Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14]Br)[CH:5]=[CH:4][C:3]1=2.CCOC(C)=O.[C:23](#[N:25])C>[C-]#N.C([N+](CC)(CC)CC)C>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:23]#[N:25])[CH:5]=[CH:4][C:3]1=2
Reactant: CC#N
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(CC#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) bromomethane (21) (100 mg, 0.44 mmol) in acetonitrile (2 mL) was added tetraethylammonium cyanide (83 mg, 0.53 mmol). The resulting golden yellow solution was stirred at rt overnight. The solvent was removed in vacuo and to give a residue that was subjected to chromatograpy (10% EtOAc/90% hexane) to give 59 mg (78%) of (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) acetonitrile (22). 1H NMR (400 MHz, CDCl3) δ7.31 (d, J=8.2 Hz, 1H, aromatic), 7.23 (d, J=1.8 Hz, 1H, aromatic), 7.08 (dd, J=8.0 and 1.8 Hz, 1H, aromatic), 3.69 (s, 2H, CH2), 1.69 (s, 4H, 2CH2), 1.28 (s, 6H, 2CH3), (s, 6H, 2CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The known compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-phenyl-methanone and 4-methoxy-benzenesulfonyl chloride and purified by flash chromatography (20% EtOAc. Hexane). 1H NMR (CDCl3) δ 9.63 (s, 1H) 7.75 (d, J=12 Hz, 1H) 7.57 (m, 3H) 7.49-7.35 (m, 5H) 7.33 (d, J=4 Hz, 1H) 6.69 (d, J=12 Hz, 2H) 3.67 (s, 3H). MS; m/z=402.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([C@@H:16]([OH:19])[CH2:17][OH:18])[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([C@@H:16]([OH:19])[CH2:17][OH:18])[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](O)CO)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CCO
Product: OC[C@H](O)[C@@H]1OCCNC[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 179.2 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-[(1S)-1,2-dihydroxyethyl]-1,4-oxazepane-4-carboxylate (450 mg) in ethanol (8 mL) was added 12 mol/kg hydrogen chloride-ethanol solution (8 mL), and the mixture was stirred at room temperature for 15 min. The solvent was evaporated under reduced pressure, and the residue was crystallized from water-ethanol-diethyl ether to give the title compound (340 mg) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:12][C:11]([Br:13])=[CH:10][C:5]=2[C:6](=O)[NH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:16])=O>>[Br:13][C:11]1[S:12][C:4]2[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([Cl:16])[C:5]=2[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c[nH]c(=O)c2cc(Br)sc12
Product: N#Cc1cnc(Cl)c2cc(Br)sc12
Reaction time: 1 h

Procedure:
2-Bromo-7-cyano-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine (99) (2.0 g, 7.84 mmol) was dissolved in phosphorus oxychloride (60 mL) and the resulting solution heated at reflux for 2 h. After this time the mixture was poured into ice and stirred for 1 h. The precipitated solid was filtered, washed with water and dried (50° C., P2O5, in vacuo), affording a brown solid (1.99 g). 1H NMR (300 MHz, d6-DMSO) δ 9.05 (s, 1H), 8.21 (s, 1H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH2:17]([O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28]([C:32]([C:34]2[CH:39]=[C:38](Cl)[N:37]=[CH:36][N:35]=2)=[O:33])=[CH:27][C:26]=1[CH3:41])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:24][C:25]1[C:26]([CH3:41])=[CH:27][C:28]([C:32]([C:34]2[N:35]=[CH:36][N:37]=[C:38]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:39]=2)=[O:33])=[CH:29][C:30]=1[CH3:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc(C)c1OCc1ccccc1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
170 mg (0.779 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one, 270 mg (0.727 mmol) (4-benzyloxy-3,5-dimethyl-phenyl)-(6-chloro-pyrimidin-4-yl)-methanone and 0.200 mL (1.42 mmol) TEA were combined in 2.0 mL DMF and stirred overnight at RT. The reaction mixture was stirred into ice water, the precipitate was suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[CH3:15][O:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][NH:19]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][CH2:22][C@@H:18]3[CH2:17][O:16][CH3:15])=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: COCC1CCCN1
Agent: [Li+]
Product: COC[C@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and 2-methoxymethyl-pyrrolidine by a procedure analogous to Example 1C. MS: 312/314 (MH+); HPLC Rf: 4.87 min; HPLC purity: 99%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].O1CC[CH2:34][CH2:33]1.C(I)C>CN(C)C=O>[CH2:33]([O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2)[CH3:34]
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)OC)[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To an ice-cooled and stirred solution of methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.2 g) and potassium carbonate (0.50 g) in N,N-dimethylformamide (10 mL)-tetrahydrofuran (30 mL) was added ethyl iodide (0.28 mL), and the mixture was stirred at room temperature for 18 h and then at 55° C. for 15 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed successively with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=25:75 to 40:60, volume ratio) to give the title compound (0.65 g, 50%) as light yellow crystals. MS 391 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32][C:33]([O:35]CC)=O)=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:45]>CO>[C:33]([CH2:32][C@@H:31]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:29]([NH:28][C@@H:21]([CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)[C:19]([NH:18][C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])=[O:20])=[O:30])(=[O:35])[NH2:45]
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)OCC)Cc1ccccc1)C(C)C
Reactant: N
Solvent: CO
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(N)=O)Cc1ccccc1)C(C)C
Reaction time: 12 h
Yield: 66 %

