Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.Cl.[Br:19][C:20]1[C:21]([C@H:28]([NH2:38])[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:19][C:20]1[C:21]([C@H:28]([NH:38][C:13](=[O:15])[CH2:12][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:17])[F:16])=[N:4]2)[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reactant: CSc1ncc(Br)c([C@H](N)Cc2cc(F)cc(F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-(3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (124 mg, 0.5 mmol) and 11F (200 mg, 0.5 mmol) were dissolved in 3 mL of DMF and cooled down to 0° C. To it were added N,N-diisopropylethylamine (435 μL, 2.5 mmol) and HATU (228 mg, 0.6 mmol). The reaction mixture was stirred at 0° C. for 5 minutes, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in methylene chloride and to it added hexanes. The precipitate was collected by vacuum filtration and dried under high vacuum overnight to afford the title compound 11G. MS (m/z) 592.25 [M+H]+.
Reaction SMILES: [Br-:1].[CH3:2][N+:3]([CH3:23])([CH2:20][CH2:21]O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].P(Br)(Br)[Br:25]>C1C=CC=CC=1>[Br-:25].[CH3:2][N+:3]([CH3:23])([CH2:20][CH2:21][Br:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCC[N+](C)(C)CCO
Reactant: BrP(Br)Br
Agent: [Br-]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC[N+](C)(C)CCBr
Reaction time: 24 h
Yield: 213.3 %

Procedure:
A total of 3.95 g (0.010 mole) of dimethyl-(2-hydroxy)ethylhexadecyl ammonium bromide and 0.9910 g (0.00366 mole) of phosphorous tribromide was slurried in 20 ml of benzene and allowed to react at room temperature (about 25° C.) with stirring for 24 hours under nitrogen. The solvent was removed in vacuo and the residue washed several times with anhydrous ether. The resulting amorphous solid was recrystallized from ethyl acetate, filtered and dried to yield 3.57 g (77%) of the desired product. Calc. % C 52.51, % H 9.49, % N 3.06, % Br 34.93; Found % C 51.80, % H 10.06, % N 3.06, % Br 34.18; m.p. 185°-190° C. The 1H NMR and IR agree with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[N:15]([CH3:33])[C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)N(C)C2=O)cc1

Procedure:
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione (Example 100) is reated with sodium hydride in DMF, followed by methyl iodide to give the title compound as colorless crystals, mp 113-115° C.
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([O:50][CH2:51][CH3:52])[CH:43]=2)=O)=[CH:36][C:35]=1[N+:53]([O-:55])=[O:54]>C1COCC1>[CH2:51]([O:50][C:44]1[CH:43]=[C:42]([C:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[C:35]([N+:53]([O-:55])=[O:54])[CH:36]=2)=[CH2:2])[CH:47]=[CH:46][C:45]=1[O:48][CH3:49])[CH3:52]
Reactant: CCOc1cc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(c1ccc(OC)c(OCC)c1)c1ccc(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65.1 %

