Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[CH:4][CH:5]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([C@H](c3ccc(Cl)cc3)N3CC(=C(c4cc(F)cc(F)c4)S(C)(=O)=O)C3)cc2)CC1
Yield: 44.4 %

Procedure:
The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane, and 0.020 g of N-methylpiperazine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.025 g of 1-{(R*)-(4-chlorophenyl)[4-(4-methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.28 (s, 3H), from 2.30 to 2.60 (unresolved complex, 8H), 2.80 (s, 3H), 3.45 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][CH3:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:30]([CH:37]([CH3:41])[C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]([CH3:29])[C:38](=[O:39])[CH:37]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:41])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC)cc3)cc2)CC1
Reactant: CC(Oc1ccccc1)C(=O)Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(C)C(=O)C(C)Oc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(3-methyl-4-methylaminomethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenoxy-propionyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1])=[O:18]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=N)c1ccccc1Cl
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1ccccc1Cl

Procedure:
starting from ethyl o-chlorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-o-chlorobenzimidate, m.p. 64°-65° C., and therefrom with 2,2,2-trifluoroethylhydrazine there is obtained 3-(o-chlorophenyl)-1-(2,2,2-trifluoroethyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, 1H-NMR(CDCl3): 4.62 (q, CH2CF3), 7.3-8.1 (8 aromatic H);
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24]>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:22](/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)\[C:23]#[N:24])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: N#CCc1ccccn1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3ccccn3)cc2c1
Yield: 96.8 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (222 mg) was condensed with 2-pyridineacetonitrile (118 mg) through Method B (production step 3), to thereby yield the target product (yield: 311 mg, 97%).
Reaction SMILES: [CH:1]1([N:7]([CH3:29])[C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([N:7]([CH3:29])[C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCSc1c(C(=O)N(C)C2CCCCC2)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)N(C)C2CCCCC2)cnn1-c1ccc(C(=O)O)cc1
Reaction time: 18 h

Procedure:
Methyl 4-[4-(cyclohexyl-methyl-carbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (Intermediate#4) (162 mg, 0.39 mmol) was dissolved in methanol (10 mL) and treated at ambient temperature with 2M aqueous sodium hydroxide solution (0.96 mL, 1.95 mmol). The mixture was stirred at ambient for 18 h. Methanol was removed by evaporation under reduced pressure and the clear solution diluted with water (25 ml). 2M HCl was added to pH4 and the mixture extracted with ethyl acetate (2×25 mL). The combined extracts were washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated to give the title compound as a white solid foam (150 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:26].[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:32]([C:28]1[O:27][CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:33]
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl
Reactant: O=S(=O)(Cl)c1ccco1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccco1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}amine (1.03 g, 2.52 mmol) and 2-furansulfonyl chloride (0.588 g, 3.53 mmol) the title compound of Step E was obtained as an off-white solid (430 mg, 0.735 mmol, 29.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.91 (d, J=0.9 Hz, 1H), 7.43-7.58 (m, 2H), 7.31-7.43 (m, 1H), 7.08 (d, J=3.5 Hz, 1H), 6.55 (dd, J=3.5, 1.8 Hz, 1H), 6.18 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.55 (t, J=4.7 Hz, 4H). MS (ESI): 537.96 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([Br:16])=[CH:11][C:10]=2[F:17])[N:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:16][C:12]1[CH:13]=[C:14]([F:15])[C:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=3[F:25])[N:3]=2)=[C:10]([F:17])[CH:11]=1
Reactant: Fc1cc(Br)cc(F)c1Cc1cccc(Br)n1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cccc(Cc3c(F)cc(Br)cc3F)n2)c(F)c1
Temperature: 90 °C
Yield: 88.9 %

