Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18])=[CH:3][C:4]=1[CH3:11])([O-:10])=[O:9]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(NCCNCCO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 42.1 %

Procedure:
2 g of 4-fluoro-2-methyl-nitrobenzene, 1.61 g of 2-(2-aminoethylamino)ethanol and 2.14 g of K2CO3 were added to a solution of 20 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 7 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 1.3 g of 2-[2-(4-nitro-3-methylphenylamino)ethylamino]ethanol (7) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][N:27]=[CH:28]2>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][N:27]=[CH:28]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2cnccc12
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2cnccc12)C(F)(F)F

Procedure:
Analogously to Example 20, 500 mg (1.6 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 500 mg (1.9 mmol) of 5-aminoisoquinoline in 16 ml of acetic acid are reacted to form 4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(isoquinolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-ol and subsequently reduced with 509 mg (2.4 mmol) of sodium triacetoxy borohydride. After chromatography on silica gel with hexane-ethyl acetate (0-60%), 221 mg of product is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C(N(CC)CC)C.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:28][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(C#Cc2cccc(N)c2)ccn1
Temperature: 70 °C
Yield: 15.5 %

Procedure:
tert-Butyl (4-bromopyridin-2-yl)carbamate (1.935 g, 7.09 mmol), copper(I) iodide (0.67 g, 3.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.20 g, 0.28 mmol) were stirred in tetrahydrofuran (22 mL) with triethylamine (1.09 mL, 7.82 mmol) under N2 at rt. 3-Ethynylaniline (0.815 mL, 7.79 mmol) was added and the mixture was heated at 70° C. for 2 hours and only very little product was observed. Thus more 3-ethynylaniline (0.41 mL, 3.9 mmol) was added and the mixture was heated at 70° C. over the weekend. The reaction mixture was filtered and concentrated to give a brown residue, which was purified by silica gel column chromatography to give the desired product (340 mg, 16%). LCMS for C18H20N3O2 (M+H)+: m/z=310.1
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:51][CH2:52][CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])(=O)=O)=CC=1>>[F:62][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[CH2:55][O:54][CH2:53][CH2:52][CH2:51][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCOCc2ccccc2F)cc1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4F)cc3)cc21

Procedure:
Analogously to Method I, 0.250 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 259b) and 0.185 g of 3-(2-fluorobenzyloxy)propyl toluene-4-sulphonate are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.27 (1:1 EtOAc-heptane); Rt=6.04.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10](=[O:11])[N:9]([CH2:12][O:13][CH3:14])[CH:8]=[C:7]([S:15][CH2:16][CH2:17][C:18](OC)=O)[CH:6]=1.CC(C)([O-])C.[K+].Cl[CH2:29][C:30]1[CH:35]=[CH:34]C(CC)=[CH:32][CH:31]=1>C1COCC1>[CH2:35]([C:30]1[CH:29]=[CH:18][C:17]([CH2:16][S:15][C:7]2[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10](=[O:11])[N:9]([CH2:12][O:13][CH3:14])[CH:8]=2)=[CH:32][CH:31]=1)[CH3:34]
Reactant: CCc1ccc(CCl)cc1
Reactant: COCOc1cc(SCCC(=O)OC)cn(COC)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
To a solution of methyl 3-{[5-(methoxymethoxy)-1-(methoxymethyl)-6-oxo-1,6-dihydropyridin-3-yl]sulfanyl}propanoate (Intermediate 16) (290 mg, 0.91 mmol) in THF (5 ml) at −45° C. was added potassium tert-butoxide (113 mg, 1.01 mmol) and the resulting mixture allowed to stir for 20 minutes. 1-(Chloromethyl)-4-ethylbenzene (170 mg, 1.10 mmol) was then added and the reaction mixture allowed to warm to room temperature and stirred for 4 hours before being quenched with water and extracted into dichlormethane. The combined organics were concentrated and subjected to column chromatography (SiO2; 0-10% methanol in dichloromethane) to yield 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (253 mg, 79%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:37][CH2:38][O:39][CH3:40])=[C:14]([NH:16][C:17]2[C:18]([NH:27][S:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)(=[O:30])=[O:29])=[N:19][C:20]3[C:25]([N:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([N:34]1[CH2:35][CH2:36][CH:31]([S:28]([NH:27][C:18]2[C:17]([NH:16][C:14]3[CH:15]=[C:10]([O:9][CH3:8])[CH:11]=[CH:12][C:13]=3[CH2:37][CH2:38][O:39][CH3:40])=[N:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)(=[O:30])=[O:29])[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: COCCc1ccc(OC)cc1Nc1nc2ccccc2nc1NS(=O)(=O)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1ccc(OC)cc1Nc1nc2ccccc2nc1NS(=O)(=O)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
Acetic anhydride (21 mg; 0.2 mmol; 1.2 eq) is added to a suspension of N-(3-{[5-methoxy-2-(2-methoxyethyl)phenyl]amino}quinoxalin-2-yl)piperidine-4-sulfonamide (100 mg; 0.17 mmol; 1 eq) in DCM (10 mL), followed by Et3N (0.06 mL; 0.43 mmol; 2.5 eq) and the reaction mixture is stirred at room temperature for 2 h. The solution is diluted to 30 mL with DCM, washed successively with 0.1 M HCl and brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. The residue is recrystallised from a mixture of DCM/n-pentane to afford 59 mg (67%) of the title compound as a pale yellow solid. 1H NMR (DMSO-d6) δ 12.25 (s, 1H), 9.15 (s, 1H), 7.95-7.81 (m, 2H), 7.50-7.44 (m, 1H), 7.37-7.26 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 6.71 (dd, J=8.4, 2.6 Hz, 1H), 4.53 (br d, J=12.8 Hz, 1H), 3.97 (br d, J=13.3 Hz, 1H), 3.78 (s, 3H), 3.60-3.36 (m, 3H), 3.25 (s, 3H), 3.10 (br t, J=12.0 Hz, 1H), 2.78 (t, J=6.0 Hz, 2H), 2.58 (br t, J=12.7 Hz, 1H), 2.19 (br d, J=12.7 Hz, 2H), 2.02 (s, 3H), 1.80-1.50 (m, 2H). HPLC (max plot) 99%; Rt 3.85 min. UPLC/MS (ES+) 512.2, (ES−) 512.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ncn2)cc1
Reaction time: 16 h