Procedure:
To a stirred suspension of triphenylmethylphosphonium bromide (1.8 g, 5.1 mmol) in THF (30 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0M solution in THF, 5.1 mL, 5.1 mmol) dropwise. The mixture was stirred at room temperature for 40 min. The Wittig reagent was then added slowly to a stirred suspension of (4-methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone (1.4 g, 4.2 mmol) in THF (30 mL) in an ice bath. The mixture was stirred at room temperature for 5 hr. The mixture was poured into ice water (100 mL). The aqueous layer was extracted with methyl chloride (4×30 mL). The combined organic layers were washed with water (2×50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent and chromatography (silica gel) gave 1-(3-ethoxy-4-methoxy-phenyl)-1-(3-nitro-4-methoxy-phenyl)-ethene as a solid (0.9 g, 67% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7.2 Hz, 3H, CH3), 3.89 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.10 (q, J=7.0 Hz, 2H, OCH2), 5.37 (d, J=9.7 Hz, 2H, CH2), 6.83-6.84 (m, 3H, CH), 7.06(d, J=8.9 Hz, 1H, CH), 7.49-7.54 (dd, J=2.3, 8.9 Hz, 1H, CH), 7.84 (d, J=2.1 Hz, 1H, CH); 13C NMR (CDCl3) δ 14.70, 55.94, 56.56, 64.35, 111.19, 112.74, 113.10, 113.68, 120.80, 125.11, 133.08, 133.66, 134.27, 139.42, 147.24, 148.03, 149.49, 152.30.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([C:21]([NH:45][N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NN1CCOCC1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NN2CCOCC2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with N-aminomorpholine (38.2 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (46 mg, 61% of theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]#[N:10])[CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:8][C:6]1[N:5]=[C:4]([C:9]#[N:10])[CH:3]=[C:2]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:7]=1
Reactant: Cc1cc(Cl)cc(C#N)n1
Reactant: Oc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cncnc2)cc(C#N)n1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
4-chloro-6-methylpicolinonitrile (4.0 g, 26 mmol, 1.0 eq), 5-hydroxypyrimidine (5.56 g, 57.9 mmol, 2.20 eq), K2CO3 (7.24 mg, 52.4 mmol, 2.0 eq) and DMF (66 mL) were added to a reaction vessel and heated at 80° C. for 16 hours. The reaction was filtered and concentrated on silica gel (25 g). The silica gel was loaded on top of a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude solid was purified by flash chromatography on silica gel to afford 4.31 g (77%) of the title compound as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.85 (s, 2H), 7.74 (d, J=2.4 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 2.48 (s, 3H); ES-MS [M+1]+: 213.2.
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([NH:25]C(OC(C)(C)C)=O)=[C:21]([F:33])[CH:20]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17].Cl>CO.O1CCOCC1>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([F:33])[CH:20]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(-c4sccc4C(N)=O)n[nH]c3c2F)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1ccsc1-c1n[nH]c2c(F)c(-c3ccc(N)c(F)c3)ccc12
Temperature: 40 °C
Yield: 127 %

Procedure:
A solution of 0.99 g of (7-fluoro-6-{3-fluoro-4-tert-butyloxycarbonylaminophenyl}-1H -indazol-3-yl)thiophene-3-carboxamide in 30 mL of methanol is admixed at ambient temperature with 2.63 mL of a 4N solution of hydrochloric acid in dioxane. The reaction mixture is heated at 40° C. for 4 h and then concentrated to dryness under reduced pressure. The solid obtained is triturated in isopropyl ether and isolated by filtration. Drying under vacuum gives 0.99 g of (7-fluoro-6-{3-fluoro-4-aminophenyl}-1H-indazol-3-yl)thiophene-3-carboxamide in the form of a yellow solid, whose characteristics are as follows:
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH:11]([CH2:19][N:20]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:20][CH2:19][CH:11]1[CH2:10][C:9](=[O:31])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Yield: 151.1 %

Procedure:
A suspension of 1-benzyl-4-(phthalimidomethyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (9.82 g, 20 mmol) and hydrazine monohydrate (16 g, 35 mmol) in ethanol (350 ml) was refluxed for 3 hours. The reaction mixture was cooled and subjected to filtration and washed with chloroform. The filtrate was concentrated under reduced pressure. The concentrate was suspended in chloroform, which was again subjected to filtration. The filtrate was concentrated under reduced pressure to afford 8.5 g (yield 86%) of the titled compound as an oily product.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.[NH2:10][C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12]1>>[CH3:12][C:11]([NH:10][CH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:13])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1(N)CC1
Reactant: O=Cc1cccnc1
Agent: Cl
Product: CCOC(=O)C(C)(C)NCc1cccnc1
Yield: 95 %

Procedure:
Prepared as in Example 12-1b from nicotinaldehyde and ethyl 1-aminocyclopropanecarboxylate hydrochloride. Yield 95%, a white solid. MS 223 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2([CH2:20][C:21]([OH:23])=[O:22])O>ClCCl>[F:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12]/[C:13]/2=[CH:20]\[C:21]([OH:23])=[O:22]
Reactant: O=C(O)CC1(O)CCc2c(F)cc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Yield: 60.9 %