Procedure:
To a solution of 2-bromo-6-(4-bromo-2,6-difluorobenzyl)pyridine (from Step C above, 7.41 g, 20.53 mmol) in toluene (200 mL) was added (2,4-difluorophenyl)boronic acid (3.89 g, 24.63 mmol), tetrakis(triphenylphosphine)palladium (2.37 g, 2.05 mmol), ethanol (20 mL) and 2M Na2CO3 (20 mL). The reaction was heated to 90° C. until complete. The mixture was cooled to room temperature and concentrated. The crude residue was diluted with EtOAc/water (1:1) and washed with 1N HCl (2×), brine (3×), dried over MgSO4, and concentrated in vacuo. The crude material was purified via silica gel chromatography (hexanes/ethyl acetate) to give the title compound (7.23 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][O:17][C:18]([C:20]1[N:21]([CH2:26][C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[N:22]=[C:23]([NH2:25])[CH:24]=1)=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[N:21]([CH2:26][C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[N:22]=[C:23]([NH:25][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([C:7]#[N:8])[CH:9]=2)[CH:24]=1)=[O:19]
Reactant: COC(=O)c1cc(N)nn1Cc1cc(F)c(F)c(F)c1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: COC(=O)c1cc(Nc2ccc(-n3cnc(C)c3)c(C#N)c2)nn1Cc1cc(F)c(F)c(F)c1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 5-amino-2-(3,4,5-trifluoro-benzyl)-2H-pyrazole-3-carboxylic acid methyl ester. The title compound was obtained as a colorless solid (Yield=15%). MS ISP (m/e): 467.2 (100) [(M+H)+].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:11]1[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
(4-Phenethyl-phenyl)-carbamic acid tert-butyl ester (Ii, 0.90 g, 3.03 mmol) was dissolved in CH2Cl2 (15 mL) and treated with TFA (15 mL). The reaction was stirred for 20 minutes, concentrated, diluted with EtOAc (200 mL), washed twice with saturated sodium bicarbonate solution and once with brine, dried over Na2SO4, and concentrated to give 0.56 g (94%) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]([NH:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[C:9]([OH:24])[C:8]2[CH2:25][N:26]([C:28]([C:30]3[N:31]=[CH:32][S:33][CH:34]=3)=[O:29])[CH2:27][C:7]1=2)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[C:9]([OH:24])[C:8]2[CH2:25][N:26]([C:28]([C:30]3[N:31]=[CH:32][S:33][CH:34]=3)=[O:29])[CH2:27][C:7]1=2)#[N:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccccc3C#N)c1=O)CN(C(=O)c1cscn1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1Cn1c2c(c(O)c(C(=O)NCC(=O)O)c1=O)CN(C(=O)c1cscn1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Step A (20 mg, 0.037 mmol) was dissolved in DCM (1.5 mL) and TFA (0.5 mL, 6.5 mmol) was added. The reaction was stirred at ambient temperature overnight. The reaction was concentrated and the residue was purified on a C-18 reverse phase chromatography column eluted with 0-100% MeCN in water. The desired fractions were concentrated affording the title compound. 480.0 (M+1); Rt=2.53 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH:10]([S:12]C(=O)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[CH2:11][CH:10]([SH:12])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)SC1CN(Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: SC1CN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
1-Benzyl-3-acetylthio-azetidine (1 g, 4.518 mmol) prepared in Preparation Example 49 was dissolved in methanol (20 ml), and oxygen was completely removed by passing nitrogen through the mixture. The resulting mixture was cooled to 0° C., 2N sodium hydroxide (2.27 ml, 4.518 mmol) was added thereto slowly, stirred at 0° C. for 30 min, and then 2N—HCl was added thereto to neutralize (pH 7) the mixture. The resulting solution was concentrated under a reduced pressure, and the concentrate was dissolved in ethyl acetate, and washed with a saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under a reduced pressure to obtain 620 mg (yield: 77%) of the title compound, which was used in the next reaction without any additional purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=1.C([Li])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:30]=[CH:29][C:28]([Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: [Li]C(C)(C)C
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc([Si](C)(C)C)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1-bromo-4-(trimethylsilyl)benzene with tert-butyl-lithium instead of n-butyllithium in analogy to Example 1a): MS (ISP): 452.0 and 454.0 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]2[O:9][C@H:8]2[C:10]([O-:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[OH:36]>C1COCC1>[OH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:10]([C@H:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:9]1)=[O:12]
Reactant: Nc1ccccc1O
Reactant: O=C([O-])[C@@H]1O[C@H]1c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1O)[C@@H]1O[C@H]1c1ccccc1
Temperature: 10 °C
Yield: 77 %

