Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][CH2:23][CH2:22][O:21][CH3:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: COCCN
Product: COCCNc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-methoxyethylamine were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxyethyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.81 (bs, 1H), 7.33 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=2.4 Hz and 9 Hz), 6.81 (d, 1H, J=9 Hz), 6.53 (s, 1H), 4.25 (bs, 2H), 3.54 (bs, 2H), 3.36 (s, 3H); LCMS: ret. time: 18.01 min.; purity: 100%; MS (m/e): 321 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[C:9]([S:20][CH3:21])=[C:10]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:11]([O:13]CC)=[O:12]>O.C(O)C>[CH3:7][C:8]1[C:9]([S:20][CH3:21])=[C:10]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1ccc(C)c(C)c1SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CSc1c(C(=O)O)ccc(C)c1C
Yield: 99.2 %

Procedure:
A solution of potassium carbonate (10.67 g) in water was added to a solution of ethyl 3,4-dimethyl-2-methylsulphenylbenzoate (21.19 g) in ethanol. The mixture was heated at reflux for 0.5 hours then partially evaporated. Water was added and the mixture was acidified to pH 1. The solid was filtered off and washed with water to give 3,4-dimethyl-2-methylsulphenylbenzoic acid (18.39 g) as a white solid, m.p. 117.8°-120.3° C.
Reaction SMILES: NN.[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1>CO>[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1ccncc1
Agent: NN
Solvent: CO
Product: NCCCc1ccncc1
Reaction time: 48 h
Yield: 83.7 %

Procedure:
Add a solution of hydrazine (4.0 mL) in methanol (200 mL) to 2-(3-pyridin-4-yl-propyl)isoindole-1,3-dione (8.0 g, 30 mmol). After 48 hours, filter the mixture and concentrate the filtrate, triturate with methylene chloride (150 mL), and filter a second time. Perform the filtrate via flash chromatography on silica gel eluting with 80:18:2 CHCl3/MeOH/concentrated NH4OH) to afford the title compound as a yellow oil (3.42 g). MS: m/e=137 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([Cl:19])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9]2)([O-:3])=[O:2].P(Cl)(Cl)(OCl)=O.CN([CH:29]=[O:30])C>ClCCl>[Cl:19][C:6]1[CH:7]=[C:8]2[C:12](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:9]2[CH:29]=[O:30]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Agent: O=P(Cl)(Cl)OCl
Solvent: ClCCl
Product: O=Cc1c(-c2ccccc2)[nH]c2c([N+](=O)[O-])cc(Cl)cc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
7-Nitro-5-chloro-2-phenyl-1H-indole (1.0 g, 3.67 mmol) prepared in Preparation 26 was dissolved in dichloromethane (20 mL). Phosphoryloxychloride (0.84 g, 5.50 mmol) and DMF (0.80 g, 11.01 mmol) were added in drops thereto at 0° C., and the mixture was stirred for 6 h at room temperature. After completion of the reaction, the reaction was quenched by saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (0.5 g, Yield 45%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:30]([O:37][C:38](ON1C(=O)CCC1=O)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C.CO>C1COCC1.C(Cl)(Cl)Cl>[C:16]([O:15][C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][C:38](=[O:39])[O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 68 h
Yield: 70.1 %

Procedure:
A solution containing the product from Example 23F (6.1 g, 15.2 mmol) in THF (150 mL) was treated with N-(benzyloxycarbonyloxy)succinimide (3.4 g, 13.6 mmol) and N,N-diisopropylethylamine (3.3 mL, 19.0 mmol), stirred at 25° C. for 68 hours and concentrated. The residue was chromatographed on silica gel eluting with 33% ethyl acetate in chloroform and then with 10% methanol in chloroform to give the title compound (5.1 g, 63% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][N:9]=2)[C:4](=[O:22])[NH:3]1.[H-].[Na+].I[CH3:27]>CN(C=O)C>[CH3:27][N:3]1[C:2]([CH3:23])([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][N:9]=2)[C:4]1=[O:22]
Reactant: CI
Reactant: CC1(C)CCN(c2cnc(C#Cc3ccccc3)cn2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cnc(C#Cc3ccccc3)cn2)CCC1(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
To a solution of 4,4-dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one (Example 164, step 2) (30 mg, 0.098 mmol) in 2 ml of DMF was added 60% sodium hydride suspension (4.7 mg, 0.118 mmol, 1.2 equiv.). After stirring at room temperature for 15 min, iodomethane (7.4 ml, 16.7 mg, 0.118 mmol, 1.2 equiv.) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and was worked up with ethyl acetate/water. Flash chromatography over a prepacked 20 g silica column eluting with a heptane to 50% ethyl acetate in heptane gradient yielded the title compound (25.4 mg, 81% yield) as an off-white solid, MS: m/e=321.3 (M+H+).
