Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(C(=O)c2cc(Cl)cc(Cl)c2)C(Cc2ccccc2)C1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](NC(c2ccccc2)c2ccccc2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
A solution of 200 mg (0.551 mmol) of (2R*,45*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 110 mg (0.606 mmol) of benzophenone in 5 ml of toluene are kept at reflux for 18 hours. The reaction mixture is then concentrated in a rotary evaporator and dissolved in 3 ml of methanol, and 69 mg (1.10 mmol) of sodium cyanoborohydride are added at RT. The reaction mixture is adjusted to pH=5 with 80 μl of acetic acid and stirred at RT for 68 hours. The title compound ##STR98## is obtained as white foam (120 mg, 41%). TLC:toluene/ethyl acetate (7:3) Rf =0.79, FD-MS:M+ =528, 530; IR:1630 cm-1.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([OH:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:41](C(OC(C)(C)C)=O)[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:45]([O:44][C:42](=[O:41])[N:15]([CH2:14][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:39])([F:40])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1)[OH:38])[CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=1[C:27]1[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=1[O:36][CH3:37])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol (Example 6 Step B, 325.0 mg, 0.561 mmol) in CH2Cl2 (15 mL) was added BOC2O (122 mg, 0.561 mmol) and DIPEA (98 μL, 0.561 mmol). The reaction was stirred at room temperature. After 5 hours, additional BOC2O (50 mg, 0.229 mmol) and DIPEA (50 μL, 0.287 mmol) were added. The reaction was stirred at room temperature for 48 hours. The reaction was then concentrated to ˜2 mL, diluted with hexanes (8 mL) and purified by flash chromatography with 10 to 20% EtOAc/hexanes to afford tert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.38 (25% EtOAc/hexanes). LCMS=580.3 (M+1−BOC)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.78 (s, 1H), 7.54-7.67 (m, 4H), 7.23-7.33 (m, 2H), 6.90-6.95 (m, 2H), 3.15-4.82 (m, 9H), 2.87 (m, 1H), 1.19-1.43 (m, 15 H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:35])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:35][N:26]([C:22]1[CH:21]=[C:20]([C:9]2[CH:10]=[CH:11][C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:8]=2[O:7][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:25]=[CH:24][CH:23]=1)[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:28]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCC)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (3.8 mmol, 3.8 eq) of 1-iodopentane and 400 mg (1.0 mmol, 1 eq) of methyl 3-[2-hydroxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 3.6 eq) of potassium carbonate at 80° C. for 12 hours, methyl 3-[3′-(1-methyl-3-pentylureido)-2-pentyloxybiphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:22][C:23]1[C:24](Cl)=[C:25]([C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C:26]([CH3:30])=[N:27][C:28]=1[CH3:29]>CC#N>[Br:22][C:23]1[C:24]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[C:25]([C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])[C:26]([CH3:30])=[N:27][C:28]=1[CH3:29]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
To a solution of 4-phenylpiperidine (1.25 g, 7.75 mmol) and DIEA (4.1 mL, 23.3 mmol) in anhydrous CH3CN (40 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.59 g, 7.75 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; concentrated, and charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-oxoacetate 2.63 g (74%). 1H NMR (500 MHz, DMSO-d6) δ 7.34-7.31 (m, 2H), 7.25-7.20 (m, 3H), 5.11-5.06 (m, 1H), 3.50 (br. s, 2H), 2.94 (br. s, 2H), 2.68-2.63 (m, 1H), 2.63 (s, 3H), 2.13 (s, 3H), 1.81-1.78 (m, 2H), 1.60 (br. s, 2H), 1.26 (d, J=6.2 Hz, 6H). UPLC (M+H)=461.05.