Procedure:
A solution of 100 mg of ethyl (R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrate in 30 ml of methanol was saturated with ammonia for 1-2 minutes and subsequently left to stand at room temperature for 12 hours. Thereafter, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel with 10% methanol in methylene chloride as the eluting agent, to obtain 63 mg (66%) of (S)-α-[(R)-α-(carbamoylmethyl)hydrocinnam-amido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide as a resin. MS: 580 (M+H)+.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[CH:10]([N:8]1[CH2:9][CH:6]([N:26]2[CH2:25][CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]2)[CH2:7]1)([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
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
A mixture of 1-benzhydrylazetidin-3-yl methanesulfonate (26.53 g, 83.68 mmol), tert-butyl piperazine-1-carboxylate (18.68 g, 100.41 mmol) and K2CO3 (23.09 g, 163.36 mmol) in CH3CN (200 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled to RT and diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (25.5 g, 80% yield).
Reaction SMILES: O[CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.S(Cl)([Cl:20])=O>>[Cl:20][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Product: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1

Procedure:
1-[2-Hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole (2.0 g) in thionyl chloride (10 ml) is warmed for one hour at 65°. The excess thionyl chloride is removed in vacuo, the residue dissolved in dichloromethane (75 ml) and shaken with excess aqueous potassium carbonate. The organic layer is washed with water, dried over MgSO4, evaporated and the residue evacuated to remove all traces of dichloromethane, affording 1-[2-chloro-4-(4-chlorophenyl)-n-butyl]imidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1occc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccoc1C(=O)O

Procedure:
A mixture of 3-methyl-2-furoic acid, methyl ester [20.0 g, 0.14 mole, 0.14 mole, Organic Synthesis 39, 49 (1959)] and 20% NaOH solution (46 mL) was refluxed under argon for 2 hours. The cooled mixture was acidified with concentrated HCl (28.5 mL). The resulting white precipitate was collected, washed with water and dried in vacuo to give the title acid (16.53 g, 94%) as a white crystalline solid, mp 132°-134° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[CH:16]=[C:17]3[O:25][CH2:24][O:23][C:18]3=[CH:19][C:20]=2[C:21]=1[SH:22])=[O:11].C(N(CC)CC)C.II>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[C:10](=[O:11])[C:12]2[CH:13]=[N:14][C:15]3[CH:16]=[C:17]4[O:25][CH2:24][O:23][C:18]4=[CH:19][C:20]=3[C:21]=2[S:22]1
Reactant: O=C(NCCc1ccccn1)c1cnc2cc3c(cc2c1S)OCO3
Agent: II
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1c2cnc3cc4c(cc3c2sn1CCc1ccccn1)OCO4
Yield: 83 %

Procedure:
To 4.1 g (0.012 mol) of 8-mercapto-[1,3]dioxolo [4,5-g]quinoline-7-carboxylic acid (2-pyridin-2-yl-ethyl)-amide (from Preparation 34) and 5 mL (0.035 mol) of triethylamine in 750 mL of methanol was added 2.95 g (0.012 mol) of iodine in 100 mL of methanol. The mixture was heated at reflux for 2 hours, cooled, and then concentrated to an oil. The residue was slurried in water, and the solid was collected and recrystallized in ethanol to give 3.5 g of the title compound, mp 200-201° C.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18][CH2:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>C(O)C.C1(C)C=CC=CC=1>[CH2:28]([O:27][P:23]([CH2:22][C:21]1[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=1[CH2:19][CH2:18][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O:24][CH2:25][CH3:26])=[O:30])[CH3:29]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOP(=O)(Cc1ccccc1CCBr)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1CP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 34 %

