Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][NH:18][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:16][CH2:15]1
Reactant: NCC1CC1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Product: N#Cc1ccc(NCC2CC2)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1A from 4-fluoro-3-(trifluoromethyl)benzonitrile and (cyclopropylmethyl)amine: MS (APCI) m/z 241 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([O:31]C)=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([OH:31])=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:33][CH:34]=1)=[O:11]
Reactant: COC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4csc(C(=O)O)c4)c3)cc2)c1
Temperature: 66 °C

Procedure:
To a stirred solution of methyl 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylate (550 mg, 1.15 mmol) in a mixture of solvents—THF/MeOH (20 ml/20 ml) was added 1 ml of 5M NaOH (5 mmol) solution. The mixture was heated in a 66° C. bath for 2 hours, cooled to room temperature and poured into 200 ml of water. 2M HCl was added until pH=5. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylic acid as off-white solid. Yield: 520 mg, 97%.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[C:29]([C:30]#[N:31])=[C:28]([CH:32]=O)[NH:27][C:26]2=[N:34][NH:35][CH:36]=[C:25]12.O>C(COC)OC>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[C:29]([C:30]#[N:31])=[C:28](/[CH:32]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:27][C:26]2=[N:34][NH:35][CH:36]=[C:25]12
Reactant: N#CC1=C(C=O)Nc2n[nH]cc2C1c1ccccc1Cl
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)/C=C/C1=C(C#N)C(c2ccccc2Cl)c2c[nH]nc2N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
To a suspension of sodium hydride (94 mg) in dimethoxyethane (10 ml) was added ethyl diethylphosphonoacetate (528 mg) and the mixture was stirred at room temperature for 15 minutes. Under ice-cooling, 4-(2-chlorophenyl)-5-cyano-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (670 mg) was added to the mixture, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (560 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([OH:27])=O)[CH:21]=2)[CH:15]=1)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:64]1[CH2:68][CH2:67][C@H:66]([OH:69])[CH2:65]1.Cl>CN(C=O)C.O>[OH:69][C@H:66]1[CH2:67][CH2:68][N:64]([C:25]([C:22]2[CH:21]=[C:20]([C:16]3[CH:15]=[C:14]([O:13][C:12]4[CH:11]=[C:10]([NH:9][C:7]([C:3]5[O:4][CH:5]=[CH:6][C:2]=5[CH3:1])=[O:8])[CH:30]=[CH:29][CH:28]=4)[CH:19]=[CH:18][N:17]=3)[NH:24][CH:23]=2)=[O:27])[CH2:65]1
Reactant: O[C@H]1CCNC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)N4CC[C@H](O)C4)c[nH]3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (60 mg, 0.15 mmol), HATU (68 mg, 0.18 mmol) and N,N-diisopropylethylamine (43 mg, 0.33 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of (S)-3-pyrrolidinol (16 mg, 0.18 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamide as white solid. Yield: 40 mg, 56%.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=1.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30](O)=[O:31].CCCP(=O)=O>CC1CCCO1>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=1)=[O:31]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: CCCP(=O)=O
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: CCOC(=O)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Temperature: 85 °C
Yield: 75.8 %

Procedure:
Pyridine (12.9 mL, 161 mmol) was added to a solution of ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (9.32 g, 40.3 mmol) and 5-bromo-2-chlorobenzoic acid (10.4 g, 44.3 mmol) in 2-methyl-tetrahydrofuran (100 mL). The reaction was heated to 85° C. before the addition of propylphosphonic anhydride (38.5 mL, 60.4 mmol, 50% solution in EtOAc) drop-wise. The reaction was heated at 85° C. for 16 hours before cooling to room temperature. The organic solution was washed with saturated aqueous sodium hydrogen carbonate solution (3×25 mL), saturated brine (30 mL) and concentrated in vacuo. The resulting solid was triturated with TBME (5×50 mL) to afford the title compound (13.7 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][C@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:6]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([C:34](=[O:36])[CH3:35])[C@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN[C@@H]2CCc3ccccc32)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-((R)-indan-1-ylaminomethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: ClC1C(OC2C=CN=C(Cl)C=2)=CC(F)=C([NH:8][C:9]([C:11]2[C:12](=[O:27])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])=[O:10])C=1.C1(C(N)=O)CC1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:18]([O:17][C:16]1[CH:15]=[CH:14][N:13]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:12](=[O:27])[C:11]=1[C:9]([NH2:8])=[O:10])[CH3:19]
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: NC(=O)C1CC1
Solvent: C1COCCO1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(N)=O
Yield: 104 %

