Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH2:12][Cl:13].[Na+].[Cl-]>CN(C)C=O.O>[Cl:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: ClCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCOc1cccnc1
Temperature: 25 °C
Yield: 119.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (2.00 g, 21.0 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.756 g of an 80% dispersion in mineral oil, 27.5 mmol) in DMF (15 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-bromo-2-chloroethane (3.60 g, 25.2 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 4 h. Water (30 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 3.96 g (66.1%) of a light-brown oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[C:8]([O:19][CH3:20])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:32]=[O:33]>O1CCCC1>[CH2:21]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][C:16]([CH:32]=[O:33])=[CH:17][CH:18]=2)=[C:8]([O:19][CH3:20])[CH:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CN(C)C=O
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Temperature: -71.5 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
In a stream of argon, in 25 ml of tetrahydrofuran was dissolved 1.5 g (4.37 mmol) of dibutyl[3-methoxy-4-[2-(thiophene-2-yl)vinyl]phenyl]amine, and 4.1 ml of n-butyllithium (1.6 mol solution in hexane) (6.56 mmol) was added dropwise thereto under cooling at −70 to −73° C. After the mixture was stirred for 1 hour, 0.43 ml (5.54 mmol) of N,N-dimethylformamide was added dropwise. After the reaction mixture was stirred for 1 hour, the bath was removed and the temperature was allowed to rise. To this mixture, 10 ml of water was added dropwise. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was dissolved in 200 ml of ether and 70 mg of iodine pieces were added thereto. After stirred at room temperature, the mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. After drying over anhydrous sodium sulfate and concentration were performed, the residue was purified by silica gel column chromatography to give 1.27 g of a reddish orange crystal (yield: 79.2%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[C:5]([Si:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)Cl)([CH3:8])([CH3:7])[CH3:6].N1C=CN=C1>>[Si:9]([O:4][CH2:1][C:2]#[CH:3])([C:5]([CH3:8])([CH3:7])[CH3:6])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Product: C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
2.9 ml of 2-propyn-1-ol, 15.6 ml of tert-butyldiphenylchlorosilane and 4.1 g of imidazole were reacted in the manner described in Example 14c. Chromatography of the raw product on silica gel [Kieselgel 60 (0.063-0.200 mm)] with petroleum ether/diisopropylether (20:1) yielded 13.3 g of the title compound in the form of crystals melting at 55°-58° C.
Reaction SMILES: [CH:1]1([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>ClCCl>[S:14]([O:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: OCC1CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Temperature: 25 °C

Procedure:
Cyclobutanemethanol(5 g, 58 mmol) was dissolved in dichloromethane (150 ml) and cooled in an ice water bath. Triethylamine (10.5 ml, 75.5 mmol) was added followed by the dropwise addition of a solution of tosyl chloride (13.3 g, 69.8 mmol) in dichloromethane (50 ml). The cooling bath was removed and the mixture allowed to warm to room temperature over 16 hours. The mixture was washed with water (2×100 ml), dried (MgSO4) and concentrated in vacuo to give cyclobutanemethanol tosylate as a yellow oil which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: COC(=O)c1ccc(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g of 4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 10 ml of MeOH:water/3:1. 230 mg of lithium hydroxide monohydrate were added to the solution, and the reaction was stirred at RT for 16 h then at 50° C. for 2 h. The solution was cooled to RT, then acidified with half-concentrated hydrochloric acid. The suspension was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield a white solid. Yield 2.2 g.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:11]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH2:1]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:11]=2[C:12]=1[S:27]([C:24]1[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ccc2oc(Cc3ccccc3)cc2c1
Product: CCc1ccc2oc(Cc3ccccc3)c(S(=O)(=O)c3ccc(O)cc3)c2c1

