Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][NH:39][CH2:40][C:41]#[CH:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:39]([CH3:38])[CH2:40][C:41]#[CH:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C#CCNC
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: C#CCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-methylprop-2-ynylamine according to conditions described in general procedure C. Mp: 97-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.88 (s, 3H), 3.26-3.33 (m, 5H), 3.77 (t, J=4.8 Hz, 4H), 4.24 (s, 2H), 6.32 (d, J=5.5 Hz, 1H), 7.06 (d, J=14.3 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.45-7.64 (m, 5H), 7.85-7.87 (m, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.32 (d, J=5.5 Hz, 1H), 10.49 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH2:35][CH2:36][CH3:37]>>[CH2:34]([N:38]1[CH2:43][CH2:42][N:41]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][NH:22][C:23]4[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:40][CH2:39]1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NNc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NNc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 10 %

Procedure:
The title compound was prepared from 4-(2-(4-(3-(3-cyanophenyl)ureido)phenylsulfonyl) hydrazinyl)benzenesulfonamide following procedure C and using 2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH2:10]O)[C:3]=1[OH:12].ClCCl.CS(Cl)(=O)=O>C(N(CC)CC)C>[Br:1][C:2]1[C:3]2[O:12][CH2:10][CH2:9][C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OCCc1cc(Cl)cc(Br)c1O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a mixture of 2-bromo-4-chloro-6-(2-hydroxyethyl)phenol (99.8 mg, 0.397 mmol), triethylamine (0.40 mL, 2.9 mmol), and dichloromethane (4 mL) at 0° C. was added methanesulfonyl chloride (56.0 μL, 0.724 mmol). The reaction was stirred at 0° C. for 1.5 hours, at which point additional methane sulfonyl chloride (10 μL) was added and the reaction mixture warmed to room temperature. After stirring overnight, the reaction mixture was re-cooled to 0° C. and triethylamine (0.2 mL) and methanesulfonyl chloride (15 μL) were added. After two hours the reaction mixture was partitioned between ethyl acetate and water, and the organic layer washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 30% ethyl acetate in heptanes) to yield 40.0 mg (40%) of 7-bromo-5-chloro-2,3-dihydrobenzofuran. 1H NMR (400 MHz, CDCl3) δ: 7.26 (d, 1H), 7.09 (d, 1H), 4.67 (t, J=8.8, 2H), 3.30 (t, J=8.8, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH3:3].[OH-].[Na+]>C1COCC1.CCO>[CH3:3][CH:2]([C:4]1[C:5]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH3:1]
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C(C)C)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C(C)C)cc2c1
Yield: 77.6 %

