Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20]COC)[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].Br[C:25]1[CH:26]=[CH:27][C:28]([CH3:38])=[C:29]([NH:31]C(=O)C(F)(F)F)[CH:30]=1.BrC1C=CC(C)=C(C=1)N>>[NH2:31][C:29]1[CH:30]=[C:25]([C:18]2[C:17]([OH:20])=[CH:16][C:6]([CH2:7][C:8]3[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)=[CH:5][C:4]=2[O:3][CH2:1][CH3:2])[CH:26]=[CH:27][C:28]=1[CH3:38]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCOC)c1I
Reactant: Cc1ccc(Br)cc1NC(=O)C(F)(F)F
Agent: Cc1ccc(Br)cc1N
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1ccc(C)c(N)c1
Yield: 30 %

Procedure:
Starting from 5-(3-ethoxy-4-iodo-5-methoxymethoxy-benzyl)-pyrimidine-2,4-diamine (2.11 g; 4,9 mmol) and N-(5-bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (prepared from 5-bromo-2-methyl-aniline analogously to example 41) (2.3 g; 8.17 mmol), 0.963 g (30%) 3′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-4′-methyl-biphenyl-2-ol is obtained as a beige powder after Suzuki coupling (in situ generation of R2—B(OH)2) and splitting off of the protective group under acid conditions.
Reaction SMILES: [O:1]1[CH2:3][C:2]21[CH2:8][CH2:7][CH2:6][N:5]1[CH:9]=[N:10][CH:11]=[C:4]21.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C)C=O>[N:12]([CH2:3][C:2]1([OH:1])[CH2:8][CH2:7][CH2:6][N:5]2[CH:9]=[N:10][CH:11]=[C:4]12)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: c1ncn2c1C1(CCC2)CO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1(O)CCCn2cncc21
Temperature: 60 °C

Procedure:
A solution of 5 mmol of 6,7-dihydro-5H-spiro[imidazo[1,5-a]pyridine-8,2′-oxirane] in 15 ml of N,N-dimethylformamide is admixed with 10 mmol of sodium azide and the reaction mixture is heated at 60° C. for 4 hours. The mixture is poured into water and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[O:32][N:31]=[C:30]([CH2:33][O:34]C3CCCCO3)[CH:29]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[O:32][N:31]=[C:30]([CH2:33][OH:34])[CH:29]=4)[CH:23]=3)[CH2:20][C:19](=[O:42])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)no3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M29) (81 mg, 0.13 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (38 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Fc1ccc2cccc(CBr)c2c1
Reactant: CCOC(=O)c1cc2cc(C)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(C)ccc2n1Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure B, 5-methyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 1-(7-fluoro-naphthalen-1-ylmethyl)-5-methyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 332.3 ([M−H]−).
Reaction SMILES: Br[C:2]([F:44])([F:43])[C:3](F)([F:41])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34](F)([F:39])[C:35]([F:38])([F:37])Br)=[CH:29][CH:28]=2)([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](F)([F:25])[C:21]([F:24])([F:23])Br)=[CH:15][CH:14]=2)[CH3:12])=[CH:7][CH:6]=1>C(#N)C>[F:25][C:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]([F:41])=[C:2]([F:43])[F:44])=[CH:10][CH:9]=2)([C:27]2[CH:28]=[CH:29][C:30]([O:33][C:34]([F:39])=[C:35]([F:37])[F:38])=[CH:31][CH:32]=2)[CH3:12])=[CH:14][CH:15]=1)=[C:21]([F:24])[F:23]
Reactant: CC(c1ccc(OC(F)(F)C(F)(F)Br)cc1)(c1ccc(OC(F)(F)C(F)(F)Br)cc1)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Solvent: CC#N
Product: CC(c1ccc(OC(F)=C(F)F)cc1)(c1ccc(OC(F)=C(F)F)cc1)c1ccc(OC(F)=C(F)F)cc1

Procedure:
A sample of impure tris-perfluorovinyl ether ("tris") (180.8 g, 93.5% tris-, 6.5% bis-perfluorovinyl ether purity as determined by gas chromotography corresponding to mole percent) is diluted with 1500 mL of hexane to make an approximately 10% (by volume) solution. The pumps are started, with hexane pumped into the bottom of the column (above the acetonitrile take-off) and acetonitrile pumped into the top of the column (below the hexane take-off). The flow rates are adjusted to 90 mL/min for hexane and 45 mL/min for acetonitrile. The hexane reservoir is allowed to drain until nearly empty, and the