Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:32]=1[C:31](=[O:34])[C:30]1[CH:35]=[CH:36][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:28][CH:29]=1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Product: COC(=O)Cc1c(C(=O)c2ccc(OC(F)(F)F)cc2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans 5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 4-(trifluoromethoxy)phenacyl bromide (Preparation is described in Example 189).
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[CH3:8][C:9]1([CH3:57])[O:13][C:12]2[C:14]([C:23]([C:41]3[C:51]4[O:52][C:53]([CH3:56])([CH3:55])[O:54][C:50]=4[CH:49]=[C:43]4[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=34)([C:25]3[C:35]4[O:36][C:37]([CH3:40])([CH3:39])[O:38][C:34]=4[CH:33]=[C:27]4[O:28][C:29]([CH3:32])([CH3:31])[O:30][C:26]=34)O)=[C:15]3[O:19][C:18]([CH3:21])([CH3:20])[O:17][C:16]3=[CH:22][C:11]=2[O:10]1.[Al].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[CH3:39][C:37]1([CH3:40])[O:36][C:35]2[C:25]([CH:23]([C:14]3[C:12]4[O:13][C:9]([CH3:57])([CH3:8])[O:10][C:11]=4[CH:22]=[C:16]4[O:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=34)[C:41]3[C:42]4[O:46][C:45]([CH3:47])([CH3:48])[O:44][C:43]=4[CH:49]=[C:50]4[O:54][C:53]([CH3:55])([CH3:56])[O:52][C:51]=34)=[C:26]3[O:30][C:29]([CH3:31])([CH3:32])[O:28][C:27]3=[CH:33][C:34]=2[O:38]1
Reactant: CC1(C)Oc2cc3c(c(C(O)(c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c2O1)OC(C)(C)O3
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [Al]
Solvent: CC#N
Product: CC1(C)Oc2cc3c(c(C(c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c2O1)OC(C)(C)O3
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Trimethylsilyl chloride (68.1 mL, 539 mmol) and sodium iodide (81.0 g, 540 mmol) were mixed in acetonitrile (500 mL), and tris(2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)methanol (62.4 g, 90.2 mmol, Example 44) and was added with efficient stirring at room temperature. The reaction flask was surrounded with aluminum foil to prevent light to enter. After stirring for 24 h, the reaction mixture was poured into 2 L of a Na2S2O3 solution (70 g of Na2S2O3 ×5 H2O in 2 L of water). A yellow precipitate was formed, filtered off and was left to dry on the filter under suction (2 h). The product was triturated with i-PrOH twice, filtered and washed with cold diisopropyl ether (15 mL) to yield 54.1 g (88%) of the product tris(2,2,6,6-tetramethyl-benzo[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methane.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].N1C=CN=C1>CN(C=O)C>[C:1]([Si:5]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A 500 mL round bottom flask was charged with tert-butyldimethylchlorosilane (73.9 g, 491 mmol) (available from Aldrich), DMF (220 mL), 2-fluorophenol (41.3 mL, 446 mmol) (available from Aldrich), and imidazole (75.9 g, 1115 mmol). The pale yellow solution was stirred for 1.5 hours at 25° C. and diluted with hexanes (1 L). The organic phase was washed with water (1×300 mL), saturated aqueous NaHCO3 (3×300 mL), water (3×300 mL) and brine (1×300 mL). The organic phase was then dried (MgSO4), and concentrated to afford 84.A (101 g, 100% yield) as a colorless liquid. The crude product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=3)=[N:9][C:8]=2[N:7]([CH2:26][CH2:27][CH2:28][C:29]([NH:31][NH2:32])=[O:30])[C:6]1=[O:33].[C:38](Cl)(Cl)=[O:39]>>[F:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=3)=[N:9][C:8]=2[N:7]([CH2:26][CH2:27][CH2:28][C:29]2[O:30][C:38](=[O:39])[NH:32][N:31]=2)[C:6]1=[O:33]
Reactant: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCC(=O)NN)cc1
Reactant: O=C(Cl)Cl
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCc2n[nH]c(=O)o2)cc1

