Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:26]=[O:27])C>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:26]=[O:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCCc3ccccc32)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCCN2Cc1ccccc1

Procedure:
The procedure was carried out as described previously in step (a) of Example 5 with Compound 5 (0.42 g, 1.88 mmol), POCl3 (355 μL, 3.76 mmol), and DMF (3.5 mL). Compound 6 was obtained (0.36 g) as a viscous liquid and used without any further purification. The structure of Compound 6 is given below:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][C@H:14]([C:25]([OH:27])=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.N1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:13][C@@H:14]([C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:17]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H](C(=O)O)C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(3R,5S)-5-{[(Benzyloxy)carbonyl]amino}-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (49.2 g), morpholine (11.4 ml), 1H-benzotriazol-1-ol (10.0 g) and triethylamine (40 ml) were dissolved in DMF (250 ml), WSC.HCl (30.0 g) was added and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (62.9 g).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH:24]3[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:26]([CH3:40])([CH3:39])[CH2:25]3)[CH2:10][C:9]2([CH3:42])[CH3:41])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[P:44]1[O:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][O:45]1>>[CH3:50][C:47]1([CH3:51])[CH2:48][O:49][P:44]([N:23]([CH:24]2[CH2:25][C:26]([CH3:40])([CH3:39])[N:27]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:28]([CH3:30])([CH3:31])[CH2:29]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([P:44]2[O:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][O:45]2)[CH:11]2[CH2:12][C:13]([CH3:15])([CH3:14])[N:8]([O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]([CH3:42])([CH3:41])[CH2:10]2)[O:45][CH2:46]1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Reactant: CC1(C)COP(Cl)OC1
Product: CC1(C)COP(N(CCCCCCN(C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)P2OCC(C)(C)CO2)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)OC1

Procedure:
The title compound is prepared from N,N'-bis(1-cyclohexyloxy-2, 2,6,6-tetramethylpiperidin-4-yl)hexamethylenediamine and 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane according to the procedure of Example 11C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[CH2:4][C:5]([CH:7]=[O:8])=O.[CH2:14]1N2CN3CN(C2)C[N:15]1C3.C([O-])(=O)C.[NH4+]>C(N)=O>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[CH2:4][C:5]1[N:15]=[CH:14][O:8][CH:7]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=CC(=O)Cc1c(Cl)cccc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: NC=O
Product: Clc1cccc(Cl)c1Cc1cocn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
21.7 g of crude 2,6-dichlorobenzylglyoxal are dissolved in 50 ml of formamide. 7.0 g of hexamethylenetetramine and 30.8 g of ammonium acetate are added and the reaction mixture is stirred at 100° C. for 2 hours, then is evaporated to dryness in vacuo. 200 ml of water are added and the pH of the aqueous phase is adjusted, while stirring, to 2-3 with concentrate hydrochloric acid. The solution is washed with toluene (3×50 ml). The aqueous solution is made alkaline with sodium hydroxide (pH=8-9) and then extracted three times with chloroform (1×100 ml and 2×50 ml). The combined chloroform extracts are washed with water, dried with sodium sulfate and evaporated to dryness. The residue, which consisted of crude product, is used in step (c) below.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5](F)[CH:4]=1)#[N:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1)#[N:2]
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C=O)c(Oc2ccccc2)c1
Temperature: 120 °C

