Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:20][CH3:21])[CH2:3][O:4][C:5]([C:7]1(O)[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH2:8]1)=[O:6].BrC(Br)CCCCCCCCCCC.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][CH:2]([CH2:20][CH3:21])[CH2:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: CCC(C)COC(=O)C1(O)C=CC(c2ccccc2)=CC1
Agent: CCCCCCCCCCCC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)COC(=O)c1ccc(-c2ccccc2)cc1
Yield: 65 %

Procedure:
63 mmols (18 g) of the ester 1a obtained in Examples 1 and 2, 0.12 mol (39.4 g) of dibromododecane and 0.25 mol (34.6 g) of potassium carbonate were refluxed in 600 ml of acetone for 8 hours. The reaction mixture was filtered and the filtrate was concentrated, purified by column chromatography and recrystallized from ethanol to obtain 21.8 g (yield 65%) of 4'-12-bromodoecyloxy) biphenyl-4-carboxylic acid 2-methylbutyl ester {monobromo compound 1d, [α]23D=+2.85 (chloroform)}.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C@@H:6]([OH:29])[C@@H:7]3[C@@H:22]2[CH2:21][C@H:20]([OH:27])[C@@:19]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.O[C@@H]1CC[C@@]2(C)[C@H](C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(O)=O)C1>>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C@H:6]([OH:29])[C@@H:7]3[C@@H:22]2[CH2:21][C@H:20]([OH:27])[C@@:19]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
The procedure of Example 1 is followed except that an equivalent amount of 3α, 7α, 12α-trihydroxy-5β-cholanoic acid (cholic acid) is substituted for the 3α, 7α-dihydroxy-5β-cholanoic acid, to yield 3α, 7β, 12α-trihydroxy-5β-cholanoic acid.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[CH3:26][O:25][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[CH:22][CH:23]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:27]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(I)cc2)cc1)OC
Reactant: OB(O)c1cccnc1
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3cccnc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 270, Step A) and 3-pyridyl boronic acid by following the procedure described for Example 270 (Steps B and C). 1H-NMR (MeOD, 300.15 MHz): δ 8.76 (s, 1H), 8.46 (s, 1H), 8.05 (d, 1H, J=8.1), 7.60 (d, 2H, J=8.7), 7.49 (dd, 1H, J=7.7, 4.8), 7.19 (d, 2H, J=8.5), 7.09 (d, 2H, J=8.7), 6.85 (d, 2H, J=8.5), 4.24 (t, 2H, J=6.1), 4.17 (t, 2H, J=6.3), 3.74 (dd, 1H, J=8.7, 3.8), 3.27 (s, 3H), 2.97 (dd, 1H, J=14.3, 3.8), 2.81 (dd, 1H, J=14.1, 8.5), 2.26 (qn, 2H, J=6.0).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)=[CH2:2].C(O)(=[O:13])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH:1]2[CH2:2][O:13]2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: C=Cc1cccc(OC)c1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 3-vinylanisole (5.0 g, 37.0 mmol) and acetic acid (2.1 mL, 37.0 mmol) in dioxane (33 mL) and H2O (78 mL) at 0° C. was added N-bromosuccinimide (7.30 g, 41.0 mmol) in three portions. The reaction was allowed to warm to RT and then 2M NaOH (50 mL) was added. The reaction was left to stir at RT overnight. The reaction mixture was then partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 5.60 g (100%) of the title compound as a slightly tinted oil.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[CH2:5]([OH:9])[CH:6]([CH3:8])[CH3:7]>>[C:2]([O:9][CH2:5][CH:6]([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)CO
Reactant: C=C(C)C
Product: CC(C)COC(C)(C)C

Procedure:
In the etherification stage, isobutene is reacted with alcohols, preferably with isobutanol, over an acidic catalyst, preferably over an acidic ion exchanger, to give ethers preferably isobutyl tert-butyl ether. According to one embodiment of the invention, the reaction is carried out in a three-stage reactor cascade, in which the reaction mixture flows through flooded fixed-bed catalysts from top to bottom. In the first reactor the inlet temperature is 0 to 60° C., preferably 10 to 50° C.; the outlet temperature is between 25 and 85° C., preferably between 35 and 75° C., and the pressure is 2 to 50 bar, preferably 3 to 20 bar. At a ratio of isobutanol to isobutene of from 0.8 to 2.0, preferably 1.0 to 1.5, the conversion is between 70 and 90%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH2:31]=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: C=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccc(F)cc1)c1ccc2c(Cl)c[nH]c2c1
Product: CN1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccc(F)cc2)CC1