Procedure:
4-Chloro-6-(4-nitro-phenoxy)-pyrimidine (1 g, 3.97 mmol), p-anisidine (514 mg, 4.178 mmol), and diisopropylethylamine (0.715 mL, 4.178 mmol) dissolved in 2-propanol (27 mL) are stirred under reflux under Ar. After 16 h, p-anisidine (245 mg, 1.99 mmol) is added and the reaction mixture is stirred for additional 20 h. After cooling the reaction mixture down to rt, compound of Stage 47.2 precipitates as white crystals: M+H=339.1; 1H-NMR (400 MHz, DMSO-d6): 9.49 (s, 1H, NH-pyrimidinyl), 8.25 (s, 1H, pyrimidine), 8.23/7.40/6.90 (d/d/d/, 9.0 Hz, 2H/4H/2H, phenyl-oxolphenyl-OMe), 6.18 (s, 1H, pyrimidinyl), 3.72 (s, 3H, CH3—O); Rf (MeOH/CH2Cl2=1:9): 0.44; HPLC (System 1): 6.15 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:18])[C:5]2[CH:11]=[C:10]([C:12]#[CH:13])[C:9](=[O:14])[N:8]([CH:15]([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[CH2:19]([N:21]([CH2:29][CH3:30])[C:22](=[O:28])[O:23][CH2:24][N:25]=[N+:26]=[N-:27])[CH3:20]>S([O-])([O-])(=O)=O.[Cu+2].CC(O)(C)C.O>[CH2:29]([N:21]([CH2:19][CH3:20])[C:22](=[O:28])[O:23][CH2:24][N:25]1[CH:13]=[C:12]([C:10]2[C:9](=[O:14])[N:8]([CH:15]([CH3:16])[CH3:17])[C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:18])[C:5]=3[CH:11]=2)[N:27]=[N:26]1)[CH3:30]
Reactant: CCN(CC)C(=O)OCN=[N+]=[N-]
Reactant: C#Cc1cc2c(C)nc(N)nc2n(C(C)C)c1=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCN(CC)C(=O)OCn1cc(-c2cc3c(C)nc(N)nc3n(C(C)C)c2=O)nn1
Reaction time: 24 h
Yield: 68.5 %

Procedure:
2-amino-6-ethynyl-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (75 mg, 0.31 mmol) and azidomethyl diethylcarbamate (80 mg, 0.46 mmol) was suspended in 1:1 t-BuOH/H2O (4 mL). To this was added saturated copper sulfate solution (0.05 mL) and stirring was continued for 24 h. The mixture was concentrated and diluted with 5 mL water. The mixture was separated and the organic phase was washed with water and evaporated. Flash chromatography of the residue over silica gel, using 0-5% MeOH/CHCl3, gave the title compound (88 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCN1CCC(NC(=O)c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.7 %