Procedure:
Ethyl ester 74 (0.45 g, 0.97 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.33 g (78%) of the title compound (75) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.19 (d, J=6.8 Hz, 6H), 2.90 (sept, J=6.8 Hz, 1H), 3.94 (s, 3H), 6.22 (d, J=15.9 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 7.04 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.06-7.15 (m, 2H), 7.18-7.30 (m, 6H), 7.62 (d, J=16.0 Hz, 1H), 7.65 (s, 1H), 7.69 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 439 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-Methoxybenzene boronic acid. MS (M+H) 383.2
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7]O)[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:34]I>C1(C)C=CC=CC=1>[I:34][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1
Reactant: II
Reactant: CC1(C)OCC(CO)O1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OCC(CI)O1
Temperature: 90 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (10 g, 75.67 mmol) in dry toluene (200 mL) was added triphenylphospine (23.82 g, 90.81 mmol), imidazole (15.45 g, 227 mmol), and iodine (24.97 g, 98.36 mmol). The mixture was stirred at 90° C. for 3 h. The solvent was then removed in vacuo and the residue was dissolved in DCM (200 mL) and washed with saturated Na2S2O3 solution water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified on column of silica gel (DCM) to give the subject compound (15.79 g, yield 86%). Intermediate 12 was characterized by the following spectroscopic data: 1H NMR (CDCl3-d1, 300 MHz) δ (ppm) 4.33 (m, 1H), 4.19 (m, 1H), 3.82 (m, 1H), 3.32 (m, 1H), 3.27 (m, 1H), 1.49 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C([O-])([O-])=O.[Na+].[Na+].Cl[CH2:18][CH2:19][N:20]=[C:21]=[O:22].[H-].[Na+]>C1COCC1>[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([N:9]2[CH2:18][CH2:19][NH:20][C:21]2=[O:22])[CH2:5][CH2:4]1
Reactant: NC1CCC(F)(F)CC1
Reactant: O=C=NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C1NCCN1C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A solution of 4,4-difluorocyclohexanamine hydrochloride (0.800 g, 4.66 mmol) in THF (20 mL) was treated with Na2CO3 (0.800 g, 7.55 mmol) followed by 1-chloro-2-isocyanatoethane (0.800 g, 7.58 mmol) and stirred at RT for 2 h. The mixture was cooled to 0° C., treated with NaH (60% in mineral oil, 0.300 g, 7.50 mmol), warmed to RT and stirred for 4 h. The mixture was poured into satd. NH4Cl solution, the layers separated and the aqueous layer extracted with DCM (3×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-(4,4-difluorocyclohexyl)imidazolidin-2-one (624 mg, 66%) as a white solid. MS (ESI) m/z: 205.1 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]2OC(=O)C(=O)[N:4]12)[CH3:2].S(=O)(=O)(O)O>CO>[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCC1Cc2ccccc2C2OC(=O)C(=O)N12
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC1Cc2ccccc2C=N1

Procedure:
To a stirred solution of 4-ethyl-5,9b-dihydro-4H-1-oxa-3a-aza-cyclopenta[a]naphthalene-2,3-dione (29.4 g, 0.12 mols) in methanol (1140 ml) was added concentrated sulfuric acid (60 ml) slowly. The reaction was then refluxed for 2 h. The solvent was evaporated and to the residue was added water (100 ml) and ethyl acetate (500 ml). The layers were then separated and the organic phase was then extracted with 2N HCl (2×200 ml). The aqueous layers were combined and made basic with concentrated ammonium hydroxide. The product was then extracted into dichloromethane and dried over magnesium sulfate. Evaporation of the solvent yielded 20.5 g.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH3:18][N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]2[CH:5]=[N:4][C:3]([CH:2]=[O:1])=[C:7]2[CH2:8]1
Reactant: CN1Cc2c(CO)ncn2-c2ccccc2C1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN1Cc2c(C=O)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 12.2 g (50 mmol) of 4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 80.0 g of manganese dioxide and 500 ml of absolute methylene chloride is stirred at room temperature for 1 hour under an argon atmosphere and subsequently the manganese dioxide is filtered off under suction over Dicalit while rinsing with methylene chloride. The filtrate is evaporated to dryness in vacuo. After warming the residue in ca 150 ml of ethyl acetate, there is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde of melting point 205°-207° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][CH:32]1[CH2:37][CH:36]([CH3:38])[CH2:35][NH:34][CH2:33]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:34]5[CH2:35][CH:36]([CH3:38])[CH2:37][CH:32]([CH3:31])[CH2:33]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: CC1CNCC(C)C1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CC(C)CC(C)C3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in 3,5-dimethylpiperidine (1 ml) was heated at 120° C. for 18 h in a sealed tube. The reaction was concentrated under vacuum, the residue purified by preparative HPLC, to give, after evaporation of the solvents under vacuum N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(3,5-dimethylpiperidin-1-yl)isonicotinamide. NMR; δH [2H6] —DMSO 10.29,(1H, s), 8.62,(1H, t), 8.21,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.20,(1H, s), 6.98,(1H, d), 4.35,(2H, m), 3.16,(2H, t), 2.30,(2H, t), 2.20,(3H, s), 1.78,(1H, m), 1.57,(2H, m), 1.04,(1H, m), 0.91,(6H, d), 0.80,(1 H, q), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.61 min, MH+497.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].Cl.[CH3:31][NH:32][CH3:33].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:32]([CH3:33])[CH3:31])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)Cc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 117.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with N,N-dimethylamine hydrochloride (120 mg, 1.47 mmol), triethylamine (0.162 mL, 1.17 mmol), acetic acid (0.084 mL, 1.5 mmol) and sodium triacetoxyborohydride (154 mg, 0.727 mmol). The reaction mixture was added with water and ethyl acetate. The mixture was added with sodium carbonate to adjust the pH to 9. Then, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(dimethylaminomethyl)indol-2-yl]isoindolinone (37.8 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:15](=[O:27])[NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][NH:21][CH2:22]3)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.O>CO.C(Cl)Cl>[CH2:22]1[C:23]2[C:18](=[C:17]([NH:16][C:15]([C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:27])[CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:20][NH:21]1
Reactant: CCOC(=O)C1(C(=O)Nc2cccc3c2CCNC3)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=C(O)C1(C(=O)Nc2cccc3c2CCNC3)Cc2ccccc2C1
Reaction time: 18 h
Yield: 98.3 %

