Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])=[CH:6][CH:5]=1)[CH3:2].II.C(Cl)CCl.[CH3:23][C:24]([CH3:26])=O>>[CH3:12][C:11]1([CH2:13][CH:14]([CH3:15])[CH3:16])[CH:23]=[C:24]([CH3:26])[C:8]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=2)[NH:10]1
Reactant: CC(C)=O
Reactant: CCOc1ccc(N=C(C)CC(C)C)cc1
Agent: II
Solvent: ClCCCl
Product: CCOc1ccc2c(c1)C(C)=CC(C)(CC(C)C)N2

Procedure:
A portion (5.98g) of this material, 4-methyl-2-pentanone p-ethoxyphenylimine, combined with iodine (0.15g), ethylene dichloride (0.5 ml) and acetone (200 ml), was refluxed for about 26 hours in a Soxhlet extractor, which was charged with molecular sieves 3A and fitted with a moisture trap at the condenser outlet. The product was evaporated to dryness in vacuo and then fractionated. Fractions with b.p.≥120° C/0.5 mm were combined and the brown oil (3.26lg) was chromatographed on silica gel (180g, mesh 70-230). Benzene (2 l.) and benzene-chloroform (9:1, 1.5 l.) eluates furnished 1,2-dihydro-2,4-dimethyl-2-isobutyl-6-ethoxyquinoline as a brown oil (1.88g).
Reaction SMILES: [C:1]1([O:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:19]CC2C=CC=CC=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O1CCCC1>[C:1]1([O:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[OH:19])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Oc1ccccc1)c1cc2cccc(OCc3ccccc3)c2[nH]1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Oc1ccccc1)c1cc2cccc(O)c2[nH]1
Yield: 87.9 %

Procedure:
Under the conditions of Example 14(C), a solution of 5.4 g of 7-benzyloxyindole-2-carboxylic acid phenyl ester in a mixture of 50 ml of methanol and 30 ml of tetrahydrofuran is hydrogenated and worked up, yielding 3.5 g of 7-hydroxyindole-2-carboxylic acid phenyl ester, mp 156°-157° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:16]=[CH:15][C:10](/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:9][CH:8]=1)[CH3:5])[CH3:2].[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>C(N(CC)CC)C>[C:20]([O:14][CH2:13]/[CH:12]=[CH:11]/[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])=[CH:16][CH:15]=1)(=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: C=C1CC(=O)O1
Reactant: CCOC(C)Oc1ccc(/C=C/CO)cc1
Solvent: CCN(CC)CC
Product: CCOC(C)Oc1ccc(/C=C/COC(=O)CC(C)=O)cc1
Yield: 70.9 %

Procedure:
A mixture of 9 g of 4(E)-(1-ethoxyethoxy)-cinnamyl alcohol and 0.5 ml of triethylamine was heated at 70°-80° C., and 6 g of diketene was slowly added dropwise thereto. After the addition was finished, the reaction mixture was heated at 110°-120° C. for 30 minutes. After the reaction was completed, the solvent was removed by evaporation under a reduced pressure, and the residue thus obtained was purified by means of a silica gel column chromatography (eluent: diethyl ether: n-hexane=1:3) to yield 8.8 g of 4(E)-(1-ethoxyethoxy)cinnamyl acetoacetate. Refractive index: D24 1.5305
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9]C)[C:3]=1[CH2:11][CH2:12][OH:13].O>C(Cl)Cl>[F:1][C:2]1[C:3]([CH2:11][CH2:12][OH:13])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(F)c(F)c1CCO
Solvent: ClCCl
Solvent: O
Product: OCCc1c(O)ccc(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
To a solution of 2-(2,3-difluoro-6-methoxyphenyl)ethanol (800 mg, 4.25 mmol) in DCM (25 mL) at 0° C. was added 1M BBR3 (17.01 mL, 17.01 mmol) solution and the resulting mixture was allowed to warm to room temp and stir for 4 h. Water (dropwise) was then added and after the bubbling stops mixture was diluted with DCM and washed with water, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-50%, EtOAc/hexane) to afford 3,4-difluoro-2-(2-hydroxyethyl)phenol (500 mg, 2.87 mmol, 67.5% yield) as clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.85 (br. s., 1H), 7.04-6.93 (m, 1H), 6.71-6.60 (m, 1H), 4.07-4.01 (m, 2H), 3.04-2.95 (m, 2H), 2.38 (br. s., 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cl)cc1
Product: COc1ccc(-c2ccccc2)cc1
Yield: 80.3 %

