Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:28][CH2:29][CH2:30][CH3:31]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4]
Reactant: COC(=O)C1CCCN1C(=O)OC(C)(C)C
Reactant: CCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC1(C(=O)OC)CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a stirred solution of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.00 g, 13.1 mmol) in THF (50 mL) at −78° C. and under nitrogen was added LHMDS (14.4 mL of 1.0 M solution in THF, 14.4 mmol) dropwise. After 30 minutes, a solution of 1-iodobutane (2.23 mL, 19.7 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at −78° C., warmed to ambient temperature over 90 minutes, then quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (4.5 g). Purification by chromatography (silica, 10% EtOAc in hexanes) gave 2-butyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.57 g, 9.01 mmol, 69%) as a clear colourless oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C1(P([Pd-4](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)C=CC=CC=1>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]4)[CH:42]=3)[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cnn(C6CCN(C(=O)OC(C)(C)C)CC6)c5)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (0.20 g, 0.40 mmol) in N,N-dimethylformamide (8 mL) and water (2 mL) was added tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.15 g, 0.40 mmol), potassium carbonate (0.22 g, 1.59 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.021 g, 0.018 mmol). The mixture was heated to 100° C. After 1 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated, and the residue purified via silica gel chromatography (5% methanol/dichloromethane elute) to provide 0.15 g (60%) of tert-butyl 4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.C1(N(C)[CH:17]=[O:18])C=CC=CC=1.P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[S:4][C:5]([CH:17]=[O:18])=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: CN(C=O)c1ccccc1
Reactant: COc1csc(OC)n1
Agent: O=C(Cl)Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1nc(OC)c(C=O)s1

Procedure:
To a stirred solution of 2,4-dimethoxythiazole (0.01 mol), which may be prepared as described in Step (a) above, in dichloromethane is added N-phenyl-N-methylformamide (0.01 mol) and phosphorous oxychloride (POCl3, 0.01 mol), or optionally phosgene or trifluoromethanesulfonic acid anhydride instead of POCl3, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated to give 2,4-dimethoxythiazole-5-carboxaldehyde, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]23[CH2:19][N:16]([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.ClCCl>[N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]34[CH2:19][N:16]([CH2:15][CH2:14]3)[CH2:17][CH2:18]4)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccc(C23CCN(CC2)C3)cn1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1cc(N2CCCC2)ncc1C12CCN(CC1)C2
Temperature: 130 °C
Yield: 41.1 %

Procedure:
0.852 g (11.98 mmol) of pyrrolidine is added to a sealed tube comprising 0.060 g (0.29 mmol) of 4-(6-chloropyridin-3-yl)-1-azabicyclo[2.2.1]heptane obtained in stage 5.1 of Example 5. The mixture is heated at 130° C. for 3 hours, cooled to ambient temperature and diluted with 40 ml of toluene and the combined mixture is concentrated under reduced pressure. The residue thus obtained is diluted with 50 ml of dichloromethane and poured into 300 ml of a saturated aqueous sodium carbonate solution. The aqueous phase is extracted twice with 100 ml of dichloromethane, and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 85/15/1.5. 0.029 g of the expected product is obtained in the form of a brown powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH2:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:12]=2)[CH:10]=1)=O)C.[CH3:47][NH2:48]>>[CH3:47][NH:48][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH2:33][CH:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:12]=2)[CH:10]=1)=[O:3]
Reactant: CCOC(=O)c1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CN
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 65 °C