Procedure:
Using alkylation method B, 3-chloro-N-[1-(4-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (373 mg, 0.87 mmol) and paraformaldehyde (520 mg, 17 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 115 mg (30%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][C:32](=[O:37])[CH2:31]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Cc4ccc(F)cc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
A mixture of 3.2 g (12 mmol) of [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid, 1.4 ml (10 mmol) of triethylamine, 1.5 g (10 mmol) of 5-amino-1,3-dihydro-indol-2-one [Tetrahedron, 24, 1376. (1957)] 3.8 g (10 mmol) of HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)] and 100 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated. Then 150 ml of 8% sodium hydrogencarbonate solution and 150 ml of chloroform is added to the mixture. The organic layer is separated and the water phase is extracted three times with 25 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and chloroform:methanol=19:1 as eluent to yield 2.67 g (68%) of the title compound. Melting Point: 195-197° C. (diethylether)
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:13][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:21]([N:18]1[CH2:19][CH2:20][CH:15]([O:14][C:12]2[CH:11]=[CH:10][C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[CH:13]=2)[CH2:16][CH2:17]1)([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)N1CCC(Oc2ccc3sc(C(=O)O)cc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.3 %

Procedure:
The above prepared 5-(1-isopropyl-piperidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid methyl ester (0.222 g, 0.666 mmol) was dissolved in 1.3 mL of THF/ethanol=1/1 and treated with 0.333 mL of aq. NaOH (3M, 1.5 eq.). The mixture was stirred for 2 h at ambient temperature and was then neutralized by adding 0.50 mL of 2M HCl (1.5 eq.). Careful evaporation of all solvents, trituration in diethyl ether, and drying afforded then 0.256 g of the title compound as white solid, contaminated with innocouos inorganic salts.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[OH-].[Na+].[CH:20](Cl)(Cl)[Cl:21]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:21][C:20]1[CH:8]=[N:9][C:10]2[C:6]([C:7]=1[CH2:11][CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1]
Reactant: Cc1cccc2c(CC3CCNCC3)c[nH]c12
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc2c(CC3CCNCC3)c(Cl)cnc12

Procedure:
The operation is as in Example 1, but starting from 9.5 g of 4-[(7-methyl-3-indolyl)-methyl]-piperidine and 0.21 g of triethylbenzylammonium chloride in 100 ml of chloroform, and 12.5 g of sodium hydroxide in solution in 25 ml of water. 5.1 g of 3-chloro-8-methyl-4[(4-piperidyl)-methyl]-quinoline are finally obtained, the monohydrochloride of which melts at 252° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10](F)[CH:9]=[C:8]([F:15])[CH:7]=2)#[N:2].[O:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:22][CH:19]1[CH2:20][CH2:21][O:16][CH2:17][CH2:18]1)[CH:9]=[C:8]([F:15])[CH:7]=2)#[N:2]
Reactant: OC1CCOCC1
Reactant: N#Cc1cnc2cc(F)cc(F)c2c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cnc2cc(F)cc(OC3CCOCC3)c2c1O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of 3-cyano-5,7-difluoro-4-hydroxyquinoline (2.06 g), tetrahydro-2H-pyran-4-ol (1.02 g) and potassium tert-butoxide (1.0M solution in tetrahydrofuran; 30.0 ml) in anhydrous tetrahydrofuran (100 ml) was stirred and heated under nitrogen at 60° C. for 1.5 hours. Acetic acid was added until pH6 was reached and then the solution was evaporated to dryness. The residue was dissolved in aqueous sodium hydroxide solution (2.0M) and the resulting solution was filtered through a GF/A glass fibre pad. The filtrate was acidified to pH5 with acetic acid and the resulting oily precipitate allowed to stand 3 days when it had become solid. The solid was collected and washed with water then air-dried. (1.8 g, 62%); NMR spectrum: (DMSOd6) 1.67 (m, 2H), 1.92 (m, 2H), 3.50 (m, 2H), 3.91 (m, 2H), 4.76 (m, 1H), 6.81 (m, 1H), 6.94 (m, 1H), 8.52 (s, 1H); Mass spectrum: M+H+ 289.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH3:19])[CH2:12][CH2:11]1.Br[C:36]1[S:37][C:38]2[CH:44]=[C:43]([C:45]([N:47]([CH3:60])[CH2:48][CH2:49][CH2:50][N:51]([CH3:59])[C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:46])[CH:42]=[CH:41][C:39]=2[N:40]=1.C(N(CC)CC)C>C(O)CCC>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:36]2[S:37][C:38]3[CH:44]=[C:43]([C:45](=[O:46])[N:47]([CH2:48][CH2:49][CH2:50][N:51]([C:52]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:58])[CH3:59])[CH3:60])[CH:42]=[CH:41][C:39]=3[N:40]=2)[CH3:19])[CH2:14][CH2:15]1
Reactant: CN(CCCN(C)C(=O)c1ccc2nc(Br)sc2c1)C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1nc2ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc2s1
Yield: 63.6 %

