Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[CH3:10][C:11]1[C:17]2[CH:18]=[CH:19][C:20]([NH:22]C([C@@H](NC([C@@H](NC([C@@H](NC(OC(C)(C)C)=O)CC3C=CC=CC=3)=O)CO)=O)CCCN=C(N)N)=O)=[CH:21][C:16]=2[O:15][C:13](=[O:14])[CH:12]=1>C(O)(=O)C>[NH2:22][C:20]1[CH:21]=[C:16]2[C:17]([C:11]([CH3:10])=[CH:12][C:13](=[O:14])[O:15]2)=[CH:18][CH:19]=1
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CO)NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)ccc12
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CC(=O)O
Product: Cc1cc(=O)oc2cc(N)ccc12
Reaction time: 1 h

Procedure:
50 μl of the solution of the trypsin-like protease obtained in Example 1 was added to 1.5 ml of 0.1M Tris-HCl buffer (pH 8.6) containing 100 μM of a synthetic substrate for trypsin Boc-Phe-Ser-Arg-MCA (MCA=methylcoumarinamide), and the mixture was subjected to incubation at 37° C. for 1 hour. 1 ml of 30% acetic acid was then added, the amount of 7-amino-4-methylcoumarin (AMC) formed was determined by fluorescent assay (fluorescence 440 nm, excitating light 380 nm), and the activity of the enzyme was calculated based thereon. An activity of forming 1 pM of AMC in 1 minute is defined as 1 unit (1 unit=1 pM AMC/min).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40].C(N(CC)C(C)C)(C)C.[CH2:52]1[O:54][C@@H:53]1[CH2:55][OH:56]>CO>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH2:52][C@H:53]([OH:54])[CH2:55][OH:56])[CH2:31][CH2:32]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:40])([F:42])[F:41]
Reactant: OC[C@@H]1CO1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C[C@H](O)CO)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of 10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt of Step B (0.50 g, 0.84 mmol) and N,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) was added (R )-(+)-glycidol (0.10 mL, 1.50 mmol). The reaction mixture was heated to 60° C. for 4 hours then cooled and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography on silica gel using a solvent system of 5% methanol in chloroform provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.38 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])[CH:13]=[N:12][CH:11]=1
Reactant: O=C1CCCN1
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 117 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.044 g, 1.09 mmol) in DMF (2 mL) was added pyrrolidin-2-one (0.081 g, 0.945 mmol) and the reaction mixture was stirred at room temperature for 20 min. Then, 3-bromo-5-chloromethyl-pyridine (0.15 g, 0.727 mmol) was added and the resulting suspension was heated at 60° C. over night. The mixture was quenched with water (2 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.217 g, 87%) as a white solid. MS: 251.1, 257.1 (M+H+).
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13]C)=[O:11])(=O)C.S(=O)(=O)(O)O>>[NH2:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([CH:15]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(=O)c1cc(NC(C)=O)c([N+](=O)[O-])cc1OCC
Agent: O=S(=O)(O)O
Product: CCOc1cc([N+](=O)[O-])c(N)cc1C(=O)OC
Temperature: 0 °C

Procedure:
A suspension of 1 5 g of ethyl 5-acetylamino-2-ethoxy-4-nitrobenzoate in 50 ml of 5 % (v/v) sulfuric acid methanolic solution was refluxed for 4 hours After cooling, the reaction solution was poured into an ice water, the resulting crystals were collected by filtration and recrystallized from methanol to give the title compound, m.p. 156°-157° C., yield of 1.01 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11](=[O:16])N(OC)C)[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH:18]1([Mg]Br)[CH2:20][CH2:19]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]([CH:18]1[CH2:20][CH2:19]1)=[O:16])[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)C1CC1
Reaction time: 4.5 h
Yield: 94 %

Procedure:
A solution of tert-butyl{(1S)-1-[methoxy(methyl)carbamoyl]propyl}carbamate (14.3 g) in tetrahydrofuran (130 mL) was ice-cooled under a nitrogen atmosphere, and 1.0 mol/L-cyclopropylmagnesium bromide/tetrahydrofuran solution (300 mL) was added. The mixture was stirred at the same temperature for 4.5 hr, saturated aqueous ammonium chloride solution (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→16%) to give the title compound as a colorless oil (yield: 10.7 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]1[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:11]=1.[NH2:16][C:17]1[O:21][N:20]=[C:19]([CH3:22])[C:18]=1[Br:23]>>[Br:23][C:18]1[C:19]([CH3:22])=[N:20][O:21][C:17]=1[NH:16][S:12]([C:9]1[S:8][C:7]([C:6]2[CH:5]=[CH:4][O:3][C:2]=2[CH3:1])=[CH:11][CH:10]=1)(=[O:14])=[O:13]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1occc1-c1ccc(S(=O)(=O)Cl)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccoc3C)s2)c1Br