Reaction SMILES: [Na].C([O:5][C@@H:6]1[C@@H:11]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=2)[C@@H:10]([O:25]C(=O)C)[C@@H:9]([CH2:29][O:30]C(=O)C)[O:8][C@H:7]1[S:34][C@@H:35]1[O:48][C@H:47]([CH2:49][O:50]C(=O)C)[C@H:42]([O:43]C(=O)C)[C@H:41]([NH:54][C:55](=[O:66])[C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[C:58]([O:64][CH3:65])[CH:57]=2)[C@H:36]1[O:37]C(=O)C)(=O)C.C[O-].[Na+].C1COCC1>CO>[CH3:63][O:62][C:60]1[CH:61]=[C:56]([CH:57]=[C:58]([O:64][CH3:65])[CH:59]=1)[C:55]([NH:54][C@H:41]1[C@@H:42]([OH:43])[C@@H:47]([CH2:49][OH:50])[O:48][C@@H:35]([S:34][C@@H:7]2[O:8][C@H:9]([CH2:29][OH:30])[C@H:10]([OH:25])[C@H:11]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=3)[C@H:6]2[OH:5])[C@@H:36]1[OH:37])=[O:66]
Reactant: COc1cc(OC)cc(C(=O)N[C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H](S[C@@H]3O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](NC(=O)c4cc(OC)cc(OC)c4)[C@H]3OC(C)=O)[C@@H]2OC(C)=O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=O)N[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](S[C@@H]3O[C@H](CO)[C@H](O)[C@H](NC(=O)c4cc(OC)cc(OC)c4)[C@H]3O)[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
Sodium (1.5 mg, 0.07 mmol) was dissolved in methanol (1 ml). Bis(2,4,6-tri-O-acetyl-3-deoxy-3-(3,5-dimethoxybenzamido)-β-D-galactopyranosyl) sulfane 14 (11 mg, 0.012 mmol) was dissolved in methanol (1 ml) and the sodium methoxide solution was added. The mixture was stirred at room temperature for 3 h. After this time, a precipitate had appeared. THF (3 ml) was added, and the precipitate dissolved. Duolite C436 (H+) was added, and the mixture was stirred for 5 minutes. After this time, the mixture was filtered and concentrated in vacuo. The residue was purified by HPLC (gradient H2O→MeCN) to give bis(3-deoxy-3-(3,5-dimethoxybenzamido)-β-D-galactopyranosyl) sulfane 19 (4.7 mg, 58%). White solid;
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:30]=[CH:31][C:32]=3[CH3:33])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 4 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.39–7.23 (m, 12H), 7.14 (br, 1H), 7.08 (d, 1H, J=8.4 Hz), 6.90 (br, 1H), 4.91 (s, 1H), 3.41 (dd, 2H, J=6.4, 12.4 Hz), 2.95 (d, 2H, J=12.4 Hz), 2.66 (m, 1H), 2.47 (m, 1H), 2.40 (t, 2H, J=6.4 Hz), 2.28 (s, 3H), 2.03–1.97 (m, 2H), 1.74–1.62 (m, 6H), 1.22 (d, 6H, J=7.2 Hz); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[N+:8]([C:11]1[CH:12]=[C:13]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:8][C:11]1[CH:12]=[C:13]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnc2[nH]cc(C(F)(F)F)c2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cnc2[nH]cc(C(F)(F)F)c2c1
Yield: 63.4 %

Procedure:
Tin chloride dihydrate (4.0 g) was added to 5-nitro-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (0.58 g) in ethyl acetate (50 mL). The resulting solution was refluxed for 3 hours. The cooled solution was treated with dilute aqueous sodium bicarbonate. The resulting slurry was filtered through celite, and the filter cake was washed with ethyl acetate. The layers were separated. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to provide 5-amino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (320 mg, 63%) as a solid.
