Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:26][C:34](=[O:35])[NH:28][N:27]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3ccc(F)cc23)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Yield: 29 %

Procedure:
To a solution of (S)-tert-butyl 3-((7-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (0.35 g, 1 mmol) in dioxane (10 mL) was added CDI (0.36 g, 2 mmol) under a nitrogen atmosphere. The mixture was heated to reflux for 2 hours and was subsequently concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (120 mg, 34%). ESI-MS m/z [M+H]+ 415.2.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[C:25]([Cl:26])=[CH:24][C:23]([C:27](=[O:29])[CH3:28])=[C:22]([OH:30])[C:21]=2[CH2:31][CH2:32][CH3:33])[C:7]=1[CH2:34][CH2:35][CH3:36].[OH-].[Na+]>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]([CH2:34][CH2:35][CH3:36])[C:8]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27](=[O:29])[CH3:28])=[C:22]([OH:30])[C:21]=1[CH2:31][CH2:32][CH3:33])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)OC)c1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)O)c1CCC
Reaction time: 20 h
Yield: 42.1 %

Procedure:
To a solution of 1.94 g (0.0036 mol) of [4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester in 60 ml of methanol was added 60 ml of 1N sodium hydroxide (0.06 mol). The mixture was stirred at 25° for 20 hours. Most of the methanol was removed in vacuo and the aqueous solution was acidified to pH 4. The gummy precipitate was dissolved in ethyl acetate and washed with sodium chloride solution. The oil obtained on concentration of the ethyl acetate extract was purified by C18 reverse phase column chromatography, eluting with 60-80% methanol in water to yield a pale yellow oil which solidified. Recrystallization from cyclohexane-ether gave 790 mg, melting point 119°-121° (42% yield) of [4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][CH:14]=1.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[C:36]([F:42])[CH:35]=1>>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][N:11]([CH2:12][C:13]2[CH:32]=[CH:31][C:16]([O:17][C:18]3[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=3)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][CH:14]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[CH3:1])=[C:36]([F:42])[CH:35]=1
Reactant: CCOC(=O)COc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Reactant: Fc1cc(Cl)ccc1CBr
Product: CCOC(=O)COc1cccc(Oc2ccc(CN(Cc3ccc(Cl)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 83B and 4-chloro-2-fluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]([CH:10]=NC)=[CH:8][NH:7][N:6]=1)=[O:4].C(O)(C(F)(F)F)=[O:14]>C1COCC1.O>[CH:10]([C:9]1[C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][NH:7][CH:8]=1)=[O:14]
Reactant: O=C(O)C(F)(F)F
Reactant: CN=Cc1c[nH]nc1C(=O)NC
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1n[nH]cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of product (3-B) (17.1 g, 0.1 mol) in THF (100 mL) was added drop-wise a solution of TFA (57 g, 0.5 mol) in H2O (100 mL) at rt. The reaction mixture was stirred overnight at rt. The yellow precipitate was filtered, washed with H2O, and dried in air to give crude product (3-C) (12.5 g, 82%, for two steps) as a light yellow solid. 1H NMR (300 MHz, d-DMSO): δ 13.93 (br, 1H), 10.33 (br, 1H), 8.52 (br, 1H), 8.44 (s, 1H), 2.79 (d, 3H). LC-MS (M+H)+=154.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[C:23]1([CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1)[OH:24].[OH-].[Na+].Cl>C(O)CCC.O>[F:19][C:18]([F:20])([F:21])[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][O:24][C:23]1[CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CCCCC(CCOc1ccc(O)cc1)C(F)(F)F
Temperature: 130 °C
Reaction time: 5 h
Yield: 53.4 %