Procedure:
Trifluoroacetic acid (39.9 g, 0.35 mol) was added dropwise to a stirred, chilled (ice-methanol bath) mixture of 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid (11.3 g, 0.05 mol) in dichloromethane (250 mL). After 35 min. the mixture was concentrated in vacuo. Dichloromethane was added to the residue and the mixture was concentrated in vacuo. This procedure was repeated once more to give 6.4 g of crude (E)-2-(4,6- difluoro-1-indanylidene) acetic acid. Recrystallization of 0.9 g from acetone: water mixtures gave 0.15 g of (E)-2-(4,6-difluoro-1-indanylidene) acetic acid as a white solid: mp 238°-239° C.; NMR (DMSO-d6): d12.25 (br, 1H), 7.23-7.65 (m, 2H), 6.46 (t, 1H), 3.20-3.28, 2.97-3.20(2 m's, 4H); steady-state nOe: irradiation at 6.46 d, observed 21.6% nOe at 7.63 d.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:42]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:25]=[CH:24][C:23]([N:26]6[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]6)=[CH:22][CH:21]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=5[F:19])[N:11]=4)=[CH:34][CH:35]=3)=[CH:40][CH:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (prepared according to general procedures A, B and C subsequently) (56 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][NH2:26])[CH:23]=2)[CH:18]=[N:17]1>>[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][NH:26][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:23]=2)[CH:18]=[N:17]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1ncc2ccc(CN)cc21
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3cnn(C)c3c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (1-methyl-1H-indazol-6-yl)methanamine.
Reaction SMILES: C[O:2][N:3]=[C:4]1[C:16]2[C:11](=[CH:12][C:13]([CH2:19][CH3:20])=[C:14]([OH:18])[C:15]=2[CH3:17])[O:10][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5]1.Cl.O.O1CCOC[CH2:24]1>>[CH2:19]([C:13]1[CH:12]=[C:11]2[C:16]([CH:4]([N:3]([OH:2])[CH3:24])[CH2:5][C:6]3([O:10]2)[CH2:9][CH2:8][CH2:7]3)=[C:15]([CH3:17])[C:14]=1[OH:18])[CH3:20]
Reactant: C1COCCO1
Reactant: CCc1cc2c(c(C)c1O)C(=NOC)CC1(CCC1)O2
Agent: Cl
Solvent: O
Product: CCc1cc2c(c(C)c1O)C(N(C)O)CC1(CCC1)O2

Procedure:
To a mixture of 7-ethyl-6-hydroxy-5-methylspiro[chroman-2,1′-cyclobutan]-4-one O-methyl oxime (530 mg) and BH3 pyridine complex (8 M, 2 mL) at 0° C., was added a solution of HCl in dioxane (4 M, 8 mL) at 1.5 mL/h. The mixture was cooled with ice-water bath, water was added to quench it, and extracted with ethyl acetate. The organic layer was washed with water, dried, and evaporated. The residue was purified by silica gel column eluting with 10% ethyl acetate in hexane, giving 7-ethyl-4-(hydroxy(methyl)amino)-5-methylspiro[chroman-2,1′-cyclobutan]-6-ol as a clear oil (412 mg) 1H-NMR (300 MHz, CDCl3) δ=6.57 (s, 1H), 5.25 (br., 1H), 4.30 (s, 1H), 3.63 (s, 3H), 2.67 (m, 4H), 2.2-1.7 (m, 9H), 1.19 (t, J=7.5 Hz, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=148.20, 145.41, 131.08, 122.82, 115.47, 114.99, 61.94, 52.60, 35.63, 34.36, 32.54, 23.14, 13.76, 13.66, 11.41 ppm. MS (m/z)=231 (100, M−N(OH)CH3).
Reaction SMILES: CO[C:3](=[O:26])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:27][NH:28][C:29]([NH2:31])=[O:30].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)=[CH:13][CH:12]=2)[C:3]([NH:31][C:29]([NH:28][CH3:27])=[O:30])=[O:26])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A mixture of 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid methyl ester (245 mg, 0.71 mmol) and methyl urea (131 mg, 1.76 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 5.5 mL, 2.12 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then partitioned between water (20 mL) and ethyl acetate (50 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (1×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 1-{3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionyl}-3-methyl-urea (79 mg, 29%) as a white foam: mp 91-95° C. (foam to gel); FAB-HRMS m/e calcd for C24H27N3O2 (M+H)+ 390.2181, found 390.2192.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC(OC)=CC=2)=[CH:12][C:11]=1[CH:26]([F:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CO.[C].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH:26]([F:32])[CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(F)CC(C)(C)C)c2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(O)cc2C(F)CC(C)(C)C)c1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
To a solution of 2′-fluoro-2-(1-fluoro-3,3-dimethylbutyl)-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl (120 mg) in methanol (5 mL) was added 10% palladium-carbon (100 mg) and, under a hydrogen atmosphere, the mixture was stirred at 70° C. for 17 hr. The reaction mixture was filtered, and the solvent of the filtrate was evaporated under reduced pressure to give a crude product of the title compound as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH:23]([CH3:25])[O:22][CH:21]([CH3:26])[CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH:23]([CH3:25])[O:22][CH:21]([CH3:26])[CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CC1CN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC(C)O1
Product: CC1CN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4)ncnc23)CC(C)O1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-(2,6-dimethyl-morpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 85°-90° C.) and piperazine.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]4[CH:23]=[C:24]([C:32]([O:34][CH3:35])=[O:33])[C:25](=[CH:30][CH:31]=4)[C:26]([O:28][CH3:29])=[O:27])[CH:15]=3)=[C:10]([CH3:36])[CH:9]=2)OCC[O:4]1)[CH3:2].S(=O)(=O)(O)O>CO.O>[CH3:36][C:10]1[CH:9]=[C:8]([C:3](=[O:4])[CH2:1][CH3:2])[CH:13]=[CH:12][C:11]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:32]([O:34][CH3:35])=[O:33])[C:25](=[CH:30][CH:31]=2)[C:26]([O:28][CH3:29])=[O:27])[CH:15]=1
Reactant: CCC1(c2ccc(-c3cccc(COc4ccc(C(=O)OC)c(C(=O)OC)c4)c3)c(C)c2)OCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CCC(=O)c1ccc(-c2cccc(COc3ccc(C(=O)OC)c(C(=O)OC)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
6.8 g (14 mmol) of dimethyl 4-[4′-(2-ethyl-[1,3]dioxolan-2-yl)-2′-methylbiphenyl-3-ylmethoxy]-phthalate are dissolved in 200 mL of methanol and 50 mL of water. 0.5 mL of sulphuric acid is added and the reaction medium is stirred at room temperature for 10 hours. After the usual treatment, the desired product is obtained, without purification, in the form of a colourless oil (m=6.05 g; Y=97%).
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[CH:16]([C:22]1[CH:32]=[C:31]([O:33][CH3:34])[C:25]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[C:24]([O:35][CH3:36])[CH:23]=1)CS(C)(=O)=O.CS(C)=O>O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:16][C:22]1[CH:32]=[C:31]([O:33][CH3:34])[C:25]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[C:24]([O:35][CH3:36])[CH:23]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1N(C)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(OC)c1N(C)C(C)=O

