Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[C:33]([C:34]([OH:36])=O)=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:37][CH3:38])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:3][CH2:2]1.[NH2:40][CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:11]([F:20])=[CH:12][C:13]([O:17][CH2:18][CH3:19])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[C:33]([C:34]([NH:40][CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])=[O:36])=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:37][CH3:38])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)CCN
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4C(=O)O)n3)c(C)c2C2CC2)c(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4C(=O)NCCS(C)(=O)=O)n3)c(C)c2C2CC2)c(F)c1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a suspension of 147 mg 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinic acid 2-11-1 (0.27 mmol, 1.0 eq) and 67.5 mg 2-aminoethylmethyl sulfone (0.55 mmol, 2.0 eq) in 2.1 mL DMF were added 191 μL N,N-diisopropylethylamine (1.10 mmol, 4.0 eq) and 157 mg (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.30 mmol, 1.1 eq). The resulting solution was stirred over night at rt and afterwards diluted with water. The precipitate was collected by filtration, washed with water and dried. The crude product was purified by preparative HPLC yielding 40 mg of analytically pure target compound (62 μmol, 22%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2Cl)cc1N
Yield: 74.6 %

Procedure:
Prepared from (4-(2-chloro-phenylethynyl)-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F5) (1.61 g, 4.3 mmol) by reduction with SnCl2.2H2O (5.3 g, 23.5 mmol) according to the general procedure G (method b). Obtained as a light brown solid (1.1 g).
Reaction SMILES: P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.[CH:25]1([CH2:30][C:31]([OH:33])=O)[CH2:29][CH2:28][CH2:27][CH2:26]1.[NH2:34][C:35]1[N:36]=[CH:37][N:38]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:39]=1[C:40]([NH2:42])=[O:41]>CN(C)C=O>[CH2:43]([N:38]1[C:39]([C:40]([NH2:42])=[O:41])=[C:35]([NH:34][C:31](=[O:33])[CH2:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[N:36]=[CH:37]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: O=C(O)CC1CCCC1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1c(NC(=O)CC2CCCC2)ncn1Cc1ccccc1
Reaction time: 1 h
Yield: 54.2 %

Procedure:
4.14 ml (20 mmol) of diphenyl chlorophosphate and 2.8 ml (20 mmol) of triethylamine were added to a solution of 2.5 ml (20 mmol) of cyclopentylacetic acid in 20 ml of N,N-dimethylformamide while cooling with ice. The solution was stirred for one hour while cooling with ice. A solution of 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 in 200 ml of N,N-dimethylformamide was added to the reaction solution, followed by stirring overnight. After concentration under vacuum, 5% aqueous solution of sodium hydrogencarbonate was added to obtain a solid precipitate. The precipitate was collected by filtration using a funnel equipped with a glass filter, washed with 5% aqueous solution of sodium hydrogencarbonate and distilled water, and dried under vacuum to obtain a crude product. This crude product was purified by suspension in hot methanol to obtain 1.77 g of 1-benzyl-4-cyclopentylacetylamino-5-imidazolecarboxamide (yield 54%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:12]([CH2:13]O)=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[CH:9][N:8]=1>>[Cl:3][CH2:13][C:12]1[C:7]([O:6][CH3:5])=[N:8][CH:9]=[N:10][C:11]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O=S(Cl)Cl
Reactant: COc1ncnc(C(F)(F)F)c1CO
Product: COc1ncnc(C(F)(F)F)c1CCl
Reaction time: 3 h
Yield: 98.3 %

Procedure:
1.19 g (10.1 mmoles) of thionyl chloride was added, at room temperature, to a solution of 0.42 g (2.02 mmoles) of (4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methanol. The mixture was stirred for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.45 g (yield: quantitative) of 5-chloromethyl-4-methoxy-6-trifluoromethylpyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([S:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:12]([OH:24])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH:13]([S:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12](=[O:24])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)[C@H](SC(=O)c2ccccc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(=O)C(SC(=O)c2ccccc2)C1
Yield: 83 %

Procedure:
Thiobenzoic acid S-((1R, 2R, 5S)-5-tert-butoxycarbonylamino-2-hydroxy-cyclohexyl)ester+(1S, 2S, 5R)diasteromer (8.7 g, 24.8 mmol) from Example 34 Step A was treated with 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one (11.02 g, 26 mmol) according to the method of Example 34 Step B. After work up and chromatography (silica, toluene/ethyl acetate=6/1) of the mixture the title compound (toluene/ethyl acetate=3/1, Rf=0.43, 7.15 g, 83% yield) was obtained as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:20]=[C:21](I)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(COC)OC>[Br:18][C:19]1[CH:24]=[C:23]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Brc1cccc(I)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: Brc1cccc(-c2cc3ccccc3c3ccccc23)c1
Reaction time: 4 h
Yield: 73.9 %