Procedure:
0.39 g of the above-obtained 3-trifluorometylheptyl p-toluenesulfonate and 0.25 g of hydroquinone were dissolved in 1 ml of butanol. To the solution was added a solution of 0.07 g of sodium hydroxide in 2 ml of butanol, followed by 5 hours of stirring at 130° C. for reaction. Then, water and 1N-hydrochloric acid were added to the reaction solution, followed by extraction with diethyl ether. The ether solution was dried with sodium sulfate, and the solvent was distilled off. The product was then purified by thin layer chromatography with methylene as the developer to obtain 0.17 g (yield:54%) of p-(3trifluoromethylheptyloxy)phenol which showed: [α]D26 -2.8, [α]43526 -4.9 (c 1, methylene chloride).
Reaction SMILES: [Br-:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:12](=[O:13])[CH:11]([CH2:14][CH2:15][CH:16]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[O:17][Si](C(C)C)(C)C)[CH:10]2[C:31]2[CH:46]=[CH:45][C:34]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N+:41]([CH3:44])([CH3:43])[CH3:42])=[CH:33][CH:32]=2)=[CH:5][CH:4]=1.Cl.C(=O)(O)[O-].[Na+]>CO>[Br-:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:12](=[O:13])[CH:11]([CH2:14][CH2:15][CH:16]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[OH:17])[CH:10]2[C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N+:41]([CH3:43])([CH3:42])[CH3:44])=[CH:45][CH:46]=2)=[CH:7][CH:8]=1
Reactant: CC(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(OCCCCC[N+](C)(C)C)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CO
Product: C[N+](C)(C)CCCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
548 mg of [5-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-(isopropyldimethyl-silanyloxy)propyl]-4-oxoazetidin-2-yl}phenoxy)pentyl]trimethylammonium bromide are dissolved in 20 ml of methanol. 1 ml of a 0.1 M aqueous HCl solution is then added, and the reaction solution is stirred at room temperature overnight. The mixture is neutralized with dilute aqueous sodium bicarbonate solution and concentrated using a rotary evaporator. The residue is purified using a 10 g SiO2 cartridge (dichloromethane/methanol 5:1). The product is obtained as a hygroscopic solid. C32H39BrF2N2O3 (617) MS (ESI): M+-80
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: O
Product: S=C=Nc1ccccc1-c1ccc(Cl)cc1

