Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([O:10]CC2C=CC=CC=2)=[C:3]1[CH2:18][O:19][CH2:20][CH3:21].[ClH:22].[CH2:23](O)C>[Pd]>[ClH:22].[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([OH:10])=[C:3]1[CH:18]([O:19][CH2:20][CH3:21])[CH3:23]
Reactant: CCOCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: CCOC(C)c1c(O)c(=O)cc(C)n1C
Yield: 83.3 %

Procedure:
1,6-Dimethyl-2-(1-ethoxymethyl)-3-benzyloxy-pyridin-4(1H)-one (3.65 g, 12 mmol) was dissolved in 40 ml of ethanol and adjusted to pH 1 with concentrated hydrochloric acid prior to hydrogenolysis for 4 hours in the presence of 5% Pd/C catalyst (0.8 g). Filtration followed by rotary evaporation gave the crude product as a white solid. Recrystallization from ethanol/diethyl ether gave the pure title compound (2.48 g, 83.3%) as a white crystalline solid. m.p. 195-199° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][C@@H:11]1[C@H:16]1[O:20][C:19]([CH3:22])([CH3:21])[N:18]([C:23](=[O:25])[CH3:24])[C@H:17]1[CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]([F:47])([F:46])[F:45])[CH:38]=1>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]([F:45])([F:46])[F:47])[CH:38]=2)[CH2:12][C@@H:11]1[C@H:16]1[O:20][C:19]([CH3:21])([CH3:22])[N:18]([C:23](=[O:25])[CH3:24])[C@H:17]1[CH2:26][C:27]1[CH:28]=[C:29]([F:34])[CH:30]=[C:31]([F:33])[CH:32]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCc3cccc(OC(F)(F)F)c3)CN2C(=O)OC(C)(C)C)OC1(C)C
Reaction time: 1 h
Yield: 102 %

Procedure:
Add 95% sodium hydride (0.008 g, 0.33 mmol) over 5 minutes to a solution of (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluorobenzyl)-2,2-dimethyloxazolidin-5-yl]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.101 g, 0.22 mmol) and 1-bromomethyl-3-trifluoromethoxy-benzene (0.054 mL, 0.333 mmol) in N,N-dimethylformamide (1 mL). Stir 1 hour and partition with ethyl acetate and water, wash with saturated aqueous sodium chloride, dry with magnesium sulfate and purify on silica gel with ethyl acetate/hexane mixtures to give the desired compound as a foam (0.141 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].[N:24]1([CH2:29][CH2:30][CH2:31]O)[CH:28]=[CH:27][N:26]=[N:25]1>>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:31][CH2:30][CH2:29][N:24]5[CH:28]=[CH:27][N:26]=[N:25]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: OCCCn1ccnn1
Reactant: COc1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cc1O
Product: COc1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cc1OCCCn1ccnn1
Yield: 42.1 %