Procedure:
To 1.03 g (44.8 mmol) of sodium in 50 mL of dry ethanol was added 9.72 g (44.8 mmol) of solid diethyl acetamidomalonate portionwise. This solution was stirred at reflux under nitrogen for 2 h. After cooling to room temperature the solvent was removed under reduced pressure yielding a tan solid. This solid was dried under vacuum about 2 h. The sodium salt of diethyl acetamidomalonate was then suspended in 50 mL of dry toluene and 15.0 g (44.8 mmol) of diethyl 2-(2-bromoethyl)benzylphosphonate in 25 mL of toluene was added dropwise. This solution was stirred at reflux under nitrogen for 36 h. After cooling the solution to room temperature the solid precipitate was removed by filtration and washed with 20 mL of toluene. The combined toluene solutions were concentrated under reduced pressure to yield a viscous oil. This oil was chromatographed on a column of silica gel with ethyl acetate as eluant. The combined fractions were concentrated under pressure to give 7.2 g (34%) of the product as a clear viscous oil. IR(neat): 1745, 1676 (C=O) cm-1. 1H NMR(CDCl3) δ 1.0-6 (m, 12H); 1.8-3.2 (complex m, 9H); 3.7-4.6 (m, 8H); 6.8-7.4 (m, 5). Anal. Calcd. for C22H34NO8P0.5H2O: C, 54.99; H, 7.34; N, 2.92. Found: C, 54.75; H, 7.37; N, 2.97.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:18])=[CH:8][C:9]=2[O:16][CH3:17])=[O:13])[CH2:31][CH2:32]1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Yield: 81.3 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (285 mg) described in Preparation Example 19 and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (377 mg) was obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)O1.Br[C:25]1[N:29]=[CH:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[CH:32][CH:31]=2)[N:26]=1.C([O-])(O)=O.[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:43][C:37]([F:42])([O:36][C:33]1[CH:34]=[CH:35][C:30]([N:27]2[CH:28]=[N:29][C:25]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:13][CH:14]=3)=[N:26]2)=[CH:31][CH:32]=1)[C:38]([F:41])([F:40])[F:39]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A microwave vial was charged with tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (178 mg, 0.559 mmol), 3-bromo-1-(4-(pentafluoroethoxy)phenyl)-1H-1,2,4-triazole (200 mg, 0.559 mmol), NaHCO3 (94 mg, 1.2 mmol), and Pd(PPh3)4 (39 mg, 0.034 mmol). Dioxane (3.8 mL) and water (1.2 mL) were added, and the capped reaction mixture was heated at 140° C. for 30 min in a Biotage Initiator® microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and allowed to stand overnight. Water (3 mL) was added to the solution, and a gummy solid formed, which was filtered and air-dried. Recrystallization of this material from MeOH/water gave the title compound as a white solid (180 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.12 (d, J=8.7 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.9 Hz, 2H), 6.61 (s, 1H), 1.54 (s, 9H); 19F NMR (376 MHz, CDCl3) 5-85.90, −87.86; ESIMS m/z 470 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[O:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=2)=[CH:6][CH:5]=1.CC(C)([O-])C.[Na+].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][N:29]=1.C(OCC)(=O)C>O1CCCC1>[N:38]1([CH2:37][CH2:36][CH2:35][CH2:34][C:31]2[CH:32]=[N:33][C:28]([O:18][CH2:17][C:15]3[N:16]=[C:12]([CH:11]=[CH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=4)[O:13][CH:14]=3)=[N:29][CH:30]=2)[CH:42]=[CH:41][N:40]=[N:39]1
Reactant: OCc1coc(C=Cc2ccc(OC(F)(F)F)cc2)n1
Reactant: Clc1ncc(CCCCn2ccnn2)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(C=Cc2nc(COc3ncc(CCCCn4ccnn4)cn3)co2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.097 g, 0.34 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (4 ml) followed by addition of sodium tert-butoxide (NaOtBu) (0.040 g, 0.41 mmol). After stirring for 15 min at r.t. 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine (0.090 g, 0.38 mmol) is added slowly and stirred for further 1.5 h at r.t. Ethyl acetate (20 ml) is added; the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate) 5-(4-[1,2,3]triazol-1-yl-butyl)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyrimidine is obtained as a colorless solid. Yield 0.104 g (63%).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([O:34]C)=[O:33])[CH2:28][CH2:27]1)=O.C([BH3-])#N.[Na+].O>CO>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C@H:26]3[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (250 mg, 0.766 mmol) in methanol (20 mL) was added trans-methyl 4-formylcyclohexanecarboxylate (130 mg, 0.766 mmol) and the reaction mixture was heated for 2 minutes to reflux. After cooling to room temperature, sodium cyanoborohydride (96 mg, 1.532 mmol) was added and the reaction mixture was stirred for 1 hour. Water (40 mL) was added. The reaction mixture was concentrated. 50 mL of ethyl acetate was added. The layers were separated. The organic layer was washed with water, brine, dried over MgSO4, filtered and evaporated. The oil was purified by preperatory HPLC (10 to 60% AcCN:water with 0.1% formic acid as modifier. Fractions were combined and evaporated. The resulting oil was dissolved in 10 ml of methanol and 5 mL of 1 M NaOH was added portion wise. The solution was stirred for 1 hour until no protected product was visible by LC-MS. The solution was concentrated, and injected on preperatory HPLC (2 to 20% AcCN:water with 0.1% formic acid as modifier. Fractions were combined 6 M HCl was added (12 mL) and evaporated. trans-4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclohexanecarboxylic acid (50 mg, 0.107 mmol, 13.98% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.39 (m, 2H), 7.07-7.29 (m, 3H), 3.67 (d, J=12.63 Hz, 2H), 3.36 (d, J=6.82 Hz, 1H), 3.22 (d, J=6.82 Hz, 2H), 2.98-3.10 (m, 4H), 2.63 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.29 (tt, J=3.54, 12.25 Hz, 1H), 2.01-2.24 (m, 5H), 1.92-2.03 (m, 2H), 1.90 (dt, 1H), 1.69-1.85 (m, 2H), 1.64 (ddd, J=4.29, 6.57, 10.61 Hz, 1H), 1.51 (qd, J=3.16, 13.01 Hz, 2H), 1.33-1.45 (m, 1H), 1.03-1.25 (m, 2H); LC-MS Rt=0.50 min; MS (ESI): 371.3 [M+H]+.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH2:19][CH2:20][CH3:21])(=O)=O)C=CC=CC=1.[OH-].[K+]>CO>[CH2:19]([C:11]1[NH:10][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1)[CH2:20][CH3:21]
Reactant: CCCc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc2cccnc2[nH]1

