Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>>[CH2:16]([O:15][C:13]([C:9]1[C:10]2[CH:11]=[CH:12][C:3]([CH2:2][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])=[N:4][C:5]=2[CH:6]=[CH:7][CH:8]=1)=[O:14])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)c1cccc2nc(CBr)ccc12
Product: CCOC(=O)c1cccc2nc(CP(=O)(OCC)OCC)ccc12
Temperature: 110 °C

Procedure:
Compound 73c (240 mg, 0.816 mmol) was treated with triethyl phosphite (2.12 mL, 12.2 mmol) and the resultant slurry was heated to 110° C. for 4 h. The reaction was concentrated in vacuo, diluted with DCM (50 mL), washed with sodium bicarbonate, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH/DCM) to afford compound 73d as an oil. Mass spectrum (LCMS, ESI pos.) Calcd. For C17H22NO5P: 352.1 (M+H). found 352.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32]([NH:34][C@@H:35]([CH2:44]O)[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32]([NH:34][C@@H:35]([CH2:44][I:25])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](CI)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
Triphenylphosphine (1.07 g, 4 mmol), imidazole (277 mg, 4 mmol) and iodine (1.02 g, 4 mmol) were dissolved into methylene chloride (12 mL) under nitrogen atmosphere. (R)-tert-butyl 3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (275 mg, 1 mmol) was dissolved into methylene chloride (4 mL) and added dropwise to the solution. After 1 h, methylene chloride (100 mL) was added and the solution was filtered through celite. The filtrate was washed with 1% sodium bisulfite solution (2×10 mL), brine (20 mL), dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography (ethyl acetate/hexanes 1:1) to give the title compound (225 mg, 58%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.05-6.95 (m, 1H), 4.04-3.97 (m, 1H), 3.77-3.65 (m, 2H), 2.55-2.50 (m, 1H), 2.38-2.27 (m, 1H), 1.39 (s, 9H), 1.36 (s, 9H).
Reaction SMILES: [C:1](/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C@H:11]([NH:15][C:16](=[O:35])C[C@@H]1C(=O)NCCN1S(C1C=CC(C)=CC=1)(=O)=O)[CH2:10][CH2:9][CH2:8]2)#[N:2].O=C1NCCN(S(C2C=[CH:51][C:49]([CH3:50])=[CH:48]C=2)(=O)=O)[C@@H]1CC(O)=O.N[C@@H]1CCCC2C=C(/C=C/C#N)C=CC1=2.CN(C([O:79]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1](/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C@H:11]([NH:15][C:16](=[O:35])[O:79][C:49]([CH3:51])([CH3:50])[CH3:48])[CH2:10][CH2:9][CH2:8]2)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)[C@H]2CC(=O)N[C@@H]2CCCc3cc(/C=C/C#N)ccc32)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)[C@H]2CC(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN=C=NCCCN(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#C/C=C/c1ccc2c(c1)CCC[C@H]2N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(/C=C/C#N)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 66 %