Yield: 53.1 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-furanyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-(2-methylfuranyl)thiophene-5-sulfonyl chloride (55 mg, 0.21 mmol) with 5-amino-4-bromo-3-methyl isoxazole (41 mg, 0.21 mmol), after purification by column chromatography using 10% MeOH/CHCl3, gave 45 mg of the pure sulfonamide as a brown semisolid, 54% yield, m.p. 123-124° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC[C@@H:49]2[O:54][C:53]3[CH:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:52]=3[O:51][CH2:50]2)(=O)=O)=CC=1>ClCCl.C(#N)C>[NH2:8][C:9]1[C:14]([C:15]([NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][C@@H:49]3[O:54][C:53]4[CH:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:52]=4[O:51][CH2:50]3)[CH2:23][CH2:24]2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(C)cc3O2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2cccnc2N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1ccc2c(c1)O[C@@H](CN1CCC(CNC(=O)c3cccnc3N)CC1)CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 2-amino-N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (0.92 g; prepared in a similar manner to that described in Example 2) in dichloromethane (10 ml) then the mixture stirred at ambient temperature for 2 hours and the solvent removed in vacuo. The crude 2-amino-N-(4-piperidylmethyl)pyridine-3-carboxamide trifluoroacetate thus produced was dissolved in anhydrous acetonitrile (10 ml) and potassium carbonate (1.5 g) was added, followed by a solution of (R)-7-methyl-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate (0.9 g) in anhydrous acetonitrile (5 ml). The mixture was heated under reflux for 18 hours then poured onto water and extracted with ether (2×100 ml). The combined extracts were washed with water then extracted with hydrochloric acid (1M; 50 ml). The acid extracts were washed with ether (100 ml) then basified with sodium hydrogen carbonate and extracted with ether (2×100 ml). These extracts were combined, washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue purified by flash chromatography on silica eluting with a 20:1 mixture of dichloromethane and methanol. Appropriate fractions were combined and evaporated to give (S)-2-amino-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide as a colourless solid (0.36 g) m.p. 143-146° C., [α]D -46.23° (c=0.53, methanol).
Reaction SMILES: N[C:2]1[C:11]([O:12]C)=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[ClH:23].N([O-])=O.[Na+]>O>[Cl:23][C:2]1[C:11]([OH:12])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: Cl
Reactant: COc1cc2c(c(N)c1OC)c(=O)c(C(=O)O)cn2C1CC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(c(Cl)c1O)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 95 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a pale brown suspension of 5-amino-1-cyclopropyl-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (9 g, 29.6 mmol) in con. HCl (60 mL) stirred at 0° C. was added dropwise a cold solution of sodium nitrite (2.143 g, 31.1 mmol) in Water (20.00 mL). Stirring continued at 0° C. for 1 h. LCMS indicated completion of reaction. HCl (80 mL, 2633 mmol) was added and the mixture was heated at 95° C. for 6 h. LCMS indicated completion of reaction. The reaction mixture was cooled down to rt and then poured into water. The precipitates were collected by filtration and dried to afford 5-chloro-1-cyclopropyl-6-hydroxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7.4 g, 23.89 mmol, 81% yield) as a pale yellow solid. LCMS: [M+H]+: 310.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH3:25])[CH:16]=2)=[N:10]1.Cl>CO.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2[NH:12][C:13](=[O:14])[N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=2)=[CH:16][C:17]=1[O:24][CH3:25]
Reactant: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-3-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one (0.200 g, 0.52 mmol) in methanol (10 mL) was added iron powder (0.060 g, 1.84 mmol) and conc. HCl (2 mL). The reaction mixture was stirred at RT for 2 h. The reaction mass was quenched in water, basified with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.150 g of desired product. 1H NMR (300 MHz, DMSO do): δ 3.80 (s, 3H), 5.34 (s, 2H), 6.66 (d, J=7.8 Hz, 1H), 7.18-7.21 (m, 2H), 7.58 (m, 1H), 7.69 (d, J=7.8 Hz, 2H), 12.27 (s, 1H); MS (m/z): 351.05 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][NH2:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])([NH:13][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CS(=O)Nc1ccc(Br)cc1