Procedure:
To a stirred suspension of potassium (2R,3S)-3-phenyloxirane-2-carboxylate (64a) (4.040 g, 20.00 mmol) in dry THF (100 mL) under nitrogen cooled in an ice-water bath was added isobutyl chloroformate (2.730 g, 20.00 mmol) slowly via syringe. NMM (0.460 mg, 4.55 mmol) was added and the mixture stirred while gradually warming to 10° C. over 75 min. The mixture was cooled to 0° C. and 2-aminophenol was added, then the cooling bath was removed and the reaction stirred at ambient temperature for 24 h. The reaction was diluted with diethyl ether (100 mL) then filtered through diatomaceous earth to remove suspended solids. Rotary evaporation of the solution afforded a yellow solid that was triturated with diethyl ether and collected by filtration. The solid was rinsed on the filter with additional diethyl ether to afford pure title compound (3.920 g, 77%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ4.00 (d, 1H, J=1.8 Hz), 4.22 (d, 1H, J=1.8 Hz), 6.80 (m, 1H), 6.87-7.00 (m, 2H), 7.40 (s, 5H), 7.95 (d, 1H, J=7.9 Hz), 9.27 (s, 1H), 9.97 (s, 1H). 13C-DEPT NMR (75 MHz, DMSO-d6) δ57.7 (CH), 58.4 (CH), 115.5 (CH), 119.4 (CH), 121.6 (CH), 125.1 (CH), 125.8 (C), 126.5 (CH), 128.9 (CH), 129.1 (CH), 135.9 (C), 147.7 (C), 165.4 (C). MS APCI, m/z=256 (M+1). LC/MS: 2.12 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([C:30]2[CH:43]=[CH:42][C:33]3[N:34]=[C:35]([CH2:37][C:38]([NH:40][NH2:41])=O)[S:36][C:32]=3[CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:19]([O:18][C:16]([NH:15][C@@H:10]([CH2:11][C:12]1[O:14][C:38]([CH2:37][C:35]2[S:36][C:32]3[CH:31]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:43]=[CH:42][C:33]=3[N:34]=2)=[N:40][N:41]=1)[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: NNC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Yield: 42 %

Procedure:
Compound 45a was prepared from (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid and 2-(6-phenylbenzo[d]thiazol-2-yl)acetohydrazide (described in WO 2011/074560) in 42% yield as a yellow solid using the general procedure given for Compound 1b. LCMS=1.13 min using analytical method (M), 571.2 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.19-7.95 (m, 2H), 7.79-7.55 (m, 3H), 7.47 (t, J=7.7 Hz, 2H), 7.42-7.27 (m, 6H), 5.56 (d, J=7.0 Hz, 1H), 5.14 (s, 2H), 4.79 (br. s., 1H), 4.65 (s, 2H), 3.52-3.23 (m, 2H), 1.49-1.32 (m, 9H).
Reaction SMILES: C(O[CH2:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:11]([OH:13])=[O:12])C1C=CC=CC=1.CC[OH:21]>[Pd]>[OH:21][CH:16]([CH2:17][CH3:18])[CH2:15][CH2:14][C@@H:10]([CH3:9])[C:11]([OH:13])=[O:12]
Reactant: CCCCC[C@H](COCc1ccccc1)C(=O)O
Reactant: CCO
Agent: [Pd]
Product: CCC(O)CC[C@@H](C)C(=O)O
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (R)-3-benzyloxy-2-pentyl-propionic acid (1.54 g, 6.16 mmol) in EtOH (100 mL) was added 10% Pd/C (310 mg). The reaction mixture was subjected to hydrogenation overnight at room temperature. After the reaction was completed, the reaction mixture was filtered through a pad of Celite, and washed with EtOH (50 mL×3). Removal of the solvent provided the title compound (0.92 g, 93%). No further purification was required. 1H NMR (400 MHz, CHCl3) δ 6.30 (br s, 1H), 3.81 (d, J=5.4 Hz, 2H), 2.64 (m, 1H), 1.69 (m, 1H), 1.56 (m, 1H), 1.41–1.27 (m, 6H), 0.91 (t, J=7.7 Hz, 3H). Mass spectrum ES+: 161 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([O:20]C)=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:37]=[CH:36][C:28]([CH2:29][N:30]2[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]2)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[CH:34]=[C:33]([NH:35][C:18]([C:14]3[N:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])[CH:17]=[CH:16][CH:15]=3)=[O:20])[CH:32]=[N:31]2)=[CH:36][CH:37]=1
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: COc1ccc(Cn2cc(N)cn2)cc1
Product: COc1ccc(Cn2cc(NC(=O)c3cccn3NC(=O)[C@H](C)NC(=O)OC(C)(C)C)cn2)cc1
Yield: 73 %