Procedure:
Bromobenzene (79 mg, 0.50 mmol) reacted with 4-methoxyphenylboronic acid (99 mg, 0.65 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in THF solvent at room temperature to give the title compound (87 mg, 95%) as a white solid. The reaction of 4-chloroanisole (71 mg, 0.50 mmol) with phenylboronic acid (92 mg, 0.75 mmol) gave the title compound (74 mg, 80%) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF in THF solvent at 40° C. 1H-NMR (400 MHz, CDCl3): δ 7.61 (m, 4H), 7.48 (t, 2H, J=7.6 Hz), 7.37 (app.t, 1H, J=7.2 Hz), 7.04 (d, 2H, J=8.8 Hz), 3.90 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 159.09, 140.76, 133.69, 128.66, 128.08, 126.67, 126.60, 114.14, 55.26. GC/MS(EI): m/z 184 (M+). Anal. Calcd for C13H12O: C, 84.75; H, 6.56. Found: C, 84.86; H, 6.76.
Reaction SMILES: [F:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([C:17]([F:20])([F:19])[F:18])[S:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3].O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([CH3:35])[C:23]=1[CH3:36]>>[F:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][O:16][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([CH3:35])[C:23]=3[CH3:36])=[C:13]([C:17]([F:20])([F:19])[F:18])[S:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CC(F)c1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(C(C)F)cc3)nsc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling [3-[4-(1-fluoroethyl)phenyl]-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1HNMR (300 MHz, CD3OD) δ 7.67 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 6.92 (d, J=8.1 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 5.53-5.75 (m, 1H), 5.06 (s, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.47 (t, J=7.5 Hz, 2H), 2.18 (s, 3H), 2.00 (s, 3H), 1.53-1.65 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H23F4NO3S, 480.1 (M−H). found 480.1.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][NH:10][C:11]=3[CH:12]=[C:4]2[CH2:3][CH2:2]1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][NH:10][C:11]=3[CH:12]=[C:4]2[CH2:3][CH2:2]1
Reactant: c1c2c(cc3c1NCC3)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCc4cc5c(cc43)CCN5)c2cc1OC
Yield: 65 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 65% yield from 1,2,3,5,6,7-hexahydro-pyrrolo[2,3-f]indole (1.7 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (LC-MS: 349 (MH+); RP18-HPLC RT: 3.51 min)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].C(O)(=O)C>O>[CH3:16][C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:24]2[NH:18][C:19](=[O:20])[NH:21][C:22]2=[O:23])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:12]=1[OH:13])([CH3:15])[CH3:17]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(C=C2NC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 50.6 %

Procedure:
A mixture of 3,5-di-t-butyl-4-hydroxybenzaldehyde (7.0 g, 30 mmoles), hydantoin (3.0 g, 30 mmoles), μ-alanine (1.4 g, 16 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 48 hours the mixture is stirred into water (300 ml), and the precipitate is filtered off, rinsed with water three times, and dried. Recrystallization from acetonitrile gave the pure product (4.8 g), mp 251°-252° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23](O)=[O:24])[CH:22]=3)[NH:19][N:18]=[CH:17]4)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.CCN(CC)CC>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23]([N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[O:24])[CH:22]=3)[NH:19][N:18]=[CH:17]4)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:26]
Reactant: C1COCCN1
Reactant: Cc1cc(-c2ncccc2-c2cc(C(=O)O)c3[nH]ncc3c2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ncccc2-c2cc(C(=O)N3CCOCC3)c3[nH]ncc3c2)ccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A capped vial containing a stir-bar, was charged with 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylic acid (100 mg, 0.28 mmol), HBTU (140 mg, 0.36 mmol), morpholine (29 mg, 0.03 mL, 0.34 mmol), NEt3 (57 mg, 0.08 mL, 0.57 mmol) and acetonitrile (3 ml) successively and stirred the contents at room temperature. After 12 h, the reaction mixture was concentrated and diluted with EtOAc (15 mL)/H2O (5 mL). Organic layer was separated, washed with brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC. Product fractions were concentrated, diluted with water and neutralized with aq. Na2CO3 solution. The resulting white precipitate was filtered and dried to obtain (5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-7-yl)(morpholino)methanone. 1H NMR (DMSO-d6): δ 13.27 (s, 1H), 8.66 (d, 1H, J=4.7 Hz), 8.17 (s, 1H), 7.97-7.92 (m, 2H), 7.48 (dd, 1H, J=4.9 and 7.6 Hz), 7.33 (d, 1H, J=7.8 Hz), 6.97-6.88 (m, 3H), 3.62-3.42 (m, 8H), 2.10 (s, 3H).19F NMR (DMSO-d6): δ −118.69 (s).LCMS: rt 4.45 min (A), purity 97%, MS (m/e) 417 (MH+)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].C(O[CH:17](N(C)C)[N:18]([CH3:20])[CH3:19])(C)(C)C>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:7]1[CH2:6][O:5][CH2:4][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:2]1=[O:1]
Reactant: COC(=O)C1COCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: COC(=O)C1COCC(=CN(C)C)C1=O