Procedure:
A 250 mL round bottom flask containing 2-(1,2,3,4-tetrahydro-isoquinolin-5-ylcarbamoyl)-indan-2-carboxylic acid ethyl ester (322, 440 mg, 1.21 mmoles) is charged with 1,4-dioxane (7 mL) and MeOH (7 mL). A stirring bar is added and stirring is initiated. After dissolution, water (3.5 mL) is added followed by the LiOH monohydrate (128 mg, 3.05 mmol). After 18 h, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (1 g) is added to the reaction flask. The reaction is capped and allowed to stir at ambient temperature. After 24 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The resultant residue is reconstituted with iPrOH/toluene (1:1, 25 mL). The solvent is removed in vacuo. This process is repeated twice. Pumping to constant weight provides an off-white solid (400 mg, 99%).
Reaction SMILES: C(P)(CC)C.C(OC)(=[O:9])C=C.N(C(C(C)C)C#N)=NC(C(C)C)C#N.[CH:26]([P:30]([CH2:37][CH2:38][C:39]([O:41]C)=[O:40])[CH2:31][CH2:32][C:33]([O:35]C)=[O:34])([CH2:28][CH3:29])[CH3:27].OO>>[CH:26]([P:30](=[O:9])([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])([CH2:28][CH3:29])[CH3:27]
Reactant: C=CC(=O)OC
Reactant: CCC(C)P(CCC(=O)OC)CCC(=O)OC
Agent: CC(C)C(C#N)N=NC(C#N)C(C)C
Agent: CCC(C)P
Agent: OO
Product: CCC(C)P(=O)(CCC(=O)O)CCC(=O)O

Procedure:
Sec. butylphosphine, 592 parts (85% purity) is reacted with 860 parts of methyl acrylate containing 4.9 parts of azobis(isovaleronitrile) at 67°-100° C. for 3.5 hours. The reaction product, sec. butylbis(carbomethoxyethyl)phosphine is reacted with 10% molar excess hydrogen peroxide (25% solution) for two hours at 60° C. to give the corresponding phosphine oxide. The latter is hydrolyzed with dilute sulfuric acid to give after recrystallization from water, sec. butyl bis(β-carboxyethyl)phosphine oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([NH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([NH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)Nc1cc(Oc2ccccc2O)c(Cl)cc1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(NC(=O)OC)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-chloro-4-fluoro-5-methoxycarbonylaminophenoxy)phenol [Intermediate compound A9-4] is dissolved in N,N-dimethylformamide, then, potassium carbonate is added, and the mixture is stirred for 1 hour at room temperature. Then, methyl bromoacetate is added at room temperature. The mixture is stirred at 60° C. for 2 hours, poured into water, extracted with ethyl acetate, and the organic layer is washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated to obtain methyl [2-(2-chloro-4-fluoro-5-methoxycarbonylaminophenoxy)phenoxy]acetate [Intermediate compound A9-22].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:4]1[C:3]([F:9])=[C:2]([C:24]2([OH:27])[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:23]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1c(Cl)cccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2F)C1
Yield: 58.8 %

