Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23]>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:25][CH2:21][CH:22]([CH3:24])[CH3:23])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: CC(C)CN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCC(C)C)c1C
Yield: 55.3 %

Procedure:
A solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (40.0 g, 181 mmol), triethylamine (26.5 mL, 190 mmol), and isobutyl amine (18.9 mL, 190 mmol) in N,N-dimethylformamide (500 mL) was stirred at room temperature over night. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL) and washed with water (3×80 mL) and brine (40 mL). The aqueous was extracted with ethyl acetate (3×50 mL) and the back-extracts washed with water (3×40 mL) and brine (30 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPFC eluting with a gradient of 10-30% ethyl acetate in hexanes to give 25.8 g of 2-chloro-N-isobutyl-5,6-dimethyl-3-nitropyridin-4-amine as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[NH:26][C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30].[CH3:36][NH:37][CH3:38]>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:24])[N:37]([CH3:38])[CH3:36])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:11]=[CH:10][C:9]=1[NH:26][C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:30])([F:31])[F:32]
Reactant: CNC
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 5 h

Procedure:
Oxalyl chloride (0.45 ml) was added to a stirred suspension of (R)-N-[2-chloro-4-(4-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 121) (1.81 g) in DCM (100 ml) containing DMF (10 drops). The mixture was stirred for 5 hours and then a solution of dimethylamine (4.2 ml, 2M solution in methanol) was added, and the solution was stirred overnight. The reaction mixture was washed with dilute hydrochloric acid solution (2×25 ml) then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-10% methanol/DCM to yield the title compound (0.68 g) as a solid. M.p. 120.5° C. (Mettler FP62 apparatus); NMR: (CDCl3): 1.70 (s, 3H), 2.90 (s, 3H), 3.10 (s, 3H), 5.20 (s, 1H), 7.5 (d, 2H), 7.85 (d, 1H), 7.90-8.00 (m, 3H), 8.60 (d, 1H), 9.40 (s, 1H); MS (ESP−): 477.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: CC(C)(C)OC(=O)CCBr
Product: CCOC(CNCCC(=O)OC(C)(C)C)OCC
Yield: 25 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2,2-diethoxyethanamine (5.82 ml, (40 mmol) was reacted with tert-butyl 3-bromopropionate (3.34 ml, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform only) to obtain the title compound (1.33 g, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:10][CH:6]([C:5]1[CH:11]=[CH:12][C:2]([Br:1])=[CH:3][CH:4]=1)[C:7]([OH:9])=[O:8])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: CC(=O)OC(C(=O)O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 4-bromomandelic acid (20.6 g, 89.0 mmol) dissolved in pyridine (50 mL) was added acetic anhydride (10 g, 98 mmol) dropwise while cooling with an ice bath. After stirring overnight at room temperature, the solvent was removed and the resulting residue dissolved in ethyl acetate (150 mL). This was washed twice with 1N HCl, brine, and then concentrated in vacuo to obtain a white solid (18.2 g, 75%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O=[C:23]([CH2:27][CH2:28][CH3:29])[C:24]([OH:26])=[O:25]>C(O)C.[Pd]>[CH2:8]([C:7]1[C:2]([NH:1][CH:23]([CH2:27][CH2:28][CH3:29])[C:24]([OH:26])=[O:25])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Reactant: CCCC(=O)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCCC(Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
4-(5-amino-6-benzylpyrazin-2-yl)phenol (100 mg, 0.36 mmol) was mixed with 2-Oxovaleric acid (84 mg, 0.72 mmol) in ethanol (20 mL). Pd/C (10% Palladium in active carbon, 40 mg) was added, and the reaction mixture heated to 65° C. Air was bubbled out by N2 gas, and a hydrogen balloon applied to the reaction flask. The reaction was continuously stirred for 4 hrs. After cooling down, it was filtered, and the resulting solution purified by flash chromatography (eluting solvent: 50% EtOAc in heptanes) to give the product as a yellow powder (70 mg, 52%). 1H NMR (300 MHz, CD2Cl2, δ): 8.31 (s, 1H), 7.82 (d, 2H, J=9.0 Hz), 7.31 (m, 5H), 6.92 (d, 2H, J=9.0 Hz), 5.34 (s, 2H), 4.20 (m, 1H), 1.10 (m, 2H), 0.98 (m, 2H), 0.87 (t, 3H); MS (ESI) m/z 378.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH2:7][OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH2:7][O:8][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nnsc1CO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nnsc1COCc1ccccc1
Reaction time: 10 h
Yield: 95.2 %

