Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C([Si](C(C)C)(C(C)C)[N:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:28][N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][CH:14]=[C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:35]5[CH:36]=[CH:37][NH:33][CH:34]=5)[CH:3]=4)[C:8](=[O:12])[NH:7][C:6]3=[O:13])=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(-c5cc[nH]c5)cc43)cc2)CC1
Temperature: 180 °C
Yield: 31.2 %

Procedure:
To a suspension of 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (0.2 g, 0.45 mmol) in N,N-dimethylformamide (5 mL) is added N-triisopropylsilyl-3-pyrrole boronic acid (0.16 g, 0.54 mmol), followed by 300 μL of 2M aqueous cesium carbonate and tetrakis triphenylphosphine palladium (30 mg, 0.025 mmol). The reaction mixture is subjected to microwave heating at 180° C. for 300 seconds. The reaction mixture is then divided into 3 fractions and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield 60 mg of 4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-6-(1H-pyrrol-3-yl)-4H-isoquinoline-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:19]=[N:20][C:21]([O:24]C)=[CH:22][CH:23]=2)[N:15]=[C:14]([S:26][CH3:27])[N:13]=1.Cl>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:13]=[C:14]([S:26][CH3:27])[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][CH:19]=2)[CH:17]=1
Reactant: COc1ccc(-c2cc(NCCc3c(F)cccc3Cl)nc(SC)n2)cn1
Agent: Cl
Solvent: CCO
Product: CSc1nc(NCCc2c(F)cccc2Cl)cc(-c2ccc(=O)[nH]c2)n1
Yield: 76.1 %

Procedure:
A solution of [2-(2-chloro-6-fluoro-phenyl)-ethyl]-[6-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrimidin-4-yl]-amine [1.5 g, 3.7 mmol, Example 30] and concentrated hydrochloric acid (5 mL) in EtOH (95%, 30 mL) is heated to 90° C. for 15 hours, and concentrated. The residue is diluted with water, and the pH of the solution is adjusted to 7. The resulting solid is filtered and dried to afford 5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methylsulfanyl-pyrimidin-4-yl}-1H-pyridin-2-one [1.1 g, 76%, Example 31]. LCMS: RT=3.12 minutes, MS: 391 (M+H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1>>[F:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13]1
Reactant: F[C@@H]1CCNC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CC[C@@H](F)C1
Yield: 58 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (R)-3-fluoropyrrolidine gave (R)-5-(3-fluoropyrrolidin-1-yl)-1-methyl-4-nitro-1H-pyrazole as a yellow solid (153 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 5.48-5.31 (m, 1H), 3.79 (s, 3H), 3.73-3.57 (m, 2H), 3.48-3.37 (m, 2H), 2.46-2.27 (m, 2H)
Reaction SMILES: CSC.B.[NH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:9]=2[O:8][N:7]=1>COCCOC>[NH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][NH2:16])=[CH:14][C:9]=2[O:8][N:7]=1
Reactant: N#Cc1ccc2c(N)noc2c1
Agent: B
Solvent: CSC
Solvent: COCCOC
Product: NCc1ccc2c(N)noc2c1
Reaction time: 0.5 h