Procedure:
4-amino-3-fluorobenzoic acid (2.115 g, 13.6 mmol), 4-Amino-1-Ethyl Piperidine (Fluorochem; 1.923 g, 15 mmol), HATU (5.7 g, 15 mmol) and DIPEA (7.1 mL, 40.8 mmol) were combined in DMA (60 mL) and the resulting yellow solution stirred at room temperature for 20 minutes. The reaction was left over the weekend at room temperature, solvent evaporated and the residue dissolved in methanol (10 mL) and loaded onto an SCX-2 column (50 g) which pre-wet with MeOH (40 mL), flushed with MeOH (4×30 ml) and eluted with 7N ammonia in MeOH (4×30 mL). Product containing, ammoniacal fractions were combined to yield the title compound as a brown solid (0.819 g, 22%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].Br[CH2:14][CH:15]1[CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:12])[CH3:11])=[C:2]([O:1][CH2:14][CH:15]2[CH2:17][O:16]2)[CH:7]=1
Reactant: CC(=O)Nc1ccc(C)cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C)cc1OCC1CO1
Temperature: 55 °C
Yield: 41.7 %

Procedure:
A mixture of N-(2-hydroxy-4-methylphenyl)acetamide (10 g, 60 mmol), 2-(bromomethyl)oxirane (9.86 g, 72 mmol, 6.0 ml) and potassium carbonate (16.8 g, 120 mmol) in DMF (100 ml) was heated at 55° C. for 2 h. Then the reaction mixture was diluted with ethyl acetate and washed with aq. HCl (1.5%), aq. sat. NaHCO3, and brine. Evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 35 to 70%) afforded the title compound (5.65 g, 25 mmol, 43%).
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([C:29]1[N:34]=[CH:33][C:32]([C:35]2[CH:36]=[N:37][N:38](C3CCCCO3)[CH:39]=2)=[CH:31][N:30]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[N:14]=2)[C@H:10]([CH2:27][CH3:28])[CH2:9]1.Cl.CO.C([O-])(O)=O.[Na+]>ClCCl>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:50])([F:52])[F:51])[CH:48]=1)[CH2:6][N:7]([C:29]1[N:30]=[CH:31][C:32]([C:35]2[CH:39]=[N:38][NH:37][CH:36]=2)=[CH:33][N:34]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[N:14]=2)[C@H:10]([CH2:27][CH3:28])[CH2:9]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C4CCCCO4)c3)cn2)CN1c1nc(N2CCC(O)CC2)ncc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cn[nH]c3)cn2)CN1c1nc(N2CCC(O)CC2)ncc1Cl
Temperature: 25 °C
Yield: 10 %

Procedure:
A 25 ml round-bottom flask is charged with 1-{4-[(2R,4S)-4-((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidin-4-ol (0.15 mmol), 1N HCl (0.8 ml, 0.8 mmol) and MeOH (2 ml). The mixture is then heated to 60 degree for 30 minutes. After cooling down to rt, sat. NaHCO3 and dichloromethane are added, then organic layer is collected. Removal of solvent and purification with reverse phase column chromatography give 1-[4-((2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]-piperidin-4-ol (11.3 mg, 0.015 mmol, 10% for 2 steps).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][CH2:6][S:7][C:8]1[N:12]([CH3:13])[N:11]=[N:10][N:9]=1)C.Cl.O>C(O)(=O)C>[CH3:13][N:12]1[C:8]([S:7][CH2:6][CH2:5][C:4]([OH:14])=[O:3])=[N:9][N:10]=[N:11]1
Reactant: CCOC(=O)CCSc1nnnn1C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1nnnc1SCCC(=O)O

