Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(Cl)Cl.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O>[CH3:33][S:34]([O:27][CH2:26][CH2:25][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:28])[CH3:29])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:22][CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)CCO)c3)ncnc21
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A mixture of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) was cooled at 0° C. To this mixture, TEA (50 μL, 0.0004 mol) was added. The reaction was stirred for 15 minutes. Methanesulfonyl chloride (23 μL, 0.00030 mol) was added and the resulting mixture was stirred for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentane-1,5-diyl dimethanesulfonate (57 mg, 80%) as an oil. MS(ES): 574 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:39][CH2:40][C:41]#[N:42].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[C:41]([CH2:40][CH2:39][N:19]1[CH2:20][CH2:21][CH:16]([C:14]([N:12]2[CH2:13][CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:10]([N:22]([CH3:37])[C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=3)[CH2:11]2)=[O:15])[CH2:17][CH2:18]1)#[N:42]
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CCC#N)CC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.090 mmol) in dichloromethane (1 mL) was added 3-bromopropionitrile (11 μL, 0.13 mmol) and an aqueous saturated solution of sodium carbonate (1000 μL). The resulting suspension was stirred for 18 h at ambient temperature. After the addition of dichloromethane (1 mL) and further 3-bromopropionitrile (11 μL, 0.13 mmol) it was stirred for 6 h at 40° C. After diluting with ethyl acetate (10 mL) the mixture was washed with an aqueous solution of sodium carbonate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:(ethyl acetate:triethylamine=95:5):methanol=20:80:0:0 to 0:0:90:10) afforded the title compound (51 mg, 93%) as an light brown foam. MS m/e: 611.2 [M]+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([NH2:10])=[O:9])=[O:5])[CH3:3].O=[C:15]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16]([OH:18])=[O:17].C([BH3-])#N.[Na+]>C(O)C.O>[C:16]([CH:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([NH2:10])=[O:9])=[O:5])[CH3:3])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([OH:18])=[O:17]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(N)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
Couple L-alanyl-L-proline amide, prepared as in Example 51, with 2-oxo-4-phenylbutyric acid employing sodium cyanoborohydride in 50% ethanol-water by the method described in example 2. After eluting from the ion-exchange resin, concentrate in vacuo to a small volume, flush with water, and freeze-dry to obtain N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline amide as a mixture of diastereoisomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[CH3:9][S:10]([CH3:13])(=[O:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1
Reactant: Fc1cccc(Br)n1
Reactant: CS(C)(=O)=O
Product: CS(=O)(=O)Cc1cccc(Br)n1
Yield: 70 %

Procedure:
The title compound was prepared from 2-bromo-6-fluoro-pyridine and dimethylsulfone following a procedure analogous to that described in Step 1 for Intermediate 14. Yield: ca. 70% of theory (crude); LC (method 3): tR=1.98 min; Mass spectrum (ESI+): m/z=250/252 (Br) [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[CH3:12][N:13]([CH3:19])[C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>>[CH3:12][N:13]([CH3:19])[C@@H:14]1[CH2:18][CH2:17][N:16]([C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:15]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Yield: 68.8 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (536 mg, 3.50 mmol) reacted with (3R)-(+)-3-dimethylamino-pyrrolidine (480 mg, 4.20 mmol) to give 3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (600 mg, 69%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9](F)=[C:8]2[C:3]=1[CH:4]=[C:5]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[N:6]=[CH:7]2.[F:21][C:22]([F:36])([F:35])[O:23]C1C=C2C(C=C(O)N=C2)=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.CCN(CC)CC>C(Cl)Cl>[F:21][C:22]([F:36])([F:35])[O:23][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[C:5]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[N:6]=[CH:7]2)=[CH:2][CH:11]=1