Product: CNS(C)(=O)=Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and methylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.85 min; Mass spectrum (ESI+): m/z=263, 265 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([F:27])[C:3]=1[C:4]#[N:5].C1(C)C=CC=CC=1.[H-].[Na+].CN([CH:40]=[O:41])C>CO>[F:27][C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:9]=[C:2]([O:41][CH3:40])[C:3]=1[C:4]#[N:5]
Reactant: CN(C)C=O
Reactant: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCOC[C@H]2C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile (360 mg, 0.96 mmol) was azeotroped with toluene (2×12 mL). The resulting residue was taken up in 7.5 mL of CH3OH as a suspension. NaH (260 mg, 60% wt in mineral oil, 6.5 mmol) was added to a chilled (ice bath) solution of CH3OH (12.5 mL) under nitrogen portion-wise. After completion of addition, the ice bath was removed. The resulting mixture was stirred at ambient temperature for 10 minutes (concentration of CH3ONa was assumed to be 0.52 mmol/mL). A 2.25 mL portion (1.17 mmol, 1.2 equiv) of this mixture was added to the above suspension at room temperature in one portion. The resulting suspension was stirred at room temperature for 2 hours. LCMS showed no conversion. After another 1 h, 5 mL of DMF was added to the mixture, which became milky. The mixture was stirred at room temperature for another 16 hours, upon which time, it became a clear solution. LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was taken up in water (20 mL) as a suspension, which was sonicated briefly, and then filtered. The solids collected were dried under house vacuum at room temperature for 1 hour. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc gave the title compound (350 mg) as a foam. LC-MS (ES) m/z=386 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]C)=O.[CH:11]([NH2:13])=O>C(Cl)Cl>[N:1]1[C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:9])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: COC(=O)c1ccsc1N
Solvent: ClCCl
Product: O=c1[nH]cnc2sccc12

Procedure:
A solution of methyl 2-aminothiophene-3-carboxylate (602.1 mg, 3.83 mmol) in formamide (5 mL) is heated at 200° C. for 12 h. The resulting tar is dissolved in CH2Cl2 (10 mL) then placed on a silica plug and eluted with 10% MeOH in CH2Cl2. The filtrate is stripped under reduce pressure and the resulting solid is washed with EtOH to yield 3H-thieno[2,3-d]pyrimid-4-one (231.4 mg, 40.%) as an orange solid. 1H NMR (DMSO) δ 12.50 (1H, brs), 8.13 (1H, s), 7.60 (1H, d, J=5.8 Hz), 7.41 (1H, d, J=6.0 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:18]=3)OCCC[O:12]2)[CH:6]=[CH:7][C:8]=1[O:9]C.[BrH:31]>>[BrH:31].[C:25]1([CH2:24][CH2:23][C:19]2[N:18]=[C:17]([C:11]([C:5]3[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([OH:2])[CH:4]=3)=[O:12])[CH:22]=[CH:21][CH:20]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(C2(c3cccc(CCc4ccccc4)n3)OCCCO2)cc1OC
Agent: Br
Product: O=C(c1ccc(O)c(O)c1)c1cccc(CCc2ccccc2)n1

Procedure:
A solution of 3.5 g. of 2-(3,4-dimethoxyphenyl)-2-(6-phenylethyl-2-pyridyl)-1,3-dioxane in 20 ml. of 48% hydrobromic acid was heated under reflux for 20 hours. The solvent was removed under reduced pressure and industrial methylated spirit was evaporated several times from the residue which crystallized upon trituration with ethyl acetate. Recrystallization from methanolethyl acetate yielded (3,4-dihydroxyphenyl) (6-phenylethyl-2-pyridyl) ketone hydrobromide, m.p. 181°C. Analysis: Calculated for C20H18NO3Br: C, 60.0; H, 4.5; N, 3.5; Br, 20.0. Found: C, 60.2; H, 4.7; N, 3.6; Br, 20.35.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13]CCCCC.C[Si](C=[N+]=[N-])(C)C>CC(C)=O>[Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CCCCCC
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
206 mg (1.0 mmol) of 2,5-Dichloro-3-aminobenzoic acid was dissolved in 4 mL of acetone. 0.7 mL (1.4 mmol) of A hexane solution of 2.0M trimethylsilyldiazomethane was added thereto and stirred at room temperature for 1.5 hours. A solvent was removed to obtain methyl 2,5-dichloro-3-aminobenzoate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:22][CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:22][CH2:21][CH:20]([N:30]3[CH2:31][CH2:32][CH2:33][C@@H:29]3[CH3:28])[CH2:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CCCN1
Reactant: CS(=O)(=O)O[C@H]1CCC(c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Reaction time: 16 h