Procedure:
The compound (133 mg, 0.298 mmol) obtained in Example 1a and the compound (132 mg, 0.298 mmol) obtained in Example 93b were dissolved in n-butanol (3 mL), triethylamine (62 μL, 0.447 mmol) was added, and the mixture was stirred with heating to reflux for 15 hours. A solution of the compound (133 mg, 0.298 mmol) obtained in Example 1a in n-butanol (2 mL) was added to the reaction mixture, and the mixture was further stirred with heating to reflux for 24 hours. Subsequently, triethylamine (62 μL, 0.447 mmol) was added to the reaction mixture, and the mixture was further stirred with heating to reflux for 24 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=100:0→50:1, v/v) to give the title compound (157 mg; yield, 64%) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[H-].[Na+].[C:17](Cl)(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([O:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])(=[O:19])[CH3:18]
Reactant: CCCc1c(C=O)ccc(OC)c1O
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(C=O)ccc(OC)c1OC(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 3-hydroxy-4-methoxy-2-propylbenzaldehyde (36.6 g) in dry dimethylformamide (50 ml) was added to a suspension of sodium hydride (4.5 g) in dry dimethylformamide (20 ml) in a nitrogen atmosphere. The mixture was stirred at 20° for 30 mins followed by the addition of acetyl chloride (13.5 ml) dropwise over a period of 15 min. The mixture was stirred at 20° for 24 hours.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[N:10](S(C)(=O)=O)[C:4]=2[CH:3]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:15]([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])[NH:10][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)c1cc2cnc(Br)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1cc2cnc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
6-Bromo-2-(diethoxymethyl)-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (Preparation 136, 202 mg, 0.54 mmole) was stirred in methanol (2.4 mL) and 1M sodium hydroxide in water (0.62 mL, 0.62 mmole) was added. The reaction was stirred at 25° C. for 6 hours. The methanol was evaporated and the residue taken up in ethyl acetate (25 mL). The solution was washed with water and brine, the organic layer was concentrated in vacuo to afford the title compound (142 mg, 89%). 1H-NMR (CDCl3, 500 MHz): δ 1.27 (t, J=6.94 Hz, 6H), 3.58-3.72 (m, 4H), 5.73 (m, 1H), 6.59 (m, 1H), 7.48 (m, 1H), 8.65 (s, 1H), 8.84 (br s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[C:21]([CH3:22])=[C:20](Cl)[N:19]=[CH:18][N:17]=1.CC(C)([O-])C.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:20]2[C:21]([CH3:22])=[C:16]([Cl:15])[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1SC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
A mixture of 4-mercapto-piperidine-1-carboxylic acid tert-butyl ester (1.5352 g, 7.06 mmol) and 4,6-dichloro-5-methyl-pyrimidine (1.1512 g, 7.06 mmol) in 15 mL of THF with sodium t-butoxide (1M in THF, 8.3 mL, 8.3 mmol) added dropwise. After 5 min, mixture was concentrated and residue was extracted with CH2Cl2 and H2O. Organic phase was dried over MgSO4, filtered and concentrated to give 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellowish solid (2.3469 g, 97%). Exact mass calculated for C15H22ClN3O2S 343.11, found 344.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C@H:33]([CH3:36])[CH2:34][OH:35]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=[C:16]([NH:32][C@H:33]([CH3:36])[CH2:34][OH:35])[N:17]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: C[C@@H](N)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@H](C)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 18 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and (R)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as a off-white amorphous solid. mp 90-95°, LC MS m/z=441 (MH+) Retention time=2.09 min.
Reaction SMILES: C(N1CCOCC1)C.ClC1C=C(Cl)C(Cl)=CC=1O[C:19](=[O:26])[C@@H:20]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1.Cl.[C:28]([O:32][C:33](=[O:38])[CH2:34][CH2:35][CH2:36][NH2:37])([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[C:28]([O:32][C:33](=[O:38])[CH:34]([C:19](=[O:26])[C@@H:20]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1)[CH2:35][CH2:36][NH2:37])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: O=C1CC[C@@H](C(=O)Oc2cc(Cl)c(Cl)cc2Cl)N1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCN)C(=O)[C@@H]1CCC(=O)N1
Reaction time: 8 h