Procedure:
A mixture of 3.24 g. of sodium methylate, 8.75 g. of β-anilino-propionitrile and 14.9 g. of 4'-[1-hydroxy-2-(methylsulfonyl)-ethyl]-2',6'-dimethoxy-N-methylacetanilide in 60 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 4 hours with the exclusion of moisture. The solution was poured into 600 ml. of water. The resulting emulsion was extracted with two 400 ml. portions of ethyl acetate. Thereafter, the ethyl acetate extracts were washed with two 150 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. Recrystallization of the residue from ethyl acetate gave 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxy-N-methyl-acetanilide having a melting point of 202°-204° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[F:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=4)([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:11][CH:10]([NH2:12])[CH2:9]1.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:7][C:8]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=4)([C:24]([F:25])([F:26])[F:27])[O:21][N:20]=3)=[CH:17][CH:18]=2)[CH2:11][CH:10]([NH:12][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH2:9]1
Reactant: O=C(Cl)C1CC1
Reactant: NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1)C1CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
Cyclopropylcarbonylchloride (14.1 μL, 0.10 mmol) is added to 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)cyclobutanamine (Preparation 16, 50.0 mg, 0.10 mmol) in DMF (1.5 mL) along with DIPEA (5.4 μL, 0.31 mmol) and DMAP (1.2 mg, 0.01 mmol). The reaction mixture is stirred for three days at room temperature. The mixture is partitioned between brine (5 mL) and EtOAc (5 mL). The organics are separated, dried over MgSO4, filtered and evaporated to give a residue, which is purified on regular silica eluting from neat DCM to 15% MeOH/DCM to give the title compound (22 mg): 1H NMR (DMSO-d6) δ: 8.83 (1H, d), 7.88 (2H, s), 7.79 (2H, d), 7.58 (2H, d), 4.61-4.53 (1H, m), 4.42-4.30 (2H, m), 2.89-2.78 (2H, m), 2.65-2.55 (2H, m), 1.50-1.44 (1H, m), 0.71-0.61 (4H, m); m/z (Cl) 548.