Procedure:
To a 300 mL flame dry 3-neck round bottom flask was added diethyl cyanophosphonate (14.86 g, 83.89 mmol) and THF (100 mL). After cooled to 0° C., sodium bis(trimethyl-silyl)amide (72.0 mL, 71.90 mmol) was added dropwise via the addition funnel. After stirred for 30 min at 0° C., It was cooled to −78° C. followed by adding (R)-tert-butyl-6-formyl-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (6.6 g, 23.97 mmol) in TBF (60 mL) dropwise via the addition funnel. It was stirred for 18 h. Acetone cyanohydrin (3.1 mL, 33.48 mmol) was then added dropwise via the addition funnel. The resulting mixture was warmed up to rt and continued to stir for 18 h. The reaction mixture was quenched with sat. NH4Cl. Solvent was evaporated in vacuo. The residue was extracted with EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4 and removed solvent. The crude product was purified by chromatography on silica gel. Elution with Hex:EtOAc mixture (70:30) gave final compound. MS m/z: 299.12 (M+H). Calc'd. for C18H22N2O2-298.23. B. (R,E)-3-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)acralonitrile The product from the previous step was deprotected using HCl in dioxane to give the title compound in quantitative yield. MS m/z: 199.12 (M+H). Calc'd. for C13H14N2-198.23. C. N-((R)-6-((E)-2-cyanovinyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-3-oxo-1-tosylpiperazin-2-yl)acetamide To a 250 mL round bottom flask was added (R)-2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid (2.0 g, 6.40 mmol), followed by (R,E)-3-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)acrylonitrile (1.26 g, 6.40 mmol), dry CH2Cl2 (70 mL), HATU (1.2 mg, 3.20 mmol), EDCI (1.4 g, 7.04 mmol) and hunig base (2.2 mL, 12.80 mmol). The resulting mixture was stirred at rt for 20 h. Removed solvent to dryness. The residue was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (95:5) gave final compound (2.1 g, 66%). MS m/z: 493.3 (M+H). Calc'd. for C26H28N4O4S -492.6. D. N-((R)-6-(3-aminopropyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-3-oxo-1-tosylpiperazin-2-yl)acetamide
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@H:13]([C:26]([N:28]([C@@H:40]([CH3:48])[CH:41]([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[CH:37][CH:36]=[CH:35]2)=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[CH2:46]([O:45][CH:41]([O:42][CH2:43][CH3:44])[C@@H:40]([N:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[CH:37][CH:36]=[CH:35]2)[C:26]([C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4](=[O:11])[NH:3][CH2:1][CH3:2])=[O:27])[CH3:48])[CH3:47]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCNC(=O)NOCC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 47 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-14) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:12][CH:11]=[C:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:9]1.CO>[Pt](=O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:9]1
Reactant: C1=C(c2nccs2)CNC1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1csc(C2CCNC2)n1
Reaction time: 3 h

Procedure:
To a solution of 2-(2,5-dihydro-1H-pyrrol-3-yl)-1,3-thiazole trifluoroacetate (2.49 g, 0.00936 mol) in methanol (100.0 mL, 2.469 mol) was added platinum dioxide (320 mg, 0.0014 mol) and the resulting mixture was hydrogenated on par shaker at 56 psi for 3 h. After filtration, the filtrate was concentrated in vacuo and dried under high vacuum to give the desired product as a solid. LC-MS (M+H) 155.2 (base).
Reaction SMILES: Cl[CH2:2][O:3][C:4]([N:6]1[C@H:11]([CH3:12])[CH2:10][O:9][C@:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([OH:13])[C@@H:7]1[CH3:22])=[O:5].[CH:23]1[CH:24]=[C:25]([CH2:28][NH:29][C:30]2[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:32]([Cl:43])[CH:31]=2)[O:26][CH:27]=1.[Cs].[I-].[Na+].CCCCCCC>O1CCCC1.C(OCC)(=O)C>[NH2:42][S:39]([C:33]1[C:32]([Cl:43])=[CH:31][C:30]([NH:29][CH2:28][C:25]2[O:26][CH:27]=[CH:23][CH:24]=2)=[C:35]([CH:34]=1)[C:36]([O:38][CH2:2][O:3][C:4]([N:6]1[C@H:11]([CH3:12])[CH2:10][O:9][C@:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([OH:13])[C@@H:7]1[CH3:22])=[O:5])=[O:37])(=[O:41])=[O:40]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1C(=O)OCCl
Agent: [Cs]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1C(=O)OCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Temperature: 60 °C
Yield: 13.3 %