Reaction SMILES: S(O)(O)(=O)=O.[OH:6][CH2:7][C@@H:8]([C@@H:10]([C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[OH:13])[OH:11])[NH2:9]>C(Cl)Cl.C(N(CC)CC)C>[C:7]([NH:9][C@H:8]([C@@H:10]([C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[OH:13])[OH:11])[CH2:7][OH:6])(=[O:6])[CH2:8][CH2:10][CH2:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
After stirring for 25 minutes at 25° C., this above-described mixture is added to a pre-prepared stirred suspension containing 4.68 g (11.5 mmoles) of phytosphingosine sulphate (purity 82%) in 15 ml of methylene chloride and 2.1 ml of triethyl amine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O[NH:29][C:30]([C:32]1[S:33][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:35][CH:36]=1)=[NH:31]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:26][N:31]=[C:30]([C:32]5[S:33][C:34]([S:37]([NH2:38])(=[O:40])=[O:39])=[CH:35][CH:36]=5)[N:29]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5ccc(S(N)(=O)=O)s5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a light yellow solid (50 mg, 17%). MS (ISN) 573.2 [(M−H)−]; mp 324° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].O.O.O.O.O.O.O.O.O.[S-2:16].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([S:16][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: [S-2]
Reactant: CC(C)CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC(C)CCSCCC(C)C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
Isoamyl bromide (21.88 g, 0.21 mol) and tetrabutylammonium bromide (1.61 g, 5 mmol) were added to a solution of sodium sulfide nonahydrate (24.02 g, 0.10 mol) in water (50 ml) and the mixture was refluxed with stirring for 6 h. The organic layer was separated, the aqueous layer was extracted with pentane (25 ml). The extract was combined with the organic layer and dried with anhydrous magnesium sulfate. Distillation gave 15.85 g, 91% of a colorless liquid, bp 49°-50° C./0.1 mm Hg, n20D=1.4514, >99% GC pure; 1H NMR (CDCl3) δ 0.95 (d, J=6 Hz, 12H, CH3), 1.47 (q, J=6 Hz, 4H, CH2), 1.68 (septet, J=6 Hz, 2H, CH), 2.51 (t, J=6 Hz, 4H, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([O:12]P(N3CCOCC3)(N3CCOCC3)=O)[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1.C(N(CC)CC)C.[CH2:41](O)[CH2:42][OH:43]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([O:12][CH2:41][CH2:42][OH:43])[CH2:9][N:8]=[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:6]=2[CH:33]=1
Reactant: OCCO
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)(N1CCOCC1)N1CCOCC1
Solvent: CCN(CC)CC
Product: OCCOC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
A suspension of 1.95 g (4.0 mmoles) of 7-chloro-2-di-(morpholino)phosphinyloxy-5-phenyl-3H-1,4-benzodiazepin in 10 ml of ethylene glycol containing 4 ml of triethylamine was heated on a steam bath for 2 hrs. A clear solution formed soon after heating began. Triethylamine was removed in vacuo. The ethylene glycol solution was poured into ice water precipitating solids which were collected and washed thoroughly with water. Remaining water was removed from the solid by dissolving in solid in ether, drying over sodium sulfate and evaporation of ether. Crystallization of the residue from ether-hexane gave colorless prisms, mp 142°-144°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[CH3:13][O-:14].[Na+].CO>C(Cl)Cl>[CH3:13][O:14][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:12])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To 1-bromo-2,5-difluoro-4-nitrobenzene (5.0 g, 21 mmol) was added 0.5 N sodium methoxide (50 mL, 25 mmol). The mixture was stirred at 60° C. for 1 h. The MeOH was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (5 g, 20 mmol, 95%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.69 (s, 1H), 7.28 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[NH:18][C:17](=[O:19])[O:16][C:15]([CH2:25][CH3:26])([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)[C:14]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:28]C(C)([O-])C.[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:18]([CH3:28])[C:17](=[O:19])[O:16][C:15]([CH2:25][CH3:26])([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)[C:14]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)[O-]
Reactant: CCC1(c2cccs2)OC(=O)Nc2ccc(Nc3ccc(F)c(Cl)c3)cc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC1(c2cccs2)OC(=O)N(C)c2ccc(Nc3ccc(F)c(Cl)c3)cc21