Procedure:
This compound was prepared starting from (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 2.89 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-4-amine (1.24 g, 6.10 mmol) following the experimental procedure described in Preparation 27a to afford 1.02 g (100% purity, 73% yield) of the title compound after purification by flash chromatography (0% to 100% AcOEt/hexanes).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH3:5][P:6](=O)([O:10]CC)[O:7][CH2:8][CH3:9]>>[C:3]([CH2:2][P:6]([CH3:5])(=[O:10])[O:7][CH2:8][CH3:9])#[N:4]
Reactant: CCOP(C)(=O)OCC
Reactant: N#CCCl
Product: CCOP(C)(=O)CC#N
Temperature: 125 °C
Yield: 95 %

Procedure:
226.5 g (3 mol) of chloroacetonitrile were heated to 60° C. 470 g (3.53 mol) of diethyl methylphosphonate were added dropwise over a period of 3 hours at 70° to 80° C. During this step heating was not necessary; the reaction was exothermic. Ethyl chloride was collected in a down-stream cold trap. After the dropwise addition was finished, the mixture was slowly heated to 125° C. and kept at this temperature until no more waste gas (ethyl chloride) could be detected. The mixture was subsequently cooled and distilled through a column under an aspirator vacuum to give 418 g of ethyl cyanomethtylmethylphosphinate (b.p. 108°-109° C., 0.0133 kPa). This correspnds to a yield of 95% of theory, based on the amount of chloroacetonitrile used. ##STR4##
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[NH2:7][C@H:8]([C:14]([NH2:16])=[O:15])[CH2:9][CH2:10][C:11](=[O:13])[NH2:12].C(=O)([O-])[O-].[K+].[K+].N[C@H](C(N)=O)CCC(=O)N>O.C(OCC)C>[C:1]([NH:16][C:14](=[O:15])[C@H:8]([CH2:9][CH2:10][C:11](=[O:13])[NH2:12])[NH2:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: NC(=O)CC[C@H](N)C(N)=O
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: C=CC(=O)NC(=O)[C@@H](N)CCC(N)=O
Reaction time: 0.17 h

Procedure:
A 5 ml portion of acrylic acid chloride and 200 ml of diethyl ether were put into a 500 ml capacity eggplant type flask and stirred on an ice bath. Next, 2 g of glutamineamide hydrochloride (mfd. by Kokusan Kagaku) was dissolved in 25 ml of deionized water, and 3 g of potassium carbonate was dissolved in 25 ml of deionized water. The glutamineamide aqueous solution was mixed with the potassium carbonate aqueous solution. The mixed liquid was added dropwise into the eggplant type flask spending 10 minutes while stirring constantly, and the mixture after completion of the dropwise addition was stirred for 24 hours. Diethyl ether layer in the thus obtained reaction liquid was discarded, and the water layer was concentrated at 25° C. under a reduced pressure. A 500 ml portion of acetone was added to the thus obtained residue and stirred for 1 hour. The insoluble solids were removed by suction filtration. By recrystallizing from the acetone layer, 0.25 g of colorless crystals were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:20]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[CH3:19])[CH2:23][CH2:22][CH2:21]1
Reactant: Cc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-methylphenyl]acetic acid (0.5 g, 1.951 mmol) was dissolved in DMF (1 ml) and azetidine (0.167 g, 2.93 mmol), DIEA (0.511 ml, 2.93 mmol), and HATU (1.484 g, 3.90 mmol) added. The mixture was stirred at RT for 1 hr. The reside was purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. to afford the title compound. LC/MS (m/z): 296 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)=[O:4].[NH3:27]>CO.ClCCl>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[CH2:17][C:16]1[C:7]2[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=2[NH:5][C:3](=[O:4])[CH2:2][N:27]=1
Reactant: N
Reactant: COc1cc(NC(=O)CBr)c(C(=O)Cc2ccc(Cl)c(Cl)c2)cc1OC
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(Cc1ccc(Cl)c(Cl)c1)=NCC(=O)N2
Temperature: 40 °C
Yield: 35 %

Procedure:
2-Bromo-N-{2-[2-(3,4-dichloro-phenyl)-acetyl]-4,5-dimethoxy-phenyl}-acetamide (5.25 g, 11.39 mmol) was placed at −10° C. under nitrogen. Ammonia in methanol (7N, 55 ml) was added dropwise at −10° C. and the reaction mixture was heated at 40° C. for 2.5 h, and then at reflux (75° C.) for 1 h. The solvent was evaporated under vacuum yielding a yellow solid which was dissolved in dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. Flashchromatography (dichloromethane/methanol, 18/1) yielded the expected product as a yellow solid (1.5 g, 35%).