Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1.[C:31](=[O:33])=[O:32]>O1CCCC1>[Br:22][C:23]1[C:24]([C:31]([OH:33])=[O:32])=[C:25]([F:30])[C:26]([F:29])=[CH:27][CH:28]=1
Reactant: O=C=O
Reactant: Fc1ccc(Br)cc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1c(Br)ccc(F)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A solution of 1.6M butyllithium in hexane (60 mL, 96 mmol) was diluted with tetrahydrofuran (180 mL) under an argon atmosphere, and cooled to −78° C. To the solution, were added dropwise 2,2,6,6-tetramethylpiperidine (16.2 g, 116 mmol) and subsequently 4-bromo-1,2-difluorobenzene (15.4 g, 80 mmol), and the mixture was stirred at the same temperature for 2 hours. The solution was carefully poured onto crushed dry ice, and the mixture was allowed to warm to room temperature. The solution was concentrated under reduced pressure, and the residue was poured into water. After the solution was washed with diethylether, the aqueous layer was made acidic by the addition of 6N hydrochloric acid, and organic matter was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (10.8 g, 57% yield).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18](Cl)[CH:19]=1>C1COCC1>[CH2:1]([O:8][C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: OCc1ccccc1
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To an 80 mL microwave pressure vessel is charged dry THF (30 mL) and benzyl alcohol (6.32 mL, 61.1 mmol). The solution is cooled to 0° C. and sodium hydride (2.44 g of a 60% dispersion in mineral oil, 61.1 mmol) is added in portions. The reaction mixture is gradually allowed to warm to room temperature with efficient stirring until the evolution of hydrogen gas ceases. The solution is re-cooled to 0° C. and 3,5-dichloro-2-cyanopyridine (5.00 g, 29.1 mmol) is added, and the solution is transferred to an unfocussed Mars 5 CEM microwave reactor to 190° C., 300 W and held for 5 hours. The reaction mixture is quenched with H2O, concentrated under reduced pressure, diluted with EtOAc and washed with 2M Na2CO3, H2O and saturated aqueous NaCl. The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to give a brown solid. The crude solid is purified over silica (EtOAc:heptane, gradient 1:1 to 1:0) to afford 8.6 g (94% yield) of the desired compound as an orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.96 (1H, d, J=2.2 Hz), 7.25-7.37 (10H, m), 6.78 (1H, d, J=2.2 Hz), 5.10 (2H, s), 5.03 (2H, s). HPLC-MS: m/z 317 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]=O)[CH:36]=1.COC(=O)C1C=CC=CC=1>>[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH:17][CH2:16][C:13]2[N:12]=[C:11]([C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])([CH:19]3[CH2:31][C:22]4[NH:23][C:24]5[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=5[C:21]=4[CH2:20]3)[F:18])[O:15][N:14]=2)[CH:36]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Solvent: COC(=O)c1ccccc1
Product: COC(=O)c1cccc(CNCc2noc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3ccccc3)n2)c1

Procedure:
In analogy to example 129.3, from (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine and methyl-3-formylbenzoate was prepared (RS,SR)-3-[{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl ester as a light yellow powder, MS: 609 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:10]1[CH:15]=CC=CC=1.[C]=O.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1Cl>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]1([N:10]=[C:15]=[O:2])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1ccccc1Cl
Reactant: c1ccncc1
Agent: [C]=O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C=Nc1ccccc1

Procedure:
1.8 g of this catalyst as well as 10 g of nitrobenzene and 1 g of pyridine are charged into the autoclave used in Example 2 and the volume is made up to a total volume of 100 ml with the addition of ortho-dichlorobenzene. By operating in an identical fashion with Example 2 at 240° C. under 200 bars of carbon monoxide at 20° C., a T.T.G. (overall conversion rate) of nitrobenzene of 100% and a phenylisocyanate selectivity of 62% are obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[N:29]=[C:30]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:31](C(OC(C)(C)C)=O)[C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[N:29]=[C:30]([CH2:39][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[NH:31][C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCOCC2)nc2nc(Cl)ccc21
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4[nH]c(CN5CCOCC5)nc4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (300 mg, 0.96 mmol) and tert-butyl 5-chloro-2-(morpholin-4-ylmethyl)-1H-imidazo[4,5-b]pyridine-1-carboxylate (340 mg, 0.96 mmol) as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Br[CH2:25]C1C=CC(C2OC3C=CC=CC=3N=2)=CC=1OC.N1CCCCC1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:25]1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CN1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1cc(-c2nc3ccccc3o2)ccc1CN1CCCCC1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]-1,3-benzoxazole, 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 0.942 mmol) was reacted with piperidine (279 μL, 2.83 mmol) and triethylamine (394 μL, 2.83 mmol) in CH2Cl2 (5 mL) to afford the desired 2-[3-methoxy-4-(piperidin-1-ylmethyl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3-d, 300 MHz) δ 7.86–7.83 (m, 1H), 7.79–7.76 (m, 1H), 7.73 (s, 1H), 7.61–7.55 (m, 2H), 7.37–7.34 (m, 2H), 3.96 (s, 3H), 3.59 (s, 2H), 2.47 (br, 4H), 1.66–1.58 (m, 4H), 1.46–1.45 (m, 2H). MS (ESI) 323 (M+)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[H-].[Na+].[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[NH2:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:1][C:21]([C:20]2[CH:24]=[CH:25][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=2)=[O:22])[CH:7]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CSc1nc(N)cc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSc1nc(N)cc(NC(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 50 °C