Procedure:
Reaction of 2-amino-4'-chlorobiphenyl (8.7 g) and thiophosgene (7.4 g) in a mixture of dioxane (10 ml) and water (10 ml) at 0°-5° C. for 20 minutes and then at ambient temperature for 3 hours yielded 4'-chloro-2-biphenylylisothiocyanate (m.p. 63° C.) as a yellow solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]2)[N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6][NH:5]1.Br[CH2:31][C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=1>CN(C)C=O>[C:39]([O:38][C:36]([C:35]1[CH:43]=[CH:44][C:32]([CH2:31][N:5]2[C:4](=[O:3])[C:8]3([CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:15])[CH2:12][CH2:13]3)[N:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:6]2)=[CH:33][CH:34]=1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.46 g, 0.0114 mol) was added portionwise at 0° C. to benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (4.00 g, 0.0109 mol) in N,N-dimethylformamide (40 mL) and the mixture stirred at 0° C. for 10 minutes. tert-Butyl 4-(bromomethyl)benzoate (3.27 g, 0.0120 mol) was added dropwise at 0° C., the mixture then allowed to warm to room temperature, and stirred for 2 hours. The reaction was quenched with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgSO4), and evaporated. The residue was purified by Biotage flash column chromatography (gradient 0 to 30% ethyl acetate/hexanes) to give product as an oil (4.97 g, 82%); 1H NMR (DMSO-d6); δ1.53 (s, 9H); 1.72 (d, J=13.6 Hz, 2H); 2.34-2.42 (m, 2H); 3.57 (m, 2H); 3.99-4.03 (m, 2H); 4.61 (s, 2H); 4.63 (s, 2H); 6.69 (d, J=8 Hz, 2H); 6.78 (t, J=7.2 Hz, 1H); 7.18 (dd, J=7.2 Hz and 8.8 Hz, 2H); 7.32-7.39 (m, 5H); 7.42 (d, J=8.4 Hz, 2H); 7.90 (d, J=8.4 Hz, 2H);
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH3:23])[CH:14]=2)=[O:12])[N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[CH3:24][N:25](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[CH3:23][O:22][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20])[C:11]([C:4]1[N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=[C:2]([C:24]#[N:25])[N:3]=1)=[O:12]
Reactant: COc1cc(C(=O)c2nc(Br)c3ccccn23)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C(=O)c2nc(C#N)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
2.17 g (18.48 mmol) of zinc cyanide and then 1.07 g (0.93 mmol) of tetrakis(triphenylphosphine)palladium(0) are added under a nitrogen atmosphere to 6.94 g (18.45 mmol) of (1-bromoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone obtained in example 20 in 160 ml of N,N-dimethylformamide. The reaction medium is heated at 90° C. for 17 h. The precipitate obtained is filtered off, washed with water, then with a saturated aqueous sodium bicarbonate solution and with water. After drying, 5.9 g of a yellow solid are collected. Melting point: 219° C.; 1H NMR (d6-DMSO): 4.01 (3H, s), 7.53-7.55 (1H, m), 7.76-7.81 (1H, m), 7.95-8.01 (2H, m), 8.08 (1H, d), 8.19 (1H, d), 9.70 (1H, d)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>CCO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=[N:31][OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccccc2C1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CC2C(=NO)CCc3ccccc32)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1-(3-benzyloxy-4-nitrobenzyl)-3,4-dihydro-1H-naphthalen-2-one (600 mg, 1.55 mmol), hydroxylamine hydrochloride (160 mg, 2.32 mmol) and sodium acetate (254 mg, 3.10 mmol) in 6 mL EtOH/H2O (2:1) is refluxed for 2 h. The solution is cooled to RT and extracted with CH2Cl2. The organic layer is washed with water, brined and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography with CH2Cl2 to give the title compound as a yellow liquid. (M+1)+=403.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C(NC(C)C)(C)C.[Li].[F:18][C:19]([F:23])([F:22])[CH2:20]I>C1COCC1>[F:18][C:19]([F:23])([F:22])[CH2:20][CH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]#[N:7])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C#N)cn1
Reactant: FC(F)(F)CI
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(CCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 6-methyl-nicotinonitrile (118 mg, 1.0 mmol) in anhydrous THF (20 mL) at −78 C under nitrogen was added lithium diisopropylamine (2M solution in THF/heptane/ethylbenzene, 550 μL, 1.1 mmol) drop-wise. The resulting solution was allowed to warm to room temperature for 5 min and then cooled back to −78 C. 1,1,1-Trifluoro-2-iodo-ethane (524 mg, 2.5 mmol) was then added to the solution drop-wise and the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 2 h. The reaction mixture was cooled at 0 C and quenched with water; the resulting solution was extracted with EtOAc (3×25 mL). Combined organics were washed with brine (25 mL), dried over magnesium sulfate and purified by silica chromatography (25% EtOAc in heptane) to afford the title compound as a pale yellow oil (191 mg, 95%). Method C HPLC-MS: MH+ requires m/z=201. Found: m/z=201, Rt=1.22 min (86%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C([O-])(=O)C.[K+].[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]1[NH:23][C:24]([C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=2)=[O:25]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]1[NH:23][C:24]([C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=2)=[O:25]
Reactant: N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=Cc1cccs1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: O=C(N[C@H]1Cc2ccccc2[C@@H]1NCc1cccs1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Thiophenecarboxaldehyde (80 μL, 0.8 mmol) and potassium acetate (90 mg, 0.9 mmol) were added to a solution of N-{(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-yl}-5-chloro-1H-indole-2-carboxamide (Method 5b, 400 mg, 0.9 mmol) in MeOH (10 mL). The reaction was stirred at ambient temperature for approximately 5 mins then macroporous triethylammonium methyl polystyrene cyanoborohydride (540 mg, 0.9 mmol) was added and the reaction stirred at ambient temperature for a further 3 h. The reaction was then filtered and the volatiles were removed by evaporation under reduced pressure to afford N-{(1S,2S)-1-[(2-thienylmethyl)amino]-2,3-dihydro-1H-inden-2-yl}-5-chloro-1H-indole-2-carboxamide which was used crude in the next stage.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:17]O>>[C:5]1([CH:11]([CH3:16])[CH2:12][C:13]([O:15][CH3:17])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(CC(=O)O)c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(C)c1ccccc1
Reaction time: 4 h

