Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])/[CH:24]=[CH:23]/[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:28])([F:29])[F:15])[CH:18]=2)=[N:8]1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: CC(F)(F)CCCCn1ccc(NC(=O)/C=C/c2cccc(C(F)(F)F)c2)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=402.06.
Reaction SMILES: I[C:2]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[N:12][N:13]([CH3:15])[CH:14]=3)=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[N:47][CH:48]=2)O1.C([O-])(O)=O.[Na+]>O1CCOCC1.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>[CH3:15][N:13]1[CH:14]=[C:10]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[N:25]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:2]([C:43]4[CH:48]=[N:47][C:46]([N:49]5[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]5)=[N:45][CH:44]=4)=[CH:3][C:4]=23)[C:11]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cn1cc(-c2ccnc3c2cc(I)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccnc3c2cc(-c2cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 95 °C

Procedure:
To a solution of 2-iodo-4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.321 mmol) and 1,1-dimethylethyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinyl]-1-piperazinecarboxylate (0.353 mmol) in 1,4-dioxane (3 ml) was added saturated NaHCO3(aq) (0.85 ml). After degassing with argon for 10 minutes, dichlorobis(triphenylphosphine)palladium(II) (0.0161 mmol) was added and the resulting mixture was heated at 95° C. overnight. Upon cooling, the reaction was concentrated and partitioned between EtOAc and H2O. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a yellow oil (quant.). ESMS [M+H]+: 722.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)(O)[CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)=[CH2:9])=[N:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(C)(O)c2ncc(Cl)cn2)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(c1ncc(Cl)cn1)[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of methyl trans-4-[1-(5-chloropyrimidin-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate (54 mg, 0.18 mmol) and triethylamine (36 mg, 0.36 mmol) in dichloromethane (2 mL) was added in portions methanesulfonyl chloride (22 mg, 0.2 mmol) at 0° C. for 10 minutes. The mixture was stirred for 3 hours at 0° C. followed by dilution with brine and extraction with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give methyl trans-4-[1-(5-chloropyrimidin-2-yl)ethenyl]cyclohexanecarboxylate. MS ESI calc'd for C14H18ClN2O2 [M+H]+ 281. found 281. 1H NMR: (400 MHz, CDCl3) δ 8.64 (s, 2H), 6.37 (s, 1H), 5.47 (s, 1H), 3.68 (s, 3H), 2.99-2.96 (m, 1H), 2.37-2.34 (m, 1H), 2.08-1.96 (m, 4H), 1.66-1.60 (m, 2H), 1.34-1.25 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.[CH3:24]C1C=CC(S(OC[C@@H](NC(OC(C)(C)C)=O)C)(=O)=O)=CC=1>>[NH2:1][C@@H:2]([CH3:24])[CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCN)c2)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(C[C@H](C)N)c2)c1

Procedure:
The title compound was synthesized according to procedure described for N-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide starting with (S)-2-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate. Synthesis of (S)-2-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate was performed according to Bioorg. Med. Chem. 16 (2008) 1966-1982. LC-MS conditions B: tR=0.55 min, [M+H]+=326.11.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:11])=[N:6][CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[Br:12]Br>C(O)(=O)C>[Br:12][C:8]1[C:9]([OH:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([OH:11])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)ncc(Br)c1O
Temperature: 70 °C
Yield: 80 %

