Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH2:9])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14].C([O:22][C:23](=O)[C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25])(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:14]([C:13]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:11]([CH3:10])[CH:12]=2)[C:23](=[O:22])[C@@H:24]([OH:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][CH:7]=1
Reactant: C=Cc1ccc(Cl)cn1
Reactant: Cc1ccc(N)cc1C
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Product: Cc1ccc(N(CCc2ccc(Cl)cn2)C(=O)[C@@H](O)c2ccccc2)cc1C

Procedure:
In analogy to example 25 step 1 and 26 step 1-2, [2-(5-Chloro-pyridin-2-yl)-ethyl]-(3,4-dimethyl-phenyl)-amine obtained by reacting 5-Chloro-2-vinyl-pyridine (CAS: 223445-06-5) with 3,4-dimethylaniline was coupled with (S)-(+)-O-acetyl-L-mandelic acid then hydrolysed to provide the title compound. MS(m/e): 395.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[C:24]([CH:28]1[CH2:33][CH2:32][CH:31](O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:24]([C@H:28]1[CH2:33][CH2:32][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C1CCC(O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1

Procedure:
(R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (2.0460 g, 0.0084108 mol) was dissolved in tetrahydrofuran (20 mL, 0.2 mol) in a 100 mL RBF equipped with a magnetic stir bar. 4-tert-Butyl-cyclohexanol (1.58 g, 0.0101 mol) was added, followed by triphenylphosphine (3.53 g, 0.0134 mol) and the mixture was stirred for a few minutes. Diisopropyl azodicarboxylate (2.65 mL, 0.0134 mol) was then slowly added and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The resulting product was adsorbed to silica gel and purified by flash chromatography (0-55% EtOAc in hexanes) to give 2.07 g of the title compound (64% yield). MS: m/z=382.23 [M+1] 1H NMR (MeOD) δ: 7.77-7.85 (m, 3H), 7.48 (dd, J=8.5, 2.0 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.16 (dd, J=8.8, 2.5 Hz, 1H), 4.49-4.54 (m, 1H), 4.41-4.46 (m, 1H), 4.32-4.41 (m, 1H), 2.25-2.35 (m, 2H), 1.94 (d, J=13.3 Hz, 2H), 1.81 (s, 3H), 1.38-1.52 (m, 2H), 1.16 (d, J=11.8 Hz, 2H), 0.92-0.98 (m, 9H)
Reaction SMILES: [CH3:1][Mg]Br.[N:4]1([C:10]2[N:11]=[C:12]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][CH:33]=3)[C:13]3[CH2:19][CH2:18][N:17]([C:20]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15][C:14]=3[N:30]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>CCOCC.C1COCC1>[N:4]1([C:10]2[N:11]=[C:12]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:40])([CH3:1])[CH3:39])=[CH:36][CH:37]=3)[C:13]3[CH2:19][CH2:18][N:17]([C:20]4[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15][C:14]=3[N:30]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(=O)c1ccc(Nc2nc(N3CCCCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Nc2nc(N3CCCCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
To a solution of methylmagnesium bromide (170 mL of a 3.0 M solution in Et2O, 0.51 mmol) in THF at 0° C. was added a solution of 1-[4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone (Example 156; 59.8 mg, 0.117 mmol) in THF. The solution was allowed to warm to rt over 1 h, and stirred at rt for an additional 5 min. The reaction mixture was then quenched with satd. aq. NH4Cl and extracted with EtOAc. The organic layers were combined, dried, and concentrated. The crude residue was purified (FCC) to give the title compound (51 mg, 83%). MS (ESI): mass calcd. for C28H33F3N6O, 526.27; m/z found, 527.3 [M+H]+. 1H NMR (CDCl3): 8.39-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H), 7.55-7.51 (m, 2H), 7.46-7.41 (m, 2H), 6.94-6.90 (m, 1H), 6.35 (s, 1H), 3.77-3.69 (m, 4H), 3.63-3.53 (m, 4H), 3.10-3.03 (m, 2H), 2.87-2.80 (m, 2H), 1.70 (s, 1H), 1.66-1.60 (m, 6H), 1.54 (s, 6H).
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][CH2:9][O:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].CNN>ClCCl>[C:1]([Si:5]([CH3:22])([CH3:23])[O:6][CH2:7][CH2:8][CH2:9][O:10][NH2:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCON1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCON
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A solution of 2-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-isoindole-1,3-dione (26.3 g, 78.3 mmol) in dichloromethane (120 mL) was cooled to 0° C. and treated with methylhydrazine (16.1 g, 78.3 mmol). The reaction mixture was stirred for 30 min at 0° C. and filtered. The filtrate was concentrated under reduced pressure, redissolved in ether, and refrigerated (4° C.) overnight. The resultant crytalline material was removed by filtration and the filtrate was concentrated under reduced pressure to afford O-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-hydroxylamine (15.95 g, 99% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.69 (br s,2H), 3.74 (t, J=6.3 Hz, 2H), 3.67 (t, J=6.3 Hz, 2H), 1.78 (quintet, J=6.3 Hz, 2H), 0.88 (s, 9H), 0.00 (s, 6H); MS (APCI+)=206.1. Anal. Calcd./Found for C9H23NO2Si: C, 52.64/52.22; H, 11.29/10.94; N, 6.82/6.46.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N2CCN(Cc3ccc(N)cc3)CC2)c1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: COc1cccc(N2CCN(Cc3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)c1