Procedure:
A mixture of 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.07 g, 0.112 mmol) and 40% aqueous methyl amine solution (3 ml) is heated to 65° C. for 12 h. The reaction mixture is concentrated in vacuo and purification of the crude residue by chromatography on silica eluting with 4% methanol in chloroform yields the title compound.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][C@H:11]([CH2:13][CH2:14][CH2:15][C@H:16]([CH2:18][CH2:19][CH2:20]/[C:21](=[CH:23]/[CH2:24][OH:25])/[CH3:22])[CH3:17])[CH3:12])[CH3:7]>C(O)(=O)C.C(OCC)(=O)C>[C:2](=[O:1])([O:25][CH2:24]/[CH:23]=[C:21](/[CH2:20][CH2:19][CH2:18][C@@H:16]([CH2:15][CH2:14][CH2:13][C@@H:11]([CH2:10][CH2:9][CH2:8][CH:6]([CH3:5])[CH3:7])[CH3:12])[CH3:17])\[CH3:22])[NH2:3]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C/C(=C\COC(N)=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
6.6 g of sodium cyanate was added to a solution of 10.0 g of phytol dissolved in 50 ml of acetic acid, in small portions. The resulting mixture was stirred for 6 hours at room temperature. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 50 ml of ethyl acetate. The solution was washed with 3% aqueous sodium hydrogen-carbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: benzene) to obtain 10.0 g (yield: 87%) of oily phytyl carbamate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Li]CCCC.[C:17](=[O:19])=[O:18].O>C1COCC1>[F:11][C:9]1[CH:10]=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[CH:5]2
Reactant: Fc1cc(Br)cc2cc[nH]c12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(F)c2[nH]ccc2c1
Reaction time: 4 h

Procedure:
To a solution of 5-bromo-7-fluoroindole 70f (1.71 mmol, 365 mg) in THF at −60° C. was added n-BuLi (1.6 M solution in hexanes, 5.2 mmol, 3.2 mL). The solution was kept at −60° C. for 4 h and was then poured onto an excess of freshly crushed dry ice. Water was added and the mixture was acidified to pH=4. The organic phase was concentrated and the residue was purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to give compound 70h.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13][CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(C)cc1Br
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(OC)c(C)cc1Br

Procedure:
A mixture of 800 mg of material from step b. 10 ml of dry reagent grade acetone, 456 mg of K2CO3, and excess methyl iodide was stirred a refluxed for 3 days. Ether extraction provided the ester in a form suitable for further transformation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: OCC1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC(CO)CC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidin-4-yl-methanol according to conditions described in general procedure C. 1H NMR (400 MHz, CDCl3) δ 1.05-1.14 (m, 2 H), 1.61-1.70 (m, 9 H), 2.74 (t, J=12.0 Hz, 2 H), 3.26 (t, J=5.5 Hz, 4 H), 3.45 (d, J=5.8 Hz, 2 H), 5.92 (d, J=5.5 Hz, 1 H), 6.74-6.77 (m, 1 H), 6.97 (d, J=7.6 Hz, 1 H), 7.25-7.29 (m, 2 H), 7.46-7.56 (m, 2 H), 7.87-7.89 (m, 2 H), 7.98 (d, J=7.7 Hz, 1 H), 8.22 (s, 2 H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:36].C(N(CC)CC)C.[CH3:44][C:45]([CH3:50])([CH3:49])[C:46](Cl)=[O:47]>ClCCl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][CH2:17][N:18]3[C@H:23]4[CH2:24][CH2:25][C@@H:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14][N:13]([C:46](=[O:47])[C:45]([CH3:50])([CH3:49])[CH3:44])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:36]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc(Cl)c(F)c2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc(Cl)c(F)c2)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 1-(8-{2-[4-(4-chloro-3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by chromatography on silica gel eluting with a dichloromethane to 1:9 methanol:dichloromethane gradient to give 1-((1R,5S)-8-{2-[4-(4-chloro-3-fluorophenyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a white foam (0.11 g, 51%). 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 1H), 7.40 (m, 1H), 7.29 (m, 1H), 7.03-7.19 (m, 4H), 4.72 (m, 1H), 3.90 (m, 2H), 3.33 (m, 4H), 2.59 (s, 3H), 2.42 (m, 2H), 1.78-2.13 (m, 14H), 1.27 (s, 9H). HRMS C33H42ClFN4O m/z 565.3109 (M+H)Cal., 565.3134 (M+H)Obs..
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=O)CC.[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].C1C=CC(CCBr)=CC=1>>[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:20](=[O:25])[C:19]2=[O:26]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Agent: BrCCc1ccccc1
Product: Cc1ccc2c(c1)C(=O)C(=O)N2CCc1ccccc1