Procedure:
A 100 mL 3-necked round bottom flask was charged with 3-nitropyridine-2,4-diol (3.5 g, 22 mmol), bromine (1.15 mL) and acetic acid (30 mL). The resulting mixture was heated at 70° C. for 15 minutes. Work-up: the mixture was poured onto crushed ice and chilled in freezer. The resulting precipitate was collected by filtration, washed with cold water and dried in vacuo, to afford 3.7 g (80%) of the product as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7](=[O:20])[CH:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34]>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:32][CH2:31][CH2:30][N:6]1[C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=2[C:10](=[O:11])[NH:9][CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]1=[O:20])(=[O:35])[CH3:34]
Reactant: CC(=O)OCCBr
Reactant: O=C1NC(Cc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCN1C(=O)C(Cc2ccccc2Cl)NC(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-chloro-3-(2-chlorobenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (0.5 g, 1.5 mmol) in N,N-dimethylformamide (10 mL), was added powdered potassium carbonate (0.31 g, 2.2 mmol) followed by 2-bromoethylacetate (0.17 mL, 1.6 mmol). The mixture was stirred at ambient temperature overnight. After 20 hours, more 2-bromoethylacetate (0.05 mL, 0.5 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×50 mL), washed with brine (50 mL), dried with anhydrous sodium sulfate, decanted, and concentrated to yield crude 2-(7-chloro-3-(2-chlorobenzyl)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)ethyl acetate, which was used directly in the next step without further purification. MS (m/z): 421.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH2:4].CC(C)=O.C([O-])([O-])=O.[K+].[K+].[C:28](Cl)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH:4][C:28](=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1cc(OCCN2CCCCC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C=Cc1ccccc1)Nc1cc(OCCN2CCCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
2-chloro-5-(2-piperidinoethoxy)aniline (500 mg, 1.9 mmol, 1 eq.) was placed in mixture of acetone (653 μL) and water (852 μL) in the presence of K2CO3(541 m g, 3.9 mmol, 2 eq.). Cinnamoyl chloride (326 mg, 1.9 mmol, 1 eq.) was then added at 0° C. The reaction mixture was allowed to warm-up to room temperature, stirred for 2 hours and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford N-(2-chloro-5-(2-(piperidin-1-yl)ethoxy)phenyl)cinnamamide (521 mg, 69%).
Reaction SMILES: N1C(=O)C2NC=NC=2NC1=O.N1C=C2C(N=CN2)=NC=1.[OH-].[Na+].[NH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[S:40][C:39]([C:41]([O:43]C)=[O:42])=[CH:38][CH:37]=3)=[CH:32][C:31]=2[C:45]#[N:46])[CH:27]=[CH:28][CH:29]=1.Cl>O1CCCC1.CO>[NH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=[O:42])=[CH:38][CH:37]=3)=[CH:32][C:31]=2[C:45]#[N:46])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(-c2ccc(-c3cccc(N)c3)c(C#N)c2)s1
Agent: Cl
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(-c2ccc(C(=O)O)s2)ccc1-c1cccc(N)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A toluene (0.5 ml) suspension of 20 mg of methyl 5-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)thiophene-2-carboxylate and 10 mg of potassium carbonate was added to 15 mg of 3-aminobenzeneboronic acid monohydrate, and in an argon atmosphere, 8 mg of tetrakis(triphenylphosphine)palladium was added thereto. The mixture was stirred overnight at 100° C., then cooled to room temperature, and filtered through Celite. The solvent was evaporated under reduced pressure to obtain methyl 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylate. (2) 0.2 ml of aqueous 1 M sodium hydroxide solution was added to a methanol (0.25 ml)/tetrahydrofuran (0.25 ml) solution of methyl 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylate, followed by stirring overnight at 60° C. 1 M hydrochloric acid was added to the reaction liquid to make it acidic, and the solvent was evaporated under reduced pressure. The residue was purified by HPLC [elution through column: SunFire (registered trademark) C18 5 μm, 19 mm×100 mm, solvent: MeOH/aqueous 0.1% formic acid solution=10/90 for 1 minute, ratio change to 95/5, taking 8 minutes, and further elution with 95/5 for 3 minutes, flow rate: 25 mL/min), thereby obtaining 2.5 mg of 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylic acid.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([NH2:10])[C:8]#[N:9].[CH3:11][C:12]1[C:16]([C:17](Cl)=[O:18])=[CH:15][S:14][N:13]=1>N1C=CC=CC=1>[C:8]([CH:7]([NH:10][C:17]([C:16]1[C:12]([CH3:11])=[N:13][S:14][CH:15]=1)=[O:18])[C:3]1[O:2][CH:6]=[CH:5][CH:4]=1)#[N:9]
Reactant: N#CC(N)c1ccco1
Reactant: Cc1nscc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nscc1C(=O)NC(C#N)c1ccco1
Temperature: 25 °C