Procedure:
Borane methylsulfide complex (2 M in THF, 1.98 mL) was added to a stirred refluxing solution of 3-amino-6-cyano-1,2-benzisoxazole (210 mg, 1.32 mmol) in DME (10 mL). After 45 min excess methyl sulfide was evaporated and the reaction mixture was cooled and quenched with 1M HCl solution (10 mL). The mixture was stirred for 30 min and then was neutralised with sodium bicarbonate solution and concentrated to dryness. The residue was triturated with 5% methanol/chloroform, filtered and the filtrate evaporated in vacuo. The residue was purified by chromatography on silica (5% methanol, chloroform/ammonia) to give the title compound as a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]([NH:25][C:26](=[N:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])SC)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH2:15]([O:22][C:23]([N:25]=[C:26]([NH:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[NH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of t-butyl 4-aminobenzoate (2.0 g, 10.3 mmol) in CH2Cl2 (20 mL) was added 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (5.6 g, 15.5 mmol), Et3N (5.0 mL, 36 mmol), and mercuric chloride (3.37 g, 12.4 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite®, and the filtrates were concentrated in vacuo and purified by column chromatography (1:1 CH2Cl2/hexanes to 100% CH2Cl2, and then 10% EtOAc/CH2Cl2) to provide tert-butyl 4-(2,3-bis(benzyloxycarbonyl)guanidino)benzoate (3.9 g, 75%). To a pressure bottle was charged 20% palladium hydroxide on carbon (2 g) followed by a solution of t-butyl 4-(2,3bis(benzyloxycarbonyl)guanidine)benzoate (3.9 g, 7.7 mmol) in EtOAc (80 mL). The mixture was stirred under hydrogen at 50 psi at room temperature overnight. The solution was filtered through Celite® and the filtrate evaporated in vacuo to provide t-butyl guanidinobenzoate (1.8 g, 100%). To the guanidine (855 mg, 3.6 mmol) in EtOAc (50 mL) was add 2M HCl in Et2O (1.9 mL, 3.8 mM). The solution was concentrated and the precipitate was collected by filtration, washed with Et2O and dried in vacuo to yield (840 mg, 85%) of the HCl salt.
Reaction SMILES: CSC1C2C=C([CH:12]=[O:13])SC=2N=CN=1.[CH3:14][S:15][C:16]1[C:17]2[S:24][CH:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[CH3:14][S:15][C:16]1[C:17]2[S:24][C:23]([CH:12]=[O:13])=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: CSc1ncnc2sc(C=O)cc12
Reactant: CSc1ncnc2ccsc12
Product: CSc1ncnc2cc(C=O)sc12

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 15 but using 4-(methylthio)thieno[3,2-d]pyrimidine (intermediate 20) in place of 4-(methylthio)thieno[2,3-d]pyrimidine. Yellow solid (434 mg, 38%);
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1)#C.ClC1C(C#N)=[C:15]([NH:19][C:20]2C=CC=[C:22]([C:26]#C)[CH:21]=2)N=CN=1.C(C1C=C(N2C3C4C(=C(C(O)=O)SC=4N=CN=3)NC2=O)C=CC=1)#C.N1CCCC1.ClCC1C=CC([N+]([O-])=O)=CC=1>>[N:19]1([CH2:15][C:8]2[CH:3]=[CH:4][C:5]([NH2:9])=[CH:6][CH:7]=2)[CH2:20][CH2:21][CH2:22][CH2:26]1
Reactant: C#Cc1cccc(N)c1
Reactant: C#Cc1cccc(Nc2ncnc(Cl)c2C#N)c1
Agent: C#Cc1cccc(N2C(=O)Nc3c(C(=O)O)sc4ncnc2c34)c1
Agent: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: C1CCNC1
Product: Nc1ccc(CN2CCCC2)cc1

