Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:24]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1>>[C:24]1([O:18][CH2:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:19]([CH3:21])[CH3:20])[N:12]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1=CCCCCCCCCCC1
Product: CC(C)c1nc(CCOC2=CCCCCCCCCCC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 82 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the enol ether with 1-methoxycyclododecene (982 mg, 5 mmol) in the same manner as the example 41 to give the compound 49 (418 mg, 82%). Mp 96-102° C. PMR (CDCl3 -0.1% d5 -Py): δH1.24 (6 H, d, J 7 Hz, (CH3)2C), 3.11 (2 H, t, J 6.2 Hz, CH2 -Im), 3.10 (1 H, m, (CH3)2CH), 3.51 (3 H, s, NCH3), 3.96 (2 H, t, J 6.2 Hz, OCH2), 4.36 (1 H, t, J 7.8 Hz, =CH), 6.80 (2 H, d, J 1.6 Hz, arom-H), 7.10 (1 H, t-like, arom-H). IR(KBr)cm-1 : 3434, 3057, 1702, 1662, 1566, 1558, 1469, 1409, 1378, 1235, 1130. Elementary analysis (for C27H38N2Ocl2S) Calcd. : C, 63.64% H, 7.52% N, 5.50% S, 6.29% Cl, 13.91% Found: C, 64.48% H, 7.69% N, 5.10% S, 6.03% Cl, 12.85%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Al].Cl[CH:11](Cl)[CH2:12][Si:13]([Cl:16])([Cl:15])[Cl:14]>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:11]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[Cl:8])[CH2:12][Si:13]([Cl:16])([Cl:15])[Cl:14]
Reactant: ClC(Cl)C[Si](Cl)(Cl)Cl
Reactant: Clc1ccc(Cl)cc1
Agent: [Al]
Solvent: CCCCCC
Product: Clc1ccc(Cl)c(C(C[Si](Cl)(Cl)Cl)c2cc(Cl)ccc2Cl)c1
Yield: 34.3 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 14.70 g (100 mmol) of 1,4-dichlorobenzene and 0.027 g (1.0 mmol) of aluminum foil were alkylated with 4.98 g (21.4 mmol) of (2,2-dichloroethyl)trichlorosilane for 1 hour at 80° C. Freshly distilled hexane (50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, the reaction products were vacuum distilled to give 3.33 g of [2,2-bis(2,5-dichlorophenyl)ethyl]trichlorosilane (bp; 161-163° C./1 torr, yield; 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:37][O:36][C:34](=[O:35])/[CH:33]=[CH:7]/[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OC)c([N+](=O)[O-])c1
Yield: 25.7 %

Procedure:
A mixture of 4-methoxy-3-nitrobenzaldehyde (1.5 g, 8.2 mmol) and methyl (triphenylphosphoranylidene)acetate (4.4 g, 13 mmol) in tetrahydrofuran (30 mL) was heated at reflux overnight. The reaction mixture was cooled and evaporated under reduced pressure; the crude residue was purified by flash chromatography (acetone/hexane, 20/80) to afford 0.5 g of (E)-3-(4-methoxy-3-nitro-phenyl)-acrylic acid methyl ester.
Reaction SMILES: C(C1[C:16]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=2)=[N:15]C2[C@H]3N(C(=O)C=2C=1C1C=CC(C(NCC2OC=CC=2)=O)=CC=1)CCC3)(=O)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:57][C:56]3[N:55]=[C:54]4[C@H:58]5[N:62]([C:63](=[O:64])[C:53]4=[C:52]([C:65]4[CH:73]=[CH:72][C:68]([C:69](O)=[O:70])=[CH:67][CH:66]=4)[C:51]=3[C:50](=[O:74])[CH2:49]2)[CH2:61][CH2:60][CH2:59]5)=[CH:44][CH:43]=1.FC1C=CC(C2CC(=O)CC(=O)C2)=CC=1.C(OC(N1CCCC1C(=O)/C(/C(OCC)=O)=C/C1C=CC(C(O)=O)=CC=1)=O)(C)(C)C>>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:57][C:56]3[N:55]=[C:54]4[C@H:58]5[N:62]([C:63](=[O:64])[C:53]4=[C:52]([C:65]4[CH:73]=[CH:72][C:68]([C:69]([NH:15][C@H:16]6[C:20]7[C:19](=[CH:24][CH:23]=[CH:22][CH:21]=7)[CH2:18][CH2:17]6)=[O:70])=[CH:67][CH:66]=4)[C:51]=3[C:50](=[O:74])[CH2:49]2)[CH2:61][CH2:60][CH2:59]5)=[CH:44][CH:43]=1
Reactant: CC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)C(=O)N1CCC[C@@H]21
Reactant: O=C(O)c1ccc(-c2c3c(nc4c2C(=O)N2CCC[C@@H]42)CC(c2ccc(F)cc2)CC3=O)cc1
Agent: CCOC(=O)/C(=C\c1ccc(C(=O)O)cc1)C(=O)C1CCCN1C(=O)OC(C)(C)C
Agent: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Product: O=C(N[C@@H]1CCc2ccccc21)c1ccc(-c2c3c(nc4c2C(=O)N2CCC[C@@H]42)CC(c2ccc(F)cc2)CC3=O)cc1
Yield: 52 %

