Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Si:4]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[N:16]3[CH:17]=[C:18]([O:21][C@H:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C@@H:25]([NH2:32])[CH2:24][CH2:23]4)[CH:19]=[CH:20][C:15]3=[N:14][N:13]=2)[CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:32][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([N:9]5[CH2:8][CH2:7][CH:6]([O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[C@@H:10]5[CH3:11])=[N:13][N:14]=4)[CH:17]=3)[CH2:23][CH2:24]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(O[Si](C(C)C)(C(C)C)C(C)C)[C@@H]5C)n4c3)c3ccccc32)cc1
Yield: 79 %

Procedure:
A solution of Intermediate 92c (210 mg, 0.39 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 159 mg, 0.390 mmol) in 1,4-dioxane (4 mL) and DIPEA (105 μL, 0.600 mmol) was stirred at 65° C. for 15.5 h and at 90° C. for 1.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a pale brown solid (242 mg, 79%). LCMS (Method 3): Rt 5.18 min, m/z 791 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]([NH2:32])[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:32][CH2:26][C:27]4[O:31][CH:30]=[CH:29][CH:28]=4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NCc1ccco1
Product: O=C(NCc1ccco1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and furfurylamine employing methods similar to those described in Example 2 and was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 11.85 (1H, br), 10.70 (1H, br), 8.39 (1H, br s), 7.61 (1H, s), 7.40 (1H, s), 7.31 (2H, m), 7.15 (2H, t, J=8.5 Hz), 6.42 (1H, s), 6.33 (1H, s), 4.54 (2H, s), 4.08 (2H, s); HRMS calcd for C21H16FN3O4+H+: 394.1202. Found: 394.1195.
Reaction SMILES: C(O[CH2:5][C:6]1[N:7]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[C:8]2[C:13]([C:14]=1[C:15](=[O:19])[C:16]([OH:18])=[O:17])=[CH:12][C:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:10][CH:9]=2)(=O)C.[OH-].[K+].Cl>>[CH2:21]([O:20][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([CH3:36])([CH3:38])[CH3:37])=[CH:33][CH:34]=1)[C:6]1[CH2:5][O:18][C:16](=[O:17])[C:15](=[O:19])[C:14]2=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)OCc1c(C(=O)C(=O)O)c2cc(OCc3ccccc3)ccc2n1Cc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(Cn2c3c(c4cc(OCc5ccccc5)ccc42)C(=O)C(=O)OC3)cc1

Procedure:
The title compound was prepared from [2-[(acetyloxy)methyl]-5-(benzyloxy)-1-(4-tert-butylbenzyl)-1H-indol-3-yl](oxo)acetic acid and aqueous potassium hydroxide in substantially the same manner, as described in step 6 of Example 1, followed by the treatment with aqueous HCl, as described in step 7 of Example 1. The product was obtained as an off-white solid; mp: 233-234° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1H NMR (400 MHz, DMSO-d6) δ 7.59-7.56 (m, 2H), 7.47 (d, 1H, J=7.33 Hz), 7.39 (t, 2H, J=7.33 Hz), 7.35-7.30 (m, 3H), 7.15 (d, 2H, J=8.40 Hz), 7.07 (dd, 1H, J=9.05 and 2.45 Hz), 5.87 (s, 2H), 5.42 (s, 2H), 5.16 (s, 2H), and 1.22 ppm (s, 9H).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[CH2:27](Br)[C:28]#[CH:29].C1(C)C=CC=CC=1>C(OCC)(=O)C.CN(C)P(=O)(N(C)C)N(C)C>[C:1]1([N:7]([C:27]#[C:28][CH3:29])[NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Reactant: C#CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CC#CN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Reaction time: 21 h

Procedure:
In a three necked 1 liter round bottom reaction vessel equipped with a mechanical stirrer and reflux condenser were placed 97.5 g (0.3 mol) of the compound of Example 8 and 200 ml of hexamethylphosphoric-triamide. The mixture was heating with stirring under nitrogen at 80°-90° C. till the solid dissolved. To this solution was added with stirring 252 g (3 mol) sodium bicarbonate powder. Over a period of about 0.5 hour 29.4 ml of an 80% w/w solution of propargyl bromide in toluene (0.315 mol propargyl bromide) were added with stirring. After the reaction had run for 21 hours an additional 4 ml of the propargyl bromide solution in toluene (0.043 mol propargyl bromide) was added and the reaction continued for an additional 68 hours. The reaction mixture was then cooled and diluted with 1 liter of ethyl acetate. The mixture was transferred to a separatory funnel, cross-washed with water/brine, then with a 2 molor aqueous citric acid and again with brine. The organic layer was dried over anhydrous magnesium sulfate, clarified and evaporated to yield 108 g of a dark oil which was purified by chromatography over silica gel to yield a solid which was recrystallized from ethyl acetate/hexane. M.p. 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([NH:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C@@H:30]([NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[CH:36][CH:37]=1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 95.1 %