Procedure:
In 10 ml of acetone was dissolved 0.40 g (3.1 mmol) of 4-methyl-1,2,3-thiadiazol-5-ylmethanol. After adding 1.6 g (12 mmol) of potassium carbonate and 0.80 g (4.5 mmol) of benzyl bromide, the resulting mixture was stirred for 10 hours with heating under reflux. After the reaction was completed, the insoluble matter was filtered off, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.65 g of the objective compound was obtained.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=1[OH:29])[CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[C:23]([C@@H:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[CH:26]=[CH:27][C:28]([OH:29])=[C:17]([Cl:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-chloro-4-hydroxy-L-phenylalanine to provide the title compound in good yield.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:24])=[C:13]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][OH:23])[C:14]=3F)[C:9](=[O:25])[C:8]([C:26]([OH:28])=[O:27])=[CH:7]2)[CH2:5][CH2:4]1.[H][H]>CN(C=O)C>[CH:3]1([N:6]2[C:15]3[C:14]4[O:23][CH2:22][C@@H:18]5[CH2:19][CH2:20][CH2:21][N:17]5[C:13]=4[C:12]([F:24])=[CH:11][C:10]=3[C:9](=[O:25])[C:8]([C:26]([OH:28])=[O:27])=[CH:7]2)[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC[C@H]3CO)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c3c(c(F)cc2c1=O)N1CCC[C@H]1CO3

Procedure:
9.2 mg of a 55% sodium hydride dispersion were added to a solution of 0.364 g (1 mmol) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[(S)-2-hydroxymethyl-1-pyrrolidinyl]-4-oxoquinoline-3-carboxylic acid in 8 ml of DMF. After completion of the hydrogen evolution, the mixture was stirred at 140° C. for 35 minutes, the solvent was evaporated, the residue was taken up in water, adjusted to pH 6 with glacial acetic acid and suction filtered. Crystallization from ethanol gave (S)-4-cyclopropyl-11-fluoro-1,4,6a,7,8,9-hexahydro-1-oxo-6H-pyrrolo[1',2':4,5][1,4]oxazino[3,2-h]quinoline-2-carboxylic acid, m.p. >275° C. (dec.), MS: 344 (M+, 58%), 300 (100), 271 (12), 245 (8), 216 (17), 189 (4), 158 (4), 41 (24).
Reaction SMILES: [ClH:1].C([NH:10][CH:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])(=O)C1C=CC=CC=1.C(O)C>O>[ClH:1].[NH2:10][CH:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]([OH:17])[C:13]([F:14])([F:15])[F:16]
Reactant: O=C(NC(Cc1ccccc1)C(O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
12 N Hydrochloric acid is added to a suspension of (2RS, 3RS)-3-benzoylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane (3.00 g, Reference compound No. 31-1), ethanol (60 ml) and water (60 ml), and the mixture is refluxed for one day. After standing, the reaction mixture is concentrated under reduced pressure, diethyl ether is added to the resulting residue, and the whole is extracted with water. The extract is concentrated under reduced pressure to give the titled reference compound (1.58 g).
Reaction SMILES: [CH:1]1([CH2:5][N:6]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[C@H:7]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:4][CH2:3][CH2:2]1.[ClH:31]>O1CCOCC1.CCOCC>[ClH:31].[CH:1]1([CH2:5][N:6]([C@H:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(CC2CCC2)C(=O)c2ccccc2C(F)(F)F)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(c1ccccc1C(F)(F)F)N(CC1CCC1)[C@H]1CCNC1
Reaction time: 1 h
Yield: 86 %