Procedure:
To a solution of 4,6-diamino-2-methylmercaptopyrimidine (50 mg, 0.032 mmol) in anhydrous tetrahydrofuran was added sodium hydride, followed by the addition of 4-t-butylbenzoyl chloride (0.084 mL, 0.32 mmol) and N, N-diisopropylethylamine. The mixture was heated at 50° C. for 16 hours after which it was subjected to aqueous work up. The product was extracted with ethyl acetate and purified by HPLC to give N-(6-amino-2-methylthiopyrimidin-4-yl)[4-(tert-butyl)phenyl]carboxamide. M+1=317.3.
Reaction SMILES: [CH2:1]([C:6]1(C(C(OC)=O)C(=O)C)[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]>O>[CH2:1]([CH:6]1[CH:10]([CH2:6][C:7](=[O:11])[CH3:8])[CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1(C(C(C)=O)C(=O)OC)CCCC1=O
Solvent: O
Product: CCCCCC1C(=O)CCC1CC(C)=O
Yield: 176 %

Procedure:
567 g of 2-n-pentyl-(1-carbomethoxy-2-oxopropyl)-1-cyclopentanone were hydrolysed using an equal weight of water according to the method described in Example 1 (b). There were obtained 391 g of 2-n-pentyl-3-(2-oxopropyl)-1-cyclopentanone (overall yield = 80% based on the amount of 2-n-pentyl-cyclopent-2-en-1-one consumed) having the physical constants shown in Example 1 (b).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)ccc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-4-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.30 (s, 9H), 7.04 (d, 1H, J=8.4 Hz), 7.25 (d, 1H, J=8.4 Hz), 7.45-7.52 (m, 4H), 7.74 (dd, 2H, J=8.8 Hz, 1.6 Hz), 7.52 (dd, 2H, J=4.4 Hz, 1.6 Hz), 7.78 (m, 2H), 7.84 (d, 1.6 Hz), 8.84 (d, 2H, J=5.6 Hz), 10.61 (s, 1H). MS: m/z 429.0 (M++1).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].[F:34][CH2:35][CH:36](O)[CH2:37][F:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:34][CH2:35][CH:36]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:37][F:38]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: OC(CF)CF
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
Reaction time: 48 h
Yield: 113.6 %

Procedure:
DIAD (7.63 mL, 38.7 mmol) was added in a dropwise fashion to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (5.00 g, 19.4 mmol), 1,3-difluoropropane-2-ol (3 mL, 38.7 mmol), and triphenylphosphine (10.16 g, 38.7 mmol) in THF (100 mL) under an inert atmosphere at 0° C. The solution was allowed to reach RT and left to stir for 2 days. The THF was removed in vacuo and the residual oil slurried with a mixture of 20% ethyl acetate in isohexane. After allowing to stir for 90 minutes the mixture was filtered and the filtrate evaporated. The residual was oil chromatographed on silica, eluting with 30% ethyl acetate in isohexane, to give the desired compound (7.41 g).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:37][CH2:36][C@H:35]1[C:38]([OH:40])=[O:39]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:37][CH2:36][C@H:35]4[C:38]([OH:40])=[O:39])=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)[C@@H]1CCN1
Product: O=C1N=C(N2CC[C@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-2-(S)-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-2-(S)-carboxylic acid following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:22]1([CH:28]([N:35]=[C:36]=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH:28]([NH:35][C:36]([N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1)=[O:37])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: CN1CCC(C(c2ccc(Cl)cc2)N2CCNCC2)CC1
Solvent: ClCCl
Product: CN1CCC(C(c2ccc(Cl)cc2)N2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 1-((4-chlorophenyl)(1-methylpiperidin-4-yl)methyl)piperazine 0.1 g (0.325 mmol) dissolved in methylene chloride (20 ml) was added diphenylmethyl isocyanate 0.071 g (0.325 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.14 g of desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:27][O:28][CH2:29][C:30]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[N:5]=[CH:4][N:3]=1)=[O:31]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of 4-amino-6-(4-nitrophenoxy)pyrimidine (560 mg, 2.41 mmol) and DIPEA (630 μL, 3.62 mmol) in DCM (15 mL) under nitrogen at 0° C. was added 2-methoxyacetyl chloride (330 μL, 3.62 mmol) dropwise over 5 min. The mixture was warmed to RT for 1 hr and the reaction was quenched by addition of a 1% solution of NH3 in MeOH (10 mL) and then evaporated in vacuo. The residue was partitioned between DCM (50 mL) and water (25 mL) and the organic layer was separated and washed with brine (25 mL) and was then dried (MgSO4). Evaporation of the volatiles in vacuo gave the title compound as a beige solid (730 mg, 97%): Rt 1.87 min (Method 2); m/z 305 (M−H)+ (ES+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:39])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:29]([C:30]5[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][CH:31]=5)=[CH:28][NH:27][C:24]4=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:40]>CO.O1CCOCC1>[ClH:40].[N:11]1([C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:29]([C:30]5[CH:31]=[CH:32][C:33]([C:36]([NH2:37])=[O:38])=[CH:34][CH:35]=5)=[CH:28][NH:27][C:24]4=[N:25][CH:26]=3)=[CH:17][CH:16]=2)=[O:39])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3cnc4[nH]cc(-c5ccc(C(N)=O)cc5)c4c3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1ccc(-c2c[nH]c3ncc(-c4ccc(C(=O)N5CCNCC5)cc4)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116 %