Procedure:
Using the procedure of Example 1, 3-ethynyl-phenylamine Compound 54a was used in place of 3-chloro-4-fluoro-phenylamine Compound 1e to prepare 4-chloro-6-(3-ethynyl-phenylamino)-pyrimidine-5-carbonitrile Compound 54b. MS 255 (MH+). Using the procedure of Example 1, Compound 54b was used in place of Compound 1f to prepare 5-(3-ethynyl-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 54c. MS 335 (M−). Using the procedure of Example 1, pyrrolidine was used in place of piperidine and combined with 1-chloromethyl-4-nitro-benzene Compound 1i and taken forward to provide 4-pyrrolidin-1-ylmethyl-phenylamine Compound 54e. MS 177 (MH+). Using the procedure of Example 2, Compound 54c was used in place of Compound 40 and Compound 54e was used in place of 3,4-dimethoxy-phenylamine Compound 2c to give Compound 15. MS 495 (MH+).
Reaction SMILES: C1(C(Cl)=O)CCCCC1.N[C@H](C(O)=O)CC(C)C.Cl.[Na+].[CH:21]1([C:27]([NH:29][C@H:30]([C:35]([O-:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[Na+].C1(C([O-])=O)CCCCC1.[Na+].C1(C(N[C@H](C(N[C@H](C([O-])=O)CC(C)C)=O)CC(C)C)=O)CCCCC1>[OH-].[Na+]>[CH:21]1([C:27]([NH:29][C@H:30]([C:35]([OH:37])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)C[C@H](NC(=O)C1CCCCC1)C(=O)[O-]
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)C1CCCCC1)C(=O)[O-]
Agent: Cl
Product: CC(C)C[C@H](NC(=O)C1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Cyclohexanoyl chloride (32.7 mL, 232 mmole) was added dropwise to a solution of (L)-leucine (37 g, 282 mmole) in aqueous sodium hydroxide (500 mL, 2 N). During the course of this addition, the reaction temperature was maintained below 45° C. using an ice/water bath, as necessary. The pH was maintained at about 10 by the addition of aliquots of 14 N NaOH, as necessary. After the addition was complete, the reaction mixture was stirred for an additional 2 hours at room temperature. The resulting clear solution was adjusted to pH 2.5 by the dropwise addition of concentrated hydrochloric acid. The precipitate was collected by filtration, re-dissolved in a minimum amount of 12 N sodium hydroxide, and re-precipitated by dropwise addition of concentrated hydrochloric acid and filtered. The crude reaction product was a white solid and contained about 85% N-cyclohexanoyl leucine sodium salt, about 10% cyclohexane carboxylic acid sodium salt, and about 5 N-cyclohexanoylleucylleucine sodium salt, by weight. The solid was washed with dilute aqueous hydrochloric acid (750 mL, 0.1 N) to provide N-cyclohexanoyl-(L)-leucine as a white crystalline solid (52.6 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:9]3[N:10]=[C:11]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:12]=[CH:13][C:14]=3[C:6]=2[CH:5]=[CH:4][N:3]=1.[ClH:40].O1CCOCC1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[C:7]2[N:8]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:9]3[N:10]=[C:11]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)=[CH:20][N:21]=4)[N:12]=[CH:13][C:14]=3[C:6]=2[CH:5]=[CH:4][N:3]=1.[ClH:40]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5ccnc(Cl)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1nccc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 197 (0.173 g, 0.315 mmol) was dissolved in 10 mL of DCM and to this was added 4N HCl in dioxane (1.97 mL, 7.88 mmol). The solution was stirred at room temperature overnight and then concentrated under vacuum to give a yellow solid. The solid obtained was sonicated in Et2O and a yellowish solid was collected on filter paper to give compound 190 as an HCl salt (0.164 g, 100%). 1H NMR (500 MHz, DMSO-d6) δ 10.56 (1 H, br. s.), 9.42 (1 H, s), 8.87 (2 H, br. s.), 8.28 (1 H, d, J=4.9 Hz), 8.19 (1 H, d, J=5.1 Hz), 8.09 (1 H, d, J=2.9 Hz), 7.97 (1 H, d, J=9.0 Hz), 7.75 (1 H, dd, J=9.3, 2.0 Hz), 5.96-6.07 (2 H, m, J=9.2, 8.9, 8.8, 8.8 Hz), 3.37-3.43 (4 H, m), 3.26-3.33 (4 H, m), 2.54-2.65 (2 H, m), 2.01-2.12 (4 H, m), 1.66-1.77 (2 H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 449.2.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:35])C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1>>[CH3:35][NH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: CN[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 102.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6) tR=0.8 min, m/z=458.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=O.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:7][C:6]3[CH:5]=[C:4]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[O:3][C:2]=3[CH3:1])[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: Cc1oc(-c2ccccc2)cc1C=O
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: Cc1oc(-c2ccccc2)cc1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using 2-methyl-5-phenyl-3-furaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 417.2 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[S:10][C:11]([O:22][CH3:23])=[C:12]([CH3:21])[C:13]=1[CH:14]=[C:15]([N+:18]([O-])=O)[CH2:16][CH3:17]>CCOCC.C1COCC1>[NH2:18][CH:15]([CH2:16][CH3:17])[CH2:14][C:13]1[C:12]([CH3:21])=[C:11]([O:22][CH3:23])[S:10][C:9]=1[O:8][CH3:7]
Reactant: CCC(=Cc1c(OC)sc(OC)c1C)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(N)Cc1c(OC)sc(OC)c1C
Reaction time: 7 h