Procedure:
Methyl 4-oxo-tetrahydro-pyran-3-carboxylate (74 mg, 0.47 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (101 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 214.4 [(M+H)+].
Reaction SMILES: [NH:1]([C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)[CH2:12][CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:2]1([NH:1][C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)[CH2:14][CH2:15]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccccc3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)N1CCN(C[C@@H]2CCCNC2)CC1
Reaction time: 2 h

Procedure:
tert-Butyl (3S)-3-{[4-(anilinocarbonyl)piperazin-1-yl]methyl}piperidine-1-carboxylate (4.0 g) was added to a mixture of dichloromethane (20 ml) and TFA (20 ml) and the reaction mixture stirred for 2 h. The solvent was removed in-vacuo and the residue dissolved in dichloromethane (20 ml) and subsequently poured into hydrochloric acid solution (1N, 20 ml). The aqueous layer was basified using potassium carbonate and extracted with dichloromethane (3×15 ml). The organic layer was dried using a phase separation cartridge and the solvent removed under reduced pressure to afford the desired compound as a white foam white (2.0 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1Br
Yield: 46 %

Procedure:
2,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,4-dichlorobenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 138-141° C., yield 46%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.[O:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](Cl)=[O:55].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:4][CH2:5][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([N:34]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[C:54]([C:50]3[O:49][CH:53]=[CH:52][CH:51]=3)=[O:55])[CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(CCC1(CCN2CCC(Nc3ccc(C)cc3)CC2)CCCCC1)(COC(C)=O)COC(C)=O
Reactant: O=C(Cl)c1ccco1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCC(CCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cc3)CC2)CCCCC1)(COC(C)=O)COC(C)=O
Reaction time: 17 h

Procedure:
To a solution of 2-(acetoxymethyl)-2-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane (synthesized in Example 13) (324 mg) dissolved in dichloromethane (4 mL) was added triethylamine (0.16 mL). 2-Furoyl chloride (0.084 mL) was added to the solution under ice cooling, and the temperature was then allowed to rise to room temperature. The solution was stirred for 17 hours. A 10% aqueous citric acid solution was added to the solution and the solution was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1:1)] to give the title compound (356 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](OC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCCC>C(Cl)Cl>[CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccn1Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: OCc1cccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
To a solution of methyl 1-benzyl-1H-pyrrole-2-carboxylate (3.00 g, 13.9 mmol) in DCM (70 mL) at −78° C. was added a 1M solution of diisobutylaluminum hydride (DIBAL-H) in heptane (35.0 mL, 34.8 mmol). After 45 min the reaction was quenched with saturated aqueous solution of NH4Cl (20 mL) and Rochell's salt (100 g). The mixture was allowed to warm to rt and was stirred for 2.5 h. The reaction mixture was extracted with EtOAc (3×). The combined organic layers were washed with H2O, saturated aq NaCl, dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The crude product was chromatographed over silica gel (0 to 20% EtOAc in heptane over 20 min) to give (1-benzyl-1H-pyrrol-2-yl)-methanol as a colorless oil (2.30 g, 88%). Rf=0.47 (1:1 heptane/EtOAc); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.27-7.35 (m, 4H) 7.08-7.10 (m, 1H) 7.06-7.08 (m, 1H) 6.73 (dd, J=2.7, 1.8 Hz, 1H) 6.19 (dd, J=3.5, 1.8 Hz, 1H) 6.12-6.16 (m, 1H) 5.21-5.23 (s, 2H) 4.53 (d, J=5.1 Hz, 2H).
Reaction SMILES: CN(C)CCCN=C=NCC.[NH:12]1[C:16]2[CH2:17][CH2:18][CH:19]([C:21]([OH:23])=O)[CH2:20][C:15]=2[N:14]=[CH:13]1.ON1C2C=CC=CC=2N=N1.[CH3:34][S:35]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:34][S:35]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH:43][C:21]([CH:19]2[CH2:18][CH2:17][C:16]3[NH:12][CH:13]=[N:14][C:15]=3[CH2:20]2)=[O:23])=[CH:40][CH:39]=1)(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C(O)C1CCc2[nH]cnc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(CNC(=O)C2CCc3[nH]cnc3C2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
At 0° C. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.23 g, 1.184 mmol) was added to a solution of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid (024 g, 1.184 mmol) and 1-hydroxybenzotriazole (0.16 g, 1.184 mmol) in DMF (5 ml). The reaction mixture was stirred for 20 min at 0° C. 4-(Methylsulfonyl)benzylamine (0.26 g, 1.184 mmol) and ethyldiisopropylamine (0.90 ml, 5.211 mmol) were added successively. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. The solvent was removed in vacuo. The crude product was purified filtered through SepPack® (5 g), using 1% TFA in water/acetonitrile (80:40) as eluent. The resulting mixture was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (50:10:1) as eluent, to give 0.32 g of the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[F:25][C:26](=[C:32]([F:34])[F:33])[CH2:27][CH2:28][C:29](O)=[O:30]>C(Cl)Cl>[F:25][C:26](=[C:32]([F:34])[F:33])[CH2:27][CH2:28][C:29]([N:3]([O:4][CH3:5])[CH3:2])=[O:30]
Reactant: O=C(O)CCC(F)=C(F)F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CCC(F)=C(F)F
Reaction time: 8 h

