Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](OC)(=O)C(OC)=O.CC(C)([O-])C.[K+].Cl>CN(C=O)C.O.C(OCC)C>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2ccccc21
Temperature: 25 °C
Yield: 95.3 %

Procedure:
The indole product from Example 56 (100 mg, 0.36 mmol) and dimethyl oxalate (46 mg, 0.39 mmol) in DMF (3 mL) were treated with potassium t-butoxide (44 mg, 0.39 mmol). The reaction was heated at reflux for 30 min. Reaction was cooled to room temperature and diluted with water (25 mL). Following extractions (3×) with ethyl acetate, the organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The dark residue was chromatographed (SiO2, 20% EtOAc/hexanes), and the resulting oil was treated with 1 M HCl (1 eq) in diethyl ether to provide the N-methyl indole product as a white solid (45 mg, 11%): mp 255-258° C.; 1H NMR (300 MHz, CD3OD) δ 7.43-7.25 (m, 3H), 7.12-7.00 (m, 2H), 6.99 (d, J=10.0 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.50 (d, J=3.1 Hz, 1H), 4.80-4.67 (m, 2H), 3.89 (dd, J=5.6, 11.9 Hz, 1H), 3.81 (s, 3H), 3.65-3.55 (m, 1H), 3.30-3.29 (m, 1H), 3.14 (s, 3H); IR (KBr) 3424, 2944, 2479, 1590, 1449 cm−1; CI MS m/z=295 [C19H19FN2+H]+.
Reaction SMILES: [CH:1]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])[CH2:6]1)([CH2:3][CH3:4])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH:1]([CH:5]1[CH2:6][C:7](=[O:12])[CH:8]([C:24](=[O:25])[NH:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=2)(=[O:22])=[O:21])[C:9](=[O:11])[CH2:10]1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCC(C)C1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CCC(C)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-sec.-butyl-1,3-cyclohexanedione with p-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-sec.-BUTYL-2-(N-p-CHLOROBENZENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 106°-107° C. (corr.).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21](O)[CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([O:1][C:2]1[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=1)[CH2:20][CH2:19]2
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OC1CCc2cc(F)ccc21
Product: N#Cc1ccnc(-n2nccc2OC2CCc3cc(F)ccc32)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 5-fluoro-2,3-dihydro-1H-inden-1-ol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.39-2.46 (1H, m), 2.59-2.64 (1H, m), 2.90-2.98 (1H, m), 3.13-3.20 (1H, m), 5.72-5.75 (1H, m), 5.84 (1H, d, J=1.6 Hz), 6.89-6.94 (1H, m), 6.98 (1H, d, J=8.8 Hz), 7.34-7.37 (2H, m), 7.62 (1H, d, J=1.6 Hz), 7.86 (1H, s), 8.64 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H13FN4O, 321. Found, 321.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:26]([OH:27])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:27][C:26]1[C:17]([OH:16])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: Oc1cc2ccccc2nc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3O)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (106 mg), 2,3-dihydroxyquinoline (50 mg), and 4-dimethylaminopyridine (124 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 150° C. for 8 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give 6,7-dimethoxy-4-(2-hydroxy-quinolin-3-yloxy)-quinoline (40 mg, yield 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23]CCO)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([Li])CCC.C(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:23])[CH3:27])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [Li]CCCC
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Agent: CC=O
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) (2 g) in THF (24 ml) at −78° C. was added n-butyllithium (2.72 ml, 2.5 M in hexanes) dropwise. The solution was stirred at −78° C. for 45 mins and acetaldehyde (604 μl) in THF (2 ml) was added dropwise. The solution was stirred for a further 2 hours, allowed to warm to room temperature slowly and stirred for a further 4.5 hours. The reaction was quenched with aqueous ammonium chloride (20 ml), diluted with ethyl acetate and the phases separated. The organics were washed successively with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; isohexane-ethyl acetate (3:2)] to afford (4R,9aR)-6-(1-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (742 mg) as a yellow oil: 1H NMR (400 MHz, CDCl3) 7.16 (1H, d, J 7 Hz), 6.35 (1H, d, J 7 Hz), 4.37–4.31 (1H, br s), 4.31–4.19 (1H, br s), 4.09–3.95 (1H, m), 3.95–3.85 (1H, m), 3.13–2.94 (2H, m), 2.79–2.55 (1H, br s), 2.54 (1H, dd, J 6 and 16 Hz), 1.48 (9H, s), 1.44 (3H, d, J 6.5 Hz), 1.25 (1.5H, R epimer, d, J 6.5 Hz) and 1.24 (1.5H, S epimer, d, J 6.5 HZ); MS (ES) 334.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].N1C=CC=CC=1.[CH:21]1[C:34]2[C:25](=[CH:26][C:27]3[C:32]([C:33]=2[S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:31]1[C:32]2[C:27](=[CH:26][C:25]3[C:34]([C:33]=2[S:35]([NH:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:4]([OH:13])[C:3]([O:2][CH3:1])=[O:14])(=[O:37])=[O:36])=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1c2ccccc2cc2ccccc12
Reactant: COC(=O)C(O)[C@@H](N)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](O)[C@@H](NS(=O)(=O)c1c2ccccc2cc2ccccc12)c1ccccc1
Reaction time: 1.5 h