Procedure:
Using the procedure of Example 12, N-(5-chloro-4-((2-chloropyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.05 g, 0.094 mmol), cyclopropancarboxamide (12 mg, 0.14 mmol), Cs2CO3 (0.05 g, 0.14 mmol), Xantphos (6 mg, 0.010 mmol), Pd2(dba)3 (5 mg, 0.005 mmol) and dioxane (2 mL) were combined to obtain N-(5-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (27 mg, 48.4% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 10.88 (s, 1H), 8.50 (d, J=7.8 Hz, 1H), 8.19 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.50 (m, 3H), 7.36 (t, J=8.7 Hz, 2H), 6.68 (dd, J=5.7, 2.4 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 1.95 (m, 1H), 1.33 (t, J=7.0 Hz, 3H), 0.76 (t, J=5.9 Hz, 4H); MS (ESI) m/z: 581.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:14]([F:17])([F:16])[F:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[N:11][CH:10]=[CH:9]2)([O-])=O.C(O)(=O)C.[OH-].[NH4+]>C(O)C.O.[Zn]>[NH2:1][C:4]1[C:5]([C:14]([F:17])([F:15])[F:16])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[N:11][CH:10]=[CH:9]2
Reactant: O=[N+]([O-])c1c(C(F)(F)F)ccc2ccncc12
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1c(C(F)(F)F)ccc2ccncc12

Procedure:
According to the procedure in Example 12, 8-nitro-7-trifluoromethylisoquinoline is heated with zinc and acetic acid in ethanol and water on a steam bath for five minutes and the reaction mixture is cooled, made alkaline with aqueous ammonium hydroxide and extracted with ethyl acetate. Removing the solvent from the extract in vacuo gives, as the residue, 8-amino-7-trifluoromethylisoquinoline.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:12][Si](C=[N+]=[N-])(C)C.CCOCC>C1(C)C=CC=CC=1.CO>[C:1]([C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc(C(C)=O)s1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of 5-acetylthiophene-2-carboxylic acid (3.24 g, 19.0 mmol) dissolved in a mixture of toluene (50 mL) and methanol (50 mL) cooled to 0° C. was added 2.0 M trimethylsilyldiazomethane in ether (19.0 mL, 38.1 mmol) dropwise. Upon complete addition, the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with the addition of acetic acid and the solvent was removed. The residue thus obtained was partitioned between ethyl acetate and saturated aqueous NaHCO3 and upon separation, the organic layer was dried over anhydrous magnesium sulfate and concentrated to afford the desired product (3.49 g, 100%). LC-MS: (FA) ES+ 185)
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17]O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].CCOCC.C(Cl)Cl.P(Br)(Br)[Br:29]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][Br:29])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)OC(=O)Nn1ccc2cc(CO)ccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nn1ccc2cc(CBr)ccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 86.4 %

