Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[O:17]=[C:15]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:14][NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:18][C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][C:29]([F:30])([F:32])[F:31])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: C1CCNC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCCC3)ccc21
Temperature: 0 °C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-oxo-2-pyrrolidin-1-yl-ethyl)amide (46 mg) was prepared by following General Procedure F using {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetic acid (47 mg), pyrrolidine (0.14 ml), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 520. 1H NMR (DMSO-d6, 400 MHz): δ 8.32 (t, 1H), 7.82 (s, 1H), 7.61 (m, 2H), 7.52 (d, 1H), 7.28 (m, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 4.02 (d, 2H), 3.57 (s, 3H), 3.49 (t, 2H), 3.34 (m 2H), 1.91 (p, 2H), and 1.79 (p, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:11]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>CN(C=O)C>[CH:3]1([S:9][C:11]2[N:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: SC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)nc1SC1CCCCC1
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
1.3 equivalents of NaH (4.9 g, 0.124 mol) were dissolved in 50 mL DMF under a nitrogen atmosphere. After the addition of 1.2 equivalents of cyclohexanethiol (14.2 mL, 0.116 mol), stirring was performed at room temperature for 1.5 h. The resultant suspension was cooled to 10° C. and 1 equivalent of 2-chloro-6-(trifluoromethyl)nicotinonitrile (20 g, 0.096 mol) in 50 mL DMF was added dropwise and stirred for 2 h at room temperature. The reaction mixture was quenched with sat. aq. NH4Cl soln., diluted with 1 l of water and extracted repeatedly with EA (3×200 mL). The combined organic phases were washed with a sat. aq. NaCl soln., dried over MgSO4 and evaporated under a vacuum. Purification performed by column chromatography (silica gel, 100-200 mesh, eluent: 2% EA in hexane) resulted in 26 g (93.8%) of product.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]>>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][N:9]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1CCBr
Product: Cc1ccccc1CCN(N=C(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-phenylhydrazine (200 mg, 0.943 mmol; Example 79A) and 1-(2-bromoethyl)-2-methylbenzene (1.46 g, 7.37 mmol; Aldrich) into the title compound: MS (DCI/NH3) m/z 391 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.P(Br)(Br)[Br:22]>C1COCC1>[Br:22][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[C:4]([CH3:10])[CH:5]=1
Reactant: Cc1cc(CO)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: Cc1cc(CBr)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a solution of (2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yl)-methanol (2.22 g, 7.9 mmol) in THF (30 ml) is added PBr3 (3.22 g, 11.9 mmol) in THF (5 ml) and the reaction is allowed to stir at room temperature for about 2 h. The reaction is cooled to 0° C. and ice water is added slowly. The mixture is extracted with ethyl acetate, dried over MgSO4, and concentrated. The resulting residue is purified by silica gel column chromatography, eluting with EtOAc/hexanes to afford 2.2 g of the titled compound as a white solid. 1H-NMR.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15].C(N(CC)C(C)C)(C)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=3)[CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1c(-c2cccc(N)c2)nsc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)nsc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a mixture of 5-amino-3-(3-aminophenyl)isothiazole-4-carboxamide (13 mg, 0.056 mmol) and N,N-diisopropylethylamine (0.029 mL, 0.17 mmol) in 1.0 mL CH2Cl2 at room temperature was added 3-(trifluoromethyl)benzoyl chloride (0.008 mL, 0.056 mmol) and the reaction stirred at room temperature. After 1 hour, additional 3-(trifluoromethyl)benzoyl chloride (0.0015 mL) was added, then again at 2 hours (0.002 mL) and 3 hours (0.0015 mL). After 4 hours the reaction was evaporated, and then treated to an aqueous Na2CO3 and EtOAc workup to yield a light yellow solid. The solid was precipitated from EtOAc/hexane to give the title compound as an off-white solid (16 mg, 68%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][NH:9][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCCCCBr
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCNCCc1ccccc1
Yield: 26.2 %