Reaction SMILES: [Br:1]([O-])(=O)=O.[Na+].[CH3:6][C:7]1[O:8][C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13].S([O-])(O)=O.[Na+].C(OCC)C>O.C1CCCCC1>[Br:1][CH2:6][C:7]1[O:8][C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Temperature: 10 °C

Procedure:
A solution of sodium bromate (8.14 g) in water (27 ml) was treated with a suspension of methyl 2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 23, 5.12 g) in cyclohexane (36 ml). The system was cooled to <10° C. in ice/water bath and treated with a solution of sodium hydrogen sulfite (9.4 g) in water (54 ml) in a drop-wise manner over 30 minutes. The reaction was allowed to warm up to 10° C. for 2 hours and then poured into diethylether (400 ml) and washed with fresh water. The organic layer was washed with 10% sodium thiosulfite solution and dried over magnesium sulfate. The crude product isolated by evaporation, was pre-adsorbed onto silica and purified by flash column chromatography using 39:1 cyclohexane:ethyl acetate as eluent to give the title compound as a white powder.
Reaction SMILES: C(Br)C=C.C[Si](C)(C)[CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[CH:8]=[CH2:7]
Reactant: C[Si](C)(C)CCCn1c(-c2nc3ccccc3o2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Solvent: O
Product: C=CCn1c(-c2nc3ccccc3o2)nc2ccccc21
Temperature: 70 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Allyl bromide (1.13 ml, 9.35 mmol) was added dropwise over 10 minutes to a heterogeneous mixture of 2-(1H-benzimidazol-2-yl)benzoxazole (second step of Example 1) (2 g, 8.5 mmol) and potassium carbonate (1.29 g) in 10 ml of DMF heated to 70° C. The heating was continued at 70° C. for 4 hours. The reaction mixture was cooled and poured into water. The precipitate obtained was filtered off, washed with water and dried. 2.3 g (yield: 96%) of 2-(1-allyl-1H-benzimidazol-2-yl)-benzoxazole were obtained in the form of a beige-colored powder.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[OH-].[Na+:37]>O>[CH3:17][C@@:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18].[Na+:37]
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A suspension of the product of Example 39I (2.71 g) in water (10 mL) and treated with 0.997N sodium hydroxide solution (5.25 mL, 5.24 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (2.46 g, 87%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.46 (m, 1 H) 0.69 (m, 6 H) 0.80 (m, 1 H) 1.29 (m, 1 H) 1.38 (m, 3 H) 1.72 (m, 1 H) 2.14 (m, 1 H) 2.90 (m, 3 H) 7.34 (m, 6 H) 8.05 (m, 1 H) 15.42 (m, 1 H). MS (ESI−) m/z 516 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:37])([CH2:31]OS(C)(=O)=O)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10].[NH:38]1[CH:42]=[N:41][CH:40]=[N:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.C(OC(C)C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]([OH:37])([CH2:31][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10]
Reactant: c1nc[nH]n1
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@](O)(Cn1cncn1)c1ccccc1F
Temperature: 80 °C
Yield: 76 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (2.2 g) was dissolved in 40 ml of dimethylformamide, to which 1.39 g of 1H-1,2,4-triazole and 5.55 g of potassium carbonate were added. The mixture was heated at 80° C. for 4 hours. The reaction solution was diluted with a mixture of 150 ml of ethyl acetate and 50 ml of diisopropyl ether, and washed with water (40 ml×2), 1N-hydrochloric acid (40 ml×2) and 20 ml of aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=1:1 to 1:2). The desired fraction was concentrated and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1.59 g of 1-[(1R,2S)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (yield: 75%) as colorless powdery crystals.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=O.[NH2:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][C@@H:18]([CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:19][OH:20])=[CH:14][CH:13]=[CH:12][CH:11]=2.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(O)C.O.C(Cl)(Cl)Cl>[CH2:23]([O:22][CH2:21][C@@H:18]1[N:17]2[C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[CH:8][C:7]=3[N:6]=[C:3]2[CH2:2][O:20][CH2:19]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cnc2ccccc2c1N[C@H](CO)COCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: c1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