Procedure:
In argon atmosphere, a mixture of 31.4 g (141 mmol) of 9-phenanthreneboronic acid, 40.0 g (141 mmol) of 3-bromoiodobenzene, 3.30 g (2.83 mmol) of tetrakis(triphenylphosphine)palladium (0), 200 ml of toluene, 50 ml of dimethoxyethane and 212 ml of a 2 M sodium carbonate aqueous solution, and the mixture was refluxed under stirring for 4 h. After the reaction, the reaction mixture was added with toluene and washed with water. The organic phase was dried over sodium sulfate, and then toluene was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 34.7 g (yield: 74%) of 9-(3-bromophenyl)phenanthrene.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:40][CH2:39][N:30]2[C:31]3[CH:32]=[C:33](I)[CH:34]=[CH:35][C:36]=3[CH2:37][CH:29]2[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH3:41][S:42][Sn](CCCC)(CCCC)CCCC.O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:40][CH2:39][N:30]2[C:31]3[CH:32]=[C:33]([S:42][CH3:41])[CH:34]=[CH:35][C:36]=3[CH2:37][CH:29]2[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN2c3cc(I)ccc3CC2C1
Reactant: CCCC[Sn](CCCC)(CCCC)SC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)N1CCN(C(=O)OC(C)(C)C)CC1C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
Triphenylphosphine (28 mg) was added in 1 portion to a stirred solution of palladium(II) acetate (6 mg) in THF (2.5 mL) at room temperate under Ar. After stirring at room temperature under Ar for 10 min a solution of 2-tert-butoxycarbonyl-7-iodo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole (0.20 g, 0.5 mmol) in THF (5 mL) was added. The reaction was stirred at room temperature for 10 min then a solution of (methylthio)tributyltin (035 g, 1 mmol) in THF (2.5 mL) was added. The reaction was heated to reflux and stirred for 2 days. After allowing to cool to room temperature the mixture was poured into water (50 mL) and extracted. with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (r×50 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-heptane (1:20)] to give the product as a yellow oil (0.08 g, 50%). NMR δH (400 MHz; CDCl3) 6.97 (1H, d, J 7.5 Hz), 6.56 (1H, dd, J 7.5, 1.5 Hz), 6.36 (1H, d, J 1l Hz), 3.94-4.26 (2H, m), 3.35-3.49 (2H, m), 2.78-2.96 (41, m), 2.49-2.55 (1H, m), 2.44 (311, s), 1.46 (9H, s).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[O:7][CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:3])[CH3:2].[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][CH2:27][C:28]1[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=1[CH3:33]>N1CCCC1.C(O)C>[CH3:37][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][C:28]1[C:29]([CH3:36])=[C:30]([CH:34]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[CH2:9][CH2:8][O:7][C:6]3[CH:20]=[CH:21][CH:22]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=3)[NH:14][C:13]2=[O:19])[NH:31][C:32]=1[CH3:33]
Reactant: CC(C)c1cccc(OCCc2cccc3c2CC(=O)N3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Solvent: CCO
Solvent: C1CCNC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCOc4cccc(C(C)C)c4)c32)c(C)c1CCCN(C)C
Temperature: 90 °C
Yield: 86.7 %