Procedure:
To a solution of 1-bromo-3-chloro-2-fluorobenzene (5.0 g, 23.8 mmol) in dry tetrahydrofuran (50 mL) under nitrogen at −78° C., was added dropwise n-butyllithium (2.5 M in tetrahydrofuran, 9.5 mL, 23.8 mmol). The mixture was stirred for 0.5 h at −78° C. after which a solution of 1-N-boc-3-pyrrolidinone (4.37 g, 23.8 mmol) in dry tetrahydrofuran (20 mL) was added drop wise. The resulting mixture was brought to ambient temperature, aqueous saturated ammonium chloride (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried (MgSO4), filtered and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/methanol, 4:1 to 1:1) gave the title compound (4.42 g). MS m/z (rel. intensity, 70 eV) 315 (M+, 1), 259 (16), 214 (31), 157 (17), 57 (bp).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([O-:10])=[O:9])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[N:11]#[N:12]>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7].[N:11]#[N:12]
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: N#N
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
addition of 10 M glutamate for 30 minutes of incubation in N2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:26](C=O)C.[Cl-].[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH2:26])=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: Cc1nccc(-c2ccc(Cl)cc2F)c1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(Cl)cc2F)c1C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(4-Chloro-2-fluorophenyl)-2-methylnicotinic acid (9 g, 33.9 mmol) (previous described in Example 16, Part E) was taken in DCM (50 mL) and cooled to 0° C. The solution was treated with oxalyl chloride (14.83 mL, 169 mmol) followed by slow addition of DMF (1 mL). The mixture was heated at 40° C. for 3 h. After cooling, the volatiles were removed under reduced pressure. The residue taken up in DCM (25 mL) was cooled to 0° C., and TEA (22.08 mL, 158 mmol) and ammonium chloride (16.94 g, 317 mmol) were added slowly. After stirring at room temperature for 1 h, the reaction mixture was washed with saturated aqueous NaHCO3 (10 mL), water (10 mL), and brine (10 mL). The organic layer was separated and dried with Na2SO4 to afford the 4-(4-chloro-2-fluorophenyl)-2-methylnicotinamide (3.5 g, 13.2 mmol, 42% crude yield) as a brown solid. The material was carried forward without further purification. LC/MS (ESI) m/e 264.4 [(M)+, calcd for C13H10ClFN2O 264.0] LC/MS retention time (method C): tR=1.58 min.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:22](Br)[CH3:23].CO>O1CCOCC1>[CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([O:14][CH2:22][CH3:23])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)C(O)C(=CC1CCCCC1)n1cncn1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(C(=CC1CCCCC1)n1cncn1)C(C)(C)C
Temperature: 50 °C
Yield: 37.7 %

Procedure:
A solution of 26.3 g (0.1 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-ol (Example 2) in 50 ml of dioxan was added dropwise to a suspension of 3 g of 80% strength sodium hydride in 100 ml of dioxan. When the addition had ended, the mixture was warmed to 50° C. for 1 hour. After cooling, 10.9 g (0.1 mol) of ethyl bromide were added dropwise and the reaction mixture was heated under reflux overnight. After cooling, 10 ml of methanol were added and the mixture was concentrated in a rotary evaporator. The residue was taken up in methylene chloride and the methylene chloride mixture was washed with water. After drying the organic phase over sodium sulphate, it was filtered and the filtrate was concentrated. The residue was distilled. 11.0 g (37.8% of theory) of 1-cyclohexyl-3-ethoxy-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-ene of boiling point 110° C./0.07 mm Hg were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1)[C:10]([NH:23][C:24]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25]1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1(N)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)C(NC(=O)OC(C)(C)C)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 500 mg (1.57 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)-phenyl]acetic acid, 243 mg (1.88 mmol) of ethyl 1-aminocyclopropanecarboxylate, 450 mg (2.35 mmol) of EDC and 317 mg (2.35 mmol) of HOBt in 10 ml of DMF was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and washed twice with 1N hydrochloric acid and once with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate and then freed from the solvent on a rotary evaporator. The residue was dried under high vacuum. This gave 650 mg (96% of theory) of the title compound.