Procedure:
To a stirring solution of (2S,3S,5R)-2-(3,5-difluorophenyl)-2-hydroxy-3,5-dimethylmorpholine-4-carboxylic acid chloromethyl ester (1410) (2.24 g, 6.67 mmol) in 150 mL of anhydrous tetrahydrofuran was added the furosemide cesium salt (10c) (3.09 gm, 6.67 mmol) and sodium iodide (1.10 gm, 7.34 mmol). The mixture was heated to ˜60° C. and monitored by TLC (1:1 heptane:ethyl acetate). After heating for 6 hours, TLC analysis indicated a slowing down of product formation with starting materials remaining. The reaction was halted so as not to allow by-product formation. The solvent was removed from the crude yellow mixture, and it was dried onto silica gel. This crude material was purified on an Optix Companion Automated Chromatography system using an 80 gm silica cartridge and eluting with ethyl acetate/heptane (0 to 70% over 50 minutes). This material was dried on a vacuum pump for 24 hours and afforded 0.560 g of (2S,3S,5R)-4-[5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethoxycarbonyl]-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (1420) as a light yellow foamy solid. Melting point range was 105° C. to 110° C. Elemental analysis calculated for [C26H26N3 0.3 EtOAc]: C, 49.76; H, 4.36; N, 6.4. found C, 50.08; H, 4.65; N, 6.23. 1H NMR (400 MHz, CDCl3) δ 0.86-0.89 (t, 3H), 1.34 (m, 3H), 3.60-3.67 (m, 1H), 4.23 (m, 1H), 4.33 (m, 1H), 4.45-4.46 (d, 2H), 4.47 (s, 1H), 5.07-5.11 (d, 2H), 6.00-6.05 (dd, 2H), 6.28 (s, 1H), 6.35 (s, 1H), 6.75-6.79 (t, 1H), 6.89 (m, 1H), 7.12-7.14 (br. d, 2H), 7.37-7.39 (d, 1H), 8.53 (br. d., 1H), 8.63 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][N:20]([CH3:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[N:11]12[CH2:17][CH:15]3[CH2:14][CH:13]([CH2:18][CH:9]([N:8]([C:4]4[CH:3]=[C:2]([C:24]5[CH:25]=[CH:26][C:21]([N:20]([CH3:30])[CH3:19])=[CH:22][CH:23]=5)[CH:7]=[N:6][CH:5]=4)[CH2:16]3)[CH2:10]1)[CH2:12]2
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: CN(C)c1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and 4-dimethylaminophenylboronic acid according to General Method B: 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (s, 1 H), 8.03 (s, 1 H), 7.48 (d, 2 H), 7.06 (s, 1 H), 6.80 (d, 2 H), 3.73-3.35 (m, 7 H), 3.06-3.03 (m, 8 H), 2.27-2.17 (m, 3 H), 2.04-1.79 (m, 3 H), 1.88-1.77 (m, 3 H); LC-MS Method D (ESI+) m/z 349.0 (M+H)+, retention time 1.24 minutes.
Reaction SMILES: [C:1]1([P:7]([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]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:21][C:22]1[S:23][C:24]([O:28][CH3:29])=[CH:25][C:26]=1[CH3:27].C(Cl)(Cl)(Cl)[Cl:31]>C1(C)C=CC=CC=1>[Cl-:31].[CH3:27][C:26]1[CH:25]=[C:24]([O:28][CH3:29])[S:23][C:22]=1[CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc(C)c(CO)s1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Product: [Cl-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
21.0 G. (80.2 mmol) of triphenylphosphine were added to a solution of 5.8 g. (36.7 mmol) of 2-hydroxymethyl-3-methyl-5-methoxythiophene in 60 ml. of dry carbon tetrachloride and 80 ml. of toluene. The temperature of the reaction mixture was slowly raised to 80° C. and heating was continued overnight. The resulting precipitate was filtered from the cold solution, washed well with cold benzene and dried in high vacuum to yield (3-methyl-5-methoxy-2-thenyl)triphenyl phosphonium chloride, m.p. 180°-185° C.
Reaction SMILES: C[N:2]([CH:4]=O)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[C:23]3[N:22]=[C:21]([C:24]4[C:29](Br)=[CH:28][CH:27]=[CH:26][C:25]=4Br)[NH:20][C:19]=3[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11]=2[CH:12]=1.[C:32]([Cu])#[N:33].[OH-].[NH4+]>C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[C:23]3[N:22]=[C:21]([C:24]4[C:29]([C:4]#[N:2])=[CH:28][CH:27]=[CH:26][C:25]=4[C:32]#[N:33])[NH:20][C:19]=3[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11]=2[CH:12]=1
Reactant: CN(C)C=O
Reactant: N#C[Cu]
Reactant: Clc1ccc2c(c1)c1ccccc1c1[nH]c(-c3c(Br)cccc3Br)nc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(C#N)c1-c1nc2c3ccc(Cl)cc3c3ccccc3c2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a DMF (300 mL) solution of 32 g (65.7 mmol) of 6-chloro-2-(2,6-dibromophenyl)-1H-phenanthro[9,10-d]imidazole from Step 5 was added 14.7 g of CuCN. The reaction was stirred overnight at 80° C., cooled down to room temperature, poured into a mixture of 1.5 L of water, 1.5 L of ethyl acetate and 200 mL of concentrated ammonium hydroxide and stirred 1 hr at room temperature. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with 10% ammonium hydroxide, water, brine, dried over sodium sulphate and volatiles were removed under reduced pressure. The residue was swished in toluene (2×200 mL) and ethyl acetate (1 L). The obtained solid was purified by flash chromatography on silica gel in 5 portions using a gradient of 60% to 80% to 100% of ethyl acetate/hexane to afford 19.9 g of 2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile as a pale yellow solid. 1H NMR (400 MHz, DMSO): δ 14.32 (s, 1H), 9.0-8.9 (m, 2H), 8.55-8.45 (m, 4H), 7.99 (t, 1H), 7.85-7.78 (m, 2H), 7.72 (t, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1>ClCCl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([CH:3]([N:4]3[CH:8]=[N:7][CH:6]=[N:5]3)[CH:2]([CH3:19])[CH3:1])=[CH:10][C:11]=2[N+:16]([O-:18])=[O:17])=[O:35])=[CH:29][CH:28]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1cncn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(c1ccc(NC(=O)Cc2ccc(Cl)cc2)c([N+](=O)[O-])c1)n1cncn1
Yield: 69.9 %