Reactant: Oc1cc2ccc(OC(F)(F)F)cc2cn1
Reactant: O=S(=O)(Oc1cc2c(Cl)ccc(F)c2cn1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1cc2ccc(OC(F)(F)F)cc2cn1)C(F)(F)F

Procedure:
By following the procedure for the preparation of trifluoromethanesulfonic acid 5-chloro-8-fluoroisoquinolin-3-yl ester, the title compound was prepared from 7-trifluoromethoxyisoquinolin-3-ol (0.98 g, 4.3 mmol), triflic anhydride (0.17 mL, 1.0 mmol), NEt3 (0.8 mL, 3.0 mmol) and CH2Cl2 (10 mL). 1H NMR (CDCl3, 300 MHz): δ=7.63 (s, 1H), 7.65 (d, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.98 (d, J=9.0 Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:35])=[CH:11][C:12]([F:34])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22](F)[C:23]=3[Cl:25])[C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:36]=[N+:37]=[N-:38].[Na+].CN(C)C=O>C(OCC)(=O)C>[N:36]([C:22]1[C:23]([Cl:25])=[C:24]2[C:19]([C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][N:15]2[C:13]2[CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([F:35])=[CH:11][C:12]=2[F:34])=[CH:20][C:21]=1[F:27])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N=[N+]=[N-])c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1,545 mg) and sodium azide (230 mg) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at 60° C. After the reaction mixture was cooled back to room temperature, ethyl acetate (100 ml) was added to the reaction mixture, and the resultant mixture was washed 3 times with water (100 ml). After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (1,280 mg) as an amorphous substance.
Reaction SMILES: C(O)C.C(OC(=O)[NH:10][CH2:11][CH2:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32]C3CCCCO3)=[CH:28][CH:27]=2)[CH:25]=1)(=[O:15])=[O:14])(C)(C)C.[ClH:40]>O>[ClH:40].[ClH:40].[NH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2)(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCS(=O)(=O)c1cc(-c2ccc(OC3CCCCO3)cc2)cc2cnccc12
Agent: Cl
Solvent: CCO
Solvent: O
Product: NCCS(=O)(=O)c1cc(-c2ccc(O)cc2)cc2cnccc12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
The 60 L reactor is charged with ethanol (24 L) and (2-{7-[4-(Tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester (2.652 kg; 5.173 moles). The (2-{7-[4-(Tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester is rinsed in with ethanol (2.6 L). Hydrochloric acid solution (31.9%; 1780 g; 15.6 moles) is diluted with water (1.42 L). This HCl solution is charged to the reactor and rinsed in with water (0.2 L). The reaction is warmed to 70° C. A yellow solution forms around 30° C. and a yellow slurry reforms near 70° C. The reaction is held at 70° C. for ½ hr and then is warmed up to reflux (78° C.). HPLC indicates a complete reaction after 1.5 hrs at reflux. Water (14.5 L) is added to the reaction over 13 minutes. The temperature drops to 69° C. The reaction is heated back to reflux (80° C.) and a solution forms. The reaction is cooled to 68° C. and solid begins forming. The reaction is held at 68° C. for ½ hr and then cools to 2° C. over 1.5 hrs. The slurry is held at 1-2° C. for 1 hr. The solid is filtered and washed with ethanol (4.6 L). The wet cake weight is 3.236 kg. The solid is dried in vacuo at 50° C. to give 2.106 kg (101.4% of theory) 4-[5-(2-amino-ethanesulfonyl)-isoquinolin-7-yl]-phenol di-hydrochloride salt. Mass Spectrum (LCMS) m/z=402.31) (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CCOCC.C([Li])CCC.[CH3:19][C:20]([CH3:22])=[O:21]>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:20]([OH:21])([CH3:22])[CH3:19])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
2,5-Dibromopyridine 3.05 g (12.5 mmol) was dissolved in 20 mL of THF and 120 mL of anhydrous ether and cooled to −78° C. 5.0 mL n-butyllithium (2.5 M, 12.5 mmol) was slowly dropped through a syringe in 30 min. After being stirred at −78° C. for 30 minutes, acetone (2 ml, 20 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by 10 ml water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After crystallization using 20% EtOAc in hexane, 1.30 g of white crystals was obtained (48% yield), MS: 215.0, 217.0 (M++1).