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using 5-methyl isatin (purchased from Fisher Scientific) and 2-phenethyl bromide (purchased from Fisher Scientific).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12]([CH3:17])[CH2:11]2)=C([CH:9]=1)C#N.[OH-].[K+].O.[C:21]([O:24]CC)(=[O:23])[CH3:22]>COCCOCCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:11][CH:12]([CH3:17])[CH2:13][CH:14]([CH3:16])[CH2:15]2)=[C:22]([CH:9]=1)[C:21]([OH:24])=[O:23]
Reactant: CC1CC(C)CN(c2ccc(Cl)cc2C#N)C1
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCO
Solvent: O
Product: CC1CC(C)CN(c2ccc(Cl)cc2C(=O)O)C1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzonitrile (1.05 g, 4.220 mmol) in Diethylene glycol monomethyl ether (2.50 mL) was added KOH (0.947 g, 16.883 mmol) and water (0.750 ml). The reaction was heated at 130–135° C. overnight. Upon cooling to rt, water and ethyl acetate was added the organic layer was discarded and the aqueous layer is acidified to pH˜6–7. The aqueous layer was then extracted with ethyl acetate three times. The combined organic layer was washed with water, brine, dried (Na2SO4), and concentrated to give required 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.850 g, 75%) as an off white solid. LCMS 268(M+1)+.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[CH3:2].[NH2:20][C@@H:21]([CH3:38])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[C:34]([F:36])[C:31]([C:32]#[N:33])=[C:30]([Cl:37])[CH:29]=2)=[N:24]1>>[C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([NH:20][C@@H:21]([CH3:38])[CH2:22][N:23]2[CH:27]=[CH:26][C:25]([C:28]3[CH:35]=[C:34]([F:36])[C:31]([C:32]#[N:33])=[C:30]([Cl:37])[CH:29]=3)=[N:24]2)=[O:11])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (400 mg, 1.4 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (389 mg, 1.4 mmol). The product was purified with flash chromatography. Yield 260 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.09 (s, 9H), 0.81 (t, 2H), 1.15 (d, 3H), 2.61 (s, 3H), 3.48 (t, 2H), 4.33-4.48 (m, 3H), 5.66 (s, 2H), 7.02 (d, 1H), 7.84-7.87 (m, 2H), 7.95 (s, 1H), 8.06 (s, 1H), 8.15 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+].[Br:20]Br>CO>[Br:20][C:4]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: Nc1cc(-c2ccccc2)c(Cl)nn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1nnc(Cl)c(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a suspension of 6-chloro-5-phenylpyridazin-3-amine (1.01 g, 4.9 mmol) from 1a in methanol (25 mL) under nitrogen was added NaHCO3 (1.09 g, 13.0 mmol). At 0° C., bromine (0.55 M in methanol, 10 mL, 5.5 mmol) was added over 5 min. After 1 h, the cold bath was removed, and the reaction mixture was stirred at room temperature for 6 h. After concentrating in vacuo, the residue was taken up in CH2Cl2 and saturated aqueous Na2S2O5, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give crude 4-bromo-6-chloro-5-phenylpyridazin-3-amine (1.28 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
A mixture of methyl 4-hydroxy-benzoate (10.0 g, 0.066 mol) and potassium carbonate (12 g, 0.086 mol), were taken in acetone (50 ml) and heated at 50° C. for 1 hour. To the reaction mixture benzyl bromide (8.2 ml, 0.072 mol) was added. The mixture was heated at 80° C. for 5 hours. The mixture was cooled to room temperature and filtered through sintered funnel, washed with acetone. Solvent was removed to obtain pure 4-benzyloxy-benzoic acid methyl ester as white solid (16 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[OH:11].Cl.[CH3:13][NH:14][O:15][CH3:16]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:8])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)c1ccc(F)c(O)c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)c(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 4-fluoro-3-hydroxybenzoic acid (1.49 g, 9.55 mmol) in DCM (40 mL) was added TEA (1.2 mL, 8.61 mmol) followed by N,O-dimethylhydroxylamine hydrochloride (1.12 g, 11.5 mmol). The reaction mixture was stirred at room temperature for 3 h, then diluted with DCM, washed with water twice, dried over Na2SO4, filtered and concentrated to yield 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide as a colorless oil (1.90 g, 100% yield). LCMS: RT=0.89 min [M+H] 200.10 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C1COCCN1
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)O
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)N1CCOCC1
Yield: 93.5 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid (0.2 g, 0.66 mmol), prepared from the step 4 of the example 5, and morpholine (0.058 g, 0.66 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-methylphenoxy)-1-morpholinoethanone as a white solid (0.228 g, 92.7% yield).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Cl:23])C(=O)C1.Cl(O)(=O)(=O)=O.O>C(Cl)(Cl)Cl>[Cl:23][C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=1
Reactant: COC(=O)c1ccsc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Cl)sc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-phenylthiophene-3-carboxylate and NCS in CHCl3 was added perchloric acid, followed by stirring at 50° C. for overnight. To the reaction mixture was added water, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue obtained was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 5-chloro-2-phenylthiophene-3-carboxylate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:13])[C:9]([O:11]C)=[O:10].[Li+].[OH-]>C1COCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C(=O)O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.9 %