Procedure:
Prepared by reacting N-{4-[1-(2-fluorobenzyl)-3-(3-hydrazinocarbonyl-propyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-acetamide with phosgene according to the general procedure of Kramer et al. as described in J. Heterocyclic Chem. 1994,31, 1439. MS, m/z(M+H)=533.1821.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][O:8][C:9]=1[CH2:10][CH3:11])=[O:4].O[Li].O>C1COCC1.O>[CH2:10]([C:9]1[O:8][N:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[C:3]([OH:4])=[O:2])[CH3:11]
Reactant: CCc1onc(-c2ccccc2)c1C(=O)OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCc1onc(-c2ccccc2)c1C(=O)O
Yield: 85.6 %

Procedure:
8.0 g (34 mmol) of 5-Ethyl-3-phenyl-isoxazole-4-carboxylic acid methyl ester (prepared according to: Synthesis 2003; 1347-1356) was dissolved in 50 mL of THF, to which 7.2 g (170 mmol) LiOH.H2O in 25 ml of H2O was added in one portion. The reaction mixture was refluxed for 12 h. After evaporation of THF, the aqueous solution was acidified with 2N HCl to pH=2. After extraction with ethyl acetate (3×100 mL), the combined organic extracts were dried over Na2SO4 and evaporated to dryness to give 5-Ethyl-3-phenyl-isoxazole-4-carboxylic acid (6.32 g) in 72.3% yield as a red solid. (m/e): 216.2 (M−; 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:37]4[CH:36]=[CH:35][C:34]([C:32]([O:31][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[O:33])=[CH:39][CH:38]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-benzyloxycarbonyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. Mass spectrum (ESI+): m/z=513 [M+H]+.
Reaction SMILES: N.CC(O)C.ClC(C1C=CC(Cl)=CC=1)(C1N(C)C=NC=1)[C:8]1[CH:9]=[CH:10][C:11]2[N:17](C)[C:16](=[O:19])[CH2:15][N:14]=[C:13](C3C=CC=C(Cl)C=3)[C:12]=2[CH:27]=1>C1COCC1>[N:17]1[C:16](=[O:19])[CH:15]=[N:14][CH:13]=[C:12]2[CH:27]=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: CN1C(=O)CN=C(c2cccc(Cl)c2)c2cc(C(Cl)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Agent: N
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=c1cncc2ccccc2n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 151.7 %

