Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:19]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][CH2:2][CH2:3]1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: C1COCCOCCNCCOCCOCCN1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)N1CCOCCOCCN(C(=O)C(C)(C)C)CCOCCOCC1

Procedure:
Analogously to Example 2 from 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane and pivalyl chloride.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH3:17])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([CH3:24])=[N:13]2)=[CH:8][CH:7]=1)=[N+]=[N-]>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:24][C:14]1[C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:16]([CH3:17])[N:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH2:1])=[CH:11][CH:10]=2)[N:13]=1
Reactant: Cc1nn(-c2ccc(CCN=[N+]=[N-])cc2)c(C)c1-c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: Cc1nn(-c2ccc(CCN)cc2)c(C)c1-c1ccccc1
Reaction time: 5 h
Yield: 91.9 %

Procedure:
To a solution of 1-[4-(2-azidoethyl)phenyl]-3,5-dimethyl-4-phenyl-1H-pyrazole (step 2, 196 mg, 0.62 mmol) in methanol (10 mL) was added Lindlar catalyst (100 mg). The resulting mixture was stirred for 5 h under hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated to give 166 mg (92%) of the title compound as colorless oil: MS (ESI) m/z 292 [M+H]+, 1H-NMR (CDCl3) δ 7.47-7.39 (4H, m), 7.34-7.29 (5H, m), 3.01 (2H, t, J=6.8 Hz), 2.81 (2H, t, J=6.8 Hz), 2.34 (3H, s), 2.30 (3H, s).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OC([N:21]1[CH:25]=[C:24]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:36]3[CH2:40][C:39]([C:45]4[CH:50]=[C:49]([Cl:51])[CH:48]=[C:47]([Cl:52])[CH:46]=4)([C:41]([F:44])([F:43])[F:42])[O:38][N:37]=3)=[CH:28][CH:27]=2)[CH:23]=[N:22]1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[Cl:51][C:49]1[CH:50]=[C:45]([C:39]2([C:41]([F:43])([F:42])[F:44])[O:38][N:37]=[C:36]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([C:24]4[CH:23]=[N:22][NH:21][CH:25]=4)=[CH:27][CH:28]=3)[CH2:40]2)[CH:46]=[C:47]([Cl:52])[CH:48]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(-c3cn[nH]c3)c3ccccc23)=NO1

Procedure:
Trifluoroacetic acid anhydride (0.18 ml) is added to a solution of 4-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalen-1-yl}-pyrazole-1-carboxylic acid tert-butyl ester (135 mg) in dichloromethane (1 ml). After 1 hour at room temperature an aqueous solution of sodium hydroxide (30%) is added. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-(3,5-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-naphthalen-1-yl]-5-trifluoromethyl-4,5-dihydro-isoxazole as a colorless solid: m.p. 117-120° C. (compound 1.17, table 1).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>CS(C)=O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:5]=1
Reactant: BrCCCCCCBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1cncc(OCCCCCCOc2cccnc2)c1
Temperature: 0 °C

