Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]=[C:15]=[S:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]#[C:18][NH2:19].CC(C)([O-])C.[K+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:29]>C(O)(C)(C)C.C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][C:27]([C:28](=[O:29])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[C:18]([NH2:19])[N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CN
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N=C=S)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(N)c(C(=O)c3cccc(F)c3)s2)CC1
Reaction time: 2 h
Yield: 62 %

Procedure:
At 20° C., a mixture of 4-isothiocyanatopiperidine-1-carboxylic acid tert-butyl ester (2.4 g, 10 mmol) (Example 1) and cyanamide (0.42 g, 10 mmol) (Aldrich) in tert-butanol (5 mL) and acetonitrile (35 mL) was treated with potassium tert-butoxide (1.0 M/THF, 10 mL, 10 mmol, Aldrich) for 15 min. 2-bromo-1-(3-fluorophenyl)ethanone (2.0 g, 9.2 mmol)(Example 2) was added and the suspension was stirred for 2 h. Solvent was removed and the solid residue purified by silica gel chromatography (60%-70% ethyl acetate/hexane) to give 2.4 g (57% yield) of 4-[4-amino-5-(3-fluorobenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSOd6, 300 MHz) δ1.36 (m, 2H, NCH2), 1.41 (s, 9H, 3CH3), 1.88 (m, 2H, NCH2), 2.88 (brd, 2H, NCH2), 3.6-4.0 (m, 1H, CH), 3.87 (m, 2H, NCH2), 7.31 (t, 1H, Aromatic), 7.38 (d, 1H, Aromatic), 7.48 (t, 1H, Aromatic), 7.51 (q, 1H, Aromatic), 8.01 (brd, 1H, NH), 8.48 (brd, 1H, NH), 8.48 (brd, 1H, NH), 8.70 (brd, 1H, NH).
Reaction SMILES: Br[C:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH3:10])=[CH:5][S:4][C:3]=1[CH:11]=[O:12].C([O-])([O-])=O.[Na+].[Na+].CCO.[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O>C1(C)C=CC=CC=1.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>[CH2:7]([C:6]1[C:2]([C:27]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=2[O:25][CH2:24][O:23][CH3:22])=[C:3]([CH:11]=[O:12])[S:4][CH:5]=1)[CH2:8][CH2:9][CH3:10]
Reactant: COCOc1cc(OC)ccc1B(O)O
Reactant: CCCCc1csc(C=O)c1Br
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: CCCCc1csc(C=O)c1-c1ccc(OC)cc1OCOC
Yield: 71.1 %

Procedure:
To a solution of 3-Bromo-4-n-butylthiophene-2-carboxaldehyde of Example 1(b) 1.87 g, 7.57 mmol) in toluene (35 mL) was added (PPh3)4Pd (0.30 g, 0.20 mmol), Na2CO3 (2 M, 9 mL), EtOH (25 mL) and (2-methoxymethoxy-4-methoxyphenyl)boronic acid (1.76 g, 8.30 mmol), respectively. The resulting mixture was stirred at reflux for 3 h. After quenching with water and extraction with EtOAc, the organic extract was washed with H2O, brine and dried (MgSO4). The solvent was removed under reduced pressure and column chromatography (silica gel, EtOAc/Hexane, 25:75) of the residue afforded the title compound as an oil (1.80 g, 71%)
Reaction SMILES: CN(C)[C:3](=[O:6])[CH2:4][CH3:5].O=P(Cl)(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]([CH3:26])[CH:22]=[CH:23][C:24]=2[CH3:25])=[CH:16][CH:15]=1.O.O.O.C([O-])(=O)C.[Na+]>ClCCCl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]([CH3:26])[C:22]([C:3](=[O:6])[CH2:4][CH3:5])=[CH:23][C:24]=2[CH3:25])=[CH:18][CH:19]=1
Reactant: Cc1ccn(C)c1-c1ccc(Cl)cc1
Reactant: CCC(=O)N(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.8 %