solution of impure tris-perfluorovinyl ether is transferred to the reservoir. After this is transferred onto the column, the reservoir is filled again with 1500 mL of hexane (saturated with acetonitrile). This is allowed to pump through the column and into the product reservoir to ensure complete washing of the product from the column. The hexane solution which exits the column contains tris-perfluorovinyl ether (99.5% purity, 49% recovery). The acetonitrile solution which exits the column contains the remainder of the product (88.35 g, 85.5% tris- and 14.5% bis-perfluorovinyl ether) and is concentrated by rotary evaporation, rediluted in hexane (750 mL) and purified by running it through the countercurrent extractor to give 50.55 g of tris-perfluorovinyl ether (98.2% purity). The acetonitrile solution from this pass contains 25.7 g of material which is 71% tris- and 28.5% bis-perfluorovinyl ether. The ether is found to have the following properties:
Reaction SMILES: O[CH:2]1[CH2:6][N:5]([C:7](=[O:24])[CH2:8][P:9]([O:21][CH2:22][CH3:23])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])[C@H:4]([C:25]([O:27][CH3:28])=[O:26])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:48]=[N+:49]=[N-:50].C1C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.N=[N+]=[N-]>C(#N)C>[N:48]([CH:2]1[CH2:6][N:5]([C:7](=[O:24])[CH2:8][P:9]([O:21][CH2:22][CH3:23])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])[C@H:4]([C:25]([O:27][CH3:28])=[O:26])[CH2:3]1)=[N+:49]=[N-:50]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC(O)C[C@H]1C(=O)OC
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CC#N
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC(N=[N+]=[N-])C[C@H]1C(=O)OC
Reaction time: 18 h

Procedure:
(S)-4-Hydroxy-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline, methyl ester (2.0 g), triphenylphosphine (2.57 g), 2.1 N hydrazoic acid/benzene (12 ml, >5 equivalents) and dry acetonitrile are stirred under argon at room temperature for 30 minutes. Diethylazocarboxylate (1.71 g) in acetonitrile (5 ml) is added dropwise over 30 minutes. After 18 hours the reaction is still incomplete (as shown by thin-layer chromatography) and triphenylphosphine (1 equivalent), diethylazocarboxylate (1 equivalent) and 2.1 N hydrazoic acid (6 ml) are added. After 4 hours the reaction is complete. Nitrogen is bubbled through the solution to remove excess hydrazoic acid and the solvent is stripped leaving an oil. The oil is chromatographed on 100 mg of silica gel, eluting first with ethyl acetate and then with 3% methanol/ethyl acetate to give 1.64 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[NH:23][S:24]([C:27]1[C:32]2=[N:33][S:34][N:35]=[C:31]2[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.COC(=O)[C@@H](NC(=O)C1C=CC(I)=CC=1N)CC1C=CC(Cl)=C(Cl)C=1.ClS(C1C2C(=NSN=2)C=CC=1)(=O)=O.N1C=CC=CC=1.NCCN(CCN)CCN>C(Cl)Cl>[N:35]1[S:34][N:33]=[C:32]2[C:27]([S:24]([NH:23][C:17]3[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=3[C:15]([NH:14][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=3)[C:3]([OH:37])=[O:2])=[O:36])(=[O:25])=[O:26])=[CH:28][CH:29]=[CH:30][C:31]=12
Reactant: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1N
Agent: NCCN(CCN)CCN
Agent: O=S(=O)(Cl)c1cccc2nsnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid methyl ester. To a solution of (S)-2-(2-amino-4-iodo-benzoylamino)-3-(3,4-dichloro-phenyl)-propionic acid methyl ester (39 mg, 0.079 mmol) in DCM (1 mL) was added 4-chlorosulfonyl-2,1,3-benzothiadiazole (37 mg, 0.158 mmol) and pyridine (30 μL, 0.371 mmol). The mixture was-shaken overnight at rt, then polymer bound tris(2-aminoethyl)amine resin was added. The resulting mixture was shaken for 2 h, and the resin was removed by filtration and rinsed with DCM. TBD methyl polystyrene resin was then added and the mixture was shaken for 2 h. The liquid was drained and the resin was washed with DCM (3×). A solution of 10% TFA in DCM (3 mL) was added to the resin and the mixture was shaken for 1.5 h. The resin was removed by filtration, washed with 10% TFA in DCM and the filtrate was concentrated to provide the desired product as a white solid (55 mg, 99%). 