Procedure:
A stirred mixture of 4-cyano-2-fluorobenzaldehyde (2.23 g, 15 mmol), phenol (1.6 g, 17 mmol) and potassium carbonate (2.35 g, 17 mmol) in dried dimethylformamide (15 ml) was heated to 120° C. for 1 hour. After cooling, the mixture was diluted with water (50 ml) and extracted with diethyl ether (2×25 ml). The extracts were washed with 0.1M sodium hydroxide (2×50 ml), brine (50 ml), dried, filtered and evaporated to a yellow oil. Flash chromatography on silica, eluting with diethyl ether:hexane 1:1, gave 4-cyano-2-phenoxybenzaldehyde as a yellow oil that crystallised on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O.Cl[C:20]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:20]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S)cc1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1nccc(-c2cccnc2Sc2ccc(N)cc2)n1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
To 4-aminothiophenol (1.70 g, 13.6 mmol) and Cs2CO3 (8.90 g, 27.2 mmol) was added DMSO (18 mL). The mixture was stirred for 5 minutes at 100° C. before 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (3.00 g, 13.6 mmol) was added. The resulting mixture was stirred for 16 hours at 130° C., then diluted with water and the resulting solid filtered. After washing the solid with water and Et2O it was dried under vacuum to yield the desired product as a tan solid. MS m/z=310 [M+1]+. Calc'd for C16H15N3S: 309.40.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[C:13]([CH:14]=1)=[C:12]([C:15]#[N:16])[CH:11]=[CH:10]2)=[O:5])C.[OH-].[Li+].Cl>O1CCCC1.C(O)C.O>[C:15]([C:12]1[CH:11]=[CH:10][N:9]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[CH:8]2)#[N:16]
Reactant: CCOC(=O)c1ccn2ccc(C#N)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: N#Cc1ccn2ccc(C(=O)O)cc12
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a mixed solution of 1-cyanoindolizine-7-carboxylic acid ethyl ester (0.42 g) in tetrahydrofuran (4.2 mL), ethanol (2.1 mL) and water (2.1 mL) was added lithium hydroxide (0.25 g) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was acidified with 2 mol/L hydrochloric acid, and a precipitated solid was collected by filtration. This solid was washed with water and n-hexane to give 1-cyanoindolizine-7-carboxylic acid (0.29 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:16][C:15]=3[CH:25]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28].C(Cl)Cl.O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][N:22]([S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:21][CH2:20]4)=[N:16][C:15]=3[CH:25]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)cc1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 7.8 %

Procedure:
Intermediate 25 (80 mg, 0.24 mmol) was dissolved in DCM (10 ml) and added TEA (35 mg, 0.35 mmol). This mixture was stirred at rt for 15 mins Reaction mixture cooled to 0° C. and added propane-1-sulphonylchloride (33 mg, 0.23 mmol). Reaction mixture stirred at rt for 2 h. Work up (DCM/H2O) afforded the crude product. Crude was purified by column chromatography on 60-120 mesh silica gel using a gradient mixture of EtOAC and Petether (70:30) as eluent to afford the titled compound (8 mg) as a white solid. M.P.: 222-225° C. 1H-NMR NMR (δ ppm, DMSO-d6, 400 MHz): 8.09 (d, J 1.3, 1H), 7.82-7.72 (m, 3H), 7.71-7.61 (m, 4H), 3.67-3.58 (m, 2H), 3.30-3.22 (m, 2H), 3.09-2.99 (m, 2H), 2.25-2.16 (m, 2H), 1.92-1.79 (m, 2H), 1.69 (hextet, J 7.6, 2H), 0.98 (t, J 7.4, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:16]2[NH:17][C:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[N:20]=2)=[C:4]([O:37][CH2:38][CH3:39])[CH:3]=1.[C:40](Cl)([Cl:42])=[O:41]>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)(=[O:9])=[O:10])=[CH:6][C:5]([C:16]2[N:17]([C:40]([Cl:42])=[O:41])[C:18]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([CH3:29])[C:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([CH3:21])[N:20]=2)=[C:4]([O:37][CH2:38][CH3:39])[CH:3]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(Cl)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-[4-chloro-2-ethoxy-5-(pyrrolidine-1-sulfonyl)phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (example 53) was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]1[C:13]2[CH2:12][CH2:11][CH2:10][N+:9]=2[CH2:8][CH2:7]1.[C:14]([Mg]Br)#[CH:15]>C1COCC1>[C:14]([C:13]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2)#[CH:15]
Reactant: C1CC2=[N+](C1)CCC2
Reactant: C#C[Mg]Br
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C#CC12CCCN1CCC2
Reaction time: 0.75 h
Yield: 71 %