Procedure:
A mixture of 1-(benzenesulfonyl)-2-propyl-1H-pyrrolo[2,3-b]pyridine (67 mg) and KOH (200 mg) in MeOH (30 mL) was heated to reflux for 3 h. The mixture was concentrated, neutralized by addition of 1N HCl, extracted (EtOAc) and purified (SiO2, 25% EtOAc/hexane) to give 2-propyl-1H-pyrrolo-[2,3-b]pyridine as a solid.
Reaction SMILES: Cl[CH:2]([CH3:24])[C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:23])[CH2:14][C:15]([NH:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=[O:16])=O.O1CCC[CH2:26]1>CN(C)C1C=CN=CC=1>[CH2:24]([CH:2]1[C:3]2=[N:5][C:6]3[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=3[C:13]([OH:23])=[C:14]2[C:15](=[N:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[O:16]1)[CH3:26]
Reactant: CC(Cl)C(=O)Nc1c(F)cccc1C(=O)CC(=O)Nc1nccs1
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Product: CCC1OC(=Nc2nccs2)c2c1nc1c(F)cccc1c2O

Procedure:
Using the procedure of Step B of Example 6, 8.5 g of the product of Step E in 85 ml of tetrahydrofuran and 3.37 g of 4-dimethylamino-pyridine were reacted to obtain 6.5 g of 1,3-dihydro-3-ethyl-1-[(2-thiazolyl)-imino]-5-fluoro-furo[3,4-b]quinoline-9-ol melting towards 210° C.