Procedure:
To an ice-cold solution of 5-hydroxymethylindole-1-carbamic acid tert-butyl ester (0.51 g, 2.1 mmol) in 4:1 Et2O/CH2Cl2 (4 mL) was added PBr3 (0.2 mL, 2.2 mmol), and the reaction mixture was stirred for 40 min. The reaction mixture was diluted with CH2Cl2, washed a saturated solution of NaHCO3 (3×10 mL), dried (Na2SO4), filtered, and the solvent was removed under reduced pressure to provide 5-bromomethyl-indole-1-carbamic acid tert-butyl ester as a yellow solid (0.59 g, 93%). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9 Hz, 1H), 7.68-7.62 (m, 2H) 7.33 (d, J=9 Hz, 1H), 6.60 (s, 1H), 4.68 (s, 2H), 1.67 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][OH:18])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: OCc1ccccc1B(O)O
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccccc2CO)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 2-(hydroxymethyl)-benzeneboronic acid gives “A63”; method 1: HPLC/MS: 1.07 min, [M+H]=321;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC[C@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Product: C[C@@H]1CCCN1[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (2R,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester by condensing 3-(3S)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester and R-(−)-2-methylpiperindine (obtained from Advanced Asymmetrics). LCMS:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)nc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)nc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(1-propylimidazol-2-yl)methyl]sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.66 g) was dissolved in methylene chloride (20 ml), and a solution of m-chloroperbenzoic acid (0.26 g) in methylene chloride (13 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(1-propylimidazol-2-yl)methyl]sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 293) (0.39 g).
Reaction SMILES: [NH3:1].[B:2]([O-:5])([O-:4])[O-:3].[Na+:6].[Na+].[Na+]>>[Na+:6].[NH4+:1].[B:2]([O-:5])([O-:4])[O-:3].[Na+:6].[Na+:6].[Na+:6]
Reactant: N
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Product: [NH4+]

Procedure:
About 100 parts by weight of powdered borax (Na2B4O7.4H2O) are added to 100 parts by weight of concentrated aqueous ammonia containing 25% ammonia while agitating. The mixture is reacted for about 4 hours at ambient temperature and pressure thereby hydrolyzing the sodium borate and splitting the molecules into smaller molecules. The ammonia reacts with the sodium borate to produce an ammonium sodium salt of polyboron oxyacid and polyammonium sodium borate which is dried and pulverized into a powder with the general formula
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([O:21][CH3:22])[CH:5]([NH2:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl.O=S(Cl)Cl.[CH3:31]O>>[ClH:19].[CH2:1]([O:2][C:3](=[O:23])[C@H:4]([O:21][CH3:22])[CH:5]([NH2:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:11][CH:12]=1)[CH3:31]
Reactant: CO
Reactant: COC(=O)[C@H](OC)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](OC)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-amino-4-(3′-chloro-biphenyl-4-yl)-2-methoxy-butyric acid methyl ester (500 mg, 1.15 mmol) in MeOH (5 mL) is added 2M NaOH aqueous solution (5 mL). After being stirred at room temperature for 2 h, the reaction mixture is acidified with 2M HCl and extracted with EtOAc. The organic layer is dried over Na2SO4 and concentrated. The residue is dissolved in EtOH (5 mL) and treated with SOCl2 (0.252 mL, 3.26 mmol). After being stirred at 55° C., the reaction mixture was cocentrated. The residue is used for a next step without further purification. HPLC retention time=1.49 minutes (condition A): MS (m+1)=348.2
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:9]1[CH:14]=[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])[N:12]=[C:11]([O:19][CH3:20])[C:10]=1[CH2:21][O:22][CH2:23][O:24][CH3:25])[CH2:7][CH3:8])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:20][O:19][C:11]1[C:10]([CH2:21][O:22][CH2:23][O:24][CH3:25])=[C:9]([C:6]([CH2:7][CH3:8])=[CH:5][CH2:4][OH:3])[CH:14]=[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])[N:12]=1
Reactant: CCOC(=O)C=C(CC)c1cc([Si](C)(C)C)nc(OC)c1COCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC(=CCO)c1cc([Si](C)(C)C)nc(OC)c1COCOC
Temperature: 0 °C
Yield: 90.6 %