Procedure:
N,N-dimethyl propionamide (3.24 g, 3.52 ml, 32.08 mmol) was cooled at 0-5° C. and and to this was added POCl3 (4.9 g, 2.9 ml, 32.08 mmol) slowly in a dropwise manner. The resulting mixture was then stirred at room temperature (about 25° C.) for 20 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (60 ml) and cooled to 0° C. To the cooled reaction mixture was then added a solution of 2-(4-chlorophenyl)-1,3-dimethyl-1H-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 6.0 g, 29.17 mmol) in 1,2-dichloroethane (60 ml) dropwise. The reaction mixture was then heated to reflux for 30 minutes. The progress of the reaction was monitored by TLC. The mixture so obtained was allowed to cool to room temperature and was diluted with aqueous solution of sodium acetate trihydrate (21.8 g, 160.4 mmol in 45 ml water). The mixture so obtained was further heated to reflux for 30 minutes, two layers were separated. The aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic layer was washed with water (1×100 ml) and dried over anhydrous Na2SO4. The solvent from the reaction mixture was evaporated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography over silica gel (100-200 mesh) using 4-6% ethyl acetate in hexanes as an eluent to obtain the title compound (6.55 g, 85.8%)
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[CH:7][CH:8]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.[CH3:17]C1(C)C(C)(C)OB(C2C=NNC=2)O1>>[C@@H:8]12[CH2:9][C@@H:5]([CH:6]=[CH:7]1)[CH2:4][C@H:3]2[CH2:17][N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: CN(C)c1cccc(CO)c1
Reactant: c1cn[nH]c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: C1=C[C@H]2C[C@@H]1C[C@H]2Cn1cccn1

Procedure:
The title compound was prepared by substituting (1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethanol for (3-(dimethylamino)phenyl)methanol and pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=1)#[N:4].Cl[C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[C:3]([C:5]1[CH:20]=[C:19]([CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1)#[N:4]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2C#N)cc1F
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 4-(2-cyano-4-(hydroxymethyl)phenoxy)-2-fluorobenzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=O)OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:33][C:34]1[CH:43]=[C:42]2[C:37](C(N)=[N:39][CH:40]=[N:41]2)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]3[C:37]4[C:42](=[CH:43][C:34]([F:33])=[CH:35][CH:36]=4)[N:41]=[CH:40][N:39]=3)=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncnc2cc(F)ccc12
Product: O=c1c(CNc2ncnc3cc(F)ccc23)cn(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
7-Chloro-3-[(7-fluoro-quinazolin-4-ylamino)-methyl]-1-phenyl-1H-quinolin-4-one was prepared according to the procedure described above for example 12-1, starting with intermediate M and 7-fluoro-quinazolin-4-amine. MS calcd. for C24H16ClFN4O [(M+H)+] 430.9, obsd. 431.3
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li:15])CCC>C(OCC)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Li+:15]
Reactant: O=C(O)c1ccccc1F
Reactant: [Li]CCCC
Solvent: CCOCC
Product: O=C([O-])c1ccccc1F
Product: [Li+]
Temperature: -78 °C