Procedure:
To a mixture of 2-phenylethylamine (1.09 g, 9 mmol) and triethylamine (1.37 g, 13.5 mmol) in toluene (50 mL) was added methyl 7-bromoheptanoate (2.0 g, 9 mmol) and refluxed overnight. The reaction mixture was filtered and concentrated. Flash column chromatography over silica gel using 100% ethyl acetate yielded a yellow oil (0.62 g, 20%) NMR (250 MHz, CDCl3), 1.12-1.40 (4H, m), 1.40-1.72 (4H, m), 2.29 (2H, t), 2.63 (2H, t), 2.75-2.96 (4H, m), 2.96-3.1 (1H, br s), 3.66 (3H, s), 7.00-7.38 (5H, m).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:21][C:22]([F:35])([F:34])[C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:25][CH:24]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([C:10]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:27][C:23]([C:22]([F:35])([F:21])[F:34])=[CH:24][N:25]=3)[CH2:29][CH2:30]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ncc(C(F)(F)F)s3)CC2)c1
Yield: 71 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-morpholin-4-yl-benzoic acid (Example A13) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as an off-white crystalline solid (yield 71%). MS (m/e): 505.3 (M+H+, 100%).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[O:17][CH:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH3:3]>C(O)C.[Pd]>[CH:2]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[O:17][CH:18]=2)[CH:7]=[C:8]([C:10]([F:12])([F:11])[F:13])[CH:9]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cc(-c2coc(CCC(=O)OC)n2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1nc(-c2cc(C(C)C)cc(C(F)(F)F)c2)co1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a nitrogen sparged solution of methyl 3-(4-(3-(prop-1-en-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 49, 0.200 g, 0.589 mmol) in ethanol (50.0 mL) was added 10% Pd/C (0.025 g) in a Parr bottle, and the mixture was vigorously shaken under an atmosphere of hydrogen (40 psi) at room temperature for 4 h. After this time, the reaction mixture was filtered through a pad of Celite, the filter cake was washed with ethanol and the filtrate was concentrated under reduced pressure to provide methyl 3-(4-(3-isopropyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.191 g, 95%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCO>[C:18]1([C:16]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[C:12]([F:13])([F:15])[F:14])=[O:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 90 °C

Procedure:
[4-Chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (compound of formula (VII)), 0.050 g, 0.15 mmol) was taken into toluene/EtOH (3 mL/0.5 mL). Then phenylboronic acid (0.30 mmol) was added followed by 2 M Na2CO3 (0.25 mL, 0.5 mmol) and finally Pd(PPh3)4 (0.009 g, 0.0075 mmol). The reaction was heated at 90° C. for 4 hours. The solvent was removed and the resulting material was purified via column chromatography using 5% ethyl acetate in hexane to elute out 0.043 g of the title compound: MS (ESI) m/z 378 ([M+H]+); Anal. Calcd for C23H14F3NO: C, 73.21; H, 3.74; N, 3.71. Found: C, 72.16; H, 3.77; N, 3.69.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54](=[N:67]O)[C:55]1[CH:56]=[C:57]([CH:62]=[CH:63][C:64]=1[O:65][CH3:66])[C:58]([O:60][CH3:61])=[O:59]>CN(C=O)C>[CH3:66][O:65][C:64]1[CH:63]=[CH:62][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:56][C:55]=1[C:54]1[N:53]=[C:10]([C:8]2[CH:7]=[CH:6][C:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=2)[O:12][N:67]=1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COC(=O)c1ccc(OC)c(C(N)=NO)c1
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: COCc1cc(-c2nc(-c3cc(C(=O)OC)ccc3OC)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Intermediate 28 (149.42 mg; 0.58 mmol) and n-ethyldiisopropylamine (198.29 μL; 1.17 mmol) in anhydrous DMF (2 mL) and cooled at 0° C., HATU (221.67 mg; 0.58 mmol) was added and the mixture stirred at RT for 10 min. After this time, Intermediate 53 (100 mg; 0.60 mmol) and DIEA (0.10 mL) in anhydrous DMF (1 mL) were added and the mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to RT, partitioned between water and Et2O, dried over MgSO4, filtered and evaporated under vacuum. Product was adsorbed on silica and purified by flash chromatography (cHex/EtOAc from 9:1 to 8:2), which gave the title compound as a colorless oil. LC/MS (Method B): 445.2 (M+H)+. HPLC (Method A) Rt 6.01 min (purity: 96.5%).
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[N:41]([C:47]1[C:48]([CH2:61][OH:62])=[C:49]([C:53]3[CH:54]=[C:55]([C:58]([OH:60])=O)[NH:56][CH:57]=3)[CH:50]=[CH:51][CH:52]=1)[N:40]=[CH:39]2)([CH3:35])([CH3:34])[CH3:33]>C1COCC1>[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[N:41]([C:47]1[C:48]([CH2:61][OH:62])=[C:49]([C:53]3[CH:54]=[C:55]([C:58]([NH2:2])=[O:60])[NH:56][CH:57]=3)[CH:50]=[CH:51][CH:52]=1)[N:40]=[CH:39]2)([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-c4c[nH]c(C(=O)O)c4)c3CO)ncc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-c4c[nH]c(C(N)=O)c4)c3CO)ncc2c1
Yield: 26.1 %

