Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Reactant: Fc1cccc(Br)c1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cccc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example, step using 1-Bromo-3-fluorobenzene instead of 3-bromopyridineto yield the final compound as a yellow oil, MS (ISP): m/e=370.3 (M+H+).
Reaction SMILES: [Cl:1]C1C=C(Cl)C(Cl)=CC=1OC(=O)[C@H](CC1C=CC=CC=1)NC(OC(C)(C)C)=O.C(OC(=O)[C@H](CCSC)N)C1C=CC=CC=1.[CH2:45]([O:52][C:53](=[O:78])[C@H:54]([CH2:74][CH2:75][S:76][CH3:77])[NH:55][C:56](=[O:73])[C@H:57]([CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[NH:58]C(OC(C)(C)C)=O)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.Cl>O1CCOCC1.C(Cl)Cl>[ClH:1].[CH2:45]([O:52][C:53](=[O:78])[C@H:54]([CH2:74][CH2:75][S:76][CH3:77])[NH:55][C:56](=[O:73])[C@H:57]([CH2:66][C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1)[NH2:58])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CSCC[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 21.2 parts N-t-butoxycarbonyl-L-phenylalanine 2,4,5-trichlorophenyl ester and 12.7 parts L-methionine benzyl ester in 200 parts methylene chloride is stirred overnight at room temperature. Completion of the reaction is determined by thin layer chromatography. The solvent is then stripped under reduced pressure and the crude residue subjected to low pressure column chromatography on silica gel. The resulting product, N-t-butoxycarbonyl-L-phenylalanyl-L-methionine benzyl ester, is dissolved in 50 parts dioxane and stirred with a 10 fold excess of 2 N HCl in dioxane for 10 minutes. The solvent is removed by evaporation under reduced pressure. The solid residue, after trituration with ethyl ether, affords pure L-phenylalanyl-L-methionine benzyl ester hydrochloride. This compound is represented by the following formula
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14].N1C=CC=CC=1.[C:22]1([CH3:34])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[C:22]1([CH3:34])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14])(=[O:31])=[O:32]
Reactant: CC1=C(c2ccc(F)cc2N)C(=O)CC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: c1ccncc1
Product: CC1=C(c2ccc(F)cc2NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)CC1

Procedure:
0.800 g (3.90 mmol) of 2-(2-amino-4-fluorophenyl)-3-methyl-2-cyclopenten-1-one, 0.339 g (4.29 mmol) of pyridine, 0.938 g (4.29 mmol) of 2-mesitylenesulfonyl chloride, and 4 mL of M.C were loaded to a 20 mL vial, and then reacted for 12 hours. The work-up was the same as in Example 7 (1.29 g, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[O:26]1[CH2:31][CH2:30][CH:29]([O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[CH:15]=[CH:16][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:18][CH:19]=4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: OC1CCOCC1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccc(O)cc3)CC2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccc(OC4CCOCC4)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
34 mg (0.10 mmol) (S)—N-{1-(4-[1-(4-Hydroxyphenyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 1.48), 15 mg (0.15 mmol) tetrahydro-4H-pyran-4-ol and 39 mg (0.15 mmol) triphenylphosphine on solid support are suspended in 2 mL anhydrous THF at 0° C. 35 mg (0.15 mmol) di-tert-Butyl azodicarboxylate are added and the mixture is allowed to warm to rt. Stirring is continued over night followed by addition of 0.5 equivalents of triphenylphosphine on solid support and 0.5 equivalents of di-tert-butyl azodicarboxylate. After stirring for 2 h at rt, the mixture is filtered over basic aluminum oxide and washed with DMF/MeOH (9:1). After evaporation the residue is purified using reversed phase HPLC (water/MeOH, 0.1% TFA) to yield the desired product.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1.O>C(#N)C>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][NH:3][CH2:1][CH3:2])=[CH:9][CH:10]=1
Reactant: CCN
Reactant: ClCc1ccc(Cl)nc1
Solvent: O
Solvent: CC#N
Product: CCNCc1ccc(Cl)nc1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
65-70% ethylamine solution (70 g, 1 mol), acetonitrile 50 mL were added into a three necked round bottom flask mounted with pressure-equalizing dropping funnel and thermometer. The solution was stirred in ice bath for 15 min to control the temperature near 0° C. Then, 2-chloro-5-(chloromethyl)pyridine (16.10 g, 0.10 mol) in 25 ml acetonitrile was added by pressure-equalizing dropping funnel in 3.5 hrs with a speed of 3 drop/min. After completion, water was added and the reaction mixture was extracted with DCM. The organic phase was collected, thereby obtaining 14 g N-((6-chloropyridin-3-yl)methyl)ethanamine as oil with 70% yield. GC-MS: m/z (%)=170 ([M]+, 20), 155 (80), 126 (100), 114 (10), 90 (12).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@:25]2([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[N-:53]=[N+:54]=[N-:55].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@:25]2([CH2:39][N:53]=[N+:54]=[N-:55])[OH:38])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:52][CH:51]=2)=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)COS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)CN=[N+]=[N-])(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A slurry of 5′-O-(4,4′-dimethoxytrityl)-3′-p-toluen-sulfonyloxymethylthymidine (0.40 g; 0.55 mmol) and NaN3 (0.11 g; 1.65 mmol) in anhydrous DMF (3 ml) was heated at 50° C. for 3 days. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml), and washed with water (3×40 ml) , then with 10% NaHCO3 (3×40 ml). The organic layer was dried over Na2SO4, concentrated and purified by chromatography on silica (EtOAc-Hexanes, 1:1) to yield 0.30 g (92%) of 5′-O-(4,4′-dimethoxytrityl)-3′- C-azidomethylthymidine as a colorless powder.