Chloroacetyl chloride (14.8 mL, 186 mol) was added to a mixture of (2R)-2-[(3-aminoquinolin-4-yl)amino]-3-(benzyloxy)propan-1-ol (28 g, 86 mmol) and triethylamine (12.0 mL, 86.5 mmol) dissolved in 432 mL of CH2Cl2 at 0° C. The reaction was stirred for 1 hour at ambient temperature. The solvent was removed under reduced pressure and the resulting dark, oily solid was treated with acetic acid (400 mL). The mixture was heated to reflux for 6 hours. The reaction was cooled to ambient temperature and the acetic acid was removed under reduced pressure. The resulting dark brown oil was concentrated from toluene (2×) and then from ethanol to afford a dark brown oil. The oil was dissolved in a mixture of ethanol (400 mL) and water (60 mL) and treated with potassium carbonate (60 g). The reaction mixture was heated at 60° C. and stirred for 1 hour. The reaction was then cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to afford a dark oil. Chromatography (SiO2, 0-30% CMA/CHCl3) gave 17 g of (11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CN1CCN(CCCCN)CC1
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)=O)nc3NC2=O)c1
Product: COc1cc(OC)cc(N2Cc3cnc(NCCCCN4CCN(C)CC4)nc3NC2=O)c1
Yield: 31 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1354 g (0.791 mmol) of 4-(4-methyl-piperazin-1-yl)-butylamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) then ethyl acetate/ethanol/triethylamine (9:3:2 v/v/v) to give 0.0401 g (31%) of the title compound: HPLC=99% pure.
Reaction SMILES: [CH:1]12[CH2:15][CH:6]([C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=31)[CH2:5][NH:4][CH2:3][CH2:2]2.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>C(O)C>[CH2:24]([N:4]1[CH2:3][CH2:2][CH:1]2[CH2:15][CH:6]([CH:7]([OH:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=32)[CH2:5]1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: O=C1c2ccccc2C2CCNCC1C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCN1CCC2CC(C1)C(O)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
20 ml of ethanol was added to 1 g of 2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one and 0.63 g of sodium carbonate, and the mixture was heated and refluxed. Then, 0.72 g of allyl bromide was gradually added to the mixture, and the reaction mixture liquid was heated and refluxed for 5 hours. The mixture was cooled and filtered, and methanol and excessive allyl bromide were distilled from the filtrate. The residue was dissolved in 20 ml of methanol and cooled with ice water, and 0.15 g of sodium boron hydride was gradually added to the solution under agitation. Then, the mixture was agitated at room temperature for 2 hours. Methanol was distilled from the reaction mixture, and 15 ml of water was added to the residue and the mixture was shaken sufficiently. Then, the mixture was extracted with ether and the extract was subjected to distillation to remove ether therefrom. The residue was recrystallized from cyclohexane to obtain 0.9 g of 4-allyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4 -benzazonin-7-ol in the form of a white crystal melting at 98° to 100° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([OH:12])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1>C1COCC1>[CH:1]1([CH2:7][C@H:8]([OH:12])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H](O)CC1CCCCC1
Agent: B
Solvent: C1CCOC1
Product: OC[C@@H](O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.6 %

Procedure:
To a solution of (S)-3-cyclohexyllactic acid (15 g) in THF (100 mL) at 0° C. was added 1M BH3-THF (130 mL), and the reaction was warmed to ambient temperature. After 5 h, the reaction was quenched cautiously with aqueous THF (1:1, 100 mL), then with 1M KOH (100 mL). The reaction was concentrated, diluted with water (200 mL), and washed with EtOAc (3×150 mL). The organic extracts were washed with brine (100 mL), dried (MgSO4), filtered and concentrated to give a colorless oil (14 g). 1H NMR (300 MHz, CDCl3) δ0.80-1.04 (m, 2H), 1.05-2.00 (m, 13H), 3.41 (dd, J=10.8, 7.5 Hz, 1H), 3.64 (dd, J=10.8, 2.7 Hz, 1H), 3.84 (m, 1H). MS(CI/NH3) m/e: (M+NH4)+ 176.