1H NMR (400 MHz, CDCl3): 11.10 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.24 (dd, J=8.8, 0.8, 1H), 8.02 (d, J=1.5, 1H), 7.75 (dd, J=8.8, 7.1, 1H), 7.37-7.32 (m, 2H), 7.16 (d, J=2.0, 1H), 6.96 (d, J=8.3, 1H), 6.92 (dd, J=8.2, 2.0, 1H), 6.67 (d, J=7.3, 1H), 4.96 (q, J=5.7, 1H), 3.83 (s, 3H), 3.20-3.12 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]4[CH2:31][CH2:30][N:29]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:28][CH2:27]4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C2CCNCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C2CCN(S(C)(=O)=O)CC2)n1
Reaction time: 8 h
Yield: 35.5 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(piperidin-4-yl)thiazole-4-carboxamide (80 mg, 0.176 mmol) was added into a flask under nitrogen atmosphere. Dry pyridine was added along with methanesulfonyl chloride (20.14 mg, 0.176 mmol) and the mixture was stirred overnight. The reaction was stopped by adding water. The reaction mixture was diluted with DCM and washed with 1M Na2CO3 and water. The product was triturated using diethyl ether. Yield 35.5%. 1H-NMR (400 MHz; CDCl3): δ 1.29 (d, 3H), 1.92 (m, 2H), 2.18 (m, 2H), 2.81 (dd, 1H), 2.84 (s, 3H), 3.08 (m, 1H), 3.89 (m, 2H), 4.34 (dd, 1H), 4.42 (dd, 1H), 4.59 (m, 1H), 6.63 (d, 1H), 7.50 (d, 1H), 7.67 (d, 1H), 7.68 (d, 1H), 7.77 (dd, 1H), 7.98 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:37])[N:16]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:26][CH:25]=3)[CH:21]=[CH:22][CH:23]=2)[CH3:17])=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH3:6]>O1CCCC1.CO>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:37])[N:16]([C:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH3:17])=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ccc(NC(=O)N(C)c2cccc(-c3ccc(CCC(=O)OCC)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(NC(=O)N(C)c2cccc(-c3ccc(CCC(=O)O)cc3)c2)cc1
Yield: 71 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, 4.8 eq) of sodium hydroxide and 490 mg (1.03 mmol, 1 eq) of ethyl 3-{3′-[3-(4-butoxyphenyl)-1-methylureido]biphenyl-4-yl}propanoate in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after recrystallization from ethyl acetate/heptane, 330 mg of 3-{3′-[3-(4-butoxyphenyl)-1-methylureido]biphenyl-4-yl}propanoic acid are obtained in the form of white crystals. (m.p.=165° C.). Yield=71%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCc1cnc(NCCc2ccc(OC)c(Br)c2)nc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: CCc1cnc(N(CCc2ccc(O)c(Br)c2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from N-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and 4-trifluoromethyl benzyl bromide.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[CH:17]=[C:16]2[CH:11]([CH2:12][CH2:13][N:14]([CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[CH2:15]2)[CH2:10][C:9]=1[O:31]CC1C=CC=CC=1)[CH3:6]>C(O)C>[CH2:5]([O:7][C:8]1[CH:17]=[C:16]2[CH:11]([CH2:12][CH2:13][N:14]([CH2:18][C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[CH2:15]2)[CH2:10][C:9]=1[OH:31])[CH3:6]
Reactant: CCOC1=C(OCc2ccccc2)CC2CCN(Cc3cc(OC)c(OC)c(OC)c3)CC2=C1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC1=C(O)CC2CCN(Cc3cc(OC)c(OC)c(OC)c3)CC2=C1
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
7-Ethoxy-6-benzyloxy-2-(3,4,5-trimethoxybenzyl)-tetrahydroisoquinoline acetate (307 mg, 0.66 mmol) was dissolved in ethanol and ethyl acetate (5 mL each), degassed, treated with 10% Pd/C (50 mg) then placed under an atmosphere of hydrogen. After 0.5 h no starting material was evident by TLC and the reaction was filtered through celite and evaporated. The resultant oil was precipitated from ethyl acetate/hexane to give a yellow powder (240 mg, 97%). 1H NMR δ 1.39 (3H, t, J 7.0), 2.68 (2H, t, J 5.7), 2.75 (2H, t, J 5.7), 3.52 (2H, s), 3.58 (2H, s), 3.83 (3H, s), 3.84 (6H, s), 4.01 (2H, q, J 7.0), 5.50 (1H, br), 6.46 (1H, s), 6.61 (2H, s) and 6.67 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25](=[O:27])[N:31]([CH2:32][CH2:33][OH:34])[CH3:30])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CNCCO