Procedure:
Using an analogous procedure to that described in Example 205, 7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg, 0.32 mmol), (prepared as described for the starting material in Example 201), was reacted with 3-(1,2,3-triazol-1-yl)propan-1-ol (61 mg, 0.48 mmol) to give 4-(indol-5-ylamino)-6-methoxy-7-(3-(1,2,3-triazol-1-yl)propoxy)quinazoline (56 mg, 42%).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].C(O[C:8](=[O:24])[CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)C.C(O)(=O)C>O>[O:1]=[C:2]1[NH:3][C:8](=[O:24])[CH2:9][N:10]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1
Reactant: N#C[O-]
Reactant: CCOC(=O)CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CC(=O)NC2=O)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
Potassium cyanate (31 mg, 0.384 mmol) was added to a solution of tert-butyl 4-[(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate (100 mg, 0.384 mmol) in water (2 mL). Acetic acid was then added to adjust pH of reaction to 4-5 and the mixture was heated at 40° C. After 16 h, the reaction was cooled to ambient temperature and purified by reverse phase HPLC(C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (33 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][OH:28])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:16]=3[N:15]=2)=[CH:10][CH:9]=1.[Mn]([O-])(=O)(=O)=[O:30].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:18][C:17]4[CH:19]=[C:20]([C:23]([F:25])([F:26])[F:24])[CH:21]=[CH:22][C:16]=4[N:15]=3)=[CH:10][CH:9]=2)=[N:6][CH:5]=[C:4]([CH:3]=1)[C:27]([OH:30])=[O:28]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: OCc1cnc(-c2ccc(-c3nc4ccc(C(F)(F)F)cc4[nH]3)cc2)c(Cl)c1
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1cnc(-c2ccc(-c3nc4ccc(C(F)(F)F)cc4[nH]3)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
0.40 g of {5-chloro-6-[4-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-phenyl]-pyridin-3-yl}-methanol (28) (0.99 mmol) prepared in Example 16 was dissolved in 4 mL of pyridine and 2 mL of distilled water. 0.59 g of potassium permanganate (3.71 mmol) was added thereto, and reacted at 110° C. for 4 hours. Then, 0.59 g of potassium permanganate (3.71 mmol) and 2 mL of distilled water were added thereto, and reacted at 110° C. for 18 hours. The resultant was cooled to room temperature, and concentrated under reduced pressure. The aqueous layer was washed with ethyl acetate, pH 1 was adjusted with concentrated hydrochloric acid, and extracted with ethyl acetate several times. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.32 g of 5-chloro-6-[4-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-phenyl]-nicotinic acid (yield 77%).
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[C:35](=O)[CH2:34][CH:33]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH2:32][C:31]=2[O:47]CC)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=O)=[CH:11][CH:10]=1)#[N:8].[OH2:50]>C(#N)C>[O:50]=[C:17]1[NH:16][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=2)[C:30]2[C:31](=[O:47])[CH2:32][CH:33]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:44])([F:46])[F:45])=[CH:41][CH:42]=3)[CH2:34][C:35]=2[N:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1
Reactant: O
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2ccc(C(F)(F)F)cc2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC(c2ccc(C(F)(F)F)cc2)C3)cc1
Temperature: 25 °C

Procedure:
Sodium tert-butoxide (211 mg, 2.19 mmol) is added to a solution of 1-((4-cyanophenyl)-(2-ethoxy-6-oxo-4-(4-(trifluoromethyl)phenyl)cyclohex-1-enyl)methyl)-3-(3-(trifluorometh yl)phenyl)urea (intermediate 17, 825 mg, 1.37 mmol) in acetonitrile (12 mL) and the mixture is stirred at room temperature over night. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 100:0 to 0:100). Yield: 135 mg; ESI mass spectrum [M+H]+=556, Retention time HPLC: 1.27 min, 1.29 min (1:1 mixture of diastereomers) (V011_S01).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:39])[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:28]2[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]2)[CH:13]=[CH:12][N:11]=1.[CH3:40]NC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:37]([S:34]([N:31]1[CH2:30][CH2:29][CH:28]([C:19]2[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=[C:16]([C:14]4[CH:13]=[CH:12][N:11]=[C:10]([N:9]5[CH2:39][CH2:3][O:5][CH2:40][CH2:8]5)[CH:15]=4)[CH:17]=3)[NH:21][CH:20]=2)[CH2:33][CH2:32]1)(=[O:36])=[O:35])[CH3:38]
Reactant: CNC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccnc(N(C)C)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccnc(N5CCOCC5)c4)cc23)CC1
Yield: 21.1 %

Procedure:
The title compound was prepared according to the general procedure of 5-[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (1 mL) for dimethylamine to afford 12 mg of the title compound (21.1%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([CH:27]([NH2:33])[CH2:28][CH2:29][N:30]=[N+]=[N-])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O>C1COCC1>[C:20]([CH:27]([NH2:33])[CH2:28][CH2:29][NH2:30])([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)C(N)CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(N)CCN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A triphenylphosphine (4.8 g; 18.3 mmol) solution in THF (15 mL) is added dropwise to a stirred solution of the above azide in THF (30 mL)/H2O (0.3 mL; 18.3 mmol); the stirring is continued for 24 hrs at r.t. After removal of the solvents to dryness in vacuum, the residue is taken up with a few of EtOH to separate a white precipitate of triphenylphosphine oxide by stirring for 6 hrs at r.t. The final EtOH removal to dryness, at low pressure, gives 3.22 g (18 mmol) of 1-BOC-propane-1,3-diamine as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:37]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][C:13](=[S:37])[NH:12][CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C1CC(=S)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 120 °C
Yield: 95.4 %