Procedure:
In the manner given in Example 1C, 1-(m-methoxyphenyl)-4-[(4-aminophenyl)methyl]piperazine and 4,7-dichloroquinoline are reacted together at reflux to give 4-[[4-[[4-(m-methoxyphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-chloroquinoline.
Reaction SMILES: [N+:1]([C:4]1C=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=CN=[C:9]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)([O-])=O.[NH4+:25].[Cl-].[CH3:27][CH2:28]O.O>[Fe]>[F:22][C:21]([F:24])([F:23])[C:17]1[CH:16]=[C:15]([NH:14][C:9]2[C:10]3[CH:11]=[CH:12][N:25]=[C:4]([NH2:1])[C:5]=3[CH:6]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cccc2c(Nc3cccc(C(F)(F)F)c3)nccc12
Reactant: CCO
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Product: Nc1nccc2c(Nc3cccc(C(F)(F)F)c3)cccc12

Procedure:
To a solution of 5-nitro-N-(3-(trifluoromethyl)phenyl)isoquinolin-1-amine (1.0 g, 3.0 mmol) in a mixture of EtOH:H2O (8:2, 10 mL) were added iron powder (1.26 g, 4.8 mmol), and NH4Cl (1.6 g, 30.0 mmol). The reaction mass was heated at reflux for 2 h and filtered. The filtrate was concentrated and the residue was purified by column chromatography to afford 0.800 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.18 (s, 1H), 8.35 (s, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.42-7.24 (m, 3H), 6.86 (d, J=7.5 Hz, 1H), 5.84 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[C:11]=2[NH:15][C:16](=[O:24])[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:6]=1.[CH:26](=O)[CH2:27][CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[ClH:25].[ClH:25].[CH2:26]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[C:11]=2[NH:15][C:16](=[O:24])[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:6]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC=O
Reactant: NCCCc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCNCCCc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Product: Cl
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A solution of N-[2-(3-aminopropyl)-6-chloro-5-quinolinyl]-cyclohexaneacetamide (0.2 g) (Example 23), acetic acid (1 drop) and butanal (0.074 mL) in tetrahydrofuran was placed in a 10 mL vial and heated at 100° C. for 30 minutes within a microwave. Once the reaction had cooled to room temperature sodium triacetoxyborohydride (0.236 g) was added and the mixture stirred for 12 hours. The solvent was removed and the residue taken up in dimethylsulfoxide (3 mL). The residue was purified by HPLC (Waters Symmetry column using 25% to 95% acetonitrile in 0.1% aqueous trifluoroacetic acid). Further purification (SiO2, ammonia:methanol:dichloromethane, 1:4:95 as eluant) followed by removal of solvent and conversion to its hydrochloride salt with 4M hydrogen chloride in 1,4-dioxane (5 mL) afforded the title product (0.021 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][C:57]([O:60][Si](C(C)(C)C)(C)C)=[CH:56][CH:55]=3)[CH:46]([O:68][CH3:69])[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2].N1C=CC=CC=1.F>O1CCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=3)[CH:46]([O:68][CH3:69])[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: *CC(*)C
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(O)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4"'-t-butyldimethylsiloxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (190 mg in 2 ml tetrahydrofuran contained in a polypropylene vial) was added 500 μl of a solution of hydrogen fluoride-pyridine complex (40% in (2:1) tetrahydrofuran:pyridine) and the mixture stirred at room temperature. After 2 hours, the reaction was quenched by the careful addition of saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel (ethyl acetate:hexane (2:1) to give the title compound (50 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>ClCCl.CN(C=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([NH:1][C:30]([NH:29][C:24]3[CH:25]=[C:26]([Cl:28])[CH:27]=[C:22]([Cl:21])[CH:23]=3)=[S:31])[CH:3]=2)[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccc(C)c(Cl)c2)cc1N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(C)c(Cl)c2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 57.6 %