Procedure:
Thionyl chloride (44 ml, 91.4 mmol) is added dropwise to methanol (30 ml) at 0° C., followed by 3-phenylbutyric acid (10 g, 60.9 mmol). The reaction is stirred for 4 hours and the solvent is evaporated. The residue is partitioned between t-butylnethyl ether and aqueous ammonia. The organic phase is washed with water and brine, dried (Na2SO4) and evaporated to afford the title compound. MH+179.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]3[CH:43]=[CH:44][CH:45]=[CH:46][C:14]1=3)=[C:7]([O:47][CH3:48])[CH:6]=[CH:5]2.[ClH:49]>CO.CCOCC>[ClH:49].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]3[CH:43]=[CH:44][CH:45]=[CH:46][C:14]1=3)=[C:7]([O:47][CH3:48])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3cc(Br)ccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a rt solution of tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (80 mg, 107 μmol) in MeOH (107 μl) was added 2 M HCl in Et2O (429 μl). The reaction was stirred at rt for 2 h then concentrated, taken up in H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (65.7 mg, 90%) as a white solid. MS m/z 645/647 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28](O)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[C@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[C@H:40]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:37]=2[N:38]2[CH2:43][C@H:42]([CH3:44])[C@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[C@H:40]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:39]2)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
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: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (31 mg, 0.075 mmol), tert-butyl methyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (30 mg, 0.079 mmol) and HATU (92 mg, 0.24 mmol) in DMF (1.0 mL), DIPEA (90 μL, 0.52 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was then purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a yellow solid (30 mg, 51%). LCMS calc. for C40H49N8O8 (M+H)+: m/z=769.4. Found: 769.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]([O:15]CC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([O:8][C:9]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
A mixture of ethyl 2,4-dibenzyloxyphenoxyacetate (2 g), 10% w/v potassium hydroxide (10 mL) and methanol (50 mL) is stirred at ambient temperature for 1 hour. The reaction is concentrated in vacuo and acidified with 1 N HCL then extracted with ethyl acetate (2×100 mL). The organic layer is washed with water (2×100 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to give a white powder. Recrystallisation from ethyl acetate/cyclohexane affords 2,4-dibenzyloxyphenoxyacetic acid (0.4 g) as a white solid, m.p. 72° C. [Elemental Analysis:- C, 72.4, H, 5.50% Calculated for C, 72.5H, 5.53%].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[C:13]1[C:22]2[C:17](=[C:18]([CH3:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:13]1[C:22]2[C:17](=[C:18]([CH3:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: Cc1cccc2c(Cl)ccnc12
Product: Cc1[nH]c2ccc(F)cc2c1-c1ccnc2c(C)cccc12

Procedure:
The sub-title compound was prepared from 5-fluoro-2-methylindole and 4-chloro-8-methylquinoline by the method of Example 31, step a).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:3][CH:2]=1.[OH-].[K+].Cl>O.CCO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1ccncc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1ccncc1
Yield: 72.1 %

Procedure:
To a solution of ethyl 3-pyridin-4-ylpropanoate (Method 7; 103.1 g, 576 mmol) in water (400 ml) and EtOH (20 ml) at room temperature was added potassium hydroxide (60 g, 1600 mmol). After 18 hours hydrochloric acid (100 ml) was added to give a white solid 62.8 g (73%). NMR (300 MHz) 8.38 (d, 2H), 7.21 (d, 2H), 2.70 (t, 2H), 2.52 (t, 2H); m/z 152.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[C:17](Cl)[N:16]=[C:15]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[N:14]=1>>[Cl:12][C:13]1[N:14]=[C:15]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[N:16]=[C:17]([NH:11][S:8](=[O:10])(=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: NS(=O)(=O)Nc1ccccn1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccccn1
Yield: 71.8 %

Procedure:
According to the procedure described in referential Example 1e), pyridine-2-sulfamic acid amide (60 mg, Referential Example 21) was reacted with 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (100 mg, Referential Example 1d)) to give pyridine-2-sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-amide (100 mg). tR=3.83 min (LC); [M−H]+=483.33 (ES−);