Procedure:
HATU (104 mg, 0.27 mmol) and triethyl amine (1 mL) were added to a solution of 4-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrole-2-carboxylic acid (95 mg, 0.23 mmol) in dry THF (15 mL). Ammonia gas was bubbled through the solution for 5 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate=2:1) to give 4-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrole-2-carboxylic acid amide (25 mg, yield 26%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.43 (s, 1H), 8.28 (d, J=8.5 Hz, 1H), 7.98-7.92 (m, 2H), 7.52-7.39 (m, 2H), 7.26-7.19 (m, 2H), 7.03 (d, J=1.6 Hz, 1H), 4.38 (s, 2H), 1.38 (s, 9H). LC-MS calcd for C24H24N4O3 (m/e) 416.18, obsd 417 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]([CH3:21])[C:10]=2C(O)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[NH2:39][C:10]1[C:11]([CH3:21])=[N:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1N
Temperature: 80 °C
Reaction time: 7.5 h
Yield: 38.7 %

Procedure:
A mixture of 4-(3-cyanophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid (3.7 g), diphenylphosphoryl azide (3.24 g), triethylamine (1.19 g) and t-butanol (35 ml) was refluxed for 5 hours. After the organic solvent was evaporated, chloroform (40 ml) and a saturated aqueous solution of sodium bicarbonate (40 ml) were added to the residue. The separated organic layer was washed with water and brine, dried and concentrated in vacuo. The residue containing 3-(t-butoxycarbonylamino)-4-(3-cyanophenyl)-2-methyl-6-phenylpyridine was dissolved with ethanol (35 ml). After conc. hydrochloric acid (2 ml) was added to the solution at 0° C., the mixture was stirred at 0° C. for 1.5 hours and further at 80° C. for 7.5 hours. The mixture was concentrated, dissolved with chloroform (40 ml) and water (40 ml) and adjusted to pH 9 with 5N sodium hydroxide. The organic layer was separated, washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (70 g) eluting with a mixture of chloroform and methanol (100:1 V/V). The fractions containing the desired compound were combined and concentrated in vacuo. The residue was triturated with diethyl ether to give 3-amino-4-(3-cyanophenyl)-2-methyl-6-phenylpyridine (1.30 g).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7](O)=O.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>O>[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7]1[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:18]=1
Reactant: CN(C)CCCC(=O)O
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: O
Product: CN(C)CCCc1nc2ccccc2[nH]1

Procedure:
Grams 10 4-dimethylaminobutyric acid hydrochloride are heated up till melting together with 6.45 g o-phenylendiamine then it is allowed to cool and 150 ml water are added thereto. The solution is washed with dichloromethane, made alkaline and extracted with dichloromethane. The extracts are collected together, filtered on charcoal, made anhydrous on sodium sulphate and evaporated to dryness. A thick oily reddish residue is obtained, which is triturated with 200 ml diethyl ether to give 5.8 g 2-(3-dimethylaminopropyl)benzimidazole melting at 117°-119° C.
Reaction SMILES: C([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH2:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([OH:21])=[O:5])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)c1cccc(NCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cccc(NCc2ccccc2)c1

