Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)C>[BrH:5].[CH2:6]([S:3][C:2](=[NH:4])[NH2:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NC(N)=S
Reactant: CCCCCCBr
Solvent: CCO
Product: Br
Product: CCCCCCSC(=N)N
Yield: 91.2 %

Procedure:
Thiourea (50 g, 657 mmol) and 1-bromohexane (119 mL, 723 mmol) were heated at reflux under nitrogen in ethanol (500 mL) for 20 h. Ethanol was evaporated, and the thick oil stirred in diethyl ether (500 mL). The product precipitated spontaneously. After filtration one obtained 144.5 g (91%) of white crystals, m.p. 75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[H-].[Na+].O1[CH:21]=[CH:20][CH2:19][C:18](=[O:22])[NH:17]1.[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:17]1[C:18](=[O:22])[CH:19]([CH2:20][CH3:21])[O:26][C:25]2[C:3]([CH:4]=[CH:8][CH3:9])=[CH:11][CH:27]=[CH:23][C:24]1=2)=[O:6]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: O=C1CC=CON1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC=Cc1cccc2c1OC(CC)C(=O)N2C(=O)c1ccc(OC)cc1OC
Yield: 84 %

Procedure:
Procedure & NMR Data: 162 mg (2.5 eq, 0.8 mmol) of 2,4-Dimethoxybenzoyl chloride was added to a mixture of 49 mg (4 eq, 1.28 mmol) of NaH and 73 mg (0.32 mmol) of oxazinone P2 in THF (14 mL). 109 mg of P9 were obtained, yield 84%.
Reaction SMILES: [CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:25])([CH3:3])[CH3:2].[H-].[Na+].[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29]>CN(C)C(=O)C>[CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][N:6]([S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])[C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)N1C(=O)NCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1C(=O)N(S(=O)(=O)C(C)C)CC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 1-isopropyl-5-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one (40 mg) in N,N-dimethylacetamide (1 mL) under argon at 0° C. was added sodium hydride dispersion (55% in mineral oil, 6 mg). The mixture was stirred at 0° C. for 1.5 h. Isopropylsulfonylchloride (19 mg) was added. The mixture was stirred for 30 min at 0° C. and overnight at room temperature. Ice cold water was added and the mixture was extracted with ethyl acetate. The org. phase was washed with water and concentrated. The product was purified using column chromatography (SiO2, cyclohexane/ethyl acetate 1:0=>0:1) to give 3-isopropyl-4-(3′-methanesulfonyl-biphenyl-3-yl)-1-(propane-2-sulfonyl)-imidazolidin-2-one (28 mg) as a colorless foam. MS: 465.3 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5]Cl.CC(C)=O.[I-:19].[Na+]>CCOCC>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][I:19]
Reactant: COc1ccc(CCl)c(OC)c1OC
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: COc1ccc(CI)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
46.64 g (215.2 mmol) of 2,3,4-trimethoxybenzyl chloride in 466 ml of abs. acetone are treated with 156.7 g (4.86 equivalents) of sodium iodide, and this mixture is stirred at RT for 2.75 h while excluding light. The reaction mixture is treated with approximately 3 l of (cold) ether, and the organic phase is washed once with 10% sodium thiophosphate solution and twice with saline (both kinds of solutions being cold). The combined aqueous phases are reextracted with ether. The combined organic phases are dried over Na2SO4 and evaporated on a RE, at approximately 30° C. The residue, which is the desired title compound, is dried again under HV and subjected to further processing as a crude product. 1H-NMR (200 MHz, CDCl3): 7.03 and 6.59 (each d; each 1H); 4.47 (s, 2H); 4.05, 3.85 and 3.84 (each s, each 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(#N)C>[CH2:38]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)([OH:19])[C:10]1=[O:18])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)cc(C2(O)C(=O)Nc3ccccc32)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: Cc1cc(C)cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)c1
Yield: 99 %

Procedure:
Using a method similar to Preparation 17 with 3-(3,5-dimethyl-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one (50 mg, 0.20 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (0.065 ml, 0.22 mmol) and benzyl bromide (0.024 mL, 0.20 mmol) in acetonitrile (1 mL) gives 68 mg (100%) of the title compound which was used without further purification.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][CH2:9][CH:10]1[S:15][C:14]2[S:16][CH:17]=[CH:18][C:13]=2[CH:12]([O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:11]1.[CH3:26][O:27][CH2:28][CH2:29]Br>O>[CH3:26][O:27][CH2:28][CH2:29][O:8][CH2:9][CH:10]1[S:15][C:14]2[S:16][CH:17]=[CH:18][C:13]=2[CH:12]([O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:11]1
Reactant: COCCOCOC1CC(CO)Sc2sccc21
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOC1CC(COCCOC)Sc2sccc21
Temperature: 25 °C
Yield: 86.1 %

