Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O.CCO.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.CCCCCC>[Cl:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(I)c(Cl)c1
Reactant: COc1ccc(B(O)O)cc1
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: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)c(Cl)c1

Procedure:
A mixture of methyl 4-iodo-3-chlorobenzoate (1.20 g, 4.05 mmol) from Step A, 4-methoxy phenyl boronic acid (1.23 g, 8.1 mmol), tetrakis(triphenylphosphine)palladium (0.23 g, 5% mol) and sodium carbonate (0.94 g, 8.9 mmol) in 50 ml of water/EtOH/toluene (1:2:4) was heated to reflux overnight. TLC (EtOAc:hexane/1:9) showed that the reaction was over. The solvents were removed. Water (30 ml) was added. The organic was extracted with methylene chloride (3×50 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/1:9 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 8.16 (d, J=1.5 Hz, 1H), 7.97 (dd, J=8, 1.5 Hz, 1H), 7.43 (m, 3H), 7.01 (d, J=6.5 Hz, 2H), 4.00 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:37]([OH:39])=O)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:55][C@H:56]([C:62]([OH:64])=[O:63])[CH2:57][CH2:58][S:59]([CH3:61])=[O:60]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:37]([NH:55][C@H:56]([C:62]([OH:64])=[O:63])[CH2:57][CH2:58][S:59]([CH3:61])=[O:60])=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)CC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)CC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: -15 °C
Reaction time: 2 h

Procedure:
10.84 Parts N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-phenylalanine and 2.0 parts N-methylmorpholine are dissolved in 200 parts dimethylformamide and cooled to -15° C. Then, 2.9 parts isobutyl chloroformate is added dropwise over a thirty minute period while keeping the temperature between -15° C. to -10° C. After the addition is completed, a solution of 3.3 parts L-methionine sulfoxide in 15 parts dimethylformamide is slowly added. The mixture is stirred for a further thirty minutes at -15° C. and then warmed to room temperature and stirred thereat for an additional 2 hours. The product is isolated by diluting the reaction mixture with 10 volumes water and extracting with ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. The residue is purified by low-pressure chromatography to afford N-t-butoxycarbonyl-L-tyrosyl-glycylglycyl-L-phenylalanyl-L-methionine sulfoxide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[Cl:18]C1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([S:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[Cl:9].[ClH:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(SCc2ccccn2)cc1Cl
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 2-(((3,4-dichlorophenyl)thio)methyl)pyridine, hydrochloride (2.0 g) in methylene chloride (50 ml) at 0° C. was treated with a solution of m-chloroperoxybenzoic acid (1.5 g) in methylene chloride (25 ml). The mixture was allowed to warm to ambient temperature and was stirred for 5 hours. The solution with washed with saturated sodium carbonate solution and water, then dried (MgSO4). The residue was dissolved in acetone and converted into the hydrochloride with ethereal HCl. N.m.r. showed approximately 35% of starting material remaining so the material was suspended in methylene chloride (50 ml) and treated with further m-chloroperoxybenzoic acid (2×500 g). The solution was washed with saturated sodium carbonate solution and water, dried (MgSO4), evaporated and the residue was dissolved in acetone and the hydrochloride precipitated with ethereal HCl solution. Recrystallisation from propan-2-ol/ether gave the title compound, hydrochloride (0.6 g) mp 178° C. decomp (Found: C44.7; H,3.2; N,4.2. C12H9Cl2NOS.HCl requires C,44.7; H,3.1; N,4.3%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:8][C:7]([CH:19]1[CH2:21][CH:20]1[C:22]#[N:23])=[N:6]2.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:24]1([C:2]2[CH:3]=[CH:4][N:5]3[C:10]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:8][C:7]([CH:19]2[CH2:21][CH:20]2[C:22]#[N:23])=[N:6]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: N#CC1CC1c1nc(NCc2ccccn2)c2c(Cl)ccn2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: N#CC1CC1c1nc(NCc2ccccn2)c2c(-c3ccccc3)ccn2n1
Temperature: 100 °C
Yield: 44.3 %