Procedure:
To a stirred and cooled (5° C.) solution of 10 parts of 4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrobenzenamine and 6.7 parts of pyridine in 195 parts of dichloromethane was added a solution of 14.4 parts of 4-chlorobenzeneacetyl chloride in 39 parts of dichloromethane under nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (99:1 by volume) as eluent. The eluent of the desired fraction was evaporated, yielding 11 parts (69.9%) of 4-chloro-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrophenyl]benzeneacetamide (interm. 112).
Reaction SMILES: [C:1]1(Cl)[C:7](=[O:8])[C:6]([Cl:9])=[C:5]([Cl:10])[C:3](=[O:4])[C:2]=1[Cl:11].C(=O)([O-])O.[Na+].[CH:18]([OH:21])([CH3:20])[CH3:19]>CC(CC)=O>[Cl:9][C:6]1[C:7](=[O:8])[C:1]([O:21][CH:18]([CH3:20])[CH3:19])=[C:2]([Cl:11])[C:3](=[O:4])[C:5]=1[Cl:10]
Reactant: CC(C)O
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)OC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O
Temperature: 55 °C

Procedure:
Chloranil (0.06 mole) and sodium hydrogen carbonate (0.075 mole) were added to 300 ml of methylethylketone (MEK). the mixture was heated to 55° C. before adding iso-propanol (0.5 mole) dropwise with stirring. When the reaction was complete (as judged by HPLC) the MEK solvent was removed from the product mixture under vacuum. The resultant orange gum was recrystallised from petroleum ether to give 2,3,5-trichloro-6-isopropoxy-1,4-benzoquinone as product.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:16]([C:18]1([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]1=[O:25])[CH3:17].[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[CH2:16]([C:18]1([C:26]2[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=2)[O:32][C:2]2[CH:9]=[C:8]([CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]1=[O:25])[CH3:17]
Reactant: N#Cc1ccc(Cn2ccnc2)cc1F
Reactant: CCC1(c2cccc(O)c2)CCCCNC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCC1(c2cccc(Oc3cc(Cn4ccnc4)ccc3C#N)c2)CCCCNC1=O