Procedure:
(3S)-3-Phenylisoserine methyl ester (I, 0.38 g, 1.95 mmol) is dissolved in methylene chloride (5 mL) and pyridine (1 mL) and the solution treated with a suspension of 9-anthracenesulfonylchloride (0.536 g, 1.95 mmol). The reaction is stirred at 23° for 90 min. The reaction is then poured into methylene chloride and extracted with hydrochloric acid (1 N) and aqueous bicarbonate (5%) and dried over magnesium sulfate. Concentration of the organic layer under reduced pressure produces crude product. This concentrate is chromatographed (silica gel 60; ethyl acetate/toluene, 20/80) to give the title compound, TLC (silica gel GF) Rf=0.38 in (ethyl acetate/toluene, 2/8); NMR(CDCl3, TMS) 3.11, 3.57, 4.18, 4.78, 6.22, 6.59, 6.67, 7.50, 7.55-7.75, 7.92, 8.09, 8.47 and 9.15 δ.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[N:8]=1)[CH3:3].[K+].[CH2:13]([O:15][C:16]([S-:18])=[S:17])[CH3:14]>C(#N)C>[CH2:13]([O:15][C:16](=[S:17])[S:18][CH:2]([C:4]1[O:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[N:8]=1)[CH3:3])[CH3:14]
Reactant: CCOC(=S)[S-]
Reactant: CC(Br)C1=NC(C)(C)C(=O)O1
Agent: [K+]
Solvent: CC#N
Product: CCOC(=S)SC(C)C1=NC(C)(C)C(=O)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
To a solution of 2-(1-bromo-ethyl)-4,4-dimethyl-4H-oxazol-5-one (3.00 g; 13.6 mmol) and 50 mL acetonitrile was added O-ethyl xanthic acid potassium salt (2.18 g; 13.6 mmol). The mixture was stirred under a nitrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered and the solid was washed with 10 mL acetontrile 10 mL. The combined filtrate was concentrated under reduced pressure to afford 2.89 g (81%) of dithiocarbonic acid S-[1-(4,4-dimethyl-5-oxo-4,5-dihydro-oxazol-2-yl)-ethyl]ester O-ethyl ester as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].Cl[C:13]([C:15]1([CH3:30])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=O>>[CH2:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][CH2:19][C:15]1([C:30]1[O:1][C:2]2[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=2)[N:11]=1)[CH3:13])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1
Reactant: Nc1c(O)cccc1C(=O)O
Product: CC1(c2nc3c(C(=O)O)cccc3o2)CCCN1C(=O)OCc1ccccc1

Procedure:
2-(1-(Benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)benzo[d]oxazole-4-carboxylic acid is prepared from 3-hydroxyanthranilic acid and benzyl 2-(chlorocarbonyl)-2-methylpyrrolidine-1-carboxylate using the conditions described in Example 3A. MS (ESI) m/e 381 [M+H]+.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]([C:15]([O:17]CC)=O)[CH2:4][NH:3][CH2:2]1.Cl.[CH3:21][NH2:22].CN>C1COCC1>[CH3:21][NH:22][C:15]([CH:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][NH:3][CH2:4]1)=[O:17]
Reactant: CCOC(=O)C1CNCCc2c1[nH]c1ccccc21
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)C1CNCCc2c1[nH]c1ccccc21
Temperature: 80 °C
Yield: 65.8 %

