Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:11]=2[O:21][CH3:22])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(P([Ni-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH3:22][O:21][C:11]1[CH:12]=[CH:13][C:14]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(OC(F)(F)F)cc1CNc1cccnc1Cl
Agent: Cl[Ni-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1CNc1cccnc1-c1ccccc1
Temperature: 4 °C
Reaction time: 0.67 h
Yield: 51.1 %

Procedure:
To a 250mL 3 neck round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were charged 98.1 mL of tetrahydrofuran, 3.27 grams (9.83 mmoles) of the 2-chloro-3-(2-methoxy-5trifluoromethoxybenzylamino) pyridine and 1.93 grams (2.95 mmoles) of bis(triphenylphosphino)nickel(II) chloride. The black reaction mixture was stirred at 25 degree celsius for 40 minutes. Phenylmagnesium bromide (1M/THF, 38.4 mL, 38.4 mmoles) was added over a 25 minute period and the resulting black slurry was stirred for 2 hours at 25 degree celsius. During this time, the reaction was monitored by thin layer chromatography assay. The reaction mixture was cooled to 4° C., and quenched with 5.89 mL acetic acid. The reaction mixture was vacuum concentrated to a low volume and partitioned between 100 mL each of toluene and water. The organic layer was washed several times with water and concentrated to an oil. The oil was purifid by column chromatography to yield 1.88 grams (51.1%) of the desired material (as an oil). The structure of this compound was assigned on the basis of high resolution NMR. 1H NMR (CDCl3) 8.05 (d, 1H), 7.63 (d, 2H), 7.45 (m, 3H), 7.12 (bs, 1H), 7.08 (m, 2H), 6.93 (dd, 1H), 6.85 (d, 1H), 4.71 (t, 1H), 4.26 (d, 2H), 3.78 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.C(=O)([O-])[O-].[K+].[K+].N1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O>[N:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=2[C:12]#[N:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1cccc(N2CCCCC2)c1C#N
Yield: 55 %

Procedure:
A mixture of 3-nitrophthalonitrile (497 mg, 2.87 mmol), freshly dried potassium carbonate (2.0 g, 14 mmol) and piperidine (10 mL) was heated at reflux for 4 h. The reaction mixture was poured into water (200 mL) to precipitate the product, which was filtered off and washed with water. The crude product was purified by recrystallisation from aqueous ethanol to give 3 as a beige powder (332 mg, 55%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[S:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2)(=[O:15])(=[O:14])[NH2:13].N1CCCCC1>C(O)C>[S:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:1][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)(=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 3-formyl-7-azaindole (1.46 g, 10 mmol), 5-sulfamoyl-2-oxindole (2,122 g, 10 mmol) and piperidine (0,255 g, 3 mmol) in absolute ethanol (50 ml) was treated for 3 h at reflux. The reaction mixture was chilled to room temperature, the precipitate filtered, the residue washed with ice-cold ethanol and dried under vacuum. Almost pure title compound was so obtained in about 70% yield. Compounds of higher purity were obtained by crystallization from ethanol.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:26][C:27]1[CH:44]=[CH:43][C:42]([C@H:45]2[C@H:50]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@@H:49]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:48]([O:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:47]([CH2:75][O:76][CH2:77][C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[O:46]2)=[CH:41][C:28]=1[CH2:29][C:30]1[CH:40]=[CH:39][C:33]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(Cl)Cl.CCN(CC)CC>[Cl:26][C:27]1[CH:44]=[CH:43][C:42]([C@H:45]2[C@H:50]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@@H:49]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[C@H:48]([O:67][CH2:68][C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[C@@H:47]([CH2:75][O:76][CH2:77][C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)[O:46]2)=[CH:41][C:28]=1[CH2:29][C:30]1[CH:40]=[CH:39][C:33]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:1](=[O:3])[CH3:2])=[CH:32][CH:31]=1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CNC2CC2)cc1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetic acid (0.11 g) and Et3N (0.14 mL) in CH2Cl2 (1 mL) at room temperature, EDCI (96 mg) and HOBt (68 mg) was added. The mixture was stirred for 30 min at room temperature. A solution of N-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)cyclopropanamine (Intermediate AQ) (40 mg) in CH2Cl2 (0.2 mL) was added dropwise. The reaction was monitored by LC-MS. After the starting material was consumed, CH2Cl2 was added to dilute the solution. The resulting mixture was then washed with H2O, 1N HCl, aqueous NaHCO3 and brine. CH2Cl2 was removed under reduced pressure, and the crude product was purified by preparative TLC to give intermediate AR (20 mg). MS ESI (m/z): 836 (M+H)+, 853 (M+NH4)+.
Reaction SMILES: Br[C:2]1[C:7]2[C:8]3[CH:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:20]=[N:19][C:9]=3[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[CH:5]=[N:4][C:3]=1[C:29]#[N:30].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([SH:44])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CC(C)([O-])C.[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([S:44][C:2]2[C:7]3[C:8]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=5)[CH:20]=[N:19][C:9]=4[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[CH:5]=[N:4][C:3]=2[C:29]#[N:30])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cn1cc(-c2cnc3c(c2)c2c(Br)c(C#N)ncc2n3COCC[Si](C)(C)C)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: COCCOC
Product: Cn1cc(-c2cnc3c(c2)c2c(SC4CCN(C(=O)OC(C)(C)C)CC4)c(C#N)ncc2n3COCC[Si](C)(C)C)cn1
Temperature: 100 °C
Yield: 68.4 %