Reaction SMILES: [C:1]([O:5]C(N1C[C@@H](C)N2[C@H](CC3C2=NC(Br)=CC=3)C1)=O)(C)(C)[CH3:2].[C:23]([O:27][C:28]([N:30]1[CH2:42][C@@H:41]([CH3:43])[N:40]2[C@H:32]([CH2:33][C:34]3[C:39]2=[N:38][C:37]([OH:44])=[CH:36][CH:35]=3)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[H-].[Na+].BrCCO>>[C:23]([O:27][C:28]([N:30]1[CH2:42][C@@H:41]([CH3:43])[N:40]2[C@H:32]([CH2:33][C:34]3[C:39]2=[N:38][C:37]([O:44][CH2:2][CH2:1][OH:5])=[CH:36][CH:35]=3)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: OCCBr
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(OCCO)nc3N21

Procedure:
This compound was prepared in analogy to Example 22 intermediate b), from (4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and 2-bromoethanol.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18](C)[C:19](=O)C(F)(F)F)=[C:14]([N+:26]([O-:28])=[O:27])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)#[N:4]>C(O)C.O>[CH3:19][NH:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]#[N:4])[CH:10]=2)=[CH:13][C:14]=1[N+:26]([O-:28])=[O:27]
Reactant: CN(C(=O)C(F)(F)F)c1ccc(Oc2ccnc(C#N)c2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNc1ccc(Oc2ccnc(C#N)c2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
NaOH (1 mL, 1N aq) was added dropwise to a solution of N-[4-(2-cyano-pyridin-4-yloxy)-2-nitro-phenyl]-2,2,2-trifluoro-N-methyl-acetamide (440 mg) in ethanol (6 mL) at RT. After 40 min, the mixture was diluted with H2O (20 mL) and cooled to 0° C. Bright orange crystals were collected, washed (H2O) and air-dried 311.1 mg (94%). M/z=271 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([O:26][CH3:27])=[CH:14][C:3]=1[C:4](OCC1C=CC=CC=1)=[O:5].C(O)(=O)C.[CH:32](N)=[NH:33]>C(O)C(C)C>[CH2:19]([O:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4](=[O:5])[NH:33][CH:32]=[N:1]2)=[CH:14][C:15]=1[O:26][CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=CN
Reactant: COc1cc(C(=O)OCc2ccccc2)c(N)cc1OCc1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Temperature: 97 °C
Reaction time: 6 h

Procedure:
Benzyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (80.0 g), formamidine acetate (32.0 g) and isobutanol (480 ml) were mixed. The reaction mixture was then heated to 97° C. and stirred at this temperature for 6 hours. The reaction mixture was then cooled to 25° C. over a period of at least an hour and then stirred at this temperature for 30 minutes. The product (7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one) was isolated by filtration, washed with isobutanol (64.2 g) and dried in the vacuum oven at a temperature of from 40 to 45° C. Yield: 60.8 g, 98%; NMR Spectrum (DMSOd6) 3.9 (s, 3H), 5.3 (s, 2H), 7.3 (s, 1H), 7.3-7.5 (m, 6H), 8.0 (s, 1H); Mass Spectrum (M+H)+=283.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]#[N:12].[N+:13]([O-])([OH:15])=[O:14].OS(O)(=O)=O>C(O)(=O)C>[C:11]([CH2:10][C:3]1[C:4]([CH3:9])=[C:5]([N+:13]([O-:15])=[O:14])[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])#[N:12]
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(C)c([N+](=O)[O-])c(C)c1CC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 2,4,6-trimethylphenylacetonitrile (4.5 g) in acetic acid (40 mL) at RT was added dropwise 70% HNO3 (20 mL) and conc. H2SO4 (5 mL). The brown reaction mixture was stirred for 1 h, poured into ice-water (500 mL). The product was extracted into ethyl acetate, the extract was washed with water, dried over MgSO4 and concentrated to give 3-cyanomethyl-1-nitro-2,4,6-trimethylbenzene as an oil (5.8 g, quantitative yield).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19]Cl)[CH:18]=1>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([CH2:19][O:11][CH2:10][CH2:9][N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:16]=[N:15][CH:14]=1