Procedure:
Tert-butyl (3S)-3-{(cyclobutylmethyl) [2-(trifluoromethyl) benzoyl]amino}pyrrolidine-1-carboxylate from preparation 28 (1.40 g, 3.3 mmol) was dissolved in 4N hydrogen chloride in Dioxane. The solution was stirred for 1 hour and the solvent removed under reduced pressure. The residue was dissolved in water and the solution washed with ether. The aqueous phase was basified by adding aqueous NaOH and extracted with ether. This ether phase was dried over Magnesium Sulfate, filtered and the solvent removed under reduced pressure to afford a gum, which was treated with 2N hydrogen chloride in ether, to afford 0.99 g (86%) of the title compound as a white foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.[NH3:32]>>[O:11]=[C:9]1[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][C:2]([NH2:32])=[O:1])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:10]1
Reactant: N
Reactant: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one using a procedure analogous to that described in Example 12 Step 2, followed by a procedure analogous to that described in Example 8 Step 2 using ammonia. LC-MS Method 2 tR=1.381 min, m/z=430.2; 1H NMR (CDCl3) 1.56 (m, 3H), 1.92-2.03 (m, 3H), 2.18-2.37 (m, 5H), 2.51 (m, 1H), 2.94 (m, 1H), 5.29-5.61 (m, 2H), 5.71 (m, 1H), 7.03 (m, 2H), 7.21-7.38 (m, 8H), 7.77 (m, 1H), 8.53 (m, 1H), 8.72 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH3:13]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)NC(=O)C2C
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−78° C.) of 6-methoxy-1,3-dihydro-indol-2-one (840 mg, 5.2 mmol, see Quallich, G. J.; Morrissey, P. M. Synthesis 1993, 51-53) in THF (20 mL) is added dropwise TMEDA (1.57 mL, 10.4 mL) followed by dropwise addition of 2.5M n-BuLi (4.16 mL, 10.4 mmol). The mixture is stirred for 15 min then warmed to −25° C. Add dropwise iodomethane (405 μL, 6.5 mmol) and let stir for 20 min. The reaction is quenched with sat NH4Cl soln, warmed to room temp and diluted with EtOAc. The organic layer is washed with sat NH4Cl soln, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 45% ethyl acetate/hexanes) to give 679 mg of title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:10]([CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[O:27]1[C:31](B(O)O)=[CH:30][C:29]2[CH:35]=[CH:36][CH:37]=[CH:38][C:28]1=2>>[O:27]1[C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[CH:30]=[C:31]1[C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[C:12]([CH3:13])=[C:11]([C:14]([N:16]2[CH2:20][CH2:19][CH:18]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:17]2)=[O:15])[C:10]([CH3:26])=[N:9]1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(Br)c3)c2C)C1
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3ccccc3-c3cc4ccccc4o3)c2C)C1
Yield: 68 %

Procedure:
In analogy to the procedure described in Example 14C], [1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and benzo[b]furan-2-boronic acid gave the title compound in 68% yield as light brown foam. MS: 457.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].F[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)[C:11]([F:12])([F:13])[F:14])[O:8][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[C:32]([C:38]([F:39])([F:41])[F:40])[CH:31]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(c1ccc(Oc2ccc(C=O)c(C(F)(F)F)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.5 %

Procedure:
To a solution of 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (100 mg, 0.24 mmol, Example 56, step 4) in N′N-dimethylacetamide (1.5 ml) were added 4-fluoro-2-(trifluoromethyl)benzaldehyde (69 mg, 0.36 mmol) and cesium carbonate (234 mg, 0.72 mmol). The mixture was stirred for 17 h at room temperature. Ice water was added and the mixture was extracted with AcOEt. The organic phase was washed with water, dried (MgSO4) and concentrated. The product was purified by column chromatography (silica gel, heptane/AcOEt 3:1) to give the title compound (91 mg) as white foam. MS (m/e, ISP neg. ion)=586.2 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:12][CH:13]2[CH2:15][CH:14]2[CH2:16][CH3:17])=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:20]([N:22]=[C:23]=[S:24])[CH3:21]>CN(C)C=O>[Cl:1][C:2]1[C:7](/[C:8](/[NH:12][CH:13]2[CH2:15][CH:14]2[CH2:16][CH3:17])=[C:9](\[C:10]#[N:11])/[C:23](=[S:24])[NH:22][CH2:20][CH3:21])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCN=C=S
Reactant: CCC1CC1NC(=CC#N)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=S)/C(C#N)=C(\NC1CC1CC)c1cccnc1Cl
Reaction time: 1 h
Yield: 29.1 %