Procedure:
In a nitrogen-purged 500 milliliter flask o-fluorobenzoic acid (7.01 grams, 50 millimoles) was added along with 100 milliliters of anhydrous diethyl ether. The flask was cooled to -78° C. and n-butyllithium (34 milliliters/1.6M in hexane, 54.4 millimoles) was slowly added to form the lithium o-fluorobenzoate. The white precipitate was allowed to warm to room temperature (slurry 1). In a separate 250 milliliter flask purged with nitrogen was added dicyclohexylphosphine (9.91 grams, 50 millimoles) along with 100 milliliters of anhydrous diethyl ether. This solution was cooled to -78° C. and n-butyllithium (36 milliliters/1.6M in hexane, 57.6 millimoles) was added dropwise. The solution was allowed to warm slowly to room temperature, whereupon it turned bright yellow near -10° C. (slurry 2). The yellow chemiluminescent phosphide was allowed to stir at room temperature for approximately 1-2 hours. Slurry 1 was recooled to -78° C. and slurry 2 was added via cannulus over 8-10 minutes. The solution was allowed to warm to room temperature overnight whereupon it assumed a dark red/rust color. The solution was then filtered and 250 milliliters of degassed deionized water was added to extract the anion. Initially upon water addition, the solution became greenish, then more yellow as more water was added. The layers were separated in a separatory funnel and the organic phase was back-extracted with two 75 milliliter portions of water. The water layers were combined and acidified to pH 3 with diluted hydrochloric acid. An off-white precipitate forms which can be isolated by filtration, water-washing, and drying at 30°-90° C. for several hours. Isolated yield of air- and water-stable 1,1-dicyclohexyl-3-oxo[3H-2,1-benzoxaphosphole] was 10.8 grams, a 68% yield.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])[CH:5]=[CH:6][CH:7]=1.[N:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)=[N+:22]=[N-:23].O.[O:39]=[C:40]1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[CH3:40][O:39][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[N:23]=[N:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=3)[CH:16]=2)=[O:12])=[CH:3][CH:2]=1
Reactant: C#CCNC(=O)c1cccnc1Nc1cccc(F)c1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(Nc2ncccc2C(=O)NCc2cn(Cc3cccc(Oc4ccccc4)c3)nn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 723.8 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 3-fluoroaniline (9f, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(3-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10f as pure product. To a solution of 2-(3-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10f, 150 mg, 0.55 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 86 mg, 0.61 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1e (220 mg, 80%); mp: 130-132° C.; 1H NMR (300 MHz, CDCl3) δ 10.62 (s, 1H), 8.31 (dd, J=3.0, 1.7 Hz, 1H), 7.83 (dd, J=3.0, 1.7 Hz, 1H), 7.78-7.73 (m, 1H), 7.59-7.53 (m, 2H), 7.36-7.18 (m, 3H), 7.12 (t, J=7.5 Hz, 1H), 6.99-6.91 (m, 5H), 6.71-6.66 (m, 2H), 5.48 (s, 2H), 4.66 ppm (d, J=5.6 Hz, 2H); MS (ESI m/z): 495 [M+H]+. Yield: 80%
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]2[CH2:61][CH2:60][N:59]([CH2:62][C:63]([NH2:65])=[O:64])[CH2:58][CH2:57]2)=[CH:52][C:51]=1[O:66][CH3:67]>CN(C=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:49][C:50]4[CH:55]=[CH:54][C:53]([CH:56]5[CH2:61][CH2:60][N:59]([CH2:62][C:63]([NH2:65])=[O:64])[CH2:58][CH2:57]5)=[CH:52][C:51]=4[O:66][CH3:67])=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc(C2CCN(CC(N)=O)CC2)ccc1N
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(CC(N)=O)CC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.1 %

Procedure:
In a 10 mL sealed tube, to N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (127.4 mg, 0.368 mmol) and N,N-Diisopropylethylamine (0.257 mL, 1.47 mmol) in 3.2 mL of anhydrous DMF was added N-Phenylbis(trifluoromethane-sulfonimide (113 mg, 0.318 mmol). After stirring at room temperature for 1 hour, 2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetamide (92 mg, 0.349 mmol) was added. The reaction mixture was heated at 65° C. overnight. The reaction was conc. in vacuo. The reaction mixture was purified via silica gel column chromatography using DCM then 500:15:10 DCM:MeOH:7N NH3/MeOH as the eluant. The collected fractions afforded 2-(4-{4-[7-(3-tert-Butylsulfamoylphenyl)pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-3-methoxyphenyl)piperidin-1-yl)-acetamide as a yellow solid (23.0 mg, 11%). MP 250-252° C. LCMS (E/I+) 592.25 (M+H). 1H NMR (DMSO-d6)-9.02 (s, 1H), 8.55 (s, 1H), 8.37 (d, 1H, J=7.84 Hz), 7.99 (d, 1H, J=7.96 Hz), 7.85 (s, 1H), 7.83 (s, 1H), 7.69 (t, 1H, J=7.86 Hz), 7.63 (s, 1H), 7.23 (d, 1H, J=4.80 Hz), 7.21 (br s, 1H), 7.15 (br s, 1H), 7.01 (d, 1H, J=4.72 Hz), 6.95 (s, 1H), 6.92 (s, 1H), 3.88 (s, 3H), 2.97-2.90 (m, 2H), 2.88 (s, 2H), 2.49-2.41 (m, 1H), 2.22-2.11 (m, 2H), 1.84-1.72 (m, 4H), 1.12 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH2:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28][OH:29])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: CCNCCO
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and Ethyl-(2-hydroxy-ethyl)-amine were converted to yield 2-({4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-amino)-ethanol, MS: 462 (MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1c(Cl)cccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=399.1, tR (minutes, Method F)=3.06. [α]D20=+31.97 (c=1.22 mg/mL,CHCl3)
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH2:21][CH3:22])[CH:5]=[C:4]([C:23]2[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:31][CH3:32])[N:3]=1.CN.[CH3:35][N:36]1C(=O)CCC1.O>CCCCCC>[CH2:31]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH2:29][CH3:30])[C:23]=1[C:4]1[N:3]=[C:2]([NH:36][CH3:35])[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH2:21][CH3:22])[CH:5]=1)[CH3:32]
Reactant: CN1CCCC1=O
Reactant: CCc1cc(-c2c(CC)cccc2CC)nc(Cl)c1CN(C)[C@H]1CCCc2ccccc21
Agent: CN
Solvent: O
Solvent: CCCCCC
Product: CCc1cc(-c2c(CC)cccc2CC)nc(NC)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 110 °C