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:23](OCC)=[O:24])[CH2:22][CH2:21][CH2:20]2)=[C:15]([C:28]#[C:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:14]=1>CN(C=O)C.O1CCOCC1>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[C:19]1([CH2:22][CH2:21][CH2:20]1)[C:23](=[O:24])[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]2[OH:9]
Reactant: CCOC(=O)C#Cc1cc(Cl)ccc1C1(C(=O)OCC)CCC1
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Benzaldehyde oxime (174 mg, 1434 μmol) in DMF (7 mL) was added to a stirred suspension of NaH (60% dispersion in mineral oil (57 mg, 1434 μmol)) in dioxane (7 mL) under a N2 atmosphere. The mixture was stirred for approximately 30 minutes before being cooled to 0° C. Ethyl 1-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)cyclobutanecarboxylate (400 mg, 1195 μmol) in DMF (7 mL) was added via syringe, and the reaction was stirred at 0° C. for 1 hour. The reaction was quenched with water, and extracted with EtOAc. The aqueous layer was separated and brought to a pH of about 4 with 10% HCl and extracted again with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give an orange oil. The crude oil was purified by silica flash chromatography (0-20% EtOAc/hexane) to give the desired compound as a white solid (155 mg). MS (m/e)=307.1 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][CH2:5][CH2:6][C@@H:7]1[NH:12][CH2:11][CH2:10][N:9]([C:13]2[C:22]3[CH:21]=[C:20]([CH3:23])[S:19][C:18]=3[NH:17][C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH2:8]1.[C:28]1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:1].[CH3:3][O:4][CH2:5][CH2:6][C@@H:7]1[N:12]([CH3:28])[CH2:11][CH2:10][N:9]([C:13]2[C:22]3[CH:21]=[C:20]([CH3:23])[S:19][C:18]=3[NH:17][C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH2:8]1
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1C
Yield: 22 %

Procedure:
In a manner such as that described in Example 269, using (S)-10-[3-(2-methoxyethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diazabenzo[f]azulene dihydrochloride into the dihydrochloride salt of the title compound (102 mg, 22%): mass Spectrum (ES): m/z 371.2 (M+1 of free base).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]1[CH2:17][C:18]([O:20]C)=[O:19].[Li+].[OH-].O.Cl>C1COCC1.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:15])([F:14])[F:16])[CH:8]=2)[N:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetate (1.2 mmol) in THF/water (2:1) was added LiOH. H2O (8.1 mmol). The resulting mixture was stirred overnight. The crude product mixture was slowly acidified with 1N HCl solution and then extracted with EtOAc. The organic phase was separated, dried (MgSO4), filtered and concentrated under vacuum to give 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid. Retention time (min)=1.783, method [1], MS (ESI) 288.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c([N+](=O)[O-])c2F)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
58 g of 3-[4-chloro-2,6-difluorophenyl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione were dissolved in 400 ml of concentrated sulfuric acid and, at 0° C., admixed dropwise with a mixture of 10.7 g of 98% strength nitric acid and 10 ml of concentrated sulfuric acid. The mixture was stirred at 0° C. for 30 minutes and then at 20° C. for 18 hours. Another 10.7 g of the acid mixture were then added dropwise at 0° C. The mixture was stirred at 20° C. for two hours and then poured into ice-water, and the resulting precipitate was filtered off with suction and washed with water until neutral. The solid was dried in a vacuum drying cabinet. Yield: 58.0 g;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[O:23][C:24]([C:28](O)=[O:29])=[C:25]([CH3:27])[N:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:24]3[O:23][C:22]([CH3:21])=[N:26][C:25]=3[CH3:27])=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1nc(C)c(C(=O)O)o1
Product: Cc1nc(C)c(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)o1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2,4-dimethyl-5-oxazolecarboxylic acid, as starting materials, MS (LC/MS): 426.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)CBr)cc1
Temperature: 50 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of N-(4-acetylphenyl)acetamide (1 g, 5.65 mmol, 1.00 equiv) in acetic acid (10 mL). This was followed by the addition of a solution of bromine (910 mg, 5.69 mmol, 1.01 equiv) in acetic acid (2 mL) dropwise with stirring at 50° C. The resulting solution was stirred for 1.5 h at 50° C. The reaction was then quenched by the addition of 100 mL of water/ice. The solids were collected by filtration and dried under vacuum. This resulted in 0.5 g (33%) of N-(4-(2-bromoacetyl)phenyl)acetamide as a white solid.