Procedure:
To a refluxing mixture of 1.4 g of lithium aluminum hydride in 10 ml of anhydrous ether and 40 ml of dry THF is slowly added 1.8 g of 1-[2,5-dimethoxy-4-methylthiophenyl]-2-nitro-1-butene. An additional 20 ml of THF is added to dissolve and wash all the nitro compound into the THF mixture. Refluxing is continued for seven hours. The mixture is cooled and ice water (3.4 ml) slowly added to decompose the excess lithium aluminum hydride. When the decomposition is complete, the mixture is filtered and the solid cake washed with THF. The filtrate is evaporated in vacuo to produce crude 2-amino-1-(2,5-dimethoxy-4-methylthiophenyl)butane. The crude is purified as the hydrochloride salt by recrystallization from isopropanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[OH:11].[C:12](=O)([O-])[O-:13].[K+].[K+].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:8][C:6]1[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]2[O:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1O
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)c(Cl)c(Cl)c2o1
Yield: 95 %

Procedure:
21.3 g of 2-amino-4,5,6-trichlorophenol, 27.6 g of anhydrous potassium carbonate and 150 ml of toluene were placed in a 300 ml round-bottom flask and 9.9 g of phosgen was slowly added to the mixture with stirring under cooling an ice-water bath. The resulting mixture was heated at reflux temperature for one hour and the reaction solution was then cooled and transferred to a 500 ml separating funnel. 150 ml of tetrahydrofuran and 150 ml of water were added into the funnel and the organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to remove the solvent, leaving yellowish white crystals. The crystals were recrystallized from a mixed solvent of methanol and acetone to give 22.7 g of 5,6,7-trichlorobenzoxazolone as white crystals having a melting point of 253°-254° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:16])[C:5]([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)=[C:6](C(=O)C)[CH:7]=1.C1C=C(Cl)C=[C:19]([C:24]([O:26]O)=[O:25])C=1>C(Cl)Cl>[C:24]([O:26][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([Cl:16])[C:5]=1[O:11][CH2:12][CH:13]1[CH2:15][O:14]1)(=[O:25])[CH3:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc(Br)cc(Cl)c1OCC1CO1
Solvent: ClCCl
Product: CC(=O)Oc1cc(Br)cc(Cl)c1OCC1CO1
Temperature: 50 °C
Yield: 149.9 %