Procedure:
Acylation of 2-benzyl-5-ethylbenzofuran with 4-methoxybenzenesulfonyl chloride followed by demethylation of the product thus formed as previously described gives 2-benzyl-5-ethyl-3-(4-hydroxyphenylsulfonyl)benzofuran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][C:26]4[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:18]1)=[N:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[CH2:36]1[O:38][C@H:37]1[CH2:39][OH:40]>C1COCC1.CO>[OH:38][C@@H:37]([CH2:39][OH:40])[CH2:36][N:13]([CH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:34][CH3:35])[N:9]=2)[N:4]=[CH:3][C:2]=1[F:1])[CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1
Reactant: OC[C@H]1CO1
Reactant: COc1ccc2ncc(F)c(CNCCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(CN(CCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)C[C@@H](O)CO)c2n1
Temperature: 70 °C
Yield: 52 %

Procedure:
A solution of the compound of Example 78 (0.05 g, 0.1 mmol) in THF/MeOH (1:1, 0.5 mL) was treated with (S)-glycidol (0.06 mL, 5 eq.). The mixture was heated at 70° C. for 3 h, concentrated in vacuo and purified by FC (EA/MeOH 19:1+1% NH4OH) to give the title compound as a colourless solid (0.03 g, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:33])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:33][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]1
Reactant: CC1CCN(CCc2ccc(N)cc2Cl)CC1
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Product: CC1CCN(CCc2ccc(NC(=O)COc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 3-chloro-4-[2-(4-methyl-piperidin-1-yl )-ethyl]-phenylamine (Z46c). The reaction mixture was poured onto ice water and the aqueous phase was extracted with EtOAc. The org. phase was dried over sodium sulphate and evaporated down i. vac. The residue was purified by column chromatography (Alox, neutral, act. II-III, gradient petroleum ether/EtOAc 3:1→1:1).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:14][CH2:15][CH2:16]Br.[OH-].[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:16][CH2:15][Br:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Oc1ccc(Cn2cccn2)cc1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccc(Cn2cccn2)cc1
Temperature: 0 °C
Yield: 47.3 %

Procedure:
To a mixture of 15 g of 4-(1-pyrazolyl)methylphenol, 32.4 g of 1,2-dibromo-ethane and 150 ml of water was added dropwise 30 ml of an aqueous solution of 4.1 g of sodium hydroxide while stirring under heating at reflux over 2 hours. Then, after heating at reflux under stirring for further 30 minutes, the reaction mixture was poured into 200 ml of ice water, which was extracted twice with 100 ml of diethyl ether. The organic layers were combined, washed with 5N aqueous sodium hydroxide solution, water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 11.44 g of 2-[4-(1-pyrazolyl)methylphenoxy]ethyl bromide as white crystals. Yield, 47%.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.[C:7]1([CH3:14])[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1>O>[CH:8](=[C:6]1[N:2]([NH2:1])[CH:3]=[N:4][NH:5]1)[CH2:7][CH2:12][CH2:11][CH2:13][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH3:14]
Reactant: Cc1ccccc1C
Reactant: Nn1cnnc1
Solvent: O
Product: CCCCCCCCCCCC=C1NN=CN1N

Procedure:
4-amino-1,2,4-triazole (8.4g.), didecyl aldehyde (18.4g.) and xylene (125 ml.) were heated in a Dean Stack apparatus until the evolution of water ceased. Concentration on the rotary afforded the product as a viscous oil which solidified upon cooling. Yield = 25g. m.p. 40°-3°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][NH:18][CH:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[C:25]([N:29]1[CH2:34][CH2:33][CH:32]([SH:35])[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([N:29]1[CH2:34][CH2:33][CH:32]([S:35][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][NH:18][CH:19]=5)[N:8]=[C:7]4[C:6]=3[CH:24]=2)[CH2:31][CH2:30]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1n[nH]cc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: CC(C)(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4c[nH]nc4C(F)(F)F)cn2CCO3)CC1
Temperature: 100 °C
Yield: 63.3 %