Reaction SMILES: CN(C)CC.[F:6][C:7]1[CH:41]=[CH:40][C:10]([CH2:11][N:12]2[CH2:39][CH2:38][N:15]3[C:16]4[N:37]=[CH:36][CH:35]=[CH:34][C:17]=4[N:18]([C:21]([CH:23]4[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]4)=O)[CH2:19][CH2:20][CH:14]3[CH2:13]2)=[CH:9][CH:8]=1>O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]2[CH2:39][CH2:38][N:15]3[C:16]4[N:37]=[CH:36][CH:35]=[CH:34][C:17]=4[N:18]([CH2:21][CH:23]4[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]4)[CH2:19][CH2:20][CH:14]3[CH2:13]2)=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC3CN(Cc4ccc(F)cc4)CCN3c3ncccc32)C1
Agent: CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CN2CCC3CN(Cc4ccc(F)cc4)CCN3c3ncccc32)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Alane-dimethylethylamine complex (0.5 M in toluene, 3.1 mL, 1.55 mmol) was added to a solution of the product of Example 69A (154 mg, 0.31 mmol) in tetrahydrofuran (5.0 mL) at room temperature under nitrogen. The cloudy solution was stirred at room temperature for 2.5 hours and then quenched by addition of methanol (1 mL), followed after minutes by water (5 mL) and 25% NaOH (0.5 mL). The aqueous layer was separated and extracted with ethyl acetate (2×6 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4) and concentrated under vacuum to provide a residue that was further purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column (30×75 mm) eluted with methanol: 10 mM (NH4)2CO3 in water (50:50-95:5) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (s, 9H), 1.62-1.87 (m, 2H), 2.12 (t, J=10.0 Hz, 1H), 2.34 (td, J=10.7, 2.7 Hz, 1H), 2.59 (d, J=10.9 Hz, 1H), 2.72-2.86 (m, 2H), 2.89-3.00 (m, 1H), 3.14-3.26 (m, 1H), 3.28 (d, J=7.5 Hz, 2H), 3.31-3.43 (m, 2H), 3.44-3.56 (m, 2H), 3.56-3.63 (m, 2H), 3.69 (dt, J=12.8, 3.1 Hz, 1H), 3.96 (td, J=8.5, 3.7 Hz, 2H), 6.75 (dd, J=7.8, 4.7 Hz, 1H), 6.96 (dd, J=7.8, 1.4 Hz, 1H), 6.98-7.06 (m, 2H), 7.31 (dd, J=8.5, 5.4 Hz, 2H), 7.86 (dd, J=4.7, 1.7 Hz, 1H); MS (DCI) m/z 482 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([N:56]1[CH:60]=[C:59]([C:61]2[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=2)[CH:58]=[N:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[CH2:49]([N:56]1[CH:60]=[C:59]([C:61]2[CH:62]=[C:63]([NH:67][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:64]=[CH:65][CH:66]=2)[CH:58]=[N:57]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 52.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-benzyl-1H-pyrazol-4-yl)-phenylamine (0.016 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 55% yield: LCMS (ESI) m/z 438 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH3:22])[C:17]([O:23][CH2:24][CH2:25][OH:26])=[CH:16][C:15]=2[F:27])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](I)[CH2:35][CH2:36][CH3:37].O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:34]([O:12][C:11](=[O:13])[CH:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH3:22])[C:17]([O:23][CH2:24][CH2:25][OH:26])=[CH:16][C:15]=1[F:27])[CH2:35][CH2:36][CH3:37]
Reactant: CCOc1cc(C(Nc2ccc(C#N)cc2)C(=O)O)c(F)cc1OCCO
Reactant: CCCCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)c(OCCO)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
The (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid (226 mg) described in example 1.25 was dissolved in DMF (2 ml). Potassium carbonate (167 mg), n-butyl iodide (556 mg) and tetrabutylammonium iodide (22 mg) were added and the mixture was stirred overnight at r.t. Water was added and the mixture was extracted with EtOAc. The org. phase was washed with water, dried, filtered and concentrated. The product was purified by chromatography (SiO2, EtOAc/hexane) to give 146 mg of (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid butyl ester as a colorless solid. MS: 453 ([M+Na]+).