Procedure:
To a degassed suspension of 5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (120 mg, 0.25 mmol), 4-mercaptopiperidine-1-carboxylic acid tert-butyl ester (54 mg, 0.25 mmol) and sodium tert-butoxide (26.4 mg, 0.28 mmol) in dimethoxyethane (0.4 mL) in a sealed 5 ml microwave vial was added a degassed solution of palladium(II) acetate (2.2 mg, 0.01 mmol) and (R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (5.5 mg, 0.01 mmol) in dimethoxyethane (1.0 mL). The reaction mixture was heated at 100° C. for 22 h then cooled to ambient temperature and concentrated in vacuo. The resultant residue was adsorbed onto HM-N then purified by flash chromatography (silica, 50 g column, Si-SPE, 0-10% (2M ammonia in MeOH) in DCM) to afford the title compound as a yellow solid (106 mg, 68%). 1H NMR (DMSO-D6, 300 MHz): 9.33 (s, 1H), 9.11-9.06 (m, 2H), 8.35 (s, 1H), 8.05-8.01 (m, 1H), 6.05 (s, 2H), 3.93 (s, 3H), 3.86-3.73 (m, 2H), 3.64-3.53 (m, 2H), 2.97-2.78 (m, 3H), 1.97-1.83 (m, 2H), 1.64-1.45 (m, 2H), 1.35 (s, 9H), 0.87-0.78 (m, 2H), −0.17 (s, 9H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.CON(C)[C:33](=[O:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:35]1([CH2:34][C:33]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=2)=[O:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CON(C)C(=O)Cc1ccccc1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-iodo-l-tritylimidazole (commercially available, 5.08 g, 13.7 mmol) in dichloromethane (100 mL) at −10° C. was treated with ethylmagnesium bromide (4.5 mL, 13.7 mmol, 3M in ether) and allowed to react for 45 m. A solution of N-methoxy-N-methyl-2-phenylacetamide, (Intermediate 13) (2.0 g, 11.2 mmol) in dichloromethane was added via syringe at −10° C. and stirred for 16 hours at room temperature. The mixture was quenched with water (50 mL) and a saturated solution of ammonium chloride (50 mL). The residue was isolated in a typical aqueous workup and purified by MPLC with 3 to 5% MeOH:CH2Cl2 to give 2-phenyl-l-(1-trityl-1H-imidazol-4-yl)ethanone, (Intermediate 14) as a solid, (4.65 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[C:24]1([S:30]([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([S:30]([N:33]2[CH:37]=[C:36]([C:2]3[CH:3]=[CH:4][C:5]4[O:14][CH2:13][CH2:12][C:11]5[S:10][C:9]([C:15]6[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=6)=[N:8][C:7]=5[C:6]=4[CH:23]=3)[CH:35]=[N:34]2)(=[O:32])=[O:31])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC1(C)OB(c2cnn(S(=O)(=O)c3ccccc3)c2)OC1(C)C
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cnn(S(=O)(=O)c4ccccc4)c3)cc1-2
Yield: 39 %

Procedure:
9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted under palladium Suzuki conditions to give 301 (39% yield). LC/MS(ESI+): m/z 519 (M+H). 1H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.62 (d, J=2.1, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 8.03 (d, J=7.6, 2H), 7.81 (t, J=7.5, 1H), 7.75-7.60 (m, 3H), 7.12 (d, J=8.4, 1H), 5.82 (dt, J=13.0, 6.6, 1H), 4.39 (t, J=4.8, 2H), 3.46 (t, J=4.9, 2H), 1.59 (d, J=6.6, 6H)
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][CH3:13].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4]=2[CH2:12][CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCc1oc2ccccc2c1C(Cl)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: CCc1oc2ccccc2c1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 77.3 %