Procedure:
To a stirred solution of (±)-2-(5-chloro-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarbonitrile (50.0 mg, 0.154 mmol) and phenylboronic acid (22.5 mg, 0.185 mmol) in a mixture of 1,4-dioxane (3 mL) and water (0.6 mL) was added 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (14.7 mg, 0.0310 mmol), Pd(OAc)2 (3.46 mg, 0.0150 mmol) followed by K2CO3 (63.8 mg, 0.462 mmol). The resulting suspension was purged with N2 gas for 5 minutes then heated at 100° C. in a sealed tube for 12 h. The reaction mixture was allowed to cool to RT and water (10 mL) was added. The reaction mixture was extracted with EtOAc (2×25 mL) and the combined organic extracts washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-101 as described in general methods) to afforded (±)-2-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarbonitrile (25.0 mg, 43.9%) as white solid. LCMS Condition B-34: retention time 2.44 min, [M+1]=367.0. HPLC Condition B-5: retention time 8.52 min, purity 99.03%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.59 (m, 2H), 2.11-2.16 (m, 1H), 2.56-2.61 (m, 1H), 4.69 (d, J=4.8 Hz, 2H), 6.71 (d, J=2.8 Hz, 1H), 7.18 (t, J=4.4 Hz, 1H), 7.27 (t, J=5.2 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.42-7.53 (m, 5H), 7.73-7.78 (m, 2H), 8.35 (td, J=1.2 Hz, J=4.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[CH:18]=1)[CH2:7]P(=O)(OCC)OCC.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][N:21]=2)[CH:18]=1)[CH:7]=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1
Reactant: CCOP(=O)(Cc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
To a suspension of sodium hydride (0.292 g, 12.17 mmol) in THF (10 mL) under inert atmosphere cooled to 0° C. was added diethyl 3-bromo-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylphosphonate (3.8 g, 8.11 mmol) as a solution in THF (10 mL) dropwise. The reaction was stirred for 30 min at 0° C. and tert-butyl 4-oxopiperidine-1-carboxylate (1.62 g, 8.11 mmol) was added as a solution in THF (10 mL). The reaction was stirred at RT for 5 h. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness to give the title compound (4.22 g, 100%). 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.22 (s, 1H), 7.18 (s, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.91 (s, 1H), 6.28 (s, 1H), 3.49 (m, 2H), 3.40 (m, 2H), 2.44 (m, 2H), 2.32 (m, 2H), 1.47 (s, 9H); m/z (513.2, 515.2, M+ H+).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:42]1[C:47]2[CH:48]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[O:50][C:46]=2[CH:45]=[CH:44][CH:43]=1.[CH2:56]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:56]([N:63]1[CH2:68][CH2:67][N:66]([C:42]2[C:47]3[CH:48]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[O:50][C:46]=3[CH:45]=[CH:44][CH:43]=2)[CH2:65][CH2:64]1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1cc2c(Cl)cccc2o1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(N3CCN(Cc4ccccc4)CC3)cccc2o1
Temperature: 25 °C

Procedure:
X-Phos (1.1 g, 2.2 mmol.), Pd2(dba)3 (1.0 g, 1.1 mmol) and cesium carbonate (14.5 g, 44 mmol) were added to a degassed solution of ethyl 4-chlorobenzofuran-2-carboxylate (Example 1b), 5.0 g, 22 mmol) and benzylpiperazine (5.8 ml, 33 mmol) in dioxane (100 mL). The reaction mixture was heated to +110° C. for 3 h, cooled to room temperature, filtered through a short pad of Celite and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography by using hexane/ethyl acetate (3/1) as eluant to give the title compound. Yield: 7.0 g (86%). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (t, 3H) 2.69 (m, 4H) 3.28 (m, 4H) 4.46 (q, 2H) 6.68 (d, 1H) 7.20-7.43 (m, 7H) 7.59 (s, 1H).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14](=O)[CH3:15])[CH:10]=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][OH:29])[CH:22]=1)[CH2:19][NH2:20]>>[C:1]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][OH:29])[CH:22]=2)[CH3:15])[CH:10]=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1ccc(O)c(CO)c1
Reactant: COC(=O)COc1cccc(CC(C)=O)c1
Product: COC(=O)COc1cccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)c1