Yield: 82.7 %

Procedure:
Methanesulfonic acid (S)-3-(4-benzyloxycarbonylamino-phenyl)cyclopentyl ester (Intermediate 12) (510 mg, 1.31 mmol, 1 equiv.) was dissolved in 8 mL of anhydrous acetonitrile. This solution was transferred into a flask containing (S)-2-methyl-pyrrolidine (445 mg, 5.24 mmol, 4 equiv.) and K2CO3 (800 mg, 5.76 mmol, 4.4 equiv.). The suspension was de-gassed by vacuum/nitrogen exchange 3 times, and then, heated on an oil bath set at 80° C. under nitrogen with stirring for 16 h. TLC (5% MeOH in DCM for SM) showed the reaction was complete. Acetonitrile was removed in vacuo. The residue was taken in water (5 mL) and DCM (20 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL), and dried (K2CO3). The solution was filtered. The filtrate was concentrated in vacuo to obtain a crude product which was purified on a silica gel column eluting with 5% 7N ammonia methanolic solution in DCM to afford 410 mg (84%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:15]=1)[O:12][C:11](=[O:21])[C:10]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=1)=[CH:9]2.B(Br)(Br)Br>ClCCl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:15]=1)[O:12][C:11](=[O:21])[C:10]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)=[CH:9]2
Reactant: COc1ccc(-c2cc3cc(CCCCO)cc(CCCCO)c3oc2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1oc2c(CCCCO)cc(CCCCO)cc2cc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6,8-Bis-(4-hydroxy-butyl)-3-(4-methoxy-phenyl)-chromen-2-one (14.3 g, 36.0 mmol) is dissolved in 270 ml dichloromethane and a solution of boron tribromide (12 ml, 126 mmol) in 30 ml dichloromethane is added under ice-cooling. The cooling is removed and the reaction mixture is stirred overnight at room temp. The solution is poured onto ice/water, acidified with 2 N hydrochloric acid, and extracted three times with ethyl acetate. The combined organic layers are washed with water and dried over sodium sulfate. The solvent is removed in vacuo and the residue is filtered through silica gel with toluene/THF (7:3). 6,8-Bis-(4-hydroxy-butyl)-3-(4-hydroxy-phenyl)-chromen-2-one is obtained as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20]CC)=[O:19])[CH:8]=1)=[O:5].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccc(F)cn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(NC(=O)c2cc(-c3ccc(F)cn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a suspension of ethyl 5-(2,4-dichloro-5-(5-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Example 116, 822 mg, 1.65 mmol) in ethanol (15 mL) was added 2M aqueous sodium hydroxide (4.1 mL, 8.23 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was diluted with water (25 mL) and neutralised with 2M aqueous hydrochloric acid. The resultant solid was filtered, washed with water and dried in vacuo to afford the title compound as a white solid (700 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[I-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([C:20]2[N:29]=[C:28](Cl)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17].O>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([C:20]2[N:29]=[C:28]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)c(Cl)c1)c1nc(Cl)c2ccccc2n1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)c(Cl)c3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a mixture of 5-methyl-1H-pyrazol-3-amine (0.26 g, 2.68 mmol), potassium iodide (0.26 g, 1.57 mmol), and TEA (0.45 mL, 3.23 mmol) in DMF (30 mL) was added (3-chloro-4-fluorophenyl)(4-chloroquinazolin-2-yl)methanone (0.495 g, 1.54 mmol) and the mixture was stirred at rt overnight. Water was added and the precipitated solid was collected by filtration to afford crude (3-chloro-4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (458 mg) which was used directly in the next step. LC-MS (ESI) m/z 382 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.CCO>O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1)[CH2:9][C:8]2=[O:10]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CC(c2ccc(Cl)cc2)Oc2ccc(Br)cc21
Yield: 89.2 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (6 g, 28 mmol), 4-chlorobenzaldehyde (3.92 g, 28 mmol), and borax (10H2O, 10.67 g, 28 mmol) in H2O (60 mL) and EtOH (36 mL) was stirred at 110° C. overnight. The mixture was filtered to give a solid cake. The cake was dissolved in EtOAc and filtered. The filtrate was dried, filtered, and concentrated to give 6-bromo-2-(4-chloro-phenyl)-chroman-4-one (8.43 g, 89%). 1H-NMR (CDCl3): 2.88 (m, 1H), 3.04 (m, 1H), 5.44 (m, 1H), 6.94 (m, 1H), 7.39 (m, 4H), 7.57 (m, 1H), 8.02 (m, 1H).