Procedure:
A solution of 3-benzylamino-benzoic acid tert-butyl ester (1 g, 3 mmol) in trifluoroacetic acid/dichloromethane (1:5 v/v) (100 ml) was stirred for 16 hrs. The reaction was concentrated to dryness in vacuo to afford the title compound as a white solid. HPLC retention time 2.59 min. Mass spectrum (ES+) m/z 227.8 (M+).
Reaction SMILES: [F:1][C:2]1[C:38]([CH3:39])=[CH:37][C:5]([CH2:6][C@H:7]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[C:8]([N:10]2[C@H](CC3C=CC=CC=3)COC2=O)=[O:9])=[CH:4][C:3]=1[CH3:40].[C-]#N.[K+].Cl.C1C[O:48]CC1.CO>>[F:1][C:2]1[C:38]([CH3:39])=[CH:37][C:5]([CH2:6][C@H:7]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[C:8]([NH:10][OH:48])=[O:9])=[CH:4][C:3]=1[CH3:40]
Reactant: C1CCOC1
Reactant: Cc1cc(COCCCC[C@@H](Cc2cc(C)c(F)c(C)c2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: Cc1cc(COCCCC[C@@H](Cc2cc(C)c(F)c(C)c2)C(=O)NO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of (R)-3-((S)-2-(4-fluoro-3,5-dimethylbenzyl)-6-(4-fluoro-3-methylbenzyloxy)hexanoyl)-4-benzyloxazolidin-2-one (0.040 g, 0.0728 mmol) in 2.5 mL of THF/MeOH/50% NH2OH—H2O (2:2:1), KCN (0.001 g, 0.015 mmol) was added. After stirring at room temperature for overnight, the reaction mixture was acidified with concentrated HCl to pH=2 and filtered. The filtrate was purified by RP-HPLC eluting with 20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the title compound as an off-white solid (0.005 g, 23% yield). LC-MS: tR=9.6 min, m/z 406 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 1.28-1.51 (m, 4H), 1.52-1.70 (m, 2H), 2.18 (s, 6H), 2.25 (s, 3H), 2.26-2.33 (m, 1H), 2.52-2.63 (m, 1H), 2.68-2.79 (m, 1H), 3.44 (t, J=6.30 Hz, 2H), 4.40 (s, 2H), 6.81 (d, J=7.03 Hz, 2H), 6.97 (t, J=9.08 Hz, 1H), 7.09-7.15 (m, 1H), 7.18 (d, J=7.32 Hz, 1H).
Reaction SMILES: [Na].[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][C:22](=[O:28])[NH:23]4)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(O)C>[C:29]([N:23]1[C:24]2[C:19](=[C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][N:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]3)[CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][C:22]1=[O:28])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCc2c(cccc2OCCCN2CCN(c3ccccc3)CC2)N1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C1CCc2c(OCCCN3CCN(c4ccccc4)CC3)cccc2N1C(=O)c1ccccc1
Yield: 84.3 %

Procedure:
0.3 Gram of sodium metal is dissolved in 80 ml of ethanol and to this solution is added 3.6 g of 5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril, then 1.5 g of benzoyl chloride are added and the solution is heated for 5 hours under refluxing conditions. The reaction mixture is concentrated under reduced pressure to dryness. To the residue thus obtained is added water and the insoluble matter is collected by filtration, washed with water and dried. The crude crystals are recrystallized from ligroin to obtain 3.9 g (yield: 86%) of 1-benzoyl-5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of pale yellowish needle-like crystals with a melting point of 113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[CH:6][C:7]=1[C:8]#[N:9].[CH3:11][C:12](OC(C)=O)=[O:13].CC(O)=O>O=[Pt]=O>[Cl:10][C:5]1[CH:6]=[C:7]([CH2:8][NH:9][C:12](=[O:13])[CH3:11])[C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: N#Cc1cc(Cl)ncc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(=O)NCc1cc(Cl)ncc1Cl
Reaction time: 6 h
Yield: 40 %

Procedure:
A mixture of 3,6-dichloro-4-cyanopyridine (prepared according to WO 9633975) (3.40 g, 19.65 mmol) and PtO2 (0.40 g) in 1:1 Ac2O/AcOH (60 mL) was shaken in a Parr hydrogenation apparatus at 30 psi H2 for 6 h. The reaction mixture was filtered through a pad a celite and the filtered solids washed with EtOAc. The combined filtrate and washings were concentrated in vacuo and the resulting white solid purified by column chromatography on a 120 g ISCO combi-flash cartridge (silica gel, 20:80 to 100:0 EtOAc/hexane) to afford N-(2,5-Dichloro-pyridin-4-ylmethyl)-acetamide (1.73 g, 40%) as a white solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:25]([C:29]1[N:30]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:31]([CH:35]=[O:36])=[C:32]([Cl:34])[N:33]=1)[CH2:26][CH2:27][CH3:28].C1CCN2C(=NCCC2)CC1>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]([NH:47][S:44]([C:41]1[CH:42]=[CH:43][C:38]([CH2:37][N:30]2[C:31]([CH:35]=[O:36])=[C:32]([Cl:34])[N:33]=[C:29]2[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:39][CH:40]=1)(=[O:46])=[O:45])=[O:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
N-Boc-glycine (2.8 g, 16 mmol, 1.0 eq) was dissolved into 50 mL THF. CDI (2.6 g, 16 mmol, 1.0 eq) was added, and the mixture heated to 80° C. for 2 hours. The solution was cooled to room temperature and added to a solution of intermediate (2c) (5.7 g, 16 mmol, 1.0 eq) in 100 mL THF followed by DBU (2.4 mL, 16 mmol, 1.0 eq). The mixture was stirred at room temperature overnight. The mixture was then concentrated, redissolved into 100 mL EtOAc, washed with saturated bicarbonate, saturated aqueous NaCl, dried over MgSO4, and evaporated. The residue was chromatographed (10% MeOH:EtOAc with 0.7% NH3) to yield intermediate (2d) (5.6 g).