Procedure:
The mixture of racemic (2′S,3R)-6-chloro-2′-(3-chlorophenyl)-4′,4′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.15 mmol) prepared in example 3b and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (100 mg, 0.25 mmol) (Aldrich) in toluene (20 mL) was heated at 120° C. for 0.5 h. The mixture was cooled to room temperature and then concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:1) to give racemic (2′S,3R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropyl-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one as a white solid (Yield 60 mg, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][O:13][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([Cl:17])[N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1cccc(OCc2ccccc2)c1
Product: Clc1cncc(OCc2cccc(OCc3ccccc3)c2)n1

Procedure:
The title compound was prepared according to the procedure of example 50, step 1, starting from 3-benzyloxybenzyl alcohol (3.46 g, 16.2 mmol), K-t-BuO (1.69 g, 15.1 mmol) and 2,6-dichloropyrazine (1.97 g, 13.2 mmol). The yield of the title compound was 2.64 g (61%) and was obtained as a semisolid. Anal. (C18H15ClN2O2) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14](F)[C:13]([F:17])=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1.[SH:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1.C(N(CC)CC)C>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([S:22][C:23]3[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=3)[C:13]([F:17])=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Br)cn1)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: Cn1ccnc1S
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1ccnc1Sc1cc(C(=O)Nc2ccc(Br)cn2)c([N+](=O)[O-])cc1F
Temperature: 130 °C
Yield: 71.7 %

Procedure:
A mixture of N-(5-bromo-pyridin-2-yl)-4,5-difluoro-2-nitro-benzamide (236 mg, 0.66 mmol), 2-mercapto-1-methylimidazole (83 mg, 0.73 mmol) and triethylamine (0.18 mL, 1.32 mmol) in 2 mL CH3CN was microwave heated to 130° C. for 10 min and the resulting solid was collected by filtration, rinsed with CH3CN, and dried under high vacuum to provide 214 mg (72%) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 3.70 (s, 3H), 6.91 (d, 1H, J=7 Hz), 7.20 (d, 1H, J=1 Hz), 7.58 (d, 1H, J=1 Hz), 8.07 (br s, 2H), 8.24 (d, 1H, J=10 Hz), 8.47 (br s, 1H), 11.39 (s, 1H); LCMS (m/z): 452/454 [C16H11BrFN5O3S+H]+.
Reaction SMILES: C([O:8][C:9](=[O:46])[CH2:10][C@H:11]([NH:23][C:24](=[O:45])[C@@H:25]([NH:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=1)[CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)C1C=CC=CC=1.CO.[H][H]>[Pd].C1COCC1>[CH:28]1([CH2:27][CH2:26][C@H:25]([NH:34][C:35](=[O:44])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=2)[C:24]([NH:23][C@H:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH2:10][C:9]([OH:46])=[O:8])=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: [H][H]
Reactant: COc1cccc(C(=O)N[C@@H](CCC2CCCCC2)C(=O)N[C@@H](CC(=O)OCc2ccccc2)CN2CCc3cc(F)ccc32)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(C(=O)N[C@@H](CCC2CCCCC2)C(=O)N[C@@H](CC(=O)O)CN2CCc3cc(F)ccc32)c1
Yield: 95 %