Procedure:
A solution of 3-amino-N-(3-chloro-4-methylphenyl)-4-methoxy-benzamide from Example 12 (0.581 g, 2.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.409 g, 2.00 mmol) in dichloromethane (40 mL) and DMF (3 mL) was allowed to stand at room temperature. After 16 hours, filtration afforded the product (0.57 g); m.p. 195-196° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25]>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:19]1[CH:20]=[CH:21][C:16]([NH2:15])=[C:17]([F:25])[CH:18]=1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: Nc1ccc(B(O)O)cc1F
Product: Nc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F

Procedure:
The title compound was synthesized using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (4-amino-3-fluorophenyl)boronic acid on a 0.059 mmol scale. 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluoroaniline was obtained as a orange solid (10 mg, 61%). 1H NMR (400 MHz, DMSO-d6): δ 9.63 (d, J=7.2 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.20 (d, J=7.2 Hz, 1H), 8.12 (dd, J=23.2, 2.0 Hz, 1H), 8.11 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 6.94 (t, J=8.8 Hz, 1H); MS (ESI) m/z [M+H]+279.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[N:21]([CH:22]4[CH2:24][CH2:23]4)[CH:20]=[N:19][CH:18]=3)[CH:12]=2)=[O:9])[CH:3]=1.B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:22]1([N:21]2[C:17]([C:13]3[CH:12]=[C:11]([NH:10][C:8]([C:4]4[CH:3]=[C:2]([C:3]5[CH:4]=[N:5][CH:6]=[CH:7][CH:2]=5)[CH:7]=[CH:6][N:5]=4)=[O:9])[CH:16]=[CH:15][CH:14]=3)=[CH:18][N:19]=[CH:20]2)[CH2:24][CH2:23]1
Reactant: O=C(Nc1cccc(-c2cncn2C2CC2)c1)c1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2cncn2C2CC2)c1)c1cc(-c2cccnc2)ccn1
Temperature: 95 °C
Yield: 46.3 %

Procedure:
A suspension of 4-bromo-N-(3-(1-cyclopropyl-1H-imidazol-5-yl)phenyl)picolinamide (75.0 mg, 0.196 mmol), boronic acid (33.8 mg, 0.274 mmol), dppf(Pd)Cl2 (14.3 mg, 0.0196), potassium carbonate (81.3 mg, 0.588 mmol) in degassed toluene (1 mL), degassed water (0.5 mL) and degassed isopropanol (0.5 mL) was heated at 95° C. for 2 hours. The aqueous phase was discarded and the solvent removed under reduced pressure from the organic portion. Purification by reverse phase HPLC provided N-(3-(1-cyclopropyl-1H-imidazol-5-yl)phenyl)-3,4′-bipyridine-2′-carboxamide (17.3 mg, 23%) as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][NH:16][C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]1.[CH3:27][O:28][CH2:29][CH2:30]Br>CN(C)C=O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]([CH2:30][CH2:29][O:28][CH3:27])[C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 17.6 mg, 0.264 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (75 mg, 0.220 mmol) in N,N-dimethyl formamide (2 mL) at 0° C. After 5 min, 2-bromoethyl methyl ether (0.025 mL, 0.264 mmol) was added and the mixture was allowed to warm to ambient temperature. After 3 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 421 (M+Na).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].[C:27]1([CH:33]2[CH2:35][O:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.CCOCC>[C:27]1([CH:33]([OH:34])[CH2:35][O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:3]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)([C:4]([F:6])([F:5])[F:7])[C:2]([F:25])([F:26])[F:1])[CH:19]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(COC(c2cccc(O)c2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: c1ccc(C2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(COC(c2cccc(OCC(O)c3ccccc3)c2)(C(F)(F)F)C(F)(F)F)cc1
Yield: 62.3 %