Procedure:
A solution of 1-[5-bromo-3-chloro-2-(oxiran-2-ylmethoxy)phenyl]ethanone (1.7 g, 5.6 mmol) and m-CPBA (2.4 g, 14 mmol) in DCM (30 ml) was heated to 50° C. After 22 h more m-CPBA (2.4 g, 14 mmol) was added and the mixture was heated at 50° C. for another 44 h and then brought to ambient temperature. The solid was filtered off and rinsed. The resulting filtrate was washed with sodium bicarbonate (saturated), brine and further dried (Na2SO4) and evaporated to dryness to give the crude title compound (2.7 g). MS m/z (rel. intensity, 70 eV) 280 (bp), 278 (84), 224 (54), 222 (52), 57 (79), 322 (M+, 5).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:5]2[N:6]([CH:22]=[N:23][CH:24]=2)[C:7]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])[CH:9]=1.C(N(CC)C(C)C)(C)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:34]([N:19]1[CH2:18][CH2:17][N:16]([C:7]2[N:6]3[CH:22]=[N:23][CH:24]=[C:5]3[C:4]([Br:3])=[CH:9][C:8]=2[C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])[CH2:21][CH2:20]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CON(C)C(=O)c1cc(Br)c2cncn2c1N1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(Br)c2cncn2c1N1CCN(C(C)=O)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 8-bromo-N-methoxy-N-methyl-5-piperazin-1-ylimidazo[1,5-a]pyridine-6-carboxamide dihydrochloride (500 mg, 1.1 mmol) in N,N-dimethylformamide (5 mL) was treated with N,N-diisopropylethylamine (0.69 mL, 4.0 mmol), followed by 4-dimethylaminopyridine (5 mg, 0.04 mmol). The reaction mixture was treated with acetic anhydride (0.13 mL, 1.4 mmol) dropwise and stirred at 20° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated sodium bicarbonate, water (3×), and brine, dried over sodium sulfate, filtered and concentrated to give the desired product (0.41 g, 89%). This material was used without purification. LCMS for C16H21BrN5O3 (M+H)+: m/z=410.1, 412.1. Found: 409.8, 411.8.
Reaction SMILES: N.C([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:20]([CH3:31])=[CH:19][C:18]=3[F:32])=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:33][CH3:34])(=O)C>CO>[CH2:24]([O:23][C:21]1[C:20]([CH3:31])=[CH:19][C:18]([F:32])=[C:17]([CH:22]=1)[NH:16][C:10]1[C:9]2[C:14](=[CH:15][C:6]([OH:5])=[C:7]([O:33][CH3:34])[CH:8]=2)[N:13]=[CH:12][N:11]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OC(C)=O
Agent: N
Solvent: CO
Product: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
Concentrated aqueous ammonia (25 ml) was added to a solution of 7-acetoxy4-(5-benzyloxy-2-fluoro-4-methylanilino)-6-methoxyquinazoline (1.5 g, 3.4 mmol) in methanol (100 ml). The mixture was stirred at ambient temperature for 30 minutes, and most of the organic volatiles were then removed by evaporation. Further water was added and the precipitate was collected by filtration, washed with water and dried to give 4-(5-benzyloxy-2-fluoro-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (1.2 g, 89%) which was used without further characterisation.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([N:37]1[CH2:38][CH2:39][N:34]([C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:35][CH2:36]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCCCC(=O)N1CCNCC1
Product: CCCCC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 9 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1 equivalent of 1-(piperazin-1-yl)pentan-1-one as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: COC(=O)CC(C1C=CC(C(F)(F)F)=CC=1)[CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[NH:13])[NH:7]1.F[C:26](F)(F)[C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=1.[ClH:41]>>[ClH:41].[NH:13]=[C:8]1[CH:9]([CH:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)[CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:10][CH2:11][CH2:12][CH2:6][NH:7]1
Reactant: COC(=O)CC(c1ccc(C(F)(F)F)cc1)C1CCCCC(=N)N1
Reactant: COC(=O)C=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Product: COC(=O)CC(c1ccc(C)cc1)C1CCCCNC1=N

Procedure:
methyl 3-[4-(trifluoromethyl)phenyl]propenoate methyl hexahydro-7-imino-b-(4-(trifluoromethyl)phenyl]-1H-azepine-2-propanoate, monohydrochloride;
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[C:4]([O:17][CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([C:31](O)=[O:32])[NH:29][CH:30]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([C:31]([NH:1][C:2]3[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8](=[O:9])[N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)=[C:4]([O:17][CH3:18])[CH:3]=3)=[O:32])[NH:29][CH:30]=2)=[CH:22][CH:21]=1
Reactant: COc1cc(N)ccc1OCC(=O)N1CCCC1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCC(=O)N1CCCC1
Yield: 95 %

Procedure:
Acylation of 2-(4-amino-2-methoxyphenoxy)-1-(pyrrolidin-1-yl)ethanone with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid to generate the title compound was achieved following the procedure described in step C of Example 1 in 95% yield. MS (ESI) 401 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=[O:11])=[C:4]([O:14][CH3:15])[CH:3]=1.C[Si](C)(C)[C:18]([F:21])([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[F:19][C:18]([F:21])([F:20])[CH:10]([OH:11])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:14][CH3:15])([CH3:12])[CH3:13]
Reactant: COc1cc(F)ccc1C(C)(C)CC=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)ccc1C(C)(C)CC(O)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To 1.89 g (8.99 mmol) of 3-(4-fluoro-2-methoxyphenyl)-3-methylbutyraldehyde was added 25 mL (12.5 mmol) of a 0.5 M solution of trimethyl(trifluoromethyl)silane in tetrahydrofuran and 2 mL (2 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added over a 2 minute period. The mixture stirred for 30 minutes and then an additional 8 mL (8 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. The mixture was then diluted with water and extracted with three 25 mL portions of EtOAc. The combined organic layers were washed with three 20 mL portions of 1 N aqueous HCl, three 20 mL portions of brine, and three 20 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to afford 2.78 g of 1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol as an oil. The oil was dried under high vacuum to a constant weight of 2.36 g (93%) and was used without further purification.