Procedure:
Using the synthetic method described earlier in the synthesis of 4-{(9aS)-3-acetyl-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl}-N-(2-furylmethyl)benzamide (Example 29), the title compound was prepared from 4-[(3aS)-6-(4-fluorophenyl)-8,10-dioxo-2,3,3a,5,6,7,8,10-octahydro-1H-pyrrolizino[1,2-b]quinolin-9-yl]benzoic acid (prepared using the enamine of 5-(4-fluorophenyl)-1,3-cyclohexanedione and Knoevenagel product 4-[(1Z)-3-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]-2-(ethoxy-carbonyl)-3-oxo-1-propenyl]benzoic acid). A portion of the crude material (100 mg) was chromatographed (silica gel/ethyl acetate) to give the title compound as a tan powder (52 mg, 52%). LCMS m/z 572 (MH+) 1H NMR (300 MHz, DMSO-d6) δ 7.90 (d, 2H), 7.40 (m, 2H), 7.10–7.35 (m, 6H), 7.10 (dd, 2H), 6.40 (d, 1H), 5.75 (m, 2H), 4.75 (d, 1H), 3.30–3.75 (m, 2H), 2.80–3.10 (m, 2H), 2.70 (m, 1H), 2.55 (m, 1H), 2.35 (m, 1H), 1.95 (m, 1H), 1.75 (m, 4H), 1.50 (m, 2H) ppm.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[OH:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35](Cl)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:19]=[C:20]([F:27])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>>[F:27][C:20]1[CH:19]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35]([O:14][C:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=3[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:17]=[C:16]([F:15])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: Cc1ccc(C2CCCCC2)c(O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C2CCCCC2)c(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 68.1 %

Procedure:
2-Cyclohexyl-5-methylphenol (28 mg, 0.15 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted using K2CO3 (50 mg, 0.36 mmol) as described above to give the title compound (40 mg, 71%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C([Li])CCC.CON(C)[C:21]([CH:23]1[CH2:26][CH:25]([O:27][C:28]2[C:33]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:32][C:31]([F:40])=[CH:30][N:29]=2)[CH2:24]1)=[O:22]>C1COCC1>[F:40][C:31]1[CH:32]=[C:33]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:28]([O:27][CH:25]2[CH2:26][CH:23]([C:21]([C:5]3[N:4]([CH2:3][O:2][CH3:1])[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[N:6]=3)=[O:22])[CH2:24]2)=[N:29][CH:30]=1
Reactant: COCn1cnc2ccccc21
Reactant: CON(C)C(=O)C1CC(Oc2ncc(F)cc2C2CCOCC2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1c(C(=O)C2CC(Oc3ncc(F)cc3C3CCOCC3)C2)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 1-(methoxymethyl)-1H-benzo[d]imidazole (1.5 g, 9.04 mmol) in THF (20 mL) at −78° C. was added butyllithium (2.5 M in hexane) (3.7 mL, 9.16 mmol). The solution was stirred at −78° C. for 30 min and a solution of 3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutanecarboxylic acid methoxy-methyl-amide (2.2 g, 6.87 mmol) in THF (20 mL) was added dropwise via cannula. The reaction mixture was stirred at −78° C. for 30 min and then warmed to RT and quenched with water. The reaction mixture was extracted with EtOAc (3×25 mL) and the organic phases were combined and washed with water (1×10 mL), brine (1×10 mL), dried over MgSO4, filtered, and concentrated to get a residue, which was purified by flash column chromatography on silica gel (10% to 60% EtOAc in hexanes) to give the product (1.2 g) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.[CH2:25](I)[CH2:26][CH2:27][CH3:28]>>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=2)=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCCCI
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Product: CCCCn1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccc1=O