Procedure:
1.3 ml of N-ethylmorpholine and 3.08 g of L-pyroglutamic acid 2,4,5-trichlorophenyl ester were added to a solution of 1.95 g (10 mmols) of 4-aminobutyric acid tert. butyl ester hydrochloride in 20 ml of dimethylformamide. The solution was left overnight at room temperature. It was concentrated, the residue was dissolved in a mixture of ethyle acetate and water, and the ethyl acetate solution was shaken with sodium bicarbonate solution, KHSO4 -solution and NaCl-solution, dried with Na2SO4 and concentrated. The residue was triturated with petroleum ether.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32](=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1)[CH3:30]>>[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32]([N:23]1[CH2:24][CH2:25][CH:20]([C@@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:33])[CH3:30]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Product: C[C@H](OC(=O)N1CCC([C@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described in Example 1. LC (method 3): tR=1.54 min; Mass spectrum (ESI+): m/z=518 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[CH2:14][NH2:15].[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([C:26](OCC)=[O:27])[N:25]=2)[CH:22]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([C:26]([NH:15][CH2:14][C:4]3[CH:5]=[C:6]([O:9][C:10]([F:12])([F:11])[F:13])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:27])[N:25]=2)[CH:22]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: COc1ccc(OC(F)(F)F)cc1CN
Product: COc1ccc(OC(F)(F)F)cc1CNC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2-methoxy-5-(trifluoromethoxy)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:17]([O-])(O)=O.[Na+]>CO>[CH3:17][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:7]=1[Br:6]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C)ccc1Br
Temperature: 25 °C

Procedure:
1 mL H2SO4 is added to 2-bromo-5-methyl-benzoic acid (7.5 g, 70 mmol) in 75 mL methanol. The reaction mixture is refluxed 16 hours and cooled to room temperature. 100 mL saturated NaHCO3 (aq) is added. Methanol is removed in vacuo. The resulting mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].[CH2:19]([O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)[CH3:20]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:19][CH3:20])=[CH:30][CH:29]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2N)c1
Reactant: CCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1

Procedure:
Using a procedure similar to 1B except starting with N1-(3-cyanobenzoyl)-1,2-benzenediamine, 4-ethoxybenzoyl chloride and triethylamine as base, the title compound was obtained as a white solid (39%); mp: 168-9° C.; IR(KBr): 1645, 1672, 2231, 3377 cm−1; MS(FD): 385(M+). NMR(300 MHz, DMSO-d6): δ1.31 (t, 3 H); 4.07 (quartet, 2 H); 7.03 (d, 2 H); 7.30 (m, 2 H); 7.60 (m, 2 H); 7.72 (t, 1 H); 7.91 (d, 2 H); 8.04 (d, 2 H); 8.21 (d, 1 H); 8.35 (s, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[S:9][C:5]=2[CH:4]=1.[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>OS(O)(=O)=O>[N+:18]([C:17]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:7][C:6]=2[CH:16]=1)([O-:20])=[O:19]
Reactant: COc1ccc2nc(-c3ccccn3)sc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2sc(-c3ccccn3)nc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methoxy -2-(pyridinyl)benzothiazole, 30 g, (0.124 mole) is dissolved in 115 cc of concentrated H2SO4 and cooled to 0°. Nitric acid, 7.9 cc (0.124 mole) is added and the solution stirred for 2 hours at room temperature. The reaction mixture is poured on ice and the pH adjusted to 10 with 50% NaOH solution. The precipitate is filtered and dried to yield 11 g of product.