Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3](C(OCC2C=CC=CC=2)=O)[CH:4]=[C:5]([CH2:7][CH2:8][O:9][CH3:10])[N:6]=1.[OH:21][C@H:22]([C@@H:26]([NH:34][C:35](=[O:59])[C:36]1[CH:41]=[C:40]([C:42]([NH:44][C@@H:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH3:46])=[O:43])[CH:39]=[C:38]([N:53]([CH3:58])[S:54]([CH3:57])(=[O:56])=[O:55])[CH:37]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:23](O)=[O:24].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.C([O-])=O.[NH4+]>CN(C=O)C.CO.[Pd]>[CH2:27]([C@H:26]([NH:34][C:35](=[O:59])[C:36]1[CH:37]=[C:38]([N:53]([CH3:58])[S:54]([CH3:57])(=[O:56])=[O:55])[CH:39]=[C:40]([C:42]([NH:44][C@@H:45]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH3:46])=[O:43])[CH:41]=1)[C@@H:22]([OH:21])[C:23]([NH:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][O:9][CH3:10])=[CH:4][N:3]=1)=[O:24])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COCCc1cn(C(=O)OCc2ccccc2)c(N)n1
Reactant: C[C@@H](NC(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C(=O)O)cc(N(C)S(C)(=O)=O)c1)c1ccccc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1cnc(NC(=O)[C@H](O)[C@H](Cc2ccccc2)NC(=O)c2cc(C(=O)N[C@H](C)c3ccccc3)cc(N(C)S(C)(=O)=O)c2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a 0.5 ml solution of benzyl 2-amino-4-(2-methoxyethyl)-1H-imidazole-1-carboxylate prepared in a similar manner to Example 32 63 mg (0.22 mmol), (2R,3S)-2-hydroxy-3-{[3-[methyl(methylsulfonyl)amino]-5-({[(1R)-1-phenylethyl]amino}carbonyl)benzoyl]amino}-4-phenylbutanoic acid obtained in Reference Example 39 63 mg (0.11 mmol) and HOBt —H2O 18 mg (0.12 mmol) in DMF was added EDC.HCl 23 mg (0.12 mmol) under ice-cooling and the mixture was heated to room temperature and stirred for 2 hours. The reaction solution then was extracted by adding ethyl acetate and 5% aqueous sodium carbonate solution. The organic layer was washed with an aqueous saturated sodium chloride solution and dried on sodium sulfate. Filtration and concentration gave a residue and the resulting residue was redissolved in methanol 2 ml and thereto were added ammonium formate 126 mg (2.00 mmol) and 10% Pd/C (containing 50%) 50 mg and the mixture was heated under reflux for 1.5 hours. The mixture was filtered to remove 10% Pd/C and concentrated. The concentrated residue was suspended in ethyl acetate and the mixture was washed with 5% sodium carbonate and an aqueous saturated sodium chloride solution. The organic layer was dried on sodium sulfate. After filtration and concentration of the mixture, the mixture was purified by a column chromatography on silica gel (eluted with a mixed solvent of chloroform and methanol) to give 50 mg (0.07 mmol) of the title compound (yield: 67%).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22]C(C)(C)C)[N:14]=[C:13]([C:27]2[N:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:30]=[CH:29][CH:28]=2)[C:12](=[O:38])[CH:11]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:8][CH2:9][C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[N:14]=[C:13]([C:27]2[N:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:30]=[CH:29][CH:28]=2)[C:12](=[O:38])[CH:11]=1
Reactant: CC(C)(C)Oc1ccccc1-n1nc(-c2ccnn2-c2ccccc2)c(=O)cc1COCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(CO)n(-c2ccccc2O)nc1-c1ccnn1-c1ccccc1
Yield: 30 %

Procedure:
A solution of 6-[(benzyloxy)methyl]-1-(2-tert-butoxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.89 g) in TFA (9 mL) was heated under reflux for 4 hr. After cooling, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (0.19 g).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C.CCCCCC.CCCCCC.O.C(COC)OC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1ccccc1)c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 15 h
Yield: 47.7 %