Procedure:
1.2 g of alpha-(2-furyl)-alpha-aminoacetonitrile hydrochloride was dissolved in 10 ml of pyridine, and with stirring at room temperature, 1.1 g of 3-methylisothiazole-4-carboxylic acid chloride was added dropwise. After the dropwise addition, the mixture was stirred for 1 hour, and distilled under reduced pressure to remove pyridine. The residue was dissolved in ethyl acetate, separated, washed with water, and dried over sodium sulfate. The ethyl acetate layer was distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with benzene-ethyl acetate gave 1.2 g (yield of the desired N-(alpha-cyanofurfuryl)-3-methylisothiazole-4-carboxylic acid amide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[C:12]3[C:7]2=[C:8]([CH:27]=1)[C:9](=[O:26])[N:10]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:11]3=[O:19])([O-])=O>[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[C:6]2[CH:15]=[C:14]([NH2:16])[CH:13]=[C:12]3[C:7]2=[C:8]([CH:27]=1)[C:9](=[O:26])[N:10]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:11]3=[O:19]
Reactant: O=C(O)CCCN1C(=O)c2cc([N+](=O)[O-])cc3cc([N+](=O)[O-])cc(c23)C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cc2c3c(cc(N)cc3c1)C(=O)N(CCCC(=O)O)C2=O
Reaction time: 24 h

Procedure:
A mixture of 4-(5,8-Dinitro-1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-butyric acid (see example 4; 0.37 g, 1 mmol), palladium on charcoal 10% and dimethylformamide (20 mL) was hydrogenated at room temperature with vigorous stirring for 24 hours. The catalyst was filtered off and the filtrate evaporated under reduced pressure. The residue was crystallized from dimethylformamide and water to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](OC(=O)C)(=O)[CH3:14].C(O)(C(F)(F)F)=O>O.CO>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[C:13]([CH3:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(C(=O)O)c1N
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c(=O)oc(C)nc12
Temperature: 140 °C
Reaction time: 3 h

Procedure:
2-Amino-3-methoxybenzoic acid (10.1 g, 60.4 mmol) was suspended in acetic anhydride (50 ml, 530 mmol). The mixture was heated to 140° C. with stirring for 180 min. The reaction mixture was cooled to room temperature and concentrated to provide Intermediate A18A (11.51 g, 100%): HPLC: RT=0.795 min (H2O/MeOH with TFA, SunFire C18 2.5 μM, 2.1×30 mm, gradient=2 min, wavelength=220 nm); MS(ES): m/z=292 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J=6.9, 2.3 Hz, 1H), 7.52-7.42 (m, 2H), 3.89 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:94][CH2:93][CH2:92][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([N:59]([CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH:74][C@H:75]([C:88]([O:90][CH3:91])=[O:89])[CH2:76][CH2:77][CH2:78][CH2:79][NH:80][C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])[CH3:60])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[H][H]>CO>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:94][CH2:93][CH2:92][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([N:59]([CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH:74][C@H:75]([C:88]([O:90][CH3:91])=[O:89])[CH2:76][CH2:77][CH2:78][CH2:79][NH:80][C:81]([O:83][C:84]([CH3:86])([CH3:87])[CH3:85])=[O:82])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])[CH3:60])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:52])[CH3:53])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N

Procedure:
100 mg of Z-Arg-Arg-Pro-Phe-His-Sta-Sar-His-Lys(Boc)-OMe (see Example 16) are dissolved in 2 ml of 95% strength MeOH and, after the addition of 10 mg of Pd-on-carbon (10% Pd), hydrogenated by passing hydrogen through until the starting material has disappeared completely (monitoring by thin layer ohromatography). The catalyst is filtered off, the filtrate is concentrated to dryness and the residue is dissolved in 2 ml of H2O and lyophilised, yielding H-Arg-Arg-Pro-Phe-His-Sta-Sar-His-Lys(Boc)-OMe; Rf (D)=0.15; Rf (M)=0.25; Rf (O)=0.22.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][Si](C(C)(C)C)(C)C)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[S:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 47.7 %

Procedure:
to a stirred solution of S-4-(tert-butyl-dimethylsilyloxy)benzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (10 g, 22 mmol) in THF (100 mL) was added a solution of TBAF in THF (1 N, 24 mL, 24 mmol). The mixture was stirred at room temperature for 40 min then diluted with water (200 mL) and extracted with EtOAc (2×250 mL). The combined organic extracts were washed successively with water (250 mL) and brine (500 mL) then dried (MgSO4), filtered and concentrated to reveal a brown oil. Trituration with EtOAc/hexane afforded the product as a white solid (3.7 g, 47%): 1H-NMR (400 MHz, d6-DMSO) 9.32 (1H, m), 7.11 dt (2H, t, J 8.5, 2.5 Hz), 6.67 (2H, t, J 8.5, 2.5 Hz), 4.02 (2H, s), 3.43 (4H, m), 3.33 (4H, m) and 1.40 (9H, s).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8]>>[CH2:7]([NH:9][C:10]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:11])[CH3:8]
Reactant: CC(C)(N)CO
Reactant: CCN=C=O
Product: CCNC(=O)NC(C)(C)CO
Yield: 94 %