Procedure:
Sodium hydride (1.32g.) was added portionwise under an atmosphere of nitrogen during 30 minutes, to a stirred solution of 3-hydroxypyridine (2.85g.) in dry dimethylsulphoxide (28ml.) cooled to below 25°C. When reaction ceased, 1,6-dibromohexane (3.66g.) was added dropwise with stirring and cooling, and the resulting mixture was stirred a further 31/2 hours. The mixture was poured into ice-water, and the precipitated product was filtered off and crystallised from petroleum ether (b.p.60°- 80°C.), to give 1,6-bis-pyrid-3-yloxyhexane, m.p. 85°C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C:21](OC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1SC(C2C=C(F)C=CC=2F)=NC=1C(OCC)=O)C1C=CC=CC=1.[Li+].[BH4-]>C1COCC1>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH2:21][OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Agent: CCOC(=O)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of a mixture of methyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate and ethyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate (7.8 g, 21.70 mmol) in THF (72.3 mL) was slowly added LiBH4 (0.946 g, 43.4 mmol) at room temperature. The reaction mixture was stirred for overnight. After quenched with water, the reaction mixture was extracted with EtOAc. The organic layers was washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to yield (5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)methanol (6.66 g, 97%) as white solid. LC/MS (uplc): MH+ 318.2, 1.03 min.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([CH2:21][OH:22])=[N:15][C:14]=2[N:13]([CH3:23])[C:11]1=[O:12])(=[O:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:1]([O:4][C@H:5]([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:25])[C:16]([CH2:21][OH:22])=[N:15][C:14]=2[N:13]([CH3:23])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(CO)nc2n(C)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CO)n2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a stirred suspension of (R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3-methylxanthine (6.35 g, 18.8 mmol) and potassium carbonate (5.2 g, 38 mmol) in dimethylformamide (55 ml) was added methyl iodide (4.0 g, 28.2 mmol). After stirring overnight at room temperature, the mixture was poured into ice cold water (250 ml) and stirred at 0-5° C. for 1 hour. The precipitate was filtered, rinsed with water (5×25 ml), and dried under vacuum to provide (R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3,7-dimethylxanthine (6.3 g, 95% yield) as a white solid.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[F-].[C:14]([C:17](=[N:22][O:23][CH2:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19])(=[O:16])[NH2:15].C(N(CC)CC)C>C(Cl)Cl.O>[NH:15]=[C:14]([O:16][CH2:6][CH3:7])[C:17](=[N:22][O:23][CH2:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC[O+](CC)CC
Reactant: CCON=C(C(N)=O)C(=O)OC
Agent: F[B-](F)(F)F
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCON=C(C(=N)OCC)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Meerwein reagent (triethyloxonium tetrafluoroborate) {prepared from bron fluoride etherate (2.84 g) by a method of Org. Syn., 46, 113 (1966)} in methylene chloride (30 ml) was added methyl 2-carbamoyl-2-ethoxyiminoacetate (syn isomer, 2.6 g) and the mixture was stirred for 18 hours at room temperature. The reaction mixture was cooled in an ice-bath and triethylamine (3 g) was added thereto, followed by an addition of water (20 ml). The organic layer was separated out, dried over magnesium sulfate and evaporated to give crude methyl 3-imino-3-ethoxy-2-ethoxyiminopropionate (syn isomer) (5.0 g) as an oil. ##STR15##
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:20][S:21]([N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH2:30][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[CH2:25][CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Product: CS(=O)(=O)N1CCCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using procedure C yielded 2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: COC(C1C=C(Cl)C2N([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)N=2)C=1)=O.[Br:39][C:40]1[CH:41]=[C:42]([O:47][CH3:48])[C:43]([NH2:46])=[N:44][CH:45]=1>>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:46]=[C:43]4[C:42]([O:47][CH3:48])=[CH:41][C:40]([Br:39])=[CH:45][N:44]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22][CH2:23]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1cc(Br)cnc1N
Reactant: COC(=O)c1cc(Cl)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Product: COc1cc(Br)cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12

Procedure:
This intermediate was prepared in analogy to 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-8-chloro-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester by using 5-bromo-3-methoxy-pyridin-2-ylamine from Step 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([C@@](O)([C@@H](O)[C@H](O)[C@H](O)CO)C(N)=O)=[CH:16][CH:15]=1.[NH2:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36].C[N:40]([CH:42]=[O:43])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[C:18]([NH:40][C:42]([NH:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36])=[O:43])[CH:17]=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc([C@](O)(C(N)=O)[C@@H](O)[C@H](O)[C@H](O)CO)cc2)C1
Reactant: NC(CO)CO
Reactant: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)NC(CO)CO)c2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.02 g (2.0 mmol) of 4-nitrophenyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]carbamate hydrochloride (intermediate 1) were dissolved in 30 ml of abs. DMF and admixed at 0° C. with a solution of 200.5 mg (2.2 mmol) of 2-amino-1,3-propanediol in 25 ml of abs. DMF. The mixture was stirred at room temperature for 3 hours. After standing overnight, the solvent was removed in vacuo and the residue partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was removed and the aqueous extracted twice more with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over Na2SO4 and concentrated. Chromatography of the crude product obtained in this way on silica gel (dichloromethane/methanol mixture) afforded 500 mg of the desired urea.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C@@H:6]1[CH2:11][O:10][CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[N:24]1[N:25]([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](O)=[O:32])[N:26]=[CH:27][CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C@@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:31]([C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[N:25]1[N:26]=[CH:27][CH:28]=[N:24]1)=[O:32]
Reactant: Ic1cccc(C[C@@H]2COCCN2)c1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1-n1nccn1)N1CCOC[C@H]1Cc1cccc(I)c1
Reaction time: 22 h