Procedure:
A solution of 3-(2-chloropyridin-3-yl)-3-[(2-ethylcyclopropyl)amino]acrylonitrile (0.15 g, 0.606 mmol, 1 eq.) in 2 ml of dimethyl formamide (DMF) was treated with NaH (60% in mineral oil, 0.029 g, 0.727 mmol, 1.2 eq.) and stirring allowed for 1 h. ethylisothiocyanate (0.105 g, 1.21 mmol, 2 eq.) was added and stirring continued overnight. The reaction was quenched with water and extracted with AcOEt. The organic layers were combined, dried over MgSO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel to give (2Z)-3-(2-chloropyridin-3-yl)-2-cyano-N-ethyl-3-[(2-ethylcyclopropyl)amino]-prop-2-enethioamide (0.059 g, 27% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:24][C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]([OH:23])=O)[C:15]=2[CH:14]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:58][C:59]([CH3:63])([CH3:62])[CH2:60][OH:61]>CN(C)C=O>[OH:61][CH2:60][C:59]([NH:58][C:21]([C:20]1[C:15]2[CH:14]=[C:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[NH:24][C:16]=2[N:17]=[CH:18][CH:19]=1)=[O:23])([CH3:63])[CH3:62]
Reactant: CC(C)(N)CO
Reactant: COc1ccc2c(c1)c(-c1cc3c(C(=O)O)ccnc3[nH]1)cn2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(-c1cc3c(C(=O)NC(C)(C)CO)ccnc3[nH]1)cn2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4 carboxylic acid [32 mg, Example 41(a)] in dry dimethylformamide (10 mL), under nitrogen, was treated with diisopropylethylamine (35 μL) followed by O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (38 mg). After stirring at room temperature for 1 hour this mixture was treated with a solution of 2-amino-2-methyl-1-propanol (10.5 μL) in dry dimethylformamide (1 mL) and stirring was then continued for a further 2 hours. The reaction mixture was evaporated and the residue was treated with saturated aqueous sodium bicarbonate solution (15 mL). This mixture was stirred for 1 hour and the resulting yellow solid was filtered, then washed well with water and then dried at 100° C. under vacuum to give the title compound (34 mg) as a yellow solid, m.p. 210-212° C.
Reaction SMILES: C([C:3]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:4]=1[O:5][C:6]1[C:14]2[N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:11][C:10]=2[CH:9]=[C:8]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:7]=1)#N.FC1C(F)=CC=C[C:39]=1[S:45](C)(=[O:47])=[O:46]>>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:3]([S:45]([CH3:39])(=[O:47])=[O:46])[C:4]=1[O:5][C:6]1[C:14]2[N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:11][C:10]=2[CH:9]=[C:8]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1cccc(F)c1F
Reactant: CS(=O)(=O)c1ccc(Oc2cc(Oc3c(F)cccc3C#N)c3nc(-c4ccccn4)[nH]c3c2)cn1
Product: CS(=O)(=O)c1ccc(Oc2cc(Oc3c(F)cccc3S(C)(=O)=O)c3nc(-c4ccccn4)[nH]c3c2)cn1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 438 (step 2) or in accordance with the method or by combining it with an ordinary method but using 4-hydroxy-6-(6-methanesulfonyl-pyridin-3-yloxy)-2-pyridin-2-yl-1H-benzimidazole obtained in Example 447 and 2,3-difluoro-methanesulfonylbenzene.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:23])(P(=O)(OC)OC)P(=O)(OC)OC)[CH:6]=[CH:7][CH:8]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:26]([NH:33][C:10](=[O:23])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: COP(=O)(OC)C(O)(Cc1cccc([Si](C)(C)C)c1)P(=O)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)NCc1ccccc1
Reaction time: 2 h

Procedure:
The iodo derivative 53 was hydrolysed as described under general procedures to give the title compound as an orange colored powder in quantitative yield. Reaction of dimethyl phenylacetylphosphonate (50b) with benzylamine To a solution of the phosphonate 50b in CHCl3 (5 ml) was added molecular sieves (4A, 0.25 g) followed by benzylamine (0.11 g, 1 mmol). After 0.5 h a catalytic amount of TsOH was added and the mixture was stirred for 2 h. The mixture was filtered and flash chromatography (silica, 3:7 EtOAc/hexane) of the filtrate provided N-benzylphenylacetamide (61), as determined by comparison with an authentic sample.
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:4]=1.[H-].[Na+].[CH:22](OC)=[O:23]>CN(C=O)C>[OH:23][CH:22]=[C:15]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:4]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CN(C)c1cccc(-c2ccccc2)c1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)N(C)c1cccc(-c2ccccc2)c1
Yield: 12.5 %

Procedure:
Methyl (N-methyl-3-phenylanilino)acetate (4.33 g) was formylated as described in Example 1 by treatment with sodium hydride (0.94 g) and methyl formate (21.01 g) in DMF (50 ml) to give methyl 3-hydroxy-2-(N-methyl-3'-phenylanilino)propenoate (0.60 g) as a brown viscous liquid. Methylation with dimethyl sulphate (0.59 g) and potassium carbonate (0.62 g) in DMF (25 ml) for 5 hours afforded on work-up and HpLC (eluent petroleum ether--ether, 70:30) on silica gel a pure sample of the title compound (260 mg) as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(CC1CCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
A solution of nickel (II) chloride hexahydrate (78 mg, 0.328 mmol) and (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid methyl ester (295 mg, 0.82 mmol) in methanol (8 mL) was cooled to 0° C. and then treated with sodium borohydride (186 mg, 4.92 mmol) in four portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 24 h. The reaction mixture was then concentrated in vacuo, and the residue was diluted with water (30 mL) and ethyl acetate (50 mL). The two layers were separated. The organic layer was washed successively with a 3N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid methyl ester (285 mg, 96%) as a viscous oil: EI-HRMS m/e calcd for C18H23ClN4O2 (M+) 362.1509, found 362.1516.