Reactant: ClCc1cncc(Br)c1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cncc(COCCN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To the NaH (484 mg, 60% in mineral oil, 12.1 mmol) in DMF (dry, 1 mL) at 0° C., is slowly added 2-morpholin-4-yl-ethanol (1.47 ml, 12.1 mmol). Then the mixture is stirred at 0° C. for 30 min. 3-bromo-5-chloromethyl-pyridine (500 mg, 2.42 mmol) is added at 0° C. The mixture is then stirred at room temperature overnight and is quenched by adding water dropwise. The mixture is partitioned between DCM and water. The DCM phase is separated and then washed with water twice. The DCM phase is evaporated under high vacuum. The residue is separated by silica gel flash column (MeOH/DCM 0 to 5% gradient, then 5%) to obtain 370 mg of 4-[2-[(5-bromo-3-pyridyl)methoxy]ethyl]morpholine.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:35]([NH:40][NH2:41])(=[O:39])[CH:36]([CH3:38])[CH3:37]>CN(C=O)C>[CH:1]1([NH:6][C:7]2[C:12]([C:13]([NH:41][NH:40][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])=[O:15])=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)C(=O)NN
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)O)cnc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1ncc2c(NC3CCCC3)c(C(=O)NNC(=O)C(C)C)cnc21
Reaction time: 0.25 h

Procedure:
Intermediate 3 (0.060 g), EDC (0.06 g) and HOBT (0.035 g) were suspended in DMF (2 ml) and stirred under nitrogen for 15 minutes. Isobutyric acid hydrazide (0.027 g) was then added and the mixture stirred under nitrogen for 18 h. Solvents were removed in vacuo and the residue partitioned between DCM and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution, then concentrated in vacuo and applied to an SPE cartridge (aminopropyl, 1 g) which was eluted with methanol. Concentration in vacuo afforded Intermediate 10. LCMS showed MH+=359; TRET=2.70 min.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:2][C:1]([CH:4]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3]
Reactant: BrBr
Reactant: CCOC(=O)C(CC(C)C)C(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC(C)C)C(=O)CBr
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution comprised of ethyl 2-acetyl-4-methylpentanoate (1.86 gm, 10 mmol) in chloroform (20 mL) was cooled to 0° C. and treated with bromine (0.6 mL, 11.0 mmol in 10 mL chloroform). The mixture was stirred for approximately 12 hours and then concentrated to provide ethyl 2-bromoacetyl-4-methylpentanoate as a crude product.
Reaction SMILES: [NH:1]([C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C@@H:2]([C:4]([NH:6][C@H:7]([C:18]([NH:20][C@H:21]([C:33]([OH:35])=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[O:19])[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:5])[CH3:3].CN1CC[O:46]CC1.C(OC(Cl)=O)C(C)C.[NH2:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62][OH:63])=[CH:60][CH:59]=1>O1CCCC1>[NH:1]([C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C@@H:2]([C:4]([NH:6][C@H:7]([C:18]([NH:20][C@H:21]([C:33]([OH:35])=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[O:19])[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:5])[CH3:3].[CH:60]1[C:61]([C:62]([OH:46])=[O:63])=[CH:64][CH:65]=[C:58]([NH2:57])[CH:59]=1
Reactant: CN1CCOCC1
Reactant: Nc1ccc(CO)cc1
Agent: C=CCOC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](C)NC(=O)OCC=C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)O)cc1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of 239 mg (0.419 mmol) Aloc-D-Ala-Trp-Lys(Aloc)-OH 28 was dissolved in dry tetrahydrofuran under an argon atmosphere and cooled to −40° C. N-methylmorpholine (48.3 μl, 1.05 equiv) and isobutylchloroformate (57.0 μl, 1.05 equiv) were added. The reaction mixture was stirred for 2 hours at a temperature below −30° C. A solution of 4-aminobenzyl alcohol (51.5 mg, 1.00 equiv) and N-methylmorpholine (50.6 μl, 1.1 equiv) in dry THF was added dropwise to the reaction mixture. After 2 hours tetrahydrofuran was evaporated and dichloromethane was added. The organic layer was washed with saturated sodium bicarbonate, a 0.5 N potassium bisulphate solution and brine, dried (Na2SO4) and evaporated to afford 265 mg (94%) of the desired product 29 as a cream coloured powder. 1H-NMR (300 MHz, CDCl3/CD3OD): δ 1.00–1.62 (m, 9H, CH3-Ala and 3 CH2-Lys), 2.90–3.70 (m, 4H, N—CH2-Lys and CH2-Trp), 4.48–4.92 (m, 7H, 2 Hα and 4 Aloc), 4.72 (s, 2H, CH2—OH), 5.00–5.50 (m, 5H, 4 Aloc and Hα), 5.35–6.05 (m, 2H, Aloc), 6.80–7.83 (m, 9H, aromatic) ppm; MS (FAB) m/e 677 (M+H)+, 699 (M+Na)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[Cl:10][C:11]1[N:12]=[C:13]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:14]2[N:20]=[CH:19][N:18]=[C:17](Cl)[C:15]=2[N:16]=1>C1C=CC=CC=1.O1CCOCC1>[CH2:1]([O:8][C:17]1[C:15]2[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:22]3[CH2:23][CH2:24][S:25](=[O:28])[CH2:26][CH2:27]3)[C:14]=2[N:20]=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Agent: [Na]