Procedure:
Using 3-[chloro(cyclohexyl)methyl]-2-ethyl-1-benzofuran (300 mg) synthesized in Example A26(2) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (255 mg) synthesized in Example 1(2) and in the same manner as in Example A22(4), the title object compound (374 mg, 77%) was obtained as a pale-brown solid.
Reaction SMILES: [C:1]([O:5][C@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[Cl:40]>>[C:1]([O:5][C@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[Cl:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1ccc(CBr)c(Cl)c1
Product: Cc1nc2c(ccn2Cc2ccc(F)cc2Cl)c(-c2ccc3c(c2)CCCO3)c1[C@@H](OC(C)(C)C)C(=O)O
Temperature: 40 °C

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from (R)-methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-2-chloro-4-fluorobenzene, but finally purified on a ChiralPak ADH column (250×30 mm i.d., 5 um; ChiralTechnologies, West Chester, Pa.) under supercritical conditions maintained at 40° C., 140 bar, with MeOH modified CO2 (25% Isopropanol, 75% CO2) delivered at a combined flow rate of 90 g/min on a PIC Preplab 200 SFC system (Avignon, France). Triggered collections were made using a Knauer selectable wavelength UV-Vis detector at 230 nm (Rt=3.67 minutes): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.42 (m, 1 H), 7.25-7.15 (m, 2 H), 7.13-7.06 (m, 2 H), 6.96-6.88 (m, 2 H), 6.30 (dd, J=3.5, 11.9 Hz, 1 H), 5.70-5.63 (m, 1 H), 5.61-5.51 (m, 2 H), 4.32-4.25 (m, 2 H), 2.95-2.79 (m, 2 H), 2.76 (d, J=1.6 Hz, 3 H), 2.15-2.04 (m, 2 H), 1.07-0.87 (s, 9 H); LC/MS (m/z) ES+=537.31 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.[CH2:24](I)[CH3:25]>>[CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][N:20]([CH2:24][CH3:25])[C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1
Reactant: CCI
Reactant: Cc1cccc(C#Cc2nc(C)n(-c3cc[nH]c(=O)c3)c2C)c1
Product: CCn1ccc(-n2c(C)nc(C#Cc3cccc(C)c3)c2C)cc1=O

Procedure:
The title compound, light brown solid, MS: m/e=332.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[2,5-dimethyl-4-m-tolylethynyl-imidazol-1-yl]-1H-pyridin-2-one and ethyl iodide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[N:11]=[C:10]([OH:17])[N:9]=2)=[CH:4][CH:3]=1.CN(C=O)C.[Br:23]N1C(=O)CCC1=O>O>[Br:23][C:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][C:10]([OH:17])=[N:11][C:12]=1[CH:14]([CH3:15])[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cc(-c2ccc(F)cc2)nc(O)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nc(O)nc(-c2ccc(F)cc2)c1Br
Temperature: -3 °C
Yield: 98.5 %

Procedure:
4-(4-Fluorophenyl)-6-isopropylpyrimidin-2-ol (8.00 g, 34.1 mmol) was charged to a reactor followed by DMF (100 mL). The suspension was stirred, cooled to −3° C. and N-bromosuccinimide (6.25 g, 34.8 mmol) added. The reaction mixture was warmed to 20° C. and stirred overnight. Water (100 mL) was charged to the reaction mixture and the crystalline mixture stirred for 1 hour before filtering off. The isolated solid was washed twice with water (25 mL) and the solid dried in a vacuum oven at 50° C. 5-Bromo-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-ol (10.45 g, 97% yield) was obtained as a white solid;
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[NH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:5][CH2:4]1)#[N:2]
Reactant: NCCCN
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: N#CC1(c2ccccc2)CCC(NCCCN)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
A mixture of 4-cyano-4-phenylcyclohexanone (5.0 g, 25.09 mmol) and 1,3-diaminopropane (5.58 g, 75.3 mmol) and p-toluenesulfonic acid (23 mg) in benzene (50 mL) was refluxed for 4 h in Dean-Stark trap to remove the water that formed. Solvent was evaporated and the residue was redissolved in methanol (40 mL) and cooled to 0° C. To this, sodium borohydride (6.4 5 g) was added in portions and the mixture was stirred at room temperature for 3 h. Solvent was evaporated, the residue was dissolved in dichloromethane (300 mL), washed with brine (3×500 mL), dried (potassium carbonate), and the solvent evaporated to leave the product as a pale yellow viscous oil (4.5 g, 72%). The 1H-NMR showed this product to be pure and found to contain the cis/trans isomers in the ratio of about 4:1.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)#[N:2].C[O-].[Na+].[C:11](O)(=[O:13])C>CO>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1](=[NH:2])[O:13][CH3:11]
Reactant: CC(=O)O
Reactant: N#Cc1cccs1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 817.7 %