Procedure:
NH3/2-propanol (40 ml) was added dropwise at 5° C. to a mixture of 7-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (described in Example B10a) (0.0075 mol) in THF (40 ml). The mixture was stirred at 5° C. for 30 min, hydrolyzed and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1 and 96/4/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetonitrile and diethyl ether. The precipitate was filtered off and dried, yielding 1.8 g (48%) of 2H-1,4-benzodiazepin-2-one, 7-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, mp. 213° C.
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:5]2=[C:6]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24](Cl)=[O:25].CO>ClCCl>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[N:7]=[CH:8][CH:9]=2)[NH:16][C:2]=1[CH3:1])=[O:25]
Reactant: Cc1cc2ccnc(NC(=O)C3CC3)c2[nH]1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: Cc1[nH]c2c(NC(=O)C3CC3)nccc2c1C(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
N-(2-Methyl-1H-pyrrolo[2,3-c]pyridin-7yl)cyclopropanecarboxamide (100 mg, 0.46 mmol) was added to a stirred suspension of aluminium chloride (620 mg, 4.65 mmol) in dry dichloromethane (5 mL) and the mixture was stirred at room temperature for about 1 hour under argon atmosphere. This was followed by drop wise addition of a solution of 2,6-dichlorobenzoyl chloride (194 mg, 0.93 mmol) in dichloromethane and stirring overnight at room temperature. After completion, methanol (10 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The residual mass was diluted with water and extracted with ethyl acetate. The combined organic layer was neutralized using aq. sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-[3-(2,6-dichlorobenzoyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (70 mg, 39%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[C:17]([CH2:19][N:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][C:21]1=[O:30])#[N:18].[OH-].[Na+]>O>[C:17]([CH2:19][N:20]1[C:25]2[CH:26]=[C:27]([N+:1]([O-:4])=[O:2])[CH:28]=[CH:29][C:24]=2[O:23][CH2:22][C:21]1=[O:30])#[N:18]
Reactant: O=[N+]([O-])O
Reactant: N#CCN1C(=O)COc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Fuming (α 1.52) nitric acid (1.3 ml) is added dropwise to 0° C. to acetic anhydride (11.3 g), and thereafter a catalytic amount of concentrated sulfuric acid is added. To the solution is added portionwise at 0° C. 4-cyanomethyl-2H-1,4-benzoxazin-3(4H)-one (1.88 g). The mixture is stirred at 0° C. for 20 minutes, treated dropwise with a cold solution which is made by dissolving sodium hydroxide (10 g) in water (87.5 ml) and cooled to 0° C., stirred at 0° C. for 30 minutes to finish the reaction, and extracted with methyl isobutyl kotone. The extract is washed with water, dried, and evaporated. The resultant solid is recrystallized from ethanol to obtain an end product 4-cyanomethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (1.3 g). mp. 173° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10](Cl)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCCCNCCCC
Product: CCCCCCCCN(CCCC)CCCC

Procedure:
N,N-dibutyloctylamine was prepared from dibutylamine and octanoyl chloride by a method similar to that in Example 14.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[C:12]([CH3:26])[C:13]([NH:16][NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[CH3:25])=O)=[N:14][CH:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:9][C:10]1[CH:11]=[C:12]([CH3:26])[C:13]2[N:14]([C:18]([C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH3:25])=[N:17][N:16]=2)[CH:15]=1
Reactant: Cc1cc(F)cnc1NNC(=O)[C@@H]1CCCN1C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(F)cn2c([C@@H]3CCCN3C)nnc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Hexachloroethane (141 mg, 0.587 mmol) was added portionwise at RT to a stirred mixture of Intermediate 105c (74 mg, 0.293 mmol), triethylamine (166 μL, 1.17 mmol) and triphenylphosphine (154 mg, 0.587 mmol) in THF (5 mL). The reaction mixture was stirred at 80° C. for 2 h, then cooled to RT and filtered. The filtrate was concentrated in vacuo and the resultant residue was purified by SCX cartridge. The cartridge was washed with 10% MeOH in DCM and the product eluted with 10% (2M NH3 in MeOH) in DCM. The product containing fractions were concentrated in vacuo and the resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM, to afford the title compound (59 mg, 86%) as a colourless oil. 1H NMR (400 MHz, CDCl3): 1.88-2.12 (3H, m), 2.15-2.53 (5H, m), 2.69 (3H, s), 3.28 (1H, t, J=7.8 Hz), 4.01-4.15 (1H, m), 6.97 (1H, d, J=8.4 Hz), 8.50 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[C:13]=2[Cl:20])[CH2:7][CH2:6]1.[CH3:22][C:23]1[NH:27][N:26]=[N:25][C:24]=1[C:28](O)=[O:29]>>[Cl:20][C:13]1[C:14]([CH3:19])=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:21])[CH2:2][NH:1][C:28]([C:24]2[N:25]=[N:26][NH:27][C:23]=2[CH3:22])=[O:29])[CH2:6][CH2:7]1
Reactant: Cc1[nH]nnc1C(=O)O
Reactant: Cc1c(Cl)ccc(OC2CCN(C[C@H](O)CN)CC2)c1Cl
Product: Cc1[nH]nnc1C(=O)NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(C)c2Cl)CC1