Procedure:
The compound was prepared as in Example 1 from 1-(3-carbomethoxymethoxyphenyl) propan-2-one (1.82 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethanamine (1.5 g) and crystallised from benzene m.p. 60°-64° as a 42:58 mixture of diastereoisomers.
Reaction SMILES: Cl.[CH3:2][P:3]1(=[O:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[I-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Cl)[CH:19]=[CH2:20]>CC(C)=O>[CH2:20]([N:6]1[CH2:7][CH2:8][P:3](=[O:9])([CH3:2])[CH2:4][CH2:5]1)[CH:19]=[CH2:18]
Reactant: CP1(=O)CCNCC1
Reactant: C=CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=CCN1CCP(C)(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-methyl-1,4-azaphosphinane 4-oxide hydrogen chloride salt (1.69 g), sodium iodide (150 mg) and Cs2CO3 (7.15 g) in acetone (50 mL) was added allyl chloride dropwise. The mixture was stirred at room temperature overnight, filtered and concentrated to provide the desired product as white solid (1.45 g).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)C.[Li+].[OH-]>C1COCC1.O>[Cl:13][C:10]1[N:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:14])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)COc1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
(6-Chloro-pyridin-3-yloxy)-acetic acid ethyl ester (800 mg, 3.71 mmol) in THF was added to a solution of 0.5 N-LiOH (2 eq) and the mixture was stirred for 1.5 hrs at room temperature. The resulting residue was dissolved in H2O, then washed three times with Et2O, and neutralized with 1N HCl to pH 5˜7. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give (6-chloro-pyridin-3-yloxy)-acetic acid (300 mg, 36%).
Reaction SMILES: [Cl-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:38][C:39]1[N:43]([CH2:44][C:45]([N:47]2[CH2:52][CH2:51][CH:50]([C:53]3[S:54][CH:55]=[C:56]([CH:58]=O)[N:57]=3)[CH2:49][CH2:48]2)=[O:46])[N:42]=[C:41]([C:60]([F:63])([F:62])[F:61])[CH:40]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:38][C:39]1[N:43]([CH2:44][C:45]([N:47]2[CH2:52][CH2:51][CH:50]([C:53]3[S:54][CH:55]=[C:56](/[CH:58]=[CH:12]\[C:3]4[CH:4]=[CH:5][C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:2]=4)[N:57]=3)[CH2:49][CH2:48]2)=[O:46])[N:42]=[C:41]([C:60]([F:63])([F:62])[F:61])[CH:40]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: c1ccc([P+](Cc2ccc3ccccc3c2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(/C=C\c3ccc4ccccc4c3)cs2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(2-Naphthylmethyl)(triphenyl)phosphonium chloride (454 mg) is dissolved in 5 ml of tetrahydrofuran and cooled to 0° C. under argon, and potassium tert.-butoxide (125 mg) is added, whereupon the colour of the solution turns to dark red. After 10 min of stirring, 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde (200 mg) is added. The mixture is stirred at 0° C. for another 30 min and then slowly warmed to room temperature. After a further 20 min, saturated ammonium chloride solution is added, and the aqueous phase is separated off. After extraction of the aqueous phase with ethyl acetate, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. After chromatographic purification, this gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[(Z)-2-(2-naphthyl)vinyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (260 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([Cl:24])[C:15]=2[Cl:25])[C:7]([CH:11]=[O:12])=[C:8](I)[N:9]=1)[CH2:2][CH2:3][CH3:4]>[Pd].C(OCC)(=O)C.O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([Cl:24])[C:15]=2[Cl:25])[C:7]([CH:11]=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(I)c(C=O)n1Cc1ccc(C(=O)OC)c(Cl)c1Cl
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)c(Cl)c1Cl
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A suspension of 34.2 g (0.069 mol) of methyl 4-[(2-butyl-5-formyl-4-iodo-1H-imidazol-1-yl)methyl]-2,3-dichlorobenzoate and 6.84 g of 10% palladium on carbon in 850 mL of ethyl acetate was shaken under hydrogen at 3 Torr for 1 hour. The mixture was filtered through Celite® and concentrated under vacuum to 300 mL. This solution was washed in turn with 5% sodium carbonate solution, water, and brine and then concentrated to an oil which crystallized on standing. This was dissolved in 25 mL of hot methanol which when cooled gave crystals. The suspension was slowly diluted with water and then filtered to give 24.39 g (96%) of crystals; mp 94°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH3:74])[CH2:65][CH2:66][CH2:67][CH:68]1[CH2:73][CH2:72][CH2:71][CH2:70][NH:69]1.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][CH2:73][CH:68]1[CH2:67][CH2:66][CH2:65][N:64]([CH3:74])[CH3:63])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN(C)CCCC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CCCN(C)C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N,N-dimethyl-N-(3-piperidin-2-yl-propyl)-amine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[O:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][C:10]=2[F:28])=[N:6][CH:7]=1.FC(F)(F)C(O)=O.CCOC(C)=O.C1COCC1>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:11][C:10]=2[F:28])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(Cl)cn3)c(F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Fc1cc(C2CNCCO2)ccc1Nc1ncc(Cl)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-(5-chloropyrimidin-2-ylamino)-3-fluorophenyl)morpholine-4-carboxylate (26 mg) in acetonitrile (1.5 ml) and water (4.5 ml) was added trifluoroacetic acid (49.0 μl). The reaction mixture was then capped and the mixture was shaken at 80° C. for 3 h. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1:1) and washed with 1 M aq. NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)-5-chloro-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (14 mg, 71%) as a white solid. MS (ISP): 311.1 ([{37Cl}M+H]+), 309.1 ([{35Cl}M+H]+).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:27]=[CH:26][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][N:15]3[CH:23]=[CH:24][CH:25]=[C:14]3[CH2:13]2)=[O:11])=[CH:8][CH:7]=1)CCC.Br[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[N+:43]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][N:15]3[CH:23]=[CH:24][CH:25]=[C:14]3[CH2:13]2)=[O:11])=[CH:26][CH:27]=1)([O-:45])=[O:44]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccc2[N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccccc21
Yield: 56.4 %