Procedure:
2-cyanothiophene (5.46 g, 50 mmol) was dissolved in methanol (25 ml), and sodium methoxide (0.27 g, 5 mmol) was added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, acetic acid (0.33 g, 5.5 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (40 ml) was added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 2-thiophenecarboximidate (6.35 g) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:30]>>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[CH2:28][N:10]2[CH2:11][CH2:12][C:13]3[C:14]([CH3:16])([CH3:17])[O:15][C:6]4[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[C:2]([OH:1])[C:7]=4[C:8]=3[CH2:9]2)=[CH:37][CH:36]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)Nc2ccc(Cl)cc2)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N-(4-chlorophenyl)acetamide according to the method of Example 1; m.p. 159°-160°.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][NH:28][C:27](=[O:31])[C:26]1=[O:32])[CH3:24].CNCCNC.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O1CCOCC1.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[C:26](=[O:32])[C:27]4=[O:31])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: CCN1CCNC(=O)C1=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc(-n3cnc(CNC(=O)c4ccc(Cl)s4)c3)cc2)C(=O)C1=O
Temperature: 110 °C
Yield: 13.6 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (70 mg, 0.16 mmol), N-ethylpiperazine-2,3-dione (45 mg, 0.32 mmol), N,N′-dimethylethylenediamine (0.020 mL, 0.19 mmol) and K2CO3 (65 mg, 0.47 mmol) in DMSO (1 mL) and dioxane (1 mL) was degassed with Ar before being charged with CuI (20 mg, 0.10 mmol). The mixture in a sealed tube was heated at 110° C. overnight. The mixture was then purified by HPLC to give the titled compound (10 mg). MS 458.1 and 460.1(M+H, Cl pattern).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:25])[NH:13][C@@H:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)[CH2:15][OH:16])([CH3:10])([CH3:9])[CH3:8].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.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>[OH:16][CH2:15][C@@H:14]([NH:13][C:12](=[O:25])[O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)[CH:19]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(Br)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(C[C@@H](CO)NC(=O)OC(C)(C)C)c2)cn1
Yield: 44.8 %

Procedure:
To 0.7 M potassium carbonate in water was added tert-butyl[(1S)-1-(3-bromobenzyl)-2-hydroxyethyl]carbamate [prepared according to Intermediate 15, Step A] (1.00 g, 3.03 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.82 g, 3.9 mmol) and 1,4-dioxane (26 mL, 340 mmol) and 2.0 M sodium carbonate in water (6.0 mL, 12 mmol). The mixture was flushed with nitrogen for 10 min. To the mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) and the mixture was heated at 100° C. for 30 min. The resulting mixture was purified on 40 g silica gel, 0-100% EtOAc in hexanes, and the pure fractions were combined, and solvent removed under vacuum to give 0.45 g of white solid. LC-MS found: 332.2 (m+1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH2:22]([NH:25][OH:26])[CH2:23][CH3:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:25]([OH:26])[CH2:22][CH2:23][CH3:24])=[O:18])[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: CCCNO
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: CCCN(O)C(=O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-propyl hydroxylamine hydrochloride in a manner similar to step 8 of example 1. 1H NMR (DMSO-d6) δ ppm 11.93 (br s, 1H), 8.88 (s, 1H), 7.99 (s, 1H), 7.88 (d, 1H, J=3.0 Hz), 7.34 (m, 2H), 7.15 (d, 2H, J=8.8 Hz), 6.69 (d, 1H, J=3.0 Hz), 5.56 (s, 2H), 3.66 (t, 2H, J=7.1 Hz), 1.64 (m, 2H), 0.83 (s, 3H). LCMS (API-ES, M+H+): 328.1. HRMS calcd for C18H19FN3O2 (M+H) 328.1456, found 328.1458. HPLC: 100% purity.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([O-:8])=[O:7].N1C=CC=CC=1>O1CCCC1>[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
Propionyl chloride (25.0 g, 270 mmol) was added dropwise to a solution of 4-nitroaniline (24.9 g, 180 mmol) and pyridine (43.7 ml, 540 mmol) in tetrahydrofuran (500 ml) under ice-cooling, the mixture was stirred under ice-cooling for 2 hour, and the solvent was distilled off under reduced pressure. The residue was poured into ice-water, and 33.5 g (95.7%) of the desired product was collected by filtration as a solid.