Procedure:
Prepared as Example 1 using (2R)-1-amino-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl]propan-2-ol (0.158 g) and 5-methyl-1H-1,2,3-triazole-4-carboxylic acid to yield the title compound as a colourless solid (0.037 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>C1COCC1.CO>[CH3:21][O:20][C:17]1[N:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(N2CCC(N)CC2)nn1
Temperature: 60 °C
Yield: 140 %

Procedure:
[1-(6-Methoxy-pyridazin-3-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.37, 1.2 mmol) was dissolved in THF:MeOH 9:1 (15 ml) and HCl in 1,4-dioxane (4M, 1.2 ml, 4.8 mmol) was added. The reaction mixture was heated to 60° C. with for 3 h. The solvent was evaporated to yield the title compound (0.35 g, 100%) as the dihydrochloric salt. 1H-NMR (CD3OD, 500 MHz): δ 8.04 (d, 1H), 7.57 (d, 1H), 4.34-4.26 (m, 2H), 4.00 (s, 3H), 3.62-3.55 (m, 1H), 3.50-3.40 (m, 2H), 2.30-2.23 (m, 2H), 1.90-1.79 (m, 2H); 13C-NMR (CD3OD, 125 MHz): δ 159.7, 152.1, 129.8, 127.0, 62.1, 55.9, 46.2, 45,9, 45.7, 30.9, 30.3, 30.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12]([C:14]2[N:15]=[C:16]3[C:22]([CH:23]=[O:24])=[CH:21][N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:17]3=[N:18][CH:19]=2)[N:11]=[CH:10]1.S(=O)(=O)([OH:35])N.Cl([O-])=O.[Na+].OP([O-])(O)=O.[K+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12]([C:14]2[N:15]=[C:16]3[C:22]([C:23]([OH:35])=[O:24])=[CH:21][N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:17]3=[N:18][CH:19]=2)[N:11]=[CH:10]1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3cn(-c4cc(F)ccc4F)cn3)cnc21
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3cn(-c4cc(F)ccc4F)cn3)cnc21
Reaction time: 1.25 h
Yield: 74.8 %

Procedure:
A mixture of 2-[1-(2,5-difluoro-phenyl)-1H-imidazol-4-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.087 g, 0.19 mmol) and sulfamic acid (0.127 g, 1.30 mmol) in 2 mL of 1,4-dioxane and 0.2 mL of water was treated dropwise with a mixture of sodium chlorite (0.031 g, 0.27 mmol) and KH2PO4 (0.335 g, 2.46 mmol)) in 1 mL of water, rinsing with 1 mL of water. The pale yellow solution was stirred 1.25 h as a white precipitate formed. The mixture was partitioned between 10 mL of water and 10 mL of ethyl acetate. The organic layer was washed with 10 mL of a sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated to afford 0.067 g (74%) of 2-[1-(2,5-difluoro-phenyl)-1H-imidazol-4-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a pale yellow solid, which was used without further purification. MS: (M+H)+=472.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([N:29]2[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]2)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: O=C(O)C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(C(=O)O)C2)no1
Temperature: 95 °C
Yield: 54.5 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (790 mg, 2.00 mmol) in dimethylsulphoxide (25 ml) was treated with 3-azetidine carboxylic acid (505 mg, 5.00 mmol) and potassium carbonate (690 mg, 5.00 mmol) and the resulting mixture was heated at 95° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the mixture treated with hydrochloric acid (1M, 25 ml) then diluted further with water (25 ml) and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (90:10) to afford the title compound as a pale yellow oil (490 mg).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][CH3:15])[NH:10][C:9](=[O:16])[C:8]=1[C:17]#[N:18]>[Pd].C(O)(=O)C.[Pt]=O>[NH2:18][CH2:17][C:8]1[C:9](=[O:16])[NH:10][C:11]([CH2:13][CH2:14][CH3:15])=[CH:12][C:7]=1[CH3:6]
Reactant: CCCc1cc(C)c(C#N)c(=O)[nH]1
Agent: O=[Pt]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCCc1cc(C)c(CN)c(=O)[nH]1
Reaction time: 12 h