Procedure:
Ethyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (1.29 g, 5 mmol; European Patent No. EP 064 317 B1) and methylamine hydrochloride (0.67 g, 10 mmol) were added to a solution of methylamine in THF (2 M, 15 mL) and the suspension was heated to 80° C. in a sealed tube under nitrogen stirring for 72 hours. Solvent was evaporated to give a crude product, which was purified by chromatography on silica gel eluting with MeOH-DCM (1:9 to 1:4) to give the title compound (0.8 g); 1H-NMR (CDCl3): δ 8.46 (1H, br s), 8.24 (1H, s), 7.48 (1H, d), ), 7.30 (1H, d), 7.16 (1H, m), 7.10 (1H, m), 3.70 (1H, d), 3.66 (1H, dd), 3.46 (1H, dd), 3.08 (2H, m), 2.87 (2H, m), 2.73 (3H, d), (3H, d), 1.9 (1H, br s); MS (ES): 244 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:15][CH2:16][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:18])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].ClC1C=CC=C[N+]=1C.[CH3:38][O:39][CH:40]([O:45][CH3:46])[CH2:41][C:42](O)=[O:43].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([N:15]([CH2:16][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:18])[C:42](=[O:43])[CH2:41][CH:40]([O:45][CH3:46])[O:39][CH3:38])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)NCC(C)Nc1ccc(Cl)c(Cl)c1
Reactant: COC(CC(=O)O)OC
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: COC(=O)[C@H](CCOCc1ccccc1)N(CC(C)Nc1ccc(Cl)c(Cl)c1)C(=O)CC(OC)OC
Yield: 95.5 %

Procedure:
A solution of 1.26 g (2.96 mmol) of (S)-4-benzyloxy-2-[2-(3,4-dichloro-phenylamino)-propylamino]-butyric acid methyl ester in 30 ml CH2Cl2 was treated with a solution of 0.91 g (3.55 mmol) of 2-chloro-1-methylpyridinium iodide and 0.48 g (3.55 mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl 3,3-dimethoxy-propionate by hydrolysis with LiOH) in 20 ml of CH2Cl2. The suspension was cooled and treated at 0° C. with 1.77 ml (7.41 mmol) of tributylamine. The cooling bath was removed after 10 min and stirring was continued over night. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over Na2SO4 to yield 1.53 g (96%) of the title compound as a 71:29 mixture of the (R) and (S) diastereomers. Yellow oil, MS: 541.2 (MH+, 2Cl).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:5]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[CH2:30])C=C.CCN(CC)CC>C(Cl)Cl>[CH:17]1([C:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:12]=3[N:4]3[CH2:1][CH:30]=[CH:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:5]=23)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C=CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3
Yield: 84 %

Procedure:
Crude methyl 1-allyl-3-cyclohexyl-2-(2-vinylphenyl)1H-indole-6-carboxylate was dissolved in DCM (0.02M) and treated with Zhan catalyst I (0.3 eq) at 35° C. for 1 h. NEt3 (7 eq) were added and the solvent was removed in vacuo. The residue was purified by chromatography (PE/EtOAc 95:5) to afford the title compound (84%); MS (ES+) m/z 372 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[N:17]([CH3:40])[N:18]=[CH:19][C:20]=2[NH:21][C:22]([C:24]2[C:29]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[N:35][CH:36]=3)=[N:28][CH:27]=[C:26]([CH:37]3[CH2:39][CH2:38]3)[N:25]=2)=[O:23])=[O:15])[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:40][N:17]1[C:16]([C:14](=[O:15])[NH:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[C:20]([NH:21][C:22]([C:24]2[C:29]([NH:30][C:31]3[CH:36]=[N:35][CH:34]=[N:33][CH:32]=3)=[N:28][CH:27]=[C:26]([CH:37]3[CH2:39][CH2:38]3)[N:25]=2)=[O:23])[CH:19]=[N:18]1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)NC1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)NC1CCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
A solution of 3-[(4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carbonyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (38 mg, 69 μmol; example 236) in 1,4-dioxane (0.38 ml) was treated with HCl in dioxane (4M; 380 μl, 1.5 mmol) and the reaction mixture was stirred at r.t. for 4 h. The precipitate was filtered off and dried to yield the product as yellow solid (25 mg, 75%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@H:8]1[C:12]2[NH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:11]=2[C:10](=[O:25])[NH:9]1.Br[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]([CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:32]2=[O:53]>O1CCOCC1.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[C:38]([NH:37][C:34]1[N:33]([CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[C:32](=[O:53])[C:31]2[C:36](=[C:27]([C:14]3[NH:13][C:12]4[C@@H:8]([CH3:7])[NH:9][C:10](=[O:25])[C:11]=4[CH:15]=3)[CH:28]=[CH:29][CH:30]=2)[N:35]=1)([CH3:39])([CH3:41])[CH3:40]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CCCO[Si](C)(C)C(C)(C)C
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 80 °C
Yield: 54.9 %