Reaction SMILES: OO.[C:3]([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([OH:20])[C:14]([CH3:22])([CH3:21])[CH2:13]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23]([OH:27])([CH3:26])([CH3:25])[CH3:24]>>[C:3]([O:11][CH:12]1[CH2:13][C:14]([CH3:22])([CH3:21])[N:15]([O:20][CH2:24][C:23]([OH:27])([CH3:26])[CH3:25])[C:16]([CH3:18])([CH3:19])[CH2:17]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: OO
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Temperature: 40 °C

Procedure:
A solution of 20.4 g (0.30 mol) of 50% aqueous hydrogen peroxide mixed with 25 mL of tert-butyl alcohol is added over three hours to a mixture of 27.6 g (0.10 mol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 7.13 g (0.036 mol) of ferrous choride tetrahydrate and 115 mL of tert-butyl alcohol at 40° C. The reaction temperature is maintained at 40° C. for twenty hours after the peroxide addition is complete. The crude reaction mixture is purified by flash chromatography on silica gel to afford 16.2 g of the title compound.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]2[N:37]([CH3:38])[CH2:36][CH2:35][N:34]([CH3:39])[C:33]2=[O:40])[CH:29]=[CH:30][CH:31]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]5[C:33](=[O:40])[N:34]([CH3:39])[CH2:35][CH2:36][N:37]5[CH3:38])[CH:27]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Product: CN1CCN(C)C(c2cccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)c2)C1=O

Procedure:
N-tert-Butyl-3-{2-[3-(1,4-dimethyl-3-oxo-piperazin-2-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzenesulfonamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1061. Product isolated as a yellow foam (74 mg, 44%). LCMS (m/e) 548 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.74 (s, 1H), 8.58 (s, 1H), 8.44 (d, 1H, J=7.9 Hz), 7.86 (d, 1H, J=7.8 Hz), 7.80 (d, 1H, J=8.2 Hz), 7.65-7.55 (m, 1H), 7.44-7.35 (m, 2H), 7.09 (d, 1H, J=7.6 Hz), 7.05 (d, 1H, J=4.8 Hz), 6.89 (s, 1H), 6.85 (d, 1H, J=4.8 Hz), 4.71 (s, 1H), 3.77-3.64 (m, 1H), 3.69 (s, 1H), 3.26-2.97 (m, 1H), 2.99 (s, 3H), 2.73-2.62 (m, 1H), 2.17 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]([C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:22][CH:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of (4-chlorophenyl)boronic acid (1.50 g, 9.59 mmol), 4-nitrobenzoyl chloride (1.78 g 9.59 mmol), bis(triphenylphosphine)palladium(II) chloride (0.137 g, 0.192 mmol) and K3PO4 (3.34 g, 19.2 mmol) in toluene (30 mL) was treated as described in WO 2010/015355 to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.N#N.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([NH:37][C@H:38]([C:46](Cl)=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])(=[O:36])=[O:35])[CH:28]=[CH:27]2>C(Cl)(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([NH:37][C@H:38]([C:46]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])(=[O:36])=[O:35])[CH:28]=[CH:27]2
Reactant: CCOC(=O)C1CCCCN1
Reactant: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)ccc2c1
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCCCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2.2 g of ethyl 2-piperidinecarboxylate and 4.1 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(6-methoxy-2-naphthalenesulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 500 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over Na2SO4 and evaporated in vacuo. The oily residue was washed with ether to give 2.9 g of powdery ethyl 1-[N2 -(6-methoxy-2-naphthalenesulfonyl)-L-arginyl]-2-piperidinecarboxylate.