Procedure:
A mixture of 4-[2-(3-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one (28 mg, 0.095 mmol), 4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (20 mg, 0.095 mmol) and 1 drop of pyrrolidine in 1.0 mL of ethanol was heated at 90° C. for 4 hours and cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane, and dried in a vacuum oven overnight to give 40 mg (87%) of 3-[4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-[2-(3-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5].ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)(O)[O-].[Na+].O>C1COCC1>[CH2:1]([C:6]1[CH:7]=[C:8]2[C:9]([O:15][C:10](=[O:25])[NH:11][C:12]2=[CH:13][CH:14]=1)=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCc1ccc2c(c1)C(=O)C(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
8.13 g of compound 15 (37.5 mmole) was dissolved in 145 ml THF. This solution was added dropwise to a solution of 12.9 g m-chloro-perbenzoic acid (74.8 mmole) in 55 ml THF and stirred overnight. To the reaction mixture 150 ml saturated sodiumbicarbonate and 500 ml water were added. The resulting suspension was extracted three times with 250 ml ethyl acetate. After evaporation compound 16 was obtained as a white solid (7.4 g, 84% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1F.[Cl:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:27][C:23]1[CH:22]=[C:21]([Cl:20])[CH:26]=[N:25][CH:24]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=C(NCc1ccco1)c1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NCc1ccco1)c1cc([N+](=O)[O-])ccc1Oc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a 0.08M solution of N-(2-furanylmethyl) 2-fluoro-5-nitrobenzamide (2.64 g, 10 mmol, from Example 35.1) in anhydrous DMSO was added 5-chloro-3-pyridinol (1.36 g, 10.5 mmol, Acros) followed by K2CO3 (1.38 g, 10 mmol). The resulting mixture was stirred at ambient temperature for 1 hr. The crude reaction mixture was diluted with a 1M solution of aqueous hydrochloric acid (125 mL) and extracted 3× with EtOAc (125 mL). The organic layers were combined and washed twice with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to yield 3.7 g (100%) of N-(2-furanylmethyl) 5-nitro-2-(3-chloro-5-pyridyloxy)benzamide as a pale yellow foam which was used without further purification.
Reaction SMILES: [OH2:1].[OH-].[Na+].[OH:4][C:5]1[CH2:9][CH2:8][C:7](=O)[C:6]=1[CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(O)(=O)C>[OH:1][CH:8]1[CH2:9][C:5](=[O:4])[C:6]([CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7]1
Reactant: O
Reactant: COC(=O)CCC#CCCC1=C(O)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)CCC#CCCC1=CC(O)CC1=O
Temperature: 100 °C
Reaction time: 25 h
Yield: 76 %

Procedure:
To the compound [VIII-1] (28.3 g, 0.12 mole) are added water (1200 g) and acetic acid (1.5 g), and the pH value thereof is adjusted to pH 4.4 with 5% aqueous sodium hydroxide solution. The mixture is heated with stirring at 100° C. for 25 hours. After completion of the reaction, the reaction solution is cooled and extracted twice with methyl isobutyl ketone (300 ml) and separated. Methyl isobutyl ketone is distilled off from the organic layer to give a mixture (21.5 g, yield; 76%) of 4-hydroxy-2-(6-methoxycarbonyl-3-hexynyl)-2-cyclopentenone (racemic 4-hydroxycyclopentenone) and 3-hydroxy-2-(6-methoxycarbonyl-3-hexynyl)-2-cyclopentenone [IX-1] (ratio thereof=6:4).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].ClS([N:24]=[C:25]=[O:26])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[N:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:25]([NH2:24])=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(C)nc1NCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1sc(C)nc1N(Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzylamino-2-methyl-thiazole-5-carboxylic acid ethyl ester (0.40 g, 1.45 mmol) in DCM (10 mL) was added chlorosulfonyl isocyanate (140 μL, 1.59 mmol) dropwise at −78° C. The mixture was allowed to warm to RT and stirred for 30 minutes. The resulting solution was concentrated in vacuo then dissolved in acetone (5 mL), before H2O (2 mL) was added dropwise. The mixture was stirred at RT for 30 minutes, then concentrated in vacuo. The resultant oil was partitioned between EtOAc and H2O. The organic layer was isolated, washed with brine, dried (MgSO4) and concentrated in vacuo to give 4-(1-benzyl-ureido)-2-methyl-thiazole-5-carboxylic acid ethyl ester as a pale brown oil. To a solution of 4-(1-benzyl-ureido)-2-methyl-thiazole-5-carboxylic acid ethyl ester in MeOH (10 mL) was added a solution of sodium methoxide in MeOH (25% w/w, 1.33 mL, 5.80 mmol) and the mixture was stirred at RT for 18 h. The crude reaction mixture was concentrated in vacuo and partitioned between EtOAc and an aqueous solution of HCl (1 M). The organic layer was isolated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated with EtOAc to give the title compound as a pale yellow solid (0.25 g, 63%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26].O>CS(C)=O>[C:29]([O:28][C:24](=[O:27])[CH2:25][CH2:26][NH:2][C@H:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCN[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl L-phenylalaninate hydrochloride (800 mg) in dimethyl sulfoxide (3.20 mL) were added potassium carbonate (429 mg) and tert-butyl acrylate (0.901 mL), followed by stirring at 150° C. for 1 hour under microwave. After cooling to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-(3-tert-butoxy-3-oxopropyl)-L-phenylalaninate (266 mg).
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:31])[CH:3]=1.C(N(CC)CC)C.[CH3:39][O:40][C:41](=[O:51])[C:42]1[CH:47]=[CH:46][C:45]([C:48]#[CH:49])=[CH:44][C:43]=1[Cl:50]>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.[Cu]I>[CH3:39][O:40][C:41](=[O:51])[C:42]1[CH:47]=[CH:46][C:45]([C:48]#[C:49][C:2]2[CH:3]=[C:4]([Cl:31])[C:5]([O:6][C:7]3[C:12]([C:13]([N:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]([CH:25]5[CH2:26][CH2:27]5)[CH2:17][CH2:16]4)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:28][C:29]=2[Cl:30])=[CH:44][C:43]=1[Cl:50]
Reactant: C#Cc1ccc(C(=O)OC)c(Cl)c1
Reactant: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#Cc2cc(Cl)c(Oc3ncccc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1Cl
Temperature: 100 °C
Yield: 33.3 %