Procedure:
N,O-dimethylhydroxyamine hydrochloride (3.5 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.9 g) and triethylamine (9.2 mL) were added to a solution of 4,5,5-trifluoropent-4-enoic acid (CAS No. 110003-22-0 (5.0 g)) in methylene chloride solution (64 mL) in a cold-water bath and stirring was carried out at room temperature overnight. The reaction solution was concentrated and diluted with ethyl acetate. The dilute solution was washed with 1 N hydrochloric acid, water and saturated brine; dried with anhydrous sodium sulfate; and concentrated to obtain the title compound (6.4 g) having the following physical properties:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[CH2:11]([N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:27])[CH:15]=[N:14]1)[CH3:12].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([N:13]1[C:17]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[C:16]([CH3:27])[CH:15]=[N:14]1)[CH3:12]
Reactant: CCn1ncc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1ncc(C)c1-c1csc(C(=O)OC)c1
Temperature: 70 °C
Yield: 79.3 %

Procedure:
A mixture of methyl 4-bromo-2-thiophenecarboxylate (300 mg, 1.36 mmol), 1-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (449 mg, 1.9 mmol), Pd(Ph3P)4 (157 mg, 0.136 mmol), and K2CO3 (536 mg, 4.07 mmol) was heated at 70° C. for 2 h, concentrated and purified on silica (EtOAc/Hex, 10-30%) to afford the title compound (0.27 g, 79%) as a syrup: LC-MS m/z=251 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred solution of 4,6-dichloro-2-methyl-5-nitro-pyrimidine (Albert et al., J. Chem. Soc., 1954, 3832, 7.5 g, 36.1 mmol) in THF (150 ml) was added 4-aminophenylethyl alcohol (2.47 g, 18.0 mmol), triethylamine (3.65 g, 36.1 mmol), and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 ml), and the mixture was extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 4.0 g (72%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][OH:32])=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:25][CH2:24][C:8]2([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]3[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=3)=[O:15])[CH2:9]2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=[O:32])=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][C:8]2([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]3[N:17]=[C:18]([CH:21]([CH3:22])[CH3:23])[S:19][CH:20]=3)=[O:15])[CH2:9]2)[CH2:24][CH2:25]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4Cl)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CC=O)ccc4Cl)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(2-chloro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 61, step d) (0.230 g) in DCM (5 mL) was cooled in ice-water, treated with trifluoroacetic acid (0.074 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.313 g) was added, then the mixture was removed from the cooling bath and stirred at room temperature for 40 minutes. The solution was diluted with saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL) and the resulting mixture was stirred vigorously for 10 minutes. The mixture was then extracted twice with ethyl acetate, the combined organic phases were washed with brine, acidified with acetic acid (0.1 mL), dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude subtitled compound as a yellow foam. Yield 0.274 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH2:12]([NH2:15])[CH2:13][CH3:14]>>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:15][CH2:12][CH2:13][CH3:14])=[O:6]
Reactant: COC(=O)c1ccccc1O
Reactant: CCCN
Product: CCCNC(=O)c1ccccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
The crude methyl 2-hydroxybenzoate was dissolved in n-propylamine (400 mL). The reaction mixture in a sealed reactor was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography to afford 120 g (84%) of 2-hydroxy-N-propylbenzamide. LCMS ESI (+) m/z 180 (M+1) detected.