Procedure:
2-Fluoro-4-imidazol-1-ylmethyl-benzonitrile (as described in Example 1, Step E) (0.065 g, 0.325 mmol), 3-ethyl-3-(3-hydroxy-phenyl)-azepan-2-one (as described in Step B above) (0.076 g, 0.325 mmol), KF.Al2O3 (0.091 g) and 18-Crown-6 (0.008 g, 0.030 mmol) were refluxed in CH3CN (8 mL) under Ar for 72 h. The solution was filtered, concentrated in vacuo, and purified using SiO2 chromatography (0.5-3.0% MeOH/CH2Cl2). The compound was treated with 1N HCl ethereal solution to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:5]([CH:18]([CH3:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=1.[I:27][CH3:28]>[N+](C)([O-])=O>[I-:27].[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[O:12][CH2:13][C:14]([CH3:16])([CH3:17])[N+:15]=2[CH3:28])=[C:5]([CH:18]([CH3:26])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=1
Reactant: COc1cc(C2=NC(C)(C)CO2)c(C(C)Cc2ccccc2)cc1OC
Reactant: CI
Solvent: C[N+](=O)[O-]
Product: COc1cc(C2=[N+](C)C(C)(C)CO2)c(C(C)Cc2ccccc2)cc1OC
Product: [I-]
Temperature: 110 °C
Yield: 95.8 %

Procedure:
To a solution of 2-[4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-4,4-dimethyl-4,5-dihydro-oxazole (7.515 g, 21.3 mmol) in 50 mL NO2CH3 was added iodomethane (2.65 mL, 42.5 mmol). The solution was warmed to 110° C. After 3 hours the solution was cooled and concentrated in vacuo to give 2-[4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-3,4,4-trimethyl-4,5-dihydro-oxazolium iodide (10.108 g) as an orange solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][O:30][C@H:31]([C:33]1[NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]=1)[CH3:32]>>[CH3:29][O:30][C@H:31]([C:33]1[N:34]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:16][CH:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32]
Reactant: CO[C@@H](C)c1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1
Product: CO[C@@H](C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1

Procedure:
Following General procedure D, 4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine from Example 126 was reacted with (S)-2-(1-methoxyethyl)-1H-benzo[d]imidazole to give 150. 1H NMR (400 MHz, DMSO) δ 8.18 (d, J=8.6 Hz, 1H), 8.01 (dd, J=6.7, 1.8 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.73 (dd, J=6.7, 2.1 Hz, 1H), 7.38-7.24 (m, 2H), 5.50 (q, J=6.4 Hz, 1H), 4.53 (br s, 4H), 3.92-3.79 (m, 6H), 3.63-3.52 (m, 4H), 3.45 (t, J=6.2 Hz, 2H), 3.09 (s, 3H), 2.97 (overlapping m, 3H), 2.25 (br s, 4H), 1.63 (d, J=6.4 Hz, 3H). LCMS: 345.3
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][N:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[N:29]=[C:30]([C:40]5[CH:39]=[N:38][C:37]([O:36][CH3:35])=[CH:42][CH:41]=5)[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccc(OC)nc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-methoxypyridine-5-boronic acid.
Reaction SMILES: C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[C:19]([N:26]1[CH2:33][CH2:32][CH2:31][C@@H:27]1[C:28]([OH:30])=O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[Cl:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1>[Cl:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][C:28]([C@H:27]2[CH2:31][CH2:32][CH2:33][N:26]2[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:30])=[CH:37][CH:36]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.82 g (19.5 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added to a suspension of 2.80 g (13.0 mmol) of N-Boc-D-proline and 1.66 g (13.0 mmol) of 4-chloroaniline in 50 ml of toluene, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered, and petroleum ether is added to the filtrate. The precipitate formed is filtered off and dried, giving tert-butyl (R)-2-(4-chlorophenyl-carbamoyl)pyrrolidine-1-carboxylate as colourless crystals; ESI 325.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.Cl>O1CCCC1.C(OCC)(=O)C>[OH:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[P:2]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Br[Mg]c1ccccc1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccccc1-c1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
12.3 g (52.4 mmol) of 6-chloro-6H-dibenz[c,e][1,2]oxa-phosphorine in 80 ml of anhydrous tetrahydrofuran are introduced, in an argon atmosphere with stirring, and 66 ml of a 2M solution of phenylmagnesium bromide in tetrahydrofuran are added dropwise. The temperature increases in the course of this from 25° to 40° C. The mixture is then stirred for 4 hours at 65° C., cooled to room temperature and 100 ml of water and 100 ml of ethyl acetate are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 19.0 g of colorless oil are obtained. By crystallization with methanol/water, 10:1, 18.1 g (98%) of colorless crystals having melting point 123° to 124° C. are obtained.