Procedure:
The compound from step 15a above (1.0 g, 4.8 mmol) was added to a solution of 0.5 M ethynylmagnesium bromide (29 mL, 14.3 mmol) in THF at room temperature. The reaction mixture was stirred for 45 minutes, quenched with 15% NaOH solution, and diluted with brine:water (1:1). The aqueous phase was extracted with CH2Cl2, and the organic phases were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 /MeOH, 90:10) to afford an amber oil (463 mg, 71%): 1H NMR (CDCl3, 300 MHz) δ 1.75-2.06 (m, 6H), 2.14-2.23 (m, 2H), 2.33 (s, 1H), 2.53-2.62 (m, 2H), 322-3.28 (m, 2H); MS (CI/NH3) m/z: 136 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH3:25])=[O:5])C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:4](=[O:5])[C:6]3[CH:7]=[N:8][C:9]4[C:10]([O:24][CH3:25])=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[N:16]([CH:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[C:34]2=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(C)CC1
Reactant: O=C=Nc1cccc(Cl)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCC(C)CC3)c12
Yield: 58.1 %

Procedure:
3-(3-Chloro-phenyl)-7-methoxy-1-(4-methyl-cyclohexyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (115 mg) was prepared from 8-methoxy-4-(4-methyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (150 mg, 0.44 mmol) and 1-chloro-3-isocyanato-benzene (0.66 mmol) following general procedure C. LCMS: m/z 450 [M+1]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([F:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(F)c1
Agent: Cl
Product: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(F)c1
Yield: 55 %

Procedure:
The title compound is prepared in 55% yield (142 mg, a white solid) from (−)-1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (197 mg, 0.72 mmol, Amine-12, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([CH3:29])[S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]=[CH:6][C@@H:7]([NH:21]C(OC(C)(C)C)=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(N(CC)C(C)C)(C)C.FC(S(O[CH2:59][P:60]([O:64][CH3:65])([O:62][CH3:63])=[O:61])(=O)=O)(F)F>C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:29])[CH:5]=[CH:6][C@@H:7]([NH:21][CH2:59][P:60]([O:64][CH3:65])([O:62][CH3:63])=[O:61])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: COP(=O)(COS(=O)(=O)C(F)(F)F)OC
Reactant: CCOC(=O)C=C[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C=C[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(S)-4-t-Butoxycarbonylamino-5-(biphenyl-4-yl)-pentenoic acid ethyl ester (1.2 g, 3.03 mmol) is stirred for 1 hour in a 1/1 mixture of trifluoroacetic acid and methylene chloride (10 mL). A saturated aqueous solution of sodium bicarbonate (10 mL) is added and the product is extracted in methylene chloride (20 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and cooled to 0° under nitrogen. To that solution is added N,N-diisopropylethylamine (0.633 mL, 3.63 mmol) in methylene chloride (2 mL), followed by a solution of dimethylphosphonomethyl trifiuoromethylsulfonate (Tetrahedron Lett., 1986, 1477; 907 mg, 3.33 mmol) in methylene chloride (2 mL). The mixture is stirred at room temperature for 18 hours. Water (20 mL) and methylene chloride (20 mL) are added. The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel, eluting with ethyl acetate to afford (S)-5-(biphenyl-4-yl)-4-[(dimethylphosphonomethyl)-amino]-2-pentenoic acid ethyl ester as a pale yellow oil (Rf=0.3 in EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([OH:30])[CH2:28][NH2:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:29][CH2:28][CH:27]([OH:30])[CH3:26])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and DL-1-amino-2-propanol employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.81 (1H, t, J=5.6 Hz), 10.81 (1H, br s), 10.10 (1H, br s), 8.18 (0.48H, s), 8.14 (052.H, s), 7.36-7.23 (3H, m), 7.14-7.08 (2H, m), 4.74 (1H, t, J=4 Hz), 3.98 (2H, s), 3.75-3.65 (1H, m), 3.29-3.15 (2H, m), 1.07-1.04 (3H, m); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found 372.1364.
Reaction SMILES: [Cl:1][C:2]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[CH3:40][NH2:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.CC(O)=O>[Cl:1][C:2]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:41][CH3:40])=[CH:12][CH:11]=1
Reactant: CN
Reactant: O=Cc1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCc1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 16.9 %