Procedure:
The title compound was synthesized in a similar manner to Example 66 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and butyl iodide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH3:15])[C:9](=[O:16])[C:8]=2[CH:17]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH3:15])[CH:9]([OH:16])[C:8]=2[CH:17]=1)([O-:3])=[O:2]
Reactant: CC1C(=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1C(O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Reaction time: 2 h
Yield: 104.6 %

Procedure:
A suspension of 6-nitro-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (40 g, 0.170 mol) in methanol (400 ml) was treated with sodium borohydride (6.4 g, 0.170 mol) at room temperature. After stirring for two hours the solvent was evaporated under reduced pressure, and the residue treated with a mixture of water and dichloromethane. After stirring the organic phase was separated and evaporated under reduced pressure to give 42.2 g of 6-nitro-2,2,3-trimethyl-4-hydroxy-3,4-dihydro-2H-1-benzopyran, as an oil, 1H NMR (CDCl3): δ 1.05 (d, 3H), 1.4 (s, 3H), 1.45 (s, 3H), 2.0-2.2 (m, 2H), 4.4 and 4.9 (multiplets cis and trans, 1H), 6.85 (m, 1H), 8.05 (m, 1H), 8.4 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][N:6]2[C:7](=[O:10])[C:8]=1[I:9].[C:15]([O-:18])(=[O:17])[CH3:16].[K+].O>CN(C=O)C>[C:15]([O:18][CH2:2][C:3]1[N:4]=[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][N:6]2[C:7](=[O:10])[C:8]=1[I:9])(=[O:17])[CH3:16]
Reactant: O=c1c(I)c(CCl)nc2ccccn12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1nc2ccccn2c(=O)c1I
Temperature: 40 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A mixture of 20.0 g (62.4 mmol) of the product from Step 2 (12) and 9.2 g (93.6 mmol) of potassium acetate in 200 mL DMF was stirred at 40° C. under nitrogen for three hours. The reaction mixture was allowed to cool to ambient temperature and the addition of excess water to the reaction solution caused the product to precipitate out of solution. The product was filtered, washed with water (3×), and drying under reduced pressure at 40° C. overnight yielded 19.4 g (56.4 mmol, 90%) of (3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (13) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O-:20])([O-])=O.[K+].[K+].BrCCCO[C:28]1[CH:33]=[CH:32][C:31]([C:34]2(C=O)[CH:39]=[CH:38][CH:37]=[CH:36][CH2:35]2)=[CH:30][C:29]=1[O:42][CH3:43]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:2][CH2:3][CH2:4][O:8][C:30]4[C:29]([O:42][CH3:43])=[CH:28][CH:33]=[CH:32][C:31]=4[C:34]4[CH:35]=[CH:36][C:37]([CH:17]=[O:20])=[CH:38][CH:39]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCBr
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(-c2ccc(C=O)cc2)c1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 173.6 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (2.3 g) and 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone (3.47 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, the acetonitrile was concentrated and the mixture was extracted into dichloromethane (200 ml). The insolubles were filtered off and the solvent was evaporated to an oil. Purification was carried out by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 600 ml; 1% methanol:dichloromethane, 600 ml; 2% methanol: 98% dichloromethane, 600 ml). The fractions containing the pure product were combined and concentrated to give 4.24 g (87%) of an off-white solid. Recrystallization from ethanol (75 ml) gave 3.9 g of 1-[4-[3-[4-(6-fluoro-1,2-benziosoxazol-3- yl)- 1-piperidinyl]-propoxy]-3-methoxyphenyl]phenylmethanone as off-white crystals, m.p.=128°-130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:3]=1.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][Br:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>>[Br-:30].[CH3:1][C:2]1[N:3]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[N+:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:5]([CH3:7])[CH:6]=1
Reactant: CCCCCCCCCCCCCCn1nc(C)cc1C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: CCCCCCCCCCCCCC[n+]1c(C)cc(C)n1Cc1ccc([N+](=O)[O-])cc1
Product: [Br-]