Procedure:
Under N2, a suspension of 60% NaH (20 g, 0.5 mol), DMF (350 ml) and 7 (38.3 g, 0.13 mol) was stirred at ambient temperature. After 2.5 h. the reaction was cooled to 0°-4° C. and 2-methoxyethylbromide (71 g, 0.51 mol) was added dropwise. After complete addition, the reaction was allowed to stir to room temperature overnight. The solution was then poured into H2O and the aqueous layer was extracted with EtOAc (3x). The organic layer was washed with saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column with silica gel and the product eluted with 20% EtOAc-hexane to yield 39 g (84%) of 8.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].CC(C)=O.[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>O.[OH-].[Na+]>[C:24]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7])(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A suspension of 20 g (0.0724 mols) of α-glutamylglutamic acid in 70 ml of water was dissolved in a 27-% sodium hydroxide aqueous solution until the pH reached 11, and 35 ml of acetone were added thereto. To the solution were added dropwise 15.8 g (0.0724 mols) of lauroyl chloride over a period of 1 hour. When adding lauroyl chloride, the temperature was maintained at 10° C., and 27-% sodium hydroxide was added dropwise simultaneously to keep the pH constant. After the addition of lauroyl chloride, the reaction solution was warmed at 30° C., and allowed to stand for 30 minutes. Subsequently, the pH was adjusted to 1 with the addition of conc. hydrochloric acid. The solid precipitate was separated by filtration, and dried to obtain 30.6 g of N-(N'-lauroyl-α-glutamyl)glutamic acid in a yield of 92%. This solid was analyzed by infrared spectrophotometry. A peak diagnostic of an amide group was observed at 1,650 cm-1 and a peak diagnostic of a carboxyl group was observed at 1,730 cm-1, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([C:64]([F:67])([F:66])[F:65])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([C:64]([F:66])([F:67])[F:65])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)c(C(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
To a solution of 98 mg (0.5 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 161 mg of TBTU (0.5 mmol) in 6 ml DMF, were added 0.43 ml (2.51 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 200 mg (0.54 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; DCM/heptane 9:1) to give 206 mg white solid (69%). MS (EI) 546.2 (M)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:32])=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:17][CH2:16]3)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:33](OCC)(=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:25]([O:24][CH2:23][CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]([NH:10][C:6]3[C:5]4[O:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:2][C:1](=[O:3])[C:4]=4[CH:9]=[CH:8][CH:7]=3)=[O:12])[CH:14]=2)[O:19]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1.[C:34]([O:36][CH2:37][CH3:38])(=[O:35])[CH3:33]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(NC(=O)c2ccc3c(c2)CCC(COCc2ccccc2)O3)c1O
Product: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc4c(c3)CCC(COCc3ccccc3)O4)c2o1
Product: CCOC(C)=O
Yield: 66 %

Procedure:
Following the process described at point A, starting from N-(3-acetyl-2-hydroxyphenyl)-2-(benzyloxymethyl)chromane-6-carboxamide and diethyl oxalate, the title compound was prepared, which was purified by warm crystallization in ethyl acetate (66% yield).
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>ClCCl>[C:8]([CH:2]([NH:1][C:23]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:24])[C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:9]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCOC(=O)C(N)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C#N)NC(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 18.3 g (143 mmol) of ethyl amino(cyano)acetate in 500 mL of anhydrous dichloromethane were added 30 mL (214 mmol) of triethylamine and 23 mL (171 mmol) of cyclohexanecarbonyl chloride, and the mixture was stirred for 3 hours at 0° C. Then, saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate to give the solid substance. The obtained solid substance was collected and the filtrate was removed under reduced pressure. The obtained residue was treated with ethyl acetate to give solid substance. This treatment was further repeated. The filtrate was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to give crude crystalline. The obtained crude crystalline was washed with ether and combined with the above all solid products to give 24.3 g (71%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7](=[O:18])[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:4]=2[N:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[CH:29]2.ClC1N=CC2N(C3C=CC=CC=3)C(=O)[C@@H](C)N(C3CCCCC3)C=2N=1.C1(N)CCCC1>>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:2]3[N:11]=[CH:10][C:9]4[N:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:7](=[O:18])[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:4]=4[N:3]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC(C)CCn1c(=O)c(=O)n(-c2ccccc2)c2cnc(Cl)nc21
Agent: C[C@@H]1C(=O)N(c2ccccc2)c2cnc(Cl)nc2N1C1CCCCC1
Agent: NC1CCCC1
Product: CC(C)CCn1c(=O)c(=O)n(-c2ccccc2)c2cnc(Nc3ccc4[nH]ncc4c3)nc21