Procedure:
To a degassed suspension of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (100 mg, 0.19 mmol, 1.0 equiv; Example 163) in triethylamine (0.73 g, 1.0 mL, 7.21 mmol, 38.0 equiv; [CAS RN 121-44-8]) under Ar was added 2-chloro-4-ethynyl-benzoic acid methyl ester (120 mg, 0.62 mmol, 3.2 equiv), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02 mmol, 0.1 equiv; [CAS RN 14221-01-3]) and copper(I) iodide (3.7 mg, 0.02 mmol, 0.1 equiv; [CAS RN 7681-65-4]). The reaction mixture was heated by microwave irradiation to 100° C. for 40 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) and eluting with a gradient of acetonitrile/water provided 40 mg (33%) of the title compound as a light brown powder. MS (ISP): 634.2 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:35]=[CH:34][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:33])[C@@H:16]3[CH2:20][C@@H:19]([NH:21][C:22](=[O:32])[CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:18][NH:17]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[ClH:1].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:33])[C@@H:16]3[CH2:20][C@@H:19]([NH:21][C:22](=[O:32])[CH2:23][NH2:24])[CH2:18][NH:17]3)=[CH:12][CH:13]=2)=[CH:34][CH:35]=1
Reactant: Cc1ccc(Oc2ccc(NC(=O)[C@@H]3C[C@@H](NC(=O)CNC(=O)OC(C)(C)C)CN3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(Oc2ccc(NC(=O)[C@@H]3C[C@@H](NC(=O)CN)CN3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (6 mL) was added to a solution of trans-4-(N-tert-butoxylcarbonylglycylamino)-L-Proline 4-(4′-methylphenoxy)phenylamide (A, 210 mg) in 1,4-dioxane (6 mL) at room temperature. After stirring at room temperature for 1 hr, the reaction mixture was concentrated in vacuo. The residue was washed with ether to give the title compound (106 mg) as colorless crystals: 1H NMR (400 MHz, D2O) δ 1.28 (s, 3 H), 2.59 (m, 2 H), 3.50 (br d, J=8.8 Hz, 1H), 3.82 (t, J=6.0 Hz, 1H), 3.87 (s, 2 H), 4.61 (br s, 1 H), 4.96 (m, 1 H), 6.92 (d, J=7.5 Hz, 2 H), 7.00 (d, J=7.8 Hz, 2 H), 7.19 (d, J=7.5 Hz, 2 H), and 7.43 (d, J=7.8 Hz, 2 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:6]2=[O:23].[CH3:24][C:25]1(OC)[CH2:29][CH2:28][CH:27](OC)O1>CC(O)=O>[CH3:24][C:25]1[N:1]([CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:12]=2[C:13]([F:15])([F:16])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:6]3=[O:23])[CH:27]=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CN)cc2c1=O
Reactant: COC1CCC(C)(OC)O1
Solvent: CC(=O)O
Product: Cc1cccn1Cc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of N-(6-aminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (150 mg, 0.43 mmol) in conc. CH3CO2H (10 mL) was added 2-methyl-2,5-dimethoxytetrahydrofurane (62.2 mg, 0.43 mmol) and the reaction mixture was stirred for 2 h at reflux temperature. Subsequently, the solvent was evaporated and the crude light-yellow residue was recrystallized from EtOAc/cyclohexane to yield N-[6-(2-methyl-pyrrol-1-ylmethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (130 mg, 0.312 mmol, 73%) as a light-orange solid. 1H-NMR (DMSO-d6, 400 MHz) 3.11 ppm (s, 3H, SO2—CH3; LC-MS rt=3.994 mn; MS: m/z 416.9 [M+H]+ Column: SunFireC18, 4.6*50 mn, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min