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Product: CN(CCO)C(=O)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 55 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 2-methylamino-ethanol in 55% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([C:27](=[O:29])[CH3:28])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(C)c4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (150.3 mg, 0.3998 mmol) in dichloromethane (15 mL) were added acetyl acetate (81.5 mg, 0.798 mmol) and N,N-diethylethanamine (81.3 mg, 0.803 mmol). The mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 10/1) to give the product as a yellow solid (120.0 mg, 71.82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:82]([CH3:84])[CH3:83])[C:10]([CH3:81])=[C:11]([S:77]([CH3:80])(=[O:79])=[O:78])[C:12]=2[C:13]2[CH:14]=[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][S:33]([C:36]5[CH:41]=[CH:40][C:39]([NH:42][C@@H:43]([CH2:62][S:63][C:64]6[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=6)[CH2:44][CH2:45][N:46]6[CH2:51][CH2:50][CH:49]([C:52]([O:54]C(P(=O)(O)O)CC)=[O:53])[CH2:48][CH2:47]6)=[C:38]([S:70]([C:73]([F:76])([F:75])[F:74])(=[O:72])=[O:71])[CH:37]=5)(=[O:35])=[O:34])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[CH:16]=[C:17]([F:19])[CH:18]=2)=[CH:4][CH:3]=1.O[CH:86]([CH3:94])[CH2:87][P:88](=[O:93])([O:91]C)[O:89]C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:82]([CH3:83])[CH3:84])[C:10]([CH3:81])=[C:11]([S:77]([CH3:80])(=[O:78])=[O:79])[C:12]=2[C:13]2[CH:14]=[C:15]([N:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH:27]=[CH:28][C:29]([NH:32][S:33]([C:36]5[CH:41]=[CH:40][C:39]([NH:42][C@@H:43]([CH2:62][S:63][C:64]6[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=6)[CH2:44][CH2:45][N:46]6[CH2:47][CH2:48][CH:49]([C:52]([O:54][CH2:94][CH2:86][CH2:87][P:88](=[O:89])([OH:93])[OH:91])=[O:53])[CH2:50][CH2:51]6)=[C:38]([S:70]([C:73]([F:74])([F:76])[F:75])(=[O:71])=[O:72])[CH:37]=5)(=[O:35])=[O:34])=[CH:30][CH:31]=4)[CH2:24][CH2:25]3)[CH:16]=[C:17]([F:19])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: COP(=O)(CC(C)O)OC
Reactant: CCC(OC(=O)C1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)Nc3ccc(N4CCN(c5cc(F)cc(-c6c(S(C)(=O)=O)c(C)n(C(C)C)c6-c6ccc(Cl)cc6)c5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CC1)P(=O)(O)O
Product: Cc1c(S(C)(=O)=O)c(-c2cc(F)cc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(C(=O)OCCCP(=O)(O)O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c(-c2ccc(Cl)cc2)n1C(C)C

Procedure:
2-(1-((R)-(3-(4-(N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrol-3-yl)-5-fluorophenyl)piperazin-1-yl)phenyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)piperidine-4-carbonyloxy)propylphosphonic acid (17). 17 was prepared from 13 and dimethyl 2-hydroxypropylphosphonate according to general procedure V. 1H NMR (300 MHz, CD3OD): δ 7.97 (d, J=2.1 Hz, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.36-7.08 (m, 13H), 6.85-6.43 (m, 4H), 5.26 (s, 1H), 4.54-4.44 (m, 1H), 4.01 (s, 1H), 3.58-2.92 (m, 16H), 2.87 (s, 3H), 2.76 (s, 3H), 2.70-2.55 (m, 1H), 2.26-1.85 (m, 8H), 1.46 (d, J=7.1 Hz, 6H), 1.38 (d, J=5.9 Hz, 3H). MS (ESI): m/z 1281.34 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:36]([O:37][CH3:38])=[CH:35][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:36]([O:37][CH3:38])=[CH:35][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCO)CC2
Yield: 58 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol. The product was isolated as a white solid (8 g, 58%), mp: 149.5-151.5° C., MS (ESI+): 547 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.91 (d, J=8 Hz, 1H), 7.58 (t, 1H), 7.53 (s, 1H), 7.26 (m, 1H), 6.68 (s, 1H), 3.89 (s, 3H), 3.65 (t, 2H), 2.90 (m, 3H), 2.77-2.69 (m, 15H).