Procedure:
This compound was prepared from 2-chloro-8-(3-methylbutyl)-5-phenyl-5,8-dihydropteridine-6,7-dione and 5-aminoindazole, according to procedures similar to the preparation of example 18 from (7R)-2-chloro-8-cyclohexyl-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one. Examples 306 and 307 was prepared according to procedures similar for the preparation of Example 305, using corresponding starting materials and intermediates. For example, for synthesis of example 307, cyclopentanamine was used in the step a of the synthesis.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:13]([C:11]1[CH:10]=[CH:9][C:3]2[C:4]([C:6]([OH:8])=[O:7])=[CH:5][S:1][C:2]=2[CH:12]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1csc2ccccc12
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1csc2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
2 g benzo[b]thiophene-3-carboxylic acid are dissolved in 11 ml acetic anhydride and cooled to 0° C. A solution of 4.4 ml concentrated nitric acid in 10 ml acetic acid is added dropwise, while not allowing the temperature to rise above 5° C. Then the mixture is stirred for 1.5 hours and then combined with 200 ml ice water. The solid is suction filtered and dried in vacuo. Then it is dissolved in hot ethanol. After cooling to ambient temperature the solid (5-nitro-benzo[b]thiophene-3-carboxylic acid, approximately 80%) is suction filtered. By elimination of the solvent in vacuo, 6-nitro-benzo[b]thiophene-3-carboxylic acid (approx. 66%) is obtained from the mother liquor.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55](=[O:73])[C@H:56]([NH2:72])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)([CH3:53])([CH3:52])[CH3:51]>C(#N)C>[C:50]([O:54][C:55](=[O:73])[C@H:56]([NH:72][C:12](=[O:14])[C@@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A solution of the product from Example Z ((S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.8 g, 3.1 mmol) and triethylamine (1.6 mL, 6.2 mmol) HBTU (1.3 g, 3.4 mmol) in acetonitrile (15 mL) was treated with HBTU (1.54 g, 4.06 mmol). The resulting solution was treated with the product from Example B ((R)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (1.08 g, 3.30 mmol), and the resulting solution was stirred at room temperature for 30 minutes and allowed to stand overnight. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (100 mL) and washed sequentially with 0.6 M aqueous NaHCO3 solution, saturated aqueous NaCl solution, and water. The organic phase was dried over MgSO4 and activate charcoal, filtered, and concentrated. The residue was purified by chromatography (silica gel, 25% ethyl acetate/hexane) to give the title compound as a white solid (1.4 g, 79%), mp=38-40° C.
Reaction SMILES: FC(F)(F)C(O[Si](C)(C)C)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:15][N:14]=1.[CH:27](OCC)(OCC)OCC.[N:37]([Si](C)(C)C)=[N+:38]=[N-:39]>C(OCC)(=O)C>[C:23]([O:22][C:20](=[O:21])[CH2:19][C:16]1[CH:15]=[N:14][C:13]([N:12]2[CH:27]=[N:37][N:38]=[N:39]2)=[N:18][CH:17]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)Cc1cnc(N)nc1
Reactant: CCOC(OCC)OCC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Si](C)(C)OC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1cnc(-n2cnnn2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Trimethylsilyl trifluoroacetate (0.14 mL, 0.81 mmol) was added to a suspension of tert-butyl (2-aminopyrimidin-5-yl)acetate (100 mg, 0.478 mmol) in Ethyl acetate (1.5 mL). The reaction mixture was stirred at RT for 5 minutes and triethyl orthoformate (0.14 mL, 0.84 mmol) was added. The reaction mixture was stirred at RT for 5 minutes and azidotrimethylsilane (0.1 mL, 0.760 mmol) was added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and washed with water and brine, dried (MgSO4), filtered and the solvent evaporated to afford the title compound: LC/MS (M+1)+ at 263 and (M+1-N2-tBu)+ at 179.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].[NH2:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH:23]=[C:22](Cl)[N:21]=1>>[NH2:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH:23]=[C:22]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)[N:21]=1
Reactant: N#Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Product: N#Cc1ccc(Nc2cc(Nc3ccc(Oc4ccnc5[nH]ccc45)c(F)c3)nc(N)n2)cc1