Procedure:
To a −78° C. mixture of 4a (100 mg, 0.26 mmol) in Et2O (3 mL) was slowly added LAH (0.26 mL, 0.26 mmol, 1.0 M solution in Et2O). The resulting mixture was allowed to warm to 0° C. and then quenched by addition of a chilled saturated aq. solution of potassium sodium tartrate. The aqueous layer was extracted 3 times with Et2O. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (hexane-EtOAc 75:25) to yield 5a (80 mg, 90%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ0.27 (s, 9H), 0.91 (t, J=7.5 Hz, 3H), 2.43 (q, J=7.5 Hz, 2H), 3.43 (s, 3H), 4.01 (s, 3H), 4.33 (d, J=6.9 Hz, 2H), 4.53 (s, 2H), 4.69 (s, 2H), 5.61 (t, J=6.9 Hz, 1H), 6.87 (s, 1H); 13C NMR (75 MHz, CDCl3) δ−1.97, 13.01, 25.27, 53.37, 55.32, 58.79, 61.58, 95.91, 115.9, 122.3, 128.7, 142.36, 152.2, 162.3, 164.3; IR (film, NaCl, cm−1) 3388, 2949, 1576, 1450, 1340, 1042, 854; LRMS (70 eV, EI) m/z (rel int %) 339 (M+), 324, 308, 294, 277, 262 (100), 248, 232, 218, 188, 174, 117, 89, 73, 59. HRMS m/z calcd for C17H29NO2Si (M+) 339.1866, found 339.1861.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[C:15]1[C:16]2[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH2:2][CH2:3][CH3:4].[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH:39][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A71) and commercially available (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[Cl:11][C:12]1[C:17]([NH2:18])=[C:16]2[O:19][CH2:20][O:21][C:15]2=[CH:14][CH:13]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][Cl:39])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][C:24]=1[C:40]#[N:41]>CN(C=O)C.O>[Cl:11][C:12]1[C:17]([NH:18][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][Cl:39])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][C:24]=2[C:40]#[N:41])=[C:16]2[O:19][CH2:20][O:21][C:15]2=[CH:14][CH:13]=1
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)c(C#N)cnc2cc1OCCCCl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 3.34 ml) was added to a solution of 6-chloro-2,3-methylenedioxyaniline (0.573 g) in DMF (12 ml) that was cooled to 0° C. and the mixture was stirred for 5 minutes. A solution of 4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline (0.5 g) in DMF (3 ml) was added and the resultant mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained the title compound as a solid (0.62 g); NMR Spectrum: DMSOd6 at 60° C.) 2.32 (m, 2H), 3.9 (m, 2H), 4.0 (s, 3H), 4.35 (m, 2H), 6.1 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.4 (s, 1H), 7.9 (s, 1H), 8.42 (s, 1H), 9.32 (s, 1H); Mass Spectrum: M+H+ 446 and 448.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[C:5]([Cl:8])[CH:4]=[C:3]([NH2:9])[C:2]=1[NH2:10].O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15].O>Cl>[Cl:7][C:6]1[C:5]([Cl:8])=[CH:4][C:3]2[C:2](=[N:10][C:13](=[O:17])[C:14](=[O:15])[N:9]=2)[CH:1]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: O=C1N=c2cc(Cl)c(Cl)cc2=NC1=O
Temperature: 125 °C
Reaction time: 2.5 h
Yield: 93982360 %

Procedure:
A suspension of 2.655 g (15.0 mmol) of 4,5-dichlorophenylene-1,2-diamine and 1.986 g (15.75 nmol) oxalic acid dihydrate (Fisher Scientific Co., used as received) in 22.5 mL of 2N aq. HCl was refluxed with stirring at 125° C. (bath temperature) for 2.5 h, (during the first 5 min heating, the suspension almost turned into a solution, then began to form a precipitate). The reaction mixture was allowed to cool to 22° C., and H2O (50 mL) was added. The precipitate was collected on a Hirsh funnel by vacuum filtration, washed with H2O (6×25 mL) and dried at 60° C. under 0.1 mmHg for 12 h affording 3.39 g (98%) of 6,7-dichloroquinoxaline-2,3-dione as a deep pink powder. Mp. >400° C. 1H NMR (DMSO-d6): δ12.016 (s, 2H), 7.234 (s, 2H). This product was used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])C(OCC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].CS(C)=O>O>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[N:16]=[CH:17][C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:1]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=CNc1ccc(Cl)cc1C(=O)c1ccccc1)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Yield: 70 %

Procedure:
A mixture of diethyl (2-benzoyl-4-chlorophenyl)aminomethylenemalonate (7.0 g), lithium chloride (3.7 g) and dimethyl sulfoxide (70 ml) was heated for 1.5 hrs. at 180° C. The mixture was diluted with water to give ethyl 6-chloro-4-phenyl-3-quinolinecarboxylate as crystals (3.8 g, 70.0%), which was recrystallized from ethanol as needles. m.p. 123°-124° C.