Procedure:
The title compound of Example 46 (300 mg, 0.476 mmol) was treated with 10% Pd/C (40 mg), MeOH (5 mL) and THF (5 mL). The atmosphere in the reaction was exchanged for hydrogen and the reaction was allowed to stir for 1 h under a balloon of hydrogen. The atmosphere was then exchanged back to nitrogen, the reaction was filtered through a pad of celite and the solvent was removed to afford 244 mg (95%) of a crystalline solid; 1H NMR (DMSO, 400 MHz) δ 0.55-0.88 (m, 2H), 1.00-1.22 (m, 7H), 2.93 (dd, 1H, J1=5.8, J2=13.6), 3.11 (dd, 1H, J1=7.6, J2=13.7), 3.25 (dd, 1H, J1=8.7, J2=17.5), 3.34 (s, 3H), 3.41-3.50 (m, 1H), 3.81 (s, 3H), 4.30-4.41 (m, 1H), 6.71-6.79 (m, 1H), 6.85-6.89 (m, 1H), 7.07-7.12 (m, 1H), 7.37 (dd, 1H, J1=J2=7.8), 7.40-7.48 (m, 2H), 7.98 (d, 1H, J=8.6), 8.32 (d, 1H, J=8.1); HPLC-MS calcd. for C30H38FN3O5 (M+H) 483.3, found 483.5.
Reaction SMILES: C[Mg]Br.O1C2[C:8](=CC=CC=2)[C:7](=[S:14])[CH:6]=[CH:5]1.F[B-](F)(F)F.[H+].C[CH2:22][O:23][CH2:24][CH3:25]>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[CH:8][C:7]([SH:14])=[CH:6][CH:5]=1
Reactant: S=c1ccoc2ccccc12
Reactant: CCOCC
Agent: C[Mg]Br
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C1CCOC1
Product: COc1ccc(S)cc1
Temperature: 10 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
Methyl magnesium bromide (50 mL of a 3M solution in ether, 0.15 mmol) was added to a solution of the crude thiochromone (20 g, prepared in Part C above) in THF (100 mL) with cooling to 10° C. The reaction mixture was then allowed to warm to room temperature and stirred for 6 hours. The mixture was then added, with vigorous stirring, to tetrafluoroboric acid (125 mL of a 50% aqueous solution) which had been diluted with ice/water (600 mL). A yellow precipitate formed, which was collected by vacuum filtration, washed thoroughly with hexanes and dried under reduced pressure to yield the desired salt (18.5 g, 55% yield over three steps from the 4-methoxybenzene thiol). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[C:26]([O:27][CH3:28])=[C:25]([F:29])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[F:19][C:20]1[C:26]([O:27][CH3:28])=[C:25]([F:29])[CH:24]=[CH:23][C:21]=1[NH:22][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COc1c(F)ccc(N)c1F
Agent: [Na+]
Product: COc1c(F)ccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1F
Yield: 67.4 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 318 mg of 2,4-difluoro-3-methoxyaniline in place of the 2,4-difluoroaniline. 255 mg of N-(2,4-difluoro-3-methoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([I:14])=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[C:15](OC(N(C)C)N(C)C)(C)(C)[CH3:16]>>[I:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([I:14])=[CH:8][C:3]=1[O:4][C:5](=[CH:15][CH3:16])[C:6]#[N:7]
Reactant: COc1cc(I)c(OCC#N)cc1I
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CC=C(C#N)Oc1cc(I)c(OC)cc1I
Temperature: 105 °C
Yield: 116.6 %

Procedure:
(2,5-Diiodo-4-methoxy-phenoxy)-acetonitrile (2.8 g, 6.75 mmol) and tert-butoxybis(dimethylamino)methane (Bredrick's reagent, 7 mL, 33.7 mmol) were combined and heated to 105° C. under nitrogen for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure to yield 3.47 g of crude 2-(2,5-diiodo-4-methoxy-phenoxy)-but-2-enenitrile, which was used directly in the following step.
Reaction SMILES: [C:1]([NH:5][NH2:6])(=[O:4])[CH2:2][CH3:3].C(O[C:10]([C:12]1[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1)=[NH:11])C>>[CH3:20][N:13]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=[C:12]1[C:10]([NH:6][NH:5][C:1](=[O:4])[CH2:2][CH3:3])=[NH:11]
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1C
Reactant: CCC(=O)NN
Product: CCC(=O)NNC(=N)c1ncc([N+](=O)[O-])n1C