Procedure:
A solution of (R)-3-(3-iodo-benzyl)-morpholine B-5 (100 mg, 0.33 mmol) and DIPEA (57 μL, 0.33 mmol) in DMF (1.5 mL) was added to a RT solution of 2-(2H-1,2,3-triazol-2-yl)benzoic acid E-2 (62 mg, 0.33 mmol), TBTU (111 mg, 0.35 mmol) and DIPEA (57 μL, 0.33 mmol) in DMF (1.5 ml) under argon and the resulting mixture was stirred for 22 h. The reaction mixture was quenched with sat. aq. NaHCO3 and stirred for 10 min before being diluted with water and extracted with DCM (3×). The combined organic extracts were washed with 2M aq. NaOH (1×), 2M aq. HCl (1×) and brine (1×), dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method F) to give the title compound as a white solid. LC-MS D: tR=0.93 min; [M+H]+=474.91.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][CH:31]=1>>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)(=[O:38])[CH3:37]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)c1ccc(Br)cc1
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (329 mg, 0.83 mmol) is coupled to 4′-bromoacetophenone (200 mg, 1.00 mmol) using Method B to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][C:17](=[O:31])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCO.C(OCC)C>CCO>[F:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:18]1[C:19]2[C:15](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][CH:20]=2)[CH2:16][C:17]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CC(=O)N3Cc2cccc(F)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: O=C1Cc2c(N3CCNCC3)cccc2N1Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
4-[1-(3-Fluoro-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (115 mg) was dissolved in 2 mL of EtOH and 500 uL of 2.0 N HCl/EtOH was added. The solution was heated to reflux on a steam bath for 30 minutes and then cooled to room temperature. Diethyl ether was added slowly to precipitate 1-(3-Fluoro-benzyl)-4-piperazin-1-yl-1,3-dihydro-indol-2-one as a hydrochloride salt. MS: 326 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH2:21]O)[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH2:21][N:46]4[C:45](=[O:47])[C:44]5=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]5[C:42]4=[O:52])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cccc(OCc2nc(-c3ccc(Cl)cc3)cs2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(OCc2nc(-c3ccc(Cl)cc3)cs2)c1
Reaction time: 16 h

Procedure:
The phenylmethylalcohol compound (1.98 grams) (Scheme C, Compound C1) was dissolved in tetrahydrofuran (100 mL). Triphenylphosphine (1.84 grams), phthalimide (1.03 grams) and diethylazodicarboxylate (1.10 mL) were added to the mixture which was then stirred for 16 hours before being evaporated in vacuo. The residue was column chromatographed (silica gel) using a mobile phase of hexane-ethyl acetate 2:1 to give a N-[3-[[4-(4-chlorophenyl)-2-thiazolyl]methoxy]phenylmethyl]phthalimide (Scheme C, Compound C2). Mp 156.5–157.5° C.; MS 461 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:32]([O:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:7]2)(=[O:24])=[O:23])=[CH:30][CH:29]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(CCCOc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (4.0 g, 7.9 mmol) dissolved in THF:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (79%); off white powder; mp 191° C.; MS: 476.5 (M+H)+.
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][CH:14]=[CH:13][C:12]=1[F:17])=O.[CH2:18]([O:20][C:21](=[O:28])[CH2:22][C:23](=O)[CH:24]([CH3:26])[CH3:25])[CH3:19]>>[CH2:18]([O:20][C:21]([C:22]1[C:23]([CH:24]([CH3:26])[CH3:25])=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[CH:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)=[O:28])[CH3:19]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccccc1F
Product: CCOC(=O)c1c(C(C)C)nc2cc(Cl)ccc2c1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 6 step A from a mixture of (2-amino-4-chloro-phenyl)-(2-fluoro-phenyl)-methanone and 4-methyl-3-oxo-pentanoic acid ethyl ester. White solid. MS (ESI): 372.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([CH3:16])[CH:9]=2)[C:3]=1[CH3:17].Br>C(O)(=O)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:16])[CH:9]=2)[C:3]=1[CH3:17]
Reactant: COc1ccc(-c2nn(C)c(Cl)c2C)cc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(-c2nn(C)c(Cl)c2C)ccc1O
Yield: 79.4 %