Procedure:
A mixture of (S)-[2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-pyridin-3-ylmethyl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (50 mg), anhydrous MeNH2 (2 mL) and NMP (3 mL) is heated in a sealed tube at 110° C. overnight. On cooling, water (10 mL) and hexane (20 mL) are added and the organic layer is separated. The organic layer is washed with brine, dried and concentrated. The residue is purified by PTLC (8:1 Hexane/EtOAc) to give the desired product. 1H NMR (CDCl3) 7.45 (d, 1H), 7.10-7.26 (m, 6H), 6.82 (br, 1H), 6.32 (s, 1H), 3.95 (m, 1H), 3.77 (m, 2H), 2.30 (s, 3H), 2.75 (m, 2H, 2.65 (m, 2H), 2.42 (m, 4H), 2.11 (s, 3H), 1.80-2.10 (m, 2H), 1.07-1.27 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.[B-](F)(F)(F)F.[N:22]([OH:24])=[O:23]>C(#N)C>[N+:22]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[NH:8][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)[C:13]#[N:14])([O-:24])=[O:23]
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Reactant: O=NO
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: N#Cc1ccc(Nc2nccc(Cl)n2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 129.1 %

Procedure:
A mixture of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.005 mol) and nitryl tetrafluoroborate (0.0025 mol) in acetonitrile (5 ml) was stirred at room temperature for 4 h. The material was quenched with saturated bicarbonate (50 ml) on cracked ice. The mixture was allowed to reach room temperature, and the yellow solid was filtered off. The solid was adsorbed onto silica and purified by column chromatography (eluent: 30%, 50%, 60%, 70% CH2Cl2 in hexanes). The solvent of the desired fraction was evaporated and the residue was dried, yielding 0.89 g (64%) of 3-nitro-4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile.(interm. 51).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].C(OC([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][N:23]([C:38]([C@H:34]4[CH2:35][CH2:36][CH2:37][NH:33]4)=[O:39])[CH2:24][CH:25]=3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCNCC3)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a stirred solution of (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole (0.038 g, 0.10 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.044 g, 0.20 mmol) in dichloromethane (1 mL) was added HATU (0.078 g, 0.20 mmol) and Et3N (0.10 mL g, 0.72 mmol). The reaction mixture was stirred at room temperature for 30 min, followed by dilution with dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to afford the desired product (0.037 g, 0.065 mmol, 65%).
Reaction SMILES: C([S:4][C:5]1[NH:6][C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)C=C.N1C2C(=CC=CC=2)[CH:27]=[CH:26][CH:25]=1.C(O[C:38](=[O:40])[CH3:39])(=O)C>>[C:38]([S:4][C:5]1[NH:6][C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:9]=1[CH2:27][CH:26]=[CH2:25])(=[O:40])[CH3:39]
Reactant: C=CCSc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Reactant: c1ccc2ncccc2c1
Reactant: CC(=O)OC(C)=O
Product: C=CCc1c(SC(C)=O)[nH]c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
A solution of 3.6 g (0.01 mole) of 2-allylthio-4,5-bis(4-chlorophenyl)pyrrole in 20 ml acetic anhydride was added dropwise to 20 ml quinoline preheated at 170°. The mixture was kept at 170° an additional 45 minutes, then cooled. Most of the acetic acid, acetic anhydride and quinoline were removed by distillation under reduced pressure. The residue was chromatographed on 125 g of Silic AR CC-7, eluting with toluene, to give, after recrystallization from hexane/methyl cyclohexane, 2.7 g of white product, m.p. 131°-2°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([OH:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([O:41][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2F)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 547.1 (M+H)+.