Procedure:
Sodium acetate (3.5 g, 42.6 mmol), palladium on carbon (0.81 g) and platinum oxide (0.1 g) were placed in a dried Parr bottle flushed with nitrogen, followed by addition of a small amount of acetic acid (to wet the catalysts). A solution of 4-methyl-2-oxo-6-propyl-1,2-dihydro-pyridine-3-carbonitrile (5 g, 28 mmol) in acetic acid was added to the Parr bottle followed by additional acetic acid (200 mL). The vessel was capped, placed on Parr apparatus and hydrogenated at 45 psi for 12 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude product was purified by preparative HPLC to afford the title compound (TFA salt) as 4.1 g. LCMS E-S (M+H))=181.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.8-11.9 (br s, 1H), 7.83-7.88 (br s, 3H), 5.99 (s, 1H), 3.77-3.81 (m, 2H), 2.37 (t, 2H), 1.53 (m, 2H), 0.83 (t, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:24])[C:5](=[N:10][NH:11][C:12]1[C:22]([F:23])=[CH:21][C:15]2[O:16][C:17]([F:20])([F:19])[O:18][C:14]=2[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:25]OC(OC)N(C)C>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[O:16][C:17]([F:20])([F:19])[O:18][C:14]=3[CH:13]=2)[CH:25]=1
Reactant: COCC(=O)C(=NNc1cc2c(cc1F)OC(F)(F)O2)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2cc3c(cc2F)OC(F)(F)O3)cc(OC)c1=O
Yield: 24 %

Procedure:
A mixture of methyl 4-methoxy-3-oxo-2-[(2,2,6-trifluoro-1,3-benzodioxol-5-yl)hydrazono]butanoate (6.31 g, 18.1 mmol) in N,N-dimethylformamide dimethyl acetal (63 mL) was heated to reflux for 2.5 h. The mixture was concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 70/30) and on basic silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (1.53 g, 24% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.79 (3H, s), 3.82 (3H, s), 7.94 (1H, d, J=9.4 Hz), 8.04 (1H, d, J=6.4 Hz), 8.54 (1H, s).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH4+].[OH-:22]>C(O)C>[NH2:9][C:4]1[C:3]([CH:2]=[O:22])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ncccc1C(Br)Br
Reactant: [OH-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ncccc1C=O
Temperature: 4 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
The compound was prepared according to the procedure as described by A. E. Moormann et al, Synthetic Communications, 17(14), 1695-1699 (1987) To a solution of 2-[3-(dibromomethyl)-2-pyridinyl]-1H-isoindole-1,3(2H)-dione (20 g, 50 mmol) in ethanol (250 ml) was added conc. NH4OH (25 ml) at 4° C. The reaction mixture was stirred 10 minutes at 4° C. then stirred at room temperature for one hour. Reaction mixture was concentrated under reduced pressure. To the concentrated residue was added con. HCl (150 ml) and mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and concentrated. To the concentrated residue was added water (25 ml) then added saturated K2CO3 to neutralize the solution. The solution was extracted with methylenechloride (3×150 ml). Combined organic solution was washed with water (3×150 ml), brine (1×200 ml), dried over Na2SO4, concentrated. The concentrated residue was suspended in ether, filtered and washed with ether to give 4.3 g (70%) yellow solid. NMR (DMSO) δ 6.69-6.73 (m, 1H), 7.51 (bs, 2H), 7.95-7.98(m, 1H), 8.20-8.22 (m, 1H), 9.82 (s, 1H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([O:33][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Oc1cccc(Cl)c1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2cnc(Oc3cccc(Cl)c3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 3-chlorophenol according to the procedure described in Example 74 to afford 2-(3-chlorophenyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=461 (M++1); Rt=4.72 min; 1H-NMR 400 MHz (CDCl3): δ 7.00-7.12. (m, 2H), 7.11-7.18 (m, 2H), 7.20-7.30 (m, 7H), 8.60 (s, 1H).