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To a stirred solution of 6-[(3-chloro-4-fluorophenyl)amino]-4-ethyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.16 g, 0.39 mmol) in DMF (4 mL) was added potassium t-butoxide (0.05 g, 0.42 mmol) at room temperature. After 10 minutes, methyl iodide (0.05 mL, 0.80 mmol) was added. After 45 minutes, the reaction solution was quenched with ammonium chloride solution (sat) and extracted with ethyl acetate. The organic layer was washed several times with brine and dried over magnesium sulfate. The solvent was removed to give 6-[(3-chloro-4-fluorophenyl)amino]-4-ethyl-1-methyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a red solid (0.12 g, 73%). 1H NMR (DMSO-d6): δ 8.31 (s, 1H), 7.53 (m, 1H), 7.27 (t, J=9.1 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 7.05 (m, 1H), 7.0 (m, 2H), 6.93 (m, 2H), 3.24 (s, 3H), 2.43 (m, 2H), 0.96 (t, J=5.9 Hz, 3H); MS (ESI) m/z 417/419 ([M+H]+); MS (ESI) m/z 415/417 ([M−H]−); Anal. calcd for C21H18ClFN2O2S: C, 60.50; H, 4.35; N, 6.72. Found: C, 60.22; H, 4.34; N, 6.63.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:6]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33]C)=[O:32])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:8])[CH2:4][CH3:5]>O1CCCC1.CO>[CH2:3]([N:6]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:8])[CH2:4][CH3:5]
Reactant: CCCCCCCNC(=O)N(CCC)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(CCC)c1cccc(-c2ccc(/C=C/C(=O)O)cc2)c1
Yield: 85 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 6.4 eq) of sodium hydroxide and 680 mg (1.55 mmol, 1 eq) of methyl (E)-3-[3′-(1-propyl-3-heptylureido)biphenyl-4-yl]acrylate in 15 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from dichloromethane/heptane, 560 mg of (E)-3-[3′-(1-propyl-3-heptylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white powder (m.p.=126° C.). Yield=85%
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[C:15]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Clc1cncc(Br)c1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)cncc1Br
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a solution of LDA (2 M solution in THF/heptane/ethylbenzene, 2.78 g, 12.97 mL, 25.95 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere and cooled to −78° C. was added a solution of 3-bromo-5-chloropyridine (5.0 g, 25.98 mmol) in anhydrous THF (40 mL) at −78° C. The reaction mixture was allowed to stir at the same temperature for 45 minutes. Then, a solution of chloro(ethoxy)methanone (28.19 g, 259.7 mmol) was added slowly over 15 minutes. After stirring for 20 minutes, the reaction mixture was quenched with saturated NaHCO3 solution. The mixture was extracted into ethyl acetate (3×100 mL), and the combined organic layers were washed with water and brine. The separated organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, and the residue was purified through CombiFlash using 0-10% ethyl acetate in hexane to provide ethyl 3-bromo-5-chloropyridine-4-carboxylate as pale yellow oil (5.84 g, 85% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.35 (t, 3H), 4.45 (q, 2H), 8.82 (s, 1H), 8.87 (s, 1H); M+265.5.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=1.[CH2:20]([O:22][C@@H:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][O:18][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][C@H:23]([O:22][CH2:20][CH3:21])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:35][CH:34]=2)=[CH:11][CH:10]=1
Reactant: C/C(=C\CO)c1ccc(-c2cccc(Cl)c2Cl)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(Cl)c3Cl)cc2)cc1)OCC
Yield: 79.9 %

Procedure:
The title compound (0.41 g, 80% yield) was prepared from (E)-3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-en-1-ol (0.293 g, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) by a procedure analogous to that described in example 52 c.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH2:17][CH2:18][CH3:19])(=O)=O.[O:22]1CCO[CH:23]1[C:27]1[CH:28]=[CH:29][C:30]([CH3:36])=[C:31](B(O)O)[CH:32]=1>>[CH3:36][C:30]1[C:29]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][C:8]=2[CH2:17][CH2:18][CH3:19])=[CH:28][C:27]([CH:23]=[O:22])=[CH:32][CH:31]=1
Reactant: Cc1ccc(C2OCCO2)cc1B(O)O
Reactant: CCCc1cc(C(=O)CC)ccc1OS(=O)(=O)C(F)(F)F
Product: CCCc1cc(C(=O)CC)ccc1-c1cc(C=O)ccc1C

Procedure:
In a manner similar to that of Example 1(g), by reacting 2 g (6.2 mmol) of 4-propionyl-2-propylphenyl 1,1,1-trifluoromethanesulfonate with 1.2 g (8 mmol) of 5-[1,3]dioxolan-2-yl-2-methylphenylboronic acid, and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (90/10), 1.42 g (78%) of product are obtained in the form of a pale yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH:44][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7](=[O:24])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOCCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CCOCCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 20.3 %

Procedure:
8-Cyclopentyl-6-(2-ethoxy-ethyl)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.86 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.10 g, 3.95 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The mixture was cooled to room temperature and purified by silica gel chromatography to give 4-{6-[8-cyclopentyl-6-(2-ethoxy-ethyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as an orange solid (0.328 g, 20.4%). 1H NMR δ (400 MHz, CDCl3) 8.54 (s, 1H), 8.26 (d, J=9.0 Hz, 1H), 7.98 (d, J=2.9 Hz, 1H), 7.45 (s, 1H), 7.38 (dd, J=2.9, 9.3 Hz, 1H), 5.90 (m, 1H), 3.70 (t, J=6.3, 1H), 3.61 (m, 4H), 3.51 (q, J=7.1, 1H), 3.11 (m, 4H), 2.84 (t, J=5.9, 1H), 2.33 (m, 2H), 2.08 (m, 2H), 1.87 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.19 (t, J=7.1, 1H).