:23])=[O:22])[CH:10]=[CH:9][N:8]=1)(=[O:13])[CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(CO)ccn1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(COS(C)(=O)=O)ccn1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-hydroxymethyl-pyridin-2-yl)-ethanone (165 mg, 1.09 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.20 mL, 1.43 mmol) followed by DMAP (13 mg, 0.10 mmol) and Ms-Cl (0.11 mL, 1.39 mmol). After stirring at 0° C. for 1 h30, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude methanesulfonic acid 2-acetyl-pyridin-4-ylmethyl ester as a brown oil. The crude material (250 mg) was dissolved in acetone (8 mL) under inert atmosphere (N2). 4-Nitro-1H-pyrazole (139 mg, 1.09 mmol) was added followed by K2CO3 (761 mg, 5.45 mmol) and TBA bromide (70 mg, 0.22 mmol). The reaction mixture was stirred at rt for 2 h and concentrated to dryness. The residue was partitioned between water (5 mL) and EA (10 mL). The layers were separated and the aq. layer extracted with EA (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:2 hept-EA)=0.41. LC-MS-conditions 02: tR=0.84 min, [M+H]+=247.33.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>[Si]=[Mo]=[Si]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Si]=[Mo]=[Si]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a powdered molybdenum disilicide from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 8.7%, wherein 4.2 g of phenyl chloroformate and 10.3 g of diphenyl carbonate were formed. Selectivity for carbonates was approximately 95%.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])[C:4](=[O:24])[O:3]1.[OH-].[Li+].Cl>O1CCCC1>[C:13]([CH2:12][O:11][N:10]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:8]([CH:7]=[C:5]([OH:6])[C:4]([OH:24])=[O:3])=[O:9])([OH:15])=[O:14]
Reactant: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(F)cc2)OCC(=O)O)O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)O
Reaction time: 2 h
Yield: 47.3 %

Procedure:
A solution of [[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-acetic acid (0.20 g, 0.56 mmol) in tetrahydrofuran (5 ml) was treated at 0° C. with 1.7 ml (1.7 mmol) of 1 M aqueous lithium hydroxide. After 2 h, the reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulphate) and evaporated in vacuo. Crystallisation of the residual solid from a mixture of ethyl acetate and hexane gave 0.083 g (47% yield) of the title material as a white solid: mp 135-138° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): (mixture of enol and keto forms, 7:3); enol form: 4.65 (2H, s, CH2), 4.92 (2H, s, CH2), 6.51 (1H, s, CH), 7.18 (2H, m, aromatics), 7.37 (2H, m, aromatics), 13.17 (1H, broad, OH). Anal. calcd for C13H12FNO7: C, 49.85; H, 3.86; N, 4.47. Found: C, 49.83; H, 3.90; N, 4.37.
Reaction SMILES: [OH:1][C:2]1[CH2:7][N:6]([CH3:8])[S:5](=[O:10])(=[O:9])[N:4]([CH3:11])[C:3]=1[C:12]([O:14]C)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[OH:1][C:2]1[CH2:7][N:6]([CH3:8])[S:5](=[O:9])(=[O:10])[N:4]([CH3:11])[C:3]=1[C:12]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:14]
Reactant: Nc1ccccn1
Reactant: COC(=O)C1=C(O)CN(C)S(=O)(=O)N1C
Product: CN1CC(O)=C(C(=O)Nc2ccccn2)N(C)S1(=O)=O
Yield: 55 %

Procedure:
The synthesis was effected analogously to Example 1 using in each case 1.0 equivalent of methyl 5,6-dihydro-4-hydroxy-2,6-dimethyl-1,1-dioxo-2H-1,2,6-thiadiazine-3-carboxylate and 2-aminopyridine. Recrystallisation from a diisopropyl ether/tetrahydrofuran mixture gives the title compound in a yield of 55%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].C[Li].C([Li])(C)(C)C.CN(C)[CH:32]=[O:33]>O1CCCC1>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([CH:32]=[O:33])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (3.25 g, Example 23a) in anhydrous tetrahydrofuran (150 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of methyllithium (1.4M in diethyl ether, 6.1 ml) was added over 2 min. The mixture was stirred at −78° C. for 10 min, then a solution tert-butyllithium (1.7M in pentane, 10.0 ml) was added dropwise. The mixture was stirred at −78° C. for a further 10 min, then dimethylformamide (1.0 ml) was added. The resulting solution was stirred at −78° C. for 30 min., quenched with saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the subtitle compound as a solid (2.76 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.C([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(OC(C)(C)C)=O.CCN(CC)CC>CCO>[CH:9]1([C:4]2[CH:5]=[C:6]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1nc(Cl)cc(C2CCCC2)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(C2CCCC2)cc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 18.1 %

Procedure:
A solution of crude 2-amino-4-chloro-6-cyclopentylpyrimidine (150 mg, 0.76 mmol), N-BOC piperazine (184 mg, 0.99 mmol) and Et3N (210 uL, 1.5 mmol) in EtOH (2 mL) was heated at 70° C. for 16 h. The reaction was cooled to rt and concentrated and the crude residue purified (2 M NH3 in MeOH/CH2Cl2) to yield a white solid (34 mg, 11%). MS (ESI): mass calcd. for C18H29N5O2, 347.2; m/z found, 348.3 [M+H]+. 1H NMR (MeOD): 6.01 (s, 1H), 3.66-3.58 (m, 4H), 3.53-3.43 (m, 4H), 3.33 (td, J=3.3, 1.6, 1H), 2.90-2.75 (m, 1H), 2.05-1.90 (m, 2H), 1.87-1.77 (m, 2H), 1.77-1.62 (m, 4H), 1.53-1.46 (m, 9H).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>O.C(O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]([C:10]2[S:4][C:3]([NH2:5])=[N:2][N:1]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: NNC(N)=S
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CCO
Product: Nc1nnc(-c2cccc(Br)c2)s1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
To a solution of thiosemicarbazide (0.493 g, 5.40 mmol, 1.0 equiv) in 6 mL of water at 70° C. is added a solution of 3-bromobenzaldehyde (0.633 ml, 5.40 mmol, 1.0 equiv) in 4.5 mL ethanol. After the precipitate is formed, iron(III) chloride hexahydrate (2.92 g, 10.81 mmol, 2.0 equiv) in 6 mL water is added and the mixture is stirred for 2.5 h at 85° C. Upon completion, the mixture is allowed to cool to room temperature and the resulting precipitate is collected by filtration and taken up in 12 mL pyridine. Ice water is then added to the pyridine slurry. The mixture is cooled then filtered to give 5-(3-bromophenyl)-1,3,4-thiadiazol-2-amine (553 mg, 39.9% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85-7.88 (m, 1H), 7.67 (d, J=8.22 Hz, 1H), 7.53-7.59 (m, 1H), 7.45 (s, 2H), 7.36 (t, J=8.02 Hz, 1H);
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7]>CO.[Pd]>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C=Cc1ccccc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccccc1F

Procedure:
17.8 gm of the compound prepared in (1) above was dissolved in 200 ml of methanol. The mixture was catalytically hydrogenated using 6 gm of 10% palladium-on-carbon as a catalyst. After the removal of the catalyst by filtration and the solvent was evaporated to produce 14.7 gm of the title compound.