Procedure:
Preparation of example 150 from the title compound of Example 7 (hydrochloride) (44 mg, 0.144 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(4-hydroxyphenyl)propanoic acid (46 mg, 0.173 mmol), triethylamine (0.060 mL, 0.43 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (66 mg, 0.173 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (74 mg, 0.137 mmol) as a yellow powder in 95% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[F:32].[C:33]([O:37][C:38]([NH:40][S:41](N1C=CC(=[N+](C)C)C=C1)(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>ClCCl>[F:32][C:4]1[CH:5]=[C:6]([CH:9]([CH3:31])[C:10](=[O:11])[NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])(=[O:42])=[O:43]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(F)c2)c1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)c(F)c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-(4-(Aminomethyl)-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide and intermediate (A) are dissolved in dichloromethane, dropwise triethylamine (0.1 equiv.). The reaction is stirred for 15 h at room temperature and quenched with water. The organic layer is extracted by dichloromethane and concentrated. After purification, tert-butyl N-(2-fluoro-4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamate is obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.C([O:11][C@@H:12]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@H:13]1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]Br)[CH:32]=1)(=O)C.C[O-].[Na+]>CN(C)C=O.O1CCCC1.CO>[N:3]1([CH2:37][C:33]2[CH:32]=[C:31]([C@@H:13]3[O:14][C@H:15]([CH2:26][OH:27])[C@@H:16]([OH:22])[C@H:17]([OH:18])[C@H:12]3[OH:11])[CH:36]=[CH:35][CH:34]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: c1cc[nH]c1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2cccc(Cn3cccc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
Sodium hydride (42 mg) was added to a solution of pyrrole (64 mg) in dimethylformamide (10 ml) under cooling with ice, and the mixture was stirred for half an hour at room temperature. After the mixture was cooled to −30° C., a solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(bromomethyl)phenyl]-D-glucitol (80 mg) in tetrahydrofuran (2 ml) was added dropwise thereto, and the resultant was stirred for one hour at room temperature. Methanol (10 ml) and sodium methoxide (44 mg) was added thereto, and the resultant was stirred for one hour at the same temperature. After the completion of the reaction, the reaction mixture was concentrated to give the residue. The resulting residue was purified by a reversed-phase column chromatography (water-methanol) to obtain (1S)-1,5-anhydro-1-[3-(1H-pyrrole-1-ylmethyl)-phenyl]-D-glucitol (18 mg).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a stirring solution of (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) (112 mg, 0.25 mmol) in DMF (2 mL) was added NEt3 (70 μl, 0.5 mmol), and methanesulfonyl chloride (21 μL, 0.275 mmol). Reaction was stirred at room temp overnight. The reaction mixture was concentrated in vacuo before partitioning between DCM (10 ml) and water (10 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at high pH to afford the compound title compound as a light brown solid (30 mg, 0.06 mmol, 24%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[CH2:12][N:11]=2)=[CH:6][C:5]=1[Cl:27].CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2([C:15]([F:17])([F:18])[F:16])[CH2:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[C:5]([Cl:27])[CH:6]=3)[CH2:14]2)[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: COC(=O)c1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: O=Cc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Yield: 25.2 %