Procedure:
A mixture of 9-bromo-2-(3-trifluoromethyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (73 mg, 0.18 mmol), 1-tert-butylpiperidine-4-thiol (63 mg, 0.37 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xantphos (35 mg, 0.06 mmol) and DIPEA (125 μL, 0.73 mmol) in dioxane (3 mL) was purged with argon and heated at 100° C. for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, on a gradient 5-95%, 0.1% HCO2H in acetonitrile/water) affording 159 (56 mg, 31%). LCMS: RT 3.11 min [M+H]+ 492.1. 1H NMR (DMSO, 400 MHz): δ 8.51 (1H, d, J=2.40 Hz), 8.26-8.25 (1H, m), 8.21 (1H, s), 7.42 (1H, s), 7.31 (1H, dd, J=8.46, 2.42 Hz), 7.01 (1H, d, J=8.46 Hz), 4.47 (4H, s), 3.12-3.01 (1H, m), 3.05-2.93 (2H, m), 2.24 (2H, t, J=11.08 Hz), 1.92 (2H, d, J=12.67 Hz), 1.48-1.47 (2H, m), 1.02 (9H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([NH:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)ncc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc(N)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-diamino-4-picoline, prepared as shown in Example 30, (50 mg, 0.41 mmol) in methylene chloride (1.0 mL) were added triethylamine (70 uL, 0.49 mmol) and acetic anhydride (43 uL, 0.45 mmol). After stirring 0.5 h at room temperature, the reaction mixture 25 was evaporated to dryness and purified by silica gel chromatography using 40:10:1 chloroform-methanol-water as eluant to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:5].[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20].O>CC(C)=O>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:19](=[O:20])[CH:18]([Cl:22])[Cl:17])=[O:5]
Reactant: Nc1ccccc1C(=O)c1cccc(Cl)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1cccc(Cl)c1)c1ccccc1NC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Amino-3'-chlorobenzophenone (6.12 g) was stirred and cooled at 15°C in solution in acetone (25 ml) while dichloroacetyl chloride (4.86 g) was added dropwise. After stirring at room temperature for 20 minutes the reaction mixture was poured into water, the acetone was removed under reduced pressure and the resulting oil extracted into chloroform. After drying over magnesium sulphate the chloroform was removed under reduced pressure and the product crystallized from ethanol. 2'-(m-Chlorobenzoyl)-2,2-dichloroacetanilide was obtained as yellow needles (6.88 g),m.p. 73°-75°C after recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)c(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)c(Cl)c1
Yield: 90.1 %

Procedure:
186 g of 2-chloro-4-methoxytoluene are dissolved in 1000 ml of carbon tetrachloride and, together with 212 g of N-bromosuccinimide, heated at reflux for 2 h while 2.4 g of AIBN are added. The solid is filtered off and washed with a small amount of carbon tetrachloride, the filtrate is concentrated, and the residue which remains is fractionated. 252 g of orange oil are obtained (Purity 82%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)[N:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[N:4]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[N:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(Oc2cccc(C=C3CCNCC3)c2)n1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
2-Methyl-6-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Example 40, Step 5), phenyl pyridazin-3-ylcarbamate (335 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):CH2Cl2) to afford the title compound (336 mg) as a foamy white solid. MS (APCI 10V) AP+ 402.0, 281.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.42 (s, 3H) 2.46 (td, J=5.84, 0.80 Hz, 2H) 2.58 (td, J=5.78, 1.13 Hz, 2H) 3.52-3.63 (m, 2H) 3.63-3.72 (m, 2H) 6.45 (s, 1H) 6.65 (dt, J=8.21, 0.69 Hz, 1H) 6.90-6.97 (m, 2H) 6.99 (dt, J=7.16, 0.48 Hz, 1H) 7.04-7.11 (m, J=8.10, 1.21, 0.84, 0.63 Hz, 1H) 7.36 (dd, J=8.86, 7.71 Hz, 1H) 7.59 (dd, J=9.11, 4.65 Hz, 1H) 7.68 (dd, J=8.08, 7.52 Hz, 1H) 8.12 (d, J=8.87 Hz, 1H) 8.79 (d, J=3.90 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].C(OCC)(=O)C>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C#N)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(CN)nc1