Procedure:
Reaction of 3,5-dimethyl-1-tetradecyl-pyrazole with 4-nitrobenzyl bromide yields 3,5-dimethyl-2(4-nitrobenzyl)-1-tetradecyl-pyrazolium bromide; m.p. 159°-161° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10](O)[CH:11]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O.N12CCCN=C1CCCCC2.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Cl:19])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)nc2[nH]nc(C)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc(Cl)nc2[nH]nc(C)c12
Temperature: 110 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
6-Hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (30.0 g), phosphorous oxychloride (12.6 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (22.3 mL) were dissolved in toluene (550 mL) at 0° C. (ice bath), then stirred at 110° C. for 5 h, then cooled to r.t. The mixture was poured into a vigorously stirred solution of potassium acetate (39.9 g) in water (1 l). The aqueous solution was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was used for the next step without further purification. 28.6 g (88%) of the title compound were obtained.
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:10])([CH3:9])[CH3:8])(=O)=O.[Si:13]([O:30][CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:26]([Si:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[O:30][CH:31]1[CH2:36][CH2:35][C:34]([O:37][Si:7]([CH3:10])([CH3:9])[CH3:8])=[CH:33][CH2:32]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](OC1CCC(=O)CC1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CC=C(O[Si](C)(C)C)CC1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trimethylsilyl trifluoromethanesulfonate (45.0 g; 198.8 mmol) is dropped into a solution of known 4{[tert-butyl(diphenyl)silyl]oxy}cyclohexanone [Okamura, W. H.; Elnagar, H. Y.; Ruther, M.; Dobreff, S. J. Org. Chem. 1993, 58, 600] (58.4 g, 165.5 mmol) and triethylamine (55.4 mL; 397.6 mmol) in dichloromethane (500 mL) at −78° C. under an atmosphere of nitrogen. After one hour the reaction mixture is allowed to warm to 0° C. and quenched with saturated NaHCO3-solution (120 mL). The organic layer is separated, dried over MgSO4 and concentrated under reduced pressure. A 1:1-mixture of tert-BuOMe and hexane is added to the biphasic residue. The organic layer is separated, washed with saturated NaHCO3-solution and dried over MgSO4. The solvent is removed under reduced pressure to deliver 69.0 g of the title compound as colourless oil.
Reaction SMILES: [CH3:1][N:2]1[S:7][C:6]2[CH2:8][CH2:9][CH2:10][C:5]=2[C:3]1=[O:4].[C:11]([SH:15])([CH3:14])([CH3:13])[CH3:12].[Na]>CO>[C:11]([S:15][S:7][C:6]1[CH2:8][CH2:9][CH2:10][C:5]=1[C:3]([NH:2][CH3:1])=[O:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cn1sc2c(c1=O)CCC2
Reactant: CC(C)(C)S
Agent: [Na]
Solvent: CO
Product: CNC(=O)C1=C(SSC(C)(C)C)CCC1

Procedure:
2-methyl-4,5-trimethylene-4-isothiazolin-3-one (0.78 parts) and sodium tertiary butyl mercaptan (0.56 parts) were stirred together in methanol (10 parts by volume) at 20° to 25° C. for 1 hour. The reactants were then drowned out into distilled water (100 parts by volume) and the disulphide reaction product (1 part) which separated was filtered and dried. The disulphide melted at 153°-5° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][CH2:68][CH2:69][CH2:70][N:71]1[CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:67][CH2:68][CH2:69][CH2:70][N:71]3[CH2:75][CH2:74][CH2:73][CH2:72]3)=[O:17])[CH:12]=2)[CH:6]=1
Reactant: NCCCN1CCCC1
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCCN5CCCC5)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (150 mg, 0.33 mmol) in 10 ml of anhydrous DMF were added HATU (152 mg, 0.40 mmol) and N,N-diisopropylethylamine (94 mg, 0.73 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)pyrrolidine (85 mg, 0.66 mmol), and stirring was continued for another 10 minutes. The mixture was poured into 50 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3-pyrrolidin-1-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 160 mg, 86%.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:5][N:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25](C(OCC)=O)[C:26]([O:28]CC)=[O:27])=[CH:21][CH:20]=2)[CH2:3]1.[OH-].[Na+]>O1CCOCC1>[CH3:1][C@@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:6][CH2:5][N:4]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:23][CH:24]=2)[CH2:3]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(CN2CCN(C(=O)OCc3ccccc3)[C@@H](C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1CN(Cc2ccc(CC(=O)O)cc2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of D7 (761 mg, 1.58 mmol), 2M NaOH solution (6 ml) and 1,4-dioxane (6 ml) was stirred at room temperature for 2 h. The solvents were removed and the residue dissolved in water and the pH adjusted to 4 with 2M HCl. The product was extracted with EtOAc and the combined extracts were dried and concentrated. The product was refluxed in toluene (˜20 ml) for 2 h and the solvent was evaporated to give the title compound as a yellow foam (505 mg). MS (ES): MH+ 383, (M−H)− 381.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].[CH:12]([NH:15][CH3:16])([CH3:14])[CH3:13]>O>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([N:15]([CH:12]([CH3:14])[CH3:13])[CH3:16])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CNC(C)C
Solvent: O
Product: CC(C)N(C)c1cc(C(=O)O)cc(Cl)n1
Temperature: 80 °C
Reaction time: 240 h
Yield: 67.6 %