Procedure:
A mixture of 5-chloro-3-(4-methoxy-3-methyl-phenyl)-1,4-dimethyl-1H-pyrazole (described in Reference Preparation example 92) 0.4 g, 47% hydrobromic acid 3 ml and acetic acid 3 ml was stirred with heating under reflux for fifteen hours. The solvent was distilled off and to the resulting residues was added ethyl acetate 20 ml, and the resulting mixture was stirred at room temperature for one hour. The precipitates were filtered and were washed with hexane, and were concentrated under reduced pressure to give 4-(5-chloro-1,4-dimethyl-1H-pyrazol-3-yl)-2-methyl-phenol 0.3 g.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH3:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH:9]=1>O>[CH:4]([O:6][C:8]1[N:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[CH:21]=[CH:22][C:23]([C@@H:26]([NH:28][C:29]([CH:31]4[CH2:32][CH2:33]4)=[O:30])[CH3:27])=[CH:24][CH:25]=3)[CH2:18][CH2:19]2)[CH:9]=1)([CH3:5])[CH3:3]
Reactant: C[C@H](NC(=O)C1CC1)c1ccc(C2CCN(c3cc(Cl)ncn3)CC2)cc1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(N2CCC(c3ccc([C@H](C)NC(=O)C4CC4)cc3)CC2)ncn1
Temperature: 80 °C

Procedure:
25 mg (1.04 mmol) Sodium hydride are added to 2 mL 2-propanol and heated at 80° C. for 10 min. After that time, 80 mg (0.21 mmol) (S)-cyclopropanecarboxylic acid (1-{4-[1-(6-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-ethyl)-amide (XIV.6) are added. The mixture is heated at 80° C. for 12 h. After that time, water is added and the mixture is extracted with dichloromethane. The solvent is evaporated and the residue is purified using reversed phase HPLC (column: Waters XBridge 5 μM; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.N1C=CC=CC=1C1C=C[C:22]([CH:23]=[O:24])=CC=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:22]/[CH:23]=[O:24])=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: O=Cc1ccnc2ccccc12
Product: O=C/C=C/c1ccnc2ccccc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 31 by substituting 4-quinolinecarboxaldehyde for the 4-(2-pyridinyl)-benzaldehyde of Reference Example 31. MS 184 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10](N(CC)CC)[CH3:11].C(OC(=O)C)(=O)C>ClCCl>[CH2:10]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:11]
Reactant: CCN(CC)CC
Reactant: NCCN1CCCCC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCNCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79 %

Procedure:
To a solution of 1-(2-aminoethyl)piperidine(5.01 g) in dichloromethane (100 ml) were added triethylamine(11 ml) and acetic anhydride(4.4 ml) and then the mixture was stirred at room temperature for 40 minutes. The reaction solution was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated under a vacuum. The residue was dropped into a suspension of lithium aluminium hydride (3.46 g) in tetrahydrofuran(100 ml). After being refluxed with heating for 1 hour, the reaction mixture was filtrated. The filtrate was concentrated, thereby yielding 4.43 g(79%) of 1-[2-(ethylamino)ethyl]piperidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Si](C)(C)C)=[CH:27][C:26]=3[F:35])[C:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:36]Cl>C(Cl)Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([I:36])=[CH:27][C:26]=3[F:35])[C:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClI
Reactant: CC(C)(C)OC(=O)c1ccc2c(cnn2C(=O)OC(C)(C)C)c1Nc1ccc([Si](C)(C)C)cc1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc2c(cnn2C(=O)OC(C)(C)C)c1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a solution of 4-(2-fluoro-4-trimethylsilanylphenylamino)-indazole-1,5-dicarboxylic acid di-tert-butyl ester (1.07 g, 2.14 mmol) in DCM (10 mL) at 0° C. was added iodine monochloride as a solution in DCM (4.2 mL, 1N, 4.2 mmol). The reaction mixture was stirred at 0° C. for 20 minutes then diluted with saturated aqueous sodium thiosulfate solution (10 mL) and extracted with DCM (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-100% DCM in cyclohexane) to yield the title compound as a pale brown solid (611 mg, 52%). LCMS (Method B): RT=5.48 min, [M+H]+=554.