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: O=S1CCN(c2nc(Cl)nc3c(OCc4ccccc4)ncnc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An alcoholate solution, prepared from 22 gm (0.2 mol) of benzyl alcohol in 100 ml of absolute benzene with 1.6 gm (0.07 mol) of sodium, was added to a solution of 15.9 gm (0.05 mol) of 2,8-dichloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]-pyrimidine in 400 ml of dioxane at about 30° C., and the mixture thus obtained was stirred at room temperature for about two hours. The reaction mixture was then evaporated in vacuo, and the residue was admixed with about 500 ml of water. The precipitate which solidified after standing for a short time, was filtered off, washed with water and dried at about 70° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>[Cu]=O>[C:14]([C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)([OH:16])=[O:15]
Reactant: Cc1n[nH]c2ccccc12
Reactant: O=C(O)c1ccccc1Cl
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nn(-c2ccccc2C(=O)O)c2ccccc12
Yield: 72.7 %

Procedure:
3-Methylindazole (3.30 g), 3.92 g of 2-chlorobenzoic acid, 3.82 g of potassium carbonate and 0.18 g of copper(II) oxide were subjected to reaction in the same manner as in Example 1 to obtain 4.58 g (72.7%) of 1-(2-carboxyphenyl)-3-methylindazole.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:21][N:20]=2)=[CH:16][CH:17]=1
Reactant: ON=C(Cl)Cc1ccc(Br)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Br)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridine-2,6-diamine (50 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 and 4-bromophenyl acetohydroximoyl chloride (150 mg, 0.602 mmol) described in Manufacturing Example 207-1-3 was added triethylamine (131 μL, 0.94 mmol), which was stirred for 2 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1, then ethyl acetate) to obtain the title compound (85 mg, 66%).
Reaction SMILES: [Br-:1].[NH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32].N1C=CC=CC=1>C(Cl)Cl>[Br-:1].[F:9][C:7]1[CH:6]=[CH:5][C:4]([CH2:10][P+:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:3]([NH:2][C:30](=[O:33])[CH:31]=[CH2:32])[CH:8]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)Nc1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80.9 %

Procedure:
A suspension of 89 g (0.19 mol) of [(2-amino-4-fluorophenyl)methyl]-triphenylphosphonium bromide in 1.5 L CH2Cl2 was stirred and 17 mL (0.21 mol) of acryloyl chloride was added dropwise. A 22.8 mL sample of pyridine was added dropwise. The mixture was heated under reflux for 45 min. The mixture was cooled, washed with K2CO3 solution, dilute hydrochloric acid and brine. It was dried (Na2SO4), concentrated and triturated with Et2O to give 80 g (81%) of [[4-fluoro-2-[(1-oxo-2-propenyl)amino]phenyl]methyl]triphenylphosphonium bromide as a yellowish solid: 1H NMR (CDCl3) δ 8.0-7.4 (m, 15H); 6.9 (m, 2H); 6.4 (m, 1H); 6.1 (d, 1H); 5.9 (d, 2H); 5.5 (d, 1H). ##STR18##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[C:41]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[C:41]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 58.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example 9) (100 mg, 0.19 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (Intermediate 65D) (69 mg, 0.20 mmol) using sodium carbonate (61 mg, 0.57 mmol) and Pd(PPh3)2Cl2 (7 mg, 0.009 mmol) in DME/water (5/0.5 mL). This afforded 72 mg (58.5% yield) of the titled compound.