Procedure:
To 1 g (2.6 mmol) of 3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenol (example 5) in 8 mL of dioxane were added 1.0 mL (8.8 mmol) of 2-phenyl-oxirane. The reaction was split in 2 portions. To each of those was added 4.28 g (13.1 mmol) of Cs2CO3 and each reaction mixture was treated for 30 min at 130° C. in the microwave. The mixtures were combined and water and ether were added. The aqueous phase was extracted with ether and the combined organic phases were washed with brine and dried (Na2SO4). After evaporation of the solvent the crude products were separated by column chromatography to give 810 mg (62%) of rac 1-phenyl-2-{3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethanol as light yellow oil, MS: 500 (M)+, and 250 mg (19%) of rac 2-phenyl-2-{3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethanol as light yellow oil, MS: 500 (M)+.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:26]1[NH:25][CH:29]=[CH:28][N:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ncc[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mix carbon tetrabromide (49.8 g, 150 mmol) and methylene chloride (75 mL) and cool to 0° C. Add, by dropwise addition, a solution of triphenylphosphine (78.6 g, 300 mmol) in methylene chloride (75 mL). Stir at 0° C. for 30 minutes. Add, by dropwise addition, a solution of 2-imidazole-carboxaldehyde (7.57 g, 78.8 mmol) in methylene chloride (75 mL). Remove the cooling bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)=[O:3].[Br:21]Br>C(Cl)(Cl)Cl>[CH:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:2]([CH2:1][Br:21])=[O:3])=[CH:5][C:6]=2[N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
In 60 ml of chloroform there was dissolved 5.4 g of 4-benzyloxy-3-nitroacetophenone and after adding dropwise to the solution a mixture of 3.2 g of bromine and 5 ml. of chloroform, with stirring, the mixture was further stirred for 30 minutes. The reaction product was concentrated under a reduced pressure and the crystalline residue thus obtained was washed with 20 ml. of benzene and dried to give 5.5 g of 4-benzyloxy-3-nitro-α-bromoacetophenone melting at 135°-136° C.
Reaction SMILES: C(O[C:4](=[O:13])[CH2:5][C:6]([C:8]1[O:12][N:11]=[CH:10][CH:9]=1)=O)C.[NH:14]([C:16]1[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([CH3:31])[C:25]([CH3:33])([CH3:32])[CH2:24]2)=[O:21])=[CH:18][CH:17]=1)[NH2:15].C(O)C>C(O)(=O)C>[O:12]1[C:8]([C:6]2[NH:15][N:14]([C:16]3[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH:23]4[CH2:24][C:25]([CH3:32])([CH3:33])[N:26]([CH3:31])[C:27]([CH3:30])([CH3:29])[CH2:28]4)=[O:21])=[CH:18][CH:17]=3)[C:4](=[O:13])[CH:5]=2)=[CH:9][CH:10]=[N:11]1
Reactant: CCOC(=O)CC(=O)c1ccno1
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-n3[nH]c(-c4ccno4)cc3=O)cc2)CC1(C)C
Temperature: 65 °C
Reaction time: 2 h

Procedure:
3-Isoxazol-5-yl-3-oxo-propionic acid ethyl ester (49 mg) and 4-Hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide (93 mg) were dissolved into ethanol (2.5 ml) and acetic acid (0.3 ml) and the solution stirred at 65° C. for 2 h. Concentration in vacuo and purification by HPLC gave the expected product. LC/MS: main peak is product (m/z: 424.3)
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:23]=[CH:22][C:13]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1ccc(CNc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
To an acetic acid (1.5 mL) and dimethyl sulfoxide (26 mL) solution of (4-((E)-2-nitro-vinyl)-benzyl)-phenyl-amine (1.53 g, 6.02 mmol) described in Manufacturing Example 73-1-4 was added sodium borohydride (364 mg, 9.63 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.5 g). This compound was used in the subsequent reaction without being purified.
Reaction SMILES: O1CCCC1.[OH-].[Li+].C([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[Br:23])=[O:12])C>O>[Br:23][C:16]1[CH:17]=[C:18]([F:22])[CH:19]=[C:20]2[C:15]=1[NH:14][C:13]([C:11]([OH:12])=[O:10])=[CH:21]2
Reactant: CCOC(=O)c1cc2cc(F)cc(Br)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(F)cc(Br)c2[nH]1

Procedure:
Tetrahydrofuran (35.2 ml), water (23.5 ml), lithium hydroxide (2.61 g, 10.9 mmol), and 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (3.11 g, 10.9 mmol) were added to a round bottom flask and mixed with a magnetic stirrer. This mixture was refluxed for 1 hour. The THF was removed via rotary evaporator, and the aqueous solution was acidified with 1M HCL, and extracted with ethyl acetate. 1H NMR (DMSO-d6): δ13.206 (bs, 1H), δ11.876 (s, 1H), δ7.498–7.445 (m, 2H), δ7.19 (d, J=2.0 Hz, 1.0H).