Procedure:
Analogously to example 25, the title compound is synthesized from 51 mg (0.21 mmol) of [3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (from example XIX) and 54 mg (0.22 mmol) of 4-[(2-amino-6-chloropyrimidin-4-yl)amino]benzonitrile (from example XLVII). Purification by preparative HPLC gives the product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])OC2C=CC=CC=2)=[C:19]([CH3:33])[C:18]=1[CH3:34])(=[O:3])[NH2:2].[CH3:35][NH2:36]>>[CH3:34][C:18]1[C:19]([CH3:33])=[C:20]([NH:23][C:24]([NH:36][CH3:35])=[O:32])[CH:21]=[CH:22][C:17]=1[O:16][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: CN
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(C)c3C)c2cc1C(N)=O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(N)=O)cc23)c(C)c1C

Procedure:
The title compound (30 mg) was obtained as colorless crystals from phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2,3-dimethylphenyl)carbamate) (56 mg) and methylamine (2M tetrahydrofuran solution), by the same procedure as in Example 11.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([N+:37]([O-:39])=[O:38])=[C:14]([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)=[CH:20][CH:19]=2)[CH:15]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.F>C1COCC1.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([NH:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:17]([NH:16][C:14]3[CH:15]=[C:10]([C:9]#[C:8][CH2:7][OH:6])[CH:11]=[CH:12][C:13]=3[N+:37]([O-:39])=[O:38])=[O:36])=[CH:19][CH:20]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1ccc(NCc2ccc(C(=O)Nc3cc(C#CCO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)ccc3[N+](=O)[O-])cc2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F
Agent: [F-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(NCc2ccc(C(=O)Nc3cc(C#CCO)ccc3[N+](=O)[O-])cc2)cc1OC
Reaction time: 12 h

Procedure:
A solution of compound 74 (871 mg, 1.24 mmol) in THF (3 mL) was treated with 1.0 M solution of tetrabutylammonium fluoride in THF (2.0 mL, 2.0 mmol) followed by 70% hydrogen fluoride in pyridine (0.1 mL), and the solution stirred under nitrogen for 12 h, diluted with ethyl acetate (200 mL) and washed with saturated NaHCO3 (50 mL) and then with water (6×100 mL), dried (Na2SO4), filtered and concentrated in vacuum. The crude material (647 mg) was pure enough for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[CH:9][NH:10][C:4]=2[C:3]=1[I:11].[H-].[Na+].S(OC)(O[CH3:18])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[CH:9][N:10]([CH3:18])[C:4]=2[C:3]=1[I:11]
Reactant: COS(=O)(=O)OC
Reactant: Clc1ncc2cc[nH]c2c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2cnc(Cl)c(I)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 6-chloro-7-iodo-1H-pyrrolo[3,2-c]pyridine (600 mg, 2.15 mmol) in N,N-dimethylformamide (8 mL) was added 60% sodium hydride (130 mg, 3.25 mmol) under argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C., and then thereto was added dropwise dimethyl sulfate (250 μL, 2.64 mmol). Then, the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and then the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→75:25) to give 6-chloro-7-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridine (540 mg, 86%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([NH:6][CH2:7][CH:8]1[O:12][CH:11]([CH3:13])[CH:10]([CH3:14])[O:9]1)([CH3:5])[C:3]#[CH:4].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>O>[CH3:5][C:2]([N:6]([CH2:7][CH:8]1[O:9][CH:10]([CH3:14])[CH:11]([CH3:13])[O:12]1)[C:29](=[O:30])[CH:28]([Br:27])[CH3:32])([CH3:1])[C:3]#[CH:4]
Reactant: CC(Br)C(=O)Cl
Reactant: C#CC(C)(C)NCC1OC(C)C(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C#CC(C)(C)N(CC1OC(C)C(C)O1)C(=O)C(C)Br

Procedure:
N-(1,1-Dimethylprop-2-ynyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine (10 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of 5° to 10° C. and α-bromopropionyl chloride (7 grams) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture reaches room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(1,1-dimethylprop-2-ynyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-α-bromopropionamide.