Procedure:
A mixture of 2,6-dichloro-isonicotinic acid (572 mg, 2.98 mmol) in isopropyl-methylamine (2.18 g, 29.8 mmol) is stirred at 80° C. for 10 days. The mixture is cooled to rt, diluted with water (50 mL), and extracted with diethyl ether (6×50 mL). The aq. phase is acidified and extracted with diethyl ether (3×50 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with a gradient of EA in heptane to give the title compound (461 mg) as a yellow powder; LC-MS: tR=0.92 min, [M+1]+=229.01; 1H NMR (CD3OD): δ 1.19 (d, J=6.7 Hz, 6H), 2.88 (s, 3H), 4.78-4.87 (m, 1H), 6.94 (s, 1H), 7.01 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N+:21]([C:24]1[C:25]([CH:35]=O)=[N:26][N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH:28]=1)([O-:23])=[O:22]>CO>[F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][C:5]2[N:19]=[C:35]([C:25]3[C:24]([N+:21]([O-:23])=[O:22])=[CH:28][N:27]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)[N:26]=3)[NH:20][C:4]=2[CH:3]=1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Reactant: Nc1cc(F)c(OCCCCN2CCCCC2)cc1N
Solvent: CO
Product: O=[N+]([O-])c1cn(C2CCCCO2)nc1-c1nc2cc(OCCCCN3CCCCC3)c(F)cc2[nH]1

Procedure:
A solution of 74 mg of 4-fluoro-5-(4-piperidin-1-ylbutoxy)benzene-1,2-diamine and 50.7 mg of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde in 4 mL of methanol is stirred at ambient temperature for 18 hours. After evaporation of the solvent under reduced pressure in a rotary evaporator, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-4 cartridge with a dichloromethane/methanol eluent of 100% to 82/18. 77 mg of 6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-5-(4-piperidin-1-ylbutoxy)-1H-benzimidazoleare isolated in the form of a yellow foam. 1H NMR (300 MHz, DMSO-d6, δ in ppm) for this batch, we observe a 60%-40% resolution of tautomers with: from 1.29 to 2.44 (m, 22H); 3.70 (m, 1H); 4.00 (m, 1H) 4.10 (t, J=6.0 Hz, 2H); 5.60 (dd, J=3.0 and 10.0 Hz, 1H); 7.21 (d, J=8.5 Hz, 0.6H); from 7.36 to 7.46 (m, 0.8H); 7.53 (d, J=11.0 Hz, 0.6H); 9.17 (s, 1H); 12.8 (broad s, 0.6H); 12.9 (broad s, 0.4H).
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N+]([O-])=O)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1.[N+](C1C=CC=C([N+]([O-])=O)C=1)([O-])=O>>[Cl:1][C:6]1[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=[C:4]([Cl:3])[CH:5]=1
Reactant: ClCl
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Agent: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1

Procedure:
A process as claimed in claim 4, which further comprises continuously introducing chlorine with a mixture of 5-chloro-1,3-dinitrobenzene and m-dinitrobenzene to the reaction at a constant rate and distilling of 1,3,5-trichlorobenzene and m-dichlorobenzene.