Procedure:
A solution of 5-methanesulfonyl-pyridine-2-carbonitrile (120 mg, 0.66 mmol) in methanol was hydrogenated over 10% Pd/C catalyst using a continuous flow hydrogenation apparatus (conditions: flow rate 1 mL/minute, 10 bars, 25° C.). The reaction was monitored by HPLC-MS and TLC (ethyl acetate) indicating the disappearance of starting material. The mixture was concentrated in vacuo and then twice diluted with ether-hexanes and concentrated to afford the title compound.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Mg].[C:8]([O:13][C:14]1([CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH:15]1CC)(=[O:12])[C:9]([O-])=[O:10].[Cl-].[NH4+]>C(OCC)C>[OH:10][C:9]([CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])([CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]([O:13][C:14]1([CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: CCC1CCCC1(CC)OC(=O)C(=O)[O-]
Reactant: C[Si](C)(C)CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC1(OC(=O)C(O)(C[Si](C)(C)C)C[Si](C)(C)C)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Under a nitrogen atmosphere, a Grignard reagent solution was prepared from 100 g of chloromethyltrimethylsilane, 20 g of magnesium and 500 ml of diethyl ether. Under a nitrogen atmosphere, the Grignard reagent solution was slowly added dropwise to a solution of 80 g of ethyl(1-ethylcyclopentyl) oxalate (which had been prepared by reacting ethyl chloroglyoxylate and 1-ethylcyclopentanol in pyridine) in 360 ml of diethyl ether at −40° C. After 2 hours of stirring at the temperature, the solution was warmed up to room temperature and stirred for further 8 hours. An aqueous solution of ammonium chloride was added for hydrolysis, followed by usual work-up procedure including extraction, washing, drying and concentration to give 102 g (crude yield 79%) of crude 1-ethylcyclopentyl 2-hydroxy-3-trimethylsilyl-2-trimethylsilylmethylpropionate.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1)=O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]3[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=3[CH:13]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)NC(=O)CO3)CC1
Yield: 93.8 %

Procedure:
A mixture of 6-formyl-4H-benzo[1,4]oxazin-3-one (1.91 g, 10.8 mmol) and 1-(tert-butoxycarbonyl)piperazine (2.0 g, 10.8 mmol) in 1,2-dichloroethane (120 mL), was cooled in an ice-bath, and treated portionwise with sodium triacetoxyborohydride (3.43 g, 16.2 mmol) over 0.3 h, with stirring under argon. The resulting mixture was stirred at room temperature for 4 h, then partitioned between dichloromethane (100 mL) and saturated aqueous sodium bicarbonate. The organic layer was separated, dried (Na2SO4) and evaporated in vacuo to give the title compound (3.52 g, 94%) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[O:13])[CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:23]([N:11]([CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:30])=[O:2])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)=[O:13])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc(CN(Cc2ccccc2)C(=O)Nc2ccc(C#N)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)N(Cc2ccccc2)Cc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Dissolved to 3-[1-benzyl-3-(4-cyano-phenyl)-ureidomethyl]-benzoic acid methyl ester (106 mg, 0.27 mmol) in 1:1 mixture of THF/MeOH (4 mL). To this was added a 15% NaOH solution and the mixture stirred overnight at room temperature. LC-MS analysis indicated the desired carboxylic acid. Concentrated the mixture and the residue was suspended in 5 mL of H2O and made acidic by the addition of 5% HCl, resulting in a white ppt., which was filtered and dried to give 101.6 mg of 3-[1-benzyl-3-(4-cyano-phenyl)-ureidomethyl]-benzoic acid.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[F:9][C:10]1[CH:11]=[C:12]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO.C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][C:19](=[N:7][OH:8])[CH2:18][CH2:17]1
Reactant: NO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=NO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sodium acetate (517 mg) and hydroxylamine hydrochloride (219 mg) are successively added to a methanol-methylene chloride solution (10--10 ml) of 1.00 g of the product of Step 2, and the mixture is stirred at room temperature for 2 days. The solvent is evaporated and the residue is dissolved in methanol, followed by addition of a silica gel (8 g). Methanol is evaporated and the residue is purified by silica gel column chromatography (solvent: chloroform/methanol=50/1-25/1) to afford the title compound.