Procedure:
To a solution of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-chloro-benzoic acid methyl ester (807 mg, 1.79 mmol) in CH2Cl2 (100 mL) was added a solution of DIBAL (1.97 mL, 1 M in CH2Cl2, 1.97 mmol) with a syringe pump at −75° C. The mixture was stirred for 25 min at this temperature, before methanol (1 mL) was added and warmed to room temperature. Saturared aqueous Na/K-tartrate solution was added and the mixture was extracted three times with CH2Cl2. The organic layers were combined, dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (190 mg, 25%).
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)([OH:6])=[O:5].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>CO>[O:17]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:16]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([C:4]([OH:6])=[O:5])=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
Sodium methoxide (1.8 g, 33.3 mmol) was added to a stirred suspension of 4-carboxybenzaldehyde (2.5 g, 16.6 mmol) and acetophenone (2.0 g uL, 16.6 mmol) in methanol (50 mL) at room temperature. The mixture was stirred at room temperature for 16 hours, and half of the volume of methanol was removed under reduced pressure. The mixture was poured into HCl 1M (50 mL) (until pH=2) and ethyl acetate was added. The separated aqueous layer was extracted with ethyl acetate (3×30 mL) dried (MgSO4 anh.), filtered and evaporated. The residue was triturated with dichloromethane-hexanes (1:1) to afford 3 g of 43 (72% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:30])[NH:15][CH2:16][C:17]2[S:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[CH:20][CH:21]=2)=[C:10]([NH2:31])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N[C:34]1N=C(N)C=CC=1C(O)=O.CI.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:32])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:30])[NH:15][CH2:16][C:17]2[S:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[CH:20][CH:21]=2)=[C:10]([NH2:31])[N:9]=1)[CH3:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc(C(=O)O)c(N)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of (6-amino-5-((5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)-carbamoyl)-pyridine-2-yl)-carbamic acid tert-butyl ester described in Preparation Example A+-2 (125 mg, 0.27 mmol) and methyl iodide (43 mg, 0.29 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (12 mg, 0.29 mmol, 60% in oil) on an ice bath, and the solution was stirred for 1 hour at room temperature. NH silica gel was added to the reaction solution, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=4:1 then 2:1), and the title compound (87 mg, 0.19 mmol, 70.5%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][N:36]([C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 64.9 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.6 g (1.68 mmol) and piperidine-4-carboxylic acid ethyl ester (0.31 g, 2.02 mmol) were used to afford 0.54 g of the required product. 1H NMR (DMSO-d6): δ 1.18 (3H, t), 1.5 (2H, m), 1.82 (2H, m), 2.6 (1H, m), 2.90 (1H, m), 3.12 (1H, m), 3.52 (1H, m), 4.08 (2H, q), 4.25 (1H, m), 6.96 (2H, d), 7.06 (1H, t), 7.26 (4H, d), 7.88 (4H, d).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C@H:38]1[OH:50]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:39][C@H:38]4[OH:50])=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and tert-butyl (3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2) the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2)(=[O:3])[CH3:2]
Reactant: Nc1cccc2ncccc12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3ncccc23)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al., J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 60 mg (0.417 mmol) of 5-aminoquinoline was added. The resulting mixture was stirred at room temperature for four hours and the final product was collected by filtration and washed with diethylether to yield the title compound (80 mg, 74.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])C2C=CC=CC=2)=O)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:8]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(c1ccccc1)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Temperature: 25 °C
Yield: 69.5 %

Procedure:
To a suspension of 4-fluoro-N-(2-hydroxyphenyl)-3-nitrobenzanilide (see Working Example 15-1) (2.00 g, 7.24 mmol) in toluene (50 mL) was added p-toluenesulfonic acid monohydrate (2.07 g, 10.9 mmol), and this was stirred and heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, and after the solvent was distilled off, saturated aqueous sodium hydrogen carbonate solution was added and this was stirred for 10 minutes at room temperature. The precipitated crystals were filtered off, and after washing with toluene the crystals were dried to yield the title compound (1.30 g, 70% yield) as yellow crystals.
Reaction SMILES: Cl[Si](C)(C)[CH3:3].[CH3:6][CH:7](O)[CH2:8][CH2:9][CH:10]([N+:12]([O-:14])=[O:13])C.[I-:16].[Na+]>C(#N)C>[I:16][CH:10]([N+:12]([O-:14])=[O:13])[CH2:9][CH2:8][CH:7]([CH3:6])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: [I-]
Reactant: CC(O)CCC(C)[N+](=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)CCC(I)[N+](=O)[O-]
Temperature: 50 °C

Procedure:
A solution of 44.7 mL (352 mmol) chlorotrimethylsilane and 50 mL acetonitrile is added dropwise to 26.0 g (177 mmol) 1-methyl-4-nitro-pentan-1-ol and 52.8 g (352 mmol) sodium iodide in 350 mL acetonitrile. Then the mixture is heated to 50° C. for 4 hours, then the solvent is distilled off and the residue is combined with 500 mL diethyl ether. It is washed successively with water, sodium thiosulphate solution and sodium chloride solution. The organic phase is dried with sodium sulphate and evaporated down. 34.2 g of red oil.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12])[CH3:3].[CH3:13][O:14][N:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:13][O:14][N:15]1[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12]
Reactant: CCCCCC=NOC
Reactant: C=C(C)C1CCCCCCC1=O
Agent: CCCCCC1C/C(C)=C/CCCCCCC(=O)N1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCCCCC1CC(C)=CCCCCCCC(=O)N1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
An argon flushed three-necked flask which was cooled by an ice-water bath was charged with 2-(prop-1-en-2-yl)cyclooctanone (1.50 g, 9.02 mmol), hexanal O-methyl oxime (1.56 g, 13.53 mmol), and SnCl4 (2.35 g, 9.02 mmol) in 1,2-dichloroethane (90 ml). The mixture was stirred for 2 days at room temperature. The completion of reaction was checked by GC analysis of reaction aliquots quenched with a solution of saturated NaHCO3 in water. The reaction mixture was quenched with sat. aqueous NaHCO3 solution (50 mL). The organic phase was separated and the aqueous layer was extracted with MTBE three times. The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated in vacuo. The crude product was purified by distillation to give the title product as a yellow oily liquid (2.38 g, 89%). E isomers>98%.