Reaction SMILES: Cl[C:2]1[C:3]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:2]2[C:3]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[C:4]([CH:7]=[CH:8][N:9]=2)[C:5]#[N:6])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccnc(Cl)c1N1CCCC1
Reactant: OB(O)c1ccccc1
Product: N#Cc1ccnc(-c2ccccc2)c1N1CCCC1
Yield: 66 %

Procedure:
Prepared in 66% yield from the product of Example 181A and phenylboronic acid according to the procedure described for Example 153A. MS (ESI+) m/z 249.8 (M+H)+; 1H NMR (DMSO-d6) δ 1.72-1.77 (m, 4H), 3.17-3.21 (m, 4H), 7.38-7.52 (m, 6H), 8.14 (d, J=4.7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][CH3:13])[CH2:9][CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH:15]([Mg]Cl)=[CH2:16]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][CH3:13])[CH2:9][C@H:10]([OH:11])[CH:15]=[CH2:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Mg]Cl
Reactant: CC[C@H](CC=O)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=C[C@@H](O)C[C@@H](CC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of ((R)-1-ethyl-3-oxo-propyl)carbamic acid tert-butyl ester (2.9 mmol; 584 mg) in THF (20 mL) is added a 1.44 M THF solution (11.6 mmol; 8.1 mL) of vinylmagnesium chloride under nitrogen at −78° C. After stirring for 30 minutes, the reaction mixture is warmed to room temperature and stirred for an additional 1.5 hours. Another 1.44 M THF solution (2.9 mmol; 2 mL) of vinylmagnesium chloride is added to the reaction mixture at room temperature. After stirring for additional 15 minutes, the solution is quenched by saturated aqueous ammonium chloride solution and extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; n-hexane/EtOAc) to give ((1R,3S)-1-ethyl-3-hydroxy-pent-4-enyl)-carbamic acid tert-butyl ester (130 mg, 20%); ESI-MS m/z: 174 [M+−tBu+2], Retention time 4.13 min (condition B).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].CCN(CC)CC.[NH:16]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:17]([C:28](ON1C(=O)CCC1=O)=[O:29])[C@@H:18]([CH3:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>CN(C=O)C.C(Cl)(Cl)Cl.CCOC(C)=O>[NH:16]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C@H:17]([C:28]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:29])[C@@H:18]([CH3:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A suspension of H-Pro-OH (1.0 g, 8.69 mmol) in DMF (15 ml) was stirred with Et3N (2.44 ml) and Boc-Thr(Bzl)-OSu (3.88 g, 9.56 mmol) at 0° C for 1 hr and 25° C for 72 hrs. The reaction was acidified to pH 3 with acetic acid and worked up as described in Example 2 to produce a crystalline product from EtOAc and petroleum ether: 3.0 g (85.0%); mp 84°-88° C; [α]D25 -52.2° (c 1, CHCl3). Anal. Calcd for C21H30N2O6 (406.48): C, 62.05; H, 7.43; N, 6.89. Found: C, 62.29; H, 7.52; N, 6.86.