Procedure:
Prepared as in Example 227d from 2-amino-2-methylpropan-1-ol and ethyl isocyanate in 94% yield. MS 161 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[CH:17][C:3]=1[NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][CH3:15])[N:8]=[C:7](Cl)[N:6]=1.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH2:36][OH:37].[H-].[Na+].Cl>CN1CCCC1=O>[Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[CH:17][C:3]=1[NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][CH3:15])[N:8]=[C:7]([O:37][CH2:36][C:35]([O:39][CH2:40][CH3:41])=[O:38])[N:6]=1
Reactant: COc1cc(Cl)c(Nc2nc(Cl)nc(OC)c2[N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Reactant: CCOC(=O)CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)COc1nc(Nc2cc(OCc3c(OC)ccc(F)c3F)c(OC)cc2Cl)c([N+](=O)[O-])c(OC)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.13 g) and ethyl glycolate (38 mg) in 1-methyl-2-pyrrolidone (2 mL) was added sodium hydride (55%, 21 mg) under ice-cooling, and the mixture was stirred at 80° C. overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=7/3−2/3) to give ethyl 2-{4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methoxy-5-nitropyrimidin-2-yloxy}acetate (22 mg). The title compound was prepared in a similar manner to that described in Example 310 using this material instead of diethyl 2-{4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methoxy-5-nitropyrimidin-2-yl}malonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:10](=[O:26])[O:11][C:12]([CH3:25])([CH3:24])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[N:6][CH:7]=1.[Cl:27]C1C(=O)NC=C(Cl)C=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:25][C:12]1([CH3:24])[O:11][C:10](=[O:26])[C:9]([O:8][C:5]2[C:4]([Cl:27])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[C:13]1[C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=c1[nH]cc(Cl)cc1Cl
Reactant: CC1(C)OC(=O)C(Oc2ccc(Cl)cn2)=C1c1ccc(S(C)(=O)=O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OC(=O)C(Oc2ncc(Cl)cc2Cl)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a R.T. solution of 2-chloroacetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (954 mg, 3 mmol, example 25) in acetonitrile (15 mL) was added 3,5-dichloro-2-pyridone (656 mg, 4.0 mmol) followed by DBU (2.28 g, 15 mmol) and the mixture was slowly warmed up to gentle reflux for 2 hours. The mixture was cooled to 25° C. the volatiles were removed in vacuo. The residue was purified on silica gel chromatography (1/1, EtOAc/Hexanes then 100% EtOAc)) to provide the title compound.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH:13]2[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H](CC#N)N1CCC(Nc2ccc(OC(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
Following General Procedure A, a solution of 4-difluoromethoxyaniline (0.50 g, 3.1 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (0.44 g, 2.6 mmol) in CH2Cl2 (10 mL), was treated with glacial AcOH (3 drops) and NaBH(OAc)3 (0.83 g, 3.9 mmol), stirring for 16 h at room temperature. Saturated aqueous NaHCO3 solution (15 mL) and 1N NaOH (2 mL) was added and the phases were separated and the aqueous extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was then purified by flash column chromatography on silica gel (1:1 EtOAc/CH2Cl2) to afford (R)-3-[4-(4-difluoromethoxy-phenylamino)-piperidin-1-yl]-butyronitrile as a white solid (0.61 g, 76%). 1H NMR (CDCl3) δ 1.20 (d, 3H, J=6.6 Hz), 1.43 (m, 2H), 2.06 (br d, 2H), 2.36 (m, 3H), 2.52 (m, 1H), 2.82 (m, 2H), 3.07 (sex, 1H, J=7.2 Hz), 3.24 (m, 1H), 6.36 (t, 1H, J=75 Hz), 6.54 (d, 2H, J=9.0 Hz), 6.95 (d, 2H, J=9.0 Hz).