Procedure:
5.43 g of 3-(1-methyltetrazol-5-ylthio)-propionic acid ethyl ester are dissolved in 20 ml of acetic acid, 4 ml of conc. HCl and 8 ml of water and the whole is stirred for 3.5 hours at 100°. After concentration of the reaction mixture by evaporation, the residue is partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous phase is separated off, acidified with 4N HCl and extracted twice with ethyl acetate. After drying and concentration by evaporation the title compound is obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:22](=[O:23])[CH2:21][CH2:20][CH:19]1[C:24]#N.C(O)(=[O:28])C>C1C=CC=CC=1.C(OCC)C>[OH:23][CH:22]1[CH2:21][CH2:20][CH:19]([CH:24]=[O:28])[CH:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:11]
Reactant: N#CC1CCC(=O)C1CCCCCCO
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=CC1CCC(O)C1CCCCCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diisobutylaluminum hydride (19.3 g., 0.125 mole) in benzene (170 ml.) was added, with rapid stirring, to a solution of 2-(6-hydroxyhexyl)-3-oxocyclopentanecarbonitrile (8.8 g., 0.042 mole) in dry diethyl ether (200 ml.) at 10°-15°C. Stirring at ambient temperature was continued for 15 minutes and the mixture was added to 2N aqueous acetic acid (170 ml.) at a temperature lower than 15°C. The organic phase was separated and the aqueous layer was extracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate, dried over magnesium sulphate and the solvents were removed in vacuo to give crude 3-hydroxy-2-(6-hydroxyhexyl)cyclopentanecarbaldehyde (8.6 g.). It was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH3-]C#N.[Na+]>CO>[C:10]1([CH:9]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CC(Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
To a solution of aniline hydrochloride (3.37 g, 26 mmol) and ethyl benzoylacetate (5 mL, 26 mmol) in MeOH (70 mL) was added NaBH3CN (1.75 g) and the mixture was stirred at room temperature for 18 h. The solvent was removed and the residue partitioned between 0.5N HCl and Et20. The aqueous phase was made basic with 1N NaOH and extracted with CHCl3. The organic phase was dried and concentrated to a residue. Purification by chromatography on silica gel (hexane: EtOAc, 5%) afforded ethyl 3-phenyl-3-(phenylamino)propionate (4.3 g, 62%). This compound was then hydrolized under basic conditions to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:19])=[O:18])[CH:15]=2)[C:10]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=2[C:42]2[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH:43]=2)=[CH:9]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:65]([OH:71])([C:67]([F:70])([F:69])[F:68])=[O:66]>C1COCC1>[F:68][C:67]([F:70])([F:69])[C:65]([OH:71])=[O:66].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17]([NH:1][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)(=[O:19])=[O:18])[CH:15]=2)[C:10]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:34][C:33]=2[C:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH:43]=2)=[CH:9]1
Reactant: Cn1cc(-c2ccc(C(F)(F)F)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)c2ccc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc21
Reactant: Nc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(C(F)(F)F)cc2C2=CCNCC2)c2ccc(S(=O)(=O)Nc3nccs3)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A flask containing a mixture of 2-aminothiazole (7.93 mg, 0.079 mmol), tert-butyl 4-(2-(1-methyl-6-((perfluorophenoxy)sulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE O) (0.053 g, 0.075 mmol), and THF (0.503 ml) was cooled to 0° C. LHMDS (1.0M in THF) (0.151 ml, 0.151 mmol) was added dropwise and the reaction was stirred for 15 minutes at 0° C. An additional equivalent of aminothiazole was added, followed by 2 equivalents of LHMDS solution. The reaction was stirred for one hour at 0° C. The reaction was quenched with saturated ammonium chloride solution, diluted with DCM, and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were concentrated. The material was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred at 50° C. overnight. The reaction was concentrated and the material was purified via column chromatography (RediSep Gold 12 g silica gel column (Teledyne Isco, Lincoln, Nebr., gradient elution 0 to 10% MeOH:DCM) to afford 1-methyl-3-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-1H-indole-6-sulfonamide 2,2,2-trifluoroacetate as a tan solid. m/z (ESI) 519.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.61 (br. s., 1 H), 8.70 (br. s., 2 H), 7.99 (s, 1 H), 7.81-7.67 (m, 5 H), 7.59-7.52 (m, 2 H), 7.24 (d, J=4.8 Hz, 1 H), 6.81 (d, J=4.5 Hz, 1 H), 5.89 (br. s., 1 H), 3.95 (s, 3 H), 3.71 (br. s., 2 H), 2.98 (br. s., 2 H), 2.11 (br. s., 3 H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3o2)cc1
Yield: 65.1 %

Procedure:
2-aminophenol 7.86 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 12.85 g of product (yield=65.12%).
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].C([O:12][C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH2:37][CH2:38][CH3:39])=[CH:22][N:23]2[CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)=[O:14])(C)(C)C>C(Cl)Cl>[C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH2:37][CH2:38][CH3:39])=[CH:22][N:23]2[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][C:36]=2[O:4][CH3:3])=[CH:19][CH:18]=1)([OH:12])=[O:14]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCc1cn(Cc2ccc(C(=O)OC)cc2)c2cc(/C=C(\C)C(=O)OC(C)(C)C)ccc12
Solvent: ClCCl
Product: CCCc1cn(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C(\C)C(=O)O)ccc12
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (20 ml), pre-cooled to 0°, was added slowly to a stirred solution of methyl E-4-[6-[2-(t-butoxycarbonyl)prop-1-enyl]-3-propylindol-1-ylmethyl]benzoate (1.22 g) in methylene chloride (10 ml) at 0° under an atmosphere of nitrogen. The mixture was stirred at 0° for 1.5 hr, then carefully evaporated at room temperature to give an oil which was crystallized from ether to give methyl E-4-[6-(2-carboxyprop-1-enyl)-3-propylindol-1-ylmethyl]-3-methoxybenzoate (0.94 g, 87%) as a yellow powder; mp 167°-169°; partial NMR (300 MHz, DMSO-d6): 0.94(t, 2H, CH2CH3), 1.65(m, 2H, CH2CH3), 2.03(d, 3H, C(CH3)), 2.65(t, 2H, CH2CH2CH3), 3.82(s, 3H, OCH3), 3.93(s, 3H, OCH3 ), 5.40(s, 2H, NCH2), 12.30(br s, about 1H, COOH).