Procedure:
Methyl 2-(2-fluorophenyl)propanoate (26.2 g, 0.144 mol) was dissolved in THF (325 ml) and LiOH (1 M, 173 ml) added. The reaction mixture was stirred at room temperature for 2.5 h, before diluting with diethyl ether and extracting with water and 1N NaOH. The aqueous layer was acidified and extracted with ethyl acetate (×2). The organic extract was washed with brine, dried and evaporated to yield 2-(2-fluorophenyl)propanoic acid (22.5 g, 100%) as an oil.
Reaction SMILES: [C:1]([NH:9][C:10](=[O:30])[NH:11][C:12]1[S:22][C:15]2[CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH2:19][C:14]=2[C:13]=1[C:23]([O:25]C(C)(C)C)=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([NH:9][C:10](=[O:30])[NH:11][C:12]1[S:22][C:15]2[CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH2:19][C:14]=2[C:13]=1[C:23]([OH:25])=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)NC(=O)c2ccccc2)sc2c1CC(C)(C)OC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)Cc2c(sc(NC(=O)NC(=O)c3ccccc3)c2C(=O)O)CO1
Temperature: 25 °C
Reaction time: 120 h
Yield: 6.7 %

Procedure:
To a solution of tert-butyl 2-(3-benzoylureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.105 g, 0.24 mmol, 1 equiv.) in DCM (10 mL) was added TFA (0.5 mL, 6.5 mmol, 27 equiv.), and the reaction was stirred at rt for 5 days. The solvent was removed under reduced pressure and the product was purified by preparatory HPLC (0-5% MeOH/DCM), followed by mass-directed reverse-phase chromatography and isolated as a white solid (6 mg, 7% yield). 1H NMR (400 MHz, DMSO) δ 13.11 (s, 1H), 11.39 (s, 1H), 8.05-7.99 (m, 2H), 7.69-7.63 (m, 1H), 7.55 (t, J=7.7 Hz, 2H), 4.62 (s, 2H), 2.71 (s, 2H), 1.22 (s, 6H). LCMS retention time: 2.872 min; LCMS purity at 215 nm=100%. HRMS m/z calculated for C18H19N2O5S [M++1]: 375.1009. found 375.1013.