Procedure:
A solution of 4-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzaldehyde, (0.0443 g, 0.080 mmol) in dichloromethane (1 ml) and AcOH (00.1 mL), was treated with CH3NH2 (40% solution in H2O, 0.073 mmol) at ambient temperature. To the mixture was added NaBH(OAc)3 (0.017 g, 0.080 mmol), and the reaction was stirred overnight. The reaction mixture was then concentrated, in vacuo, to an oil, which was then dissolved in DMSO and purified via reverse-phase HPLC to afford the title compound (0.007 g, 15%); MS (ES+) m/e 568 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](C2C=CC=CC=2C(O)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])#[N:2].[OH:24]O>C1COCC1>[OH:24][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: OO
Reactant: CC[C@H](C)COc1ccc(-c2ccccc2C(=O)O)cc1C#N
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc(O)cc1C#N

Procedure:
A mixture of compound 47 (3.00 g, 0.014 mol), hydrogen peroxide (30%, w/v, 150 ml) and THF (200 ml) was heated under reflux for 3 h. The water/THF mixture was removed in vacuo and the oily residue was dissolved in diethyl ether and washed with water. The ether was dried (MgSO4) and evaporated in vacuo to give a viscous, fawn oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:18](=[S:20])=[S:19]>CS(C)=O.O>[OH:15][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]([C:18]([SH:20])=[S:19])=[CH:8][C:7]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
The compound 4-hydroxy-3,5-di-tert.-butyl dithiobenzoic acid was prepared by dissolving 2,6 -di-tert.-butyl phenol (20.6 g) in dimethylsulfoxide (60 cm3). To this well stirred solution under a nitrogen blanket was added KOH (5.6 g) dissolved in a minimum amount of water. After the addition was completed carbon disulfide (7.6 g) was added while maintaining the temperature between 20°-25° C. The mixture was maintained at this temperature for 1 hour, then at 60° C. for 2 hours, cooled and poured into water (250 cm.3). After acidification (10% HCl), extraction into diethyl ether and drying over Na2SO4 the product was isolated by rotoevaporation.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[CH2:47]([NH2:51])[CH:48]([CH3:50])[CH3:49]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:51][CH2:47][CH:48]([CH3:50])[CH3:49])[CH2:13][CH2:14][S:15][CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CN
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(C)C
Yield: 97.7 %

Procedure:
(S)-2-tert-butoxycarbonylamino-4-methylsulfanyl-butyric acid (D95) (2.0 g, 8.0 mmol, 1 equiv), EDAC.HCl (1.84 g, 9.6 mmol, 1.2 equiv), HOBT (1.47 g, 9.6 mmol, 1.2 equiv), 4-ethylmorpholine (1.76 g, 16 mmol, 2 equiv) and iso-butylamine (952 ml, 9.6 mmol, 1.2 equiv) in CH2Cl2 (10 ml) were stirred at room temperature for 16 h. The solution was concentrated in vacuo and the residue dissolved in AcOEt. The organic phase was washed with 2N aqueous HCl solution, saturated aqueous NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo to give ((S)-1-isobutylcarbamoyl-3-methylsulfanyl-propyl)-carbamic acid tert-butyl ester (D96) (2.38 g, 98%) as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1.[OH-].[Na+].Cl.O>C(O)C>[F:14][C:2]([F:1])([F:13])[C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1csc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1csc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of ethyl 2-(trifluoromethyl)-1,3-thiazole-4-carboxylate (278 mg) in ethanol (3.5 ml) was added 2M sodium hydroxide solution (2.4 ml) and the mixture stirred at RT for 1 h. The mixture was acidified by the addition of 2M hydrochloric acid solution (2.5 ml) and the mixture blown to dryness. The residue was treated with water (2 ml) and extracted with ethyl acetate (3×5 ml). The combined organic extracts were dried over sodium sulphate and evaporated to give the title compound (168 mg) as a beige solid.