Procedure:
Similarly, 2-propionylhydrazine is reacted with ethyl-1-methyl-5-nitro-2-imidazolecarboximidate to afford 2-(1-methyl-5-nitro-2-imidazolecarboximidoyl)-1-propionylhydrazine (IIIO).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:31])[NH:13][C:14](=[O:30])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][S:28][CH3:29])[CH:17]=2)=[CH:3]1.ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:31])[NH:13][C:14](=[O:30])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:40])[CH:17]=2)=[CH:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cn(CCCS(C)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
116 mg of the product of Example 96 in 5 ml of dichloromethane were treated at 0° C. with 60 mg of 85% metachloroperbenzoic acid in 5 ml of dichloromethane. The solution was allowed to warm to room temperature and was then stirred for 1 hour. The solution was washed with aqueous sodium bicarbonate and dried. The solution was concentrated and the residue was crystallized from ethyl acetate/hexane to give 84 mg of rac-3-(1-methyl-3-indolyl)-4-[1-(3-methylsulphinylpropyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 140° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[C:40]([O:43][CH:44](Br)[CH3:45])(=[O:42])[CH3:41]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([O:12][CH:44]([O:43][C:40](=[O:42])[CH3:41])[CH3:45])=[O:11]
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)O)c1ccc(F)cc1F
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)[C@@H](c1ccc(F)cc1F)N1C(=O)[C@@H](C2Cc3ccccc3C2)NC(=O)[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoic acid (example 22) (0.130 g) was stirred in anhydrous DMF (1 mL) and anhydrous potassium carbonate (0.020 g, 0.5 eq.) was added. The mixture was stirred at room temperature for 1 hour then cooled to −10° C. (ice-salt bath). The heterogeneous mixture was treated with 1-bromoethyl acetate (0.120 mL, excess) and stirred for 3.5 hours keeping the bath temperature between −10 and −5° C. It was then partitioned between DCM and 1M HCl aq. (20 mL each). The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure to give a purple gum; this was purified by SPE cartridge (5 g, silica eluted with (i) cyclohexane×2, (ii) DCM×2, (iii) diethyl ether×2, (iv) ethyl acetate×2, (v) methanol×2 to give 1-(acetyloxy)ethyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate (0.081 g) as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:18])[C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)/C=C/C(O)=O>CCOC(C)=O.CO>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:18])[C:9]([CH3:10])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccccn1)C(N)c1cccc(F)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(c1ccccn1)[C@H](N)c1cccc(F)c1

Procedure:
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine is prepared starting from racemic 1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC chromatography. The free base was dissolved in EtOAc and a solution of fumaric acid (1.0 eq) in MeOH is added. The solvent is removed in vacuo and the residue is triturated with Et2O/hexanes (1:1), collected by filtration and air-dried. 1HNMR (300 MHz, DMSO-d6) δ 1.19 (s, 3 H), 1.31 (s, 3 H), 4.48 (s, 1 H), 6.55 (s, 2 H), 6.85-6.95 (m, 2 H), 7.01 (t, J=8.9 Hz, 1 H), 7.18-7.34 (m, 3 H), 7.64-7.77 (m, 1 H), 8.59 (d, J=3.8 Hz, 1 H). MS: m/z 245.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:17][N:18](C)[CH:19]=[O:20]>C(OCC)(=O)C>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:18]1[CH2:17][C@H:9]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:8][C:19]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCCCOCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCC[C@@H]1CC(=O)N(CCCCCOCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of the compound of Example 2(c) (0.42 g, 2.9 mmol) in dry dimethylformamide (10 mL) under argon was slowly added sodium hydride (60% in mineral oil, 0.14 g, 3.5 mmol) at 0° C. After stirring at 0° C. for 30 minutes, 5-benzyloxypentyl bromide (0.9 g, 3.5 mmol) was dropwise added. The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50 mL). The organic solution was washed with water (4×30 mL), brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 EtOAc/hexanes) to afford 0.73 g (95%) of the title compound as a clear oil: 1H NMR (CDCl3) δ 7.33 (m, 5H), 4.51 (s, 2H), 3.45 (m, 3H), 3.27 (t, 2H), 2.99 (dd, 1H), 2.52 (dd, 1H), 2.32 (m, 1H), 2.06 (m, 1H), 1.24-1.71 (m, 12H), 0.93 (t, 3H). MS(ES) m/e 318 [M+H]+.