Procedure:
Potassium carbonate (Mallinkrodt; 0.091 g, 0.657 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (Aldrich; 5.82 mg, 8.22 μmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 0.086 g, 0.329 mmol), 8-bromo-2-(tert-butylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)quinazolin-4(3H)-one (500b; 0.077 g, 0.164 mmol) were combined in 2 mL dioxane and 0.4 mL water. Argon was bubbled into the reaction for 1 min. The reaction was sealed and heated to 80° C. for 1 h. The reaction was adsorbed onto 1 g silica gel and The material was and purified by silica gel chromatography (12 g column) using 0-100% EtOAc/hexanes. The product-containing fractions were concentrated to afford (R)-2-(tert-butylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (0.047 g, 0.090 mmol, 54.6% yield) as a light-yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.52 (1H, br. s.), 7.88-8.23 (2H, m), 7.22 (1H, t, J=7.7 Hz), 6.84 (1H, d, J=1.2 Hz), 5.89 (1H, br. s.), 5.31 (1H, s), 4.68 (1H, q, J=6.7 Hz), 4.18 (2H, t, J=7.1 Hz), 3.79 (2H, t, J=5.3 Hz), 1.92-2.02 (2H, m), 1.65 (9H, s), 1.54 (3H, d, J=6.8 Hz), 0.96 (9H, s), 0.15 (6H, s). m/z (ESI, +ve ion) 524.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[CH3:23]>CN1CCCC1=O>[CH3:23][C:14]1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[C:18]([CH3:19])[C:13]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (NaH; 60% dispersion in mineral oil; 64.11 g, 1.603 mol) in 350 mL of N-methylpyrrolidone (NMP) is cooled to 0° C. and treated with a solution of 4-methoxyphenol (208.4 g, 1.679 mol) over 30 min. The mixture is warmed to room temperature (RT) and after 30 min, 4-chloro-3,5-dimethylnitrobenzene (283.2 g, 1.526 mol; prepared by the method described by Yokoyama et. al. in EP580550) is added in one portion and the reaction is heated at 120° C. for 2 h. The reaction is cooled to room temperature (RT) and quenched with water (1500 mL). The suspension is cooled to 0° C., stirred for 30 min, then filtered and the filtercake is washed with water and dried in vacuo. The crude product, ethyl acetate (EtOAc; 2100 mL) and charcoal (42.6 g) were heated to reflux and the solids were removed by filtration through celite while hot. The filtrate is concentrated under reduced pressure to ca. 800 mL and the resulting suspension is cooled to 0° C. and stirred for 30 min. The product is collected by vacuum filtration, washed with cold EtOAc and dried in vacuo to afford 3,5-dimethyl-4-(4′-methoxyphenoxy)nitrobenzene: NMR (CDCl3) 2.22 (s, 6H), 3.78 (s, 3H), 6.68 (d, 2H, J=8.7), 6.82 (d, 2H, J=8.7), 8.02 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.CN.[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:36][CH3:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 35 mg, 0.081 mmol), methanamine-HCl (8.24 mg, 0.122 mmol), HATU (40.2 mg, 0.106 mmol), and 4-methylmorpholine (32.9 mg, 0.325 mmol) were added to DMF (1 mL). The reaction mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention 13.0 min) to provide (R/S)-2-hydroxy-N-methyl-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (30 mg, 0.066 mmol, 82% yield): LCMS=444.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.07-8.15 (2 H, m), 7.51-7.71(7 H, m), 5.11(1 H, s), 3.35(1 H, s), 2.79 (3 H, s); HPLC peak RT=7.4 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH:15]([F:17])[F:16])[N:12]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:24]1([S:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([S:30]([C:33]2[CH:34]=[C:35]([NH:39][C:21]([C:20]3[CH:19]=[N:18][N:12]4[C:13]([CH:15]([F:16])[F:17])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:23])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.7) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 582.1 [(M+H)+]; mp 231° C.
Reaction SMILES: Cl.[C:2]1([C:8]2[O:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=O)[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20]>>[F:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][O:37][CH2:36][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][C:11]2[N:12]=[C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:9][CH:10]=2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])=[CH:40][CH:41]=1
Reactant: O=C(O)Cc1coc(-c2ccccc2)n1
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cc1coc(-c2ccccc2)n1)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 70 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-phenyloxazol-4-yl)acetic acid hydrochloride and (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 44, (S)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-phenyloxazol-4-yl)acetamido)propanamide (160 g, 70%). 1H-NMR (400 MHz, CDCl3): σ 8.45 (s, 1H), 8.00 (m, 2H), 7.50-7.45 (m, 2H), 7.40-7.30 (m, 7H), 7.05-6.80 (m, 8H), 4.79-4.73 (m, 1H), 4.63 (m, 2H), 4.00-3.70 (m, 4H). MS (EI) for C33H27F2N3O5 found 584 (MH+).