Procedure:
A mixture of 3.0 g of 10,11-dihydro-10-[4-(tributylstannyl)benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 200 mg of tetrakis(triphenylphosphine)palladium(O) and 2.0 g of 1-bromo-2-nitrobenzene in 200 ml of toluene is refluxed for 16 hours. The reaction mixture is filtered and the filtrate evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 1.2 g of the desired product as a solid. Mass spectrum: M+H:410.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[O:7])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH2:21].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:17][O:18][C:19](=[O:30])[CH:20]([NH:21][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)C2CCCCC2=O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Solvent: COc1ccccc1
Solvent: O
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 37.9 %

Procedure:
To a mixture of 2-(4-methylbenzoyl)cyclohexanone (97.2 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-[(2-(4-methyl benzoyl)phenyl)-amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (59.1 g, 38%).
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][C:11]([CH3:14])=[N:10][CH:9]=3.Cl.O1CCOCC1>CO>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:18]1[CH:2]=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[C:11]([CH3:14])[CH:12]=3)[C:7](=[O:15])[N:6]([CH3:16])[C:5]=2[CH:17]=1
Reactant: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-bromo-2,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (30 mg, 0.058 mmol) in MeOH (3 mL) at 0° C. was added 4M HCl in 1,4-dioxane (0.362 mL, 1.447 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford (S)-8-((2-amino-4-methylpentyl)oxy)-2,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (6 mg, 0.014 mmol, 24% yield) as an off-white solid. LC/MS (ESI) m/e 418.0 [(M+H)+, calcd for C20H25BrN3O2 418.1]; LC/MS retention time (method H): tR=1.70 min; HPLC retention time (method A): tR=6.33 min; HPLC retention time (method B): tR=7.19 min. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.31 (s, 1H), 9.28-9.33 (m, 1H), 8.58 (s, 1H), 8.08 (s, 1H), 7.09 (s, 1H), 4.42 (dd, J=9.79, 3.26 Hz, 1H), 4.25 (dd, J=9.91, 6.15 Hz, 1H), 3.78 (s, 3H), 3.63 (br. s., 1H), 2.73 (s, 3H), 2.00 (br. s., 4H), 1.85-1.92 (m, 1H), 1.71-1.80 (m, 1H), 1.57-1.66 (m, 1H), 1.06 (dd, J=6.40, 4.64 Hz, 6H).