Procedure:
A solution of 4-{4-[3-(4-carbamoyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoyl}-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.19 mmol) in MeOH (3 ml) was treated with 4 N HCl in dioxane (2.5 ml) and stirred at room temperature for 1 hr. The mixture was evaporated, taken up in MeOH and evaporated again. This was repeated twice to give 102 mg (116%) of the title compound. MS ESI (m/z): MS ESI (m/z): 426.4 (M+1)+, calc. 425.
Reaction SMILES: CO[C:3]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)[CH2:4]1.C(NC(C)C)(C)C.C([Li])CCC.[C:31]([OH:36])(=O)[C:32](O)=O.ClP(=O)(OCC)[O:39][CH2:40]C>CCCCCC.C(N=CC)(C)(C)C.O1CCCC1>[CH3:40][O:39][C:12]1[CH:13]=[C:8]([C:6]([C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([O:17][CH3:18])[CH:4]=2)=[CH:32][CH:31]=[O:36])[CH:9]=[CH:10][CH:11]=1
Reactant: COC1(OC)C=CC=C(C(=O)c2ccccc2)C1
Reactant: CCOP(=O)(Cl)OCC
Reactant: O=C(O)C(=O)O
Agent: CC=NC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=CC=O)c2cccc(OC)c2)c1
Reaction time: 30 h

Procedure:
The compound was prepared according to the procedure described in Example 84 except that the reaction was worked up after 30 hours. The following reagents were used: 3,3-dimethoxybenzophenone (48.5 g), diisopropylamine (64.4 mL), 1.55M n-butyl lithium in hexane (286 mL), acetaldehyde N-tertbutylimine (29.5 mL), diethyl chlorophosphonate (33.2 mL) and tetrahydrofurane (400 mL). The work up, varied only in that the oxalic acid catalyzed hydrolysis was done at 85° C. over two hours, furnished 53 g of essentially pure 3,3-bis(3-methoxyphenyl)-2-propenal as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH:22]=2)=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1
Reactant: CC1(C)C=C(c2ccc(F)cc2C2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C=C(c2ccc(F)cc2C2CCNCC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 118.2 %

Procedure:
To a solution of 4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine-1-carboxylic acid t-butyl ester (245 mg, 0.59 mmol) produced in Example (106f) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL), followed by stirring for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give 220 mg of a crude product of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:9][CH:8]=1)[CH3:2].O.[OH-].[Li+]>C1COCC1>[CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Temperature: 150 °C
Yield: 308.2 %

Procedure:
Methyl 2-[2-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoate (0.200 g, 0.115 mmol) was dissolved in 3 ml THF in a Smith synthesiser vial and then 1.5 ml water and lithium hydroxide (0.032 g, 1.335 mmol) were added to the vial. The vial was capped and put in the microwave oven (Smith synthesiser). The reaction was then heated to 150° C. for 6 minutes. According to LC-MS the reaction was complete. The solvent was evaporated. The residue was dissolved in diethyl ether (30 ml) and washed with NaHCO3 (sat) (2×20 ml). The basic water layer was acidified to pH 1 with 2M HCl. The water layer was extracted with three portions of 20 ml of DCM which were combined, dried and evaporated to give 160 mg of pure desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:27])[C:10]([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[O:15][CH2:14]2)([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC.C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:27])[C:10]([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[O:15][CH2:14]2)([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)c2cc(F)cc(F)c2)CO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)c2cc(F)cc(F)c2)CO1
Reaction time: 18 h
Yield: 61.8 %

Procedure:
A solution of 1-(3,5-difluorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-ol (0.96 g) in dichloromethane was added to a stirred mixture of pyridinium chlorochromate (0.83 g) and powdered molecular sieve (4A) in dichloromethane at 20° C. After 18 hours, ether and charcoal were added, the mixture filtered through hyflo and evaporated to give 1-(3,5-difluorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-one (0.59 g) as a beige solid, m.p. 156.8-157.8° C.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C1CCNCC1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN2CCCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with piperidine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-piperidin-1-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as yellow solid, MS: 503 (MH+).