Procedure:
Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.60 M hexane solution, 459 μl, 0.734 mmol) was added to a dimethoxyethane solution (50 ml) of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (202 mg, 0.667 mmol) obtained in Example 5. The temperature of the resulting mxiture was then elevated to room temperature. After the reaction mixture was cooled to −78° C., benzylbromide (87.2 μl, 0.734 mmol) was added dropwise thereto. While elevating the temperature of the reaction mixture to room temperature, stirring was conducted for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=6:1 eluate was concentrated. The solid thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (125 mg, 0.318 mmol, 48%) was obtained as colorless needle crystals.
Reaction SMILES: C([NH:6][O:7][CH2:8][CH2:9][CH2:10][CH:11]1[NH:15]C(=O)N[C:12]1=[O:17])(OCC)=O.[OH2:18].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:15][CH:11]([CH2:10][CH2:9][CH2:8][O:7][NH2:6])[C:12]([OH:17])=[O:18]
Reactant: O
Reactant: CCOC(=O)NOCCCC1NC(=O)NC1=O
Agent: [Ba+2]
Agent: [OH-]
Product: NOCCCC(N)C(=O)O

Procedure:
Mix 5-[3-(carbethoxyaminooxy)-propyl]-hydantoin (2.45 g, 10 mmol), barium hydroxide octahydrate (18.15 g, 10 mmol) and water (55 mL). Reflux for 12 hours, remove the white solid by filtration, extract the filter cake with boiling water (25 ml) and finally wash with hot water (25 mL). Combine the filtrate and washings, treat with ammonium carbonate (5.7 g) and heat with stirring. Filter off the barium carbonate, wash the filter cake with hot water and evaporate the filtrate and washings in vacuo to give 2-amino-5-aminooxy-pentanoic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][C:16]1[N:17]=[C:18]([NH:21][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]=[CH:4][N:3]=2)[S:19][CH:20]=1
Reactant: Cc1csc(N)n1
Reactant: Clc1cc(Oc2ccccc2)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1csc(Nc2cc(Oc3ccccc3)ncn2)n1
Yield: 18.4 %

Procedure:
Using the method of Example 3, Step B, 4-chloro-6-phenoxypyrimidine (0.697 g, 3.37 mmol), 4-methylthiazol-2-amine (7.66 mL, 3.07 mmol), potassium phosphate (0.716 g, 3.37 mmol), Pd2(dba)3 (0.0702 g, 0.0766 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0488 g, 0.0843 mmol) in toluene (3 mL) and water (3 mL) to afford 4-methyl-N-(6-phenoxypyrimidin-4-yl)thiazol-2-amine (0.161 g, 18.5% yield) as off white solid. 1H NMR (CDCl3), 8.56 (d, 1H), 7.43 (m, 2H), 7.28 (dt, 1H), 7.14 (m, 2H), 6.46 (d, 1H), 6.29 (s, 1H), 6.20 (m, 2H), 2.27 (d, 3H); Mass spectrum (esi) m/z=385 (100) (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=O.Cl.CO>O>[OH:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:8]2[CH2:7][C:6](=[O:10])[C:5]3[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][C:4]=3[O:9]2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=c1ccoc2cc(O)ccc12
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1CC(=Cc2ccc(O)c(O)c2)Oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
After 7-hydroxy-4(4H)-benzopyranone 0.5 g and 3,4-dihydroxybenzaldehyde 0.42 g were added to a mixture of concentrated hydrochloric acid 25 ml and methanol 35 ml, the mixture was refluxed for 2.5 hours and cooled to room temperature, and water 250 ml was added. The mixture was allowed to stand for 18 hours and the precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.61 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([OH:23])=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[OH:22].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH:23][C:5]1[C:4]([CH2:3][O:2][CH3:1])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:22])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1
Reactant: COCc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COCc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 37.3 %

Procedure:
262 mg (828 μmol) of 2-methoxymethyl-estra-1,3,5(10)-triene-3,17β-diol was dissolved in acetone, cooled to −70° C., and mixed in portions with Jones reagent (1.6 mmol). After 45 minutes, it was quenched with methanol, mixed with water and extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a rotary evaporator. Flash chromatography (n-hexane/ethyl acetate) yielded 97 mg (37%) of the desired product as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:44])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:44])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1ccccc1

Procedure:
To a solution of 73 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-ethoxycarbonylmethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 1 ml of DCM, 0.2 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]4([CH2:22][CH2:21][C:20]5[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=5[CH2:18][CH2:17]4)[C:14](=O)[C:13]=3[CH:28]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C[Si]([N:33]=[C:34]=[N:35][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]4([CH2:22][CH2:21][C:20]5[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=5[CH2:18][CH2:17]4)[C:14](=[N:35][C:34]#[N:33])[C:13]=3[CH:28]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1c2cc(-c3cc(F)cc(Cl)c3)ccc2OC12CCc1ccccc1CC2
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(-c3cc(F)cc(Cl)c3)ccc2OC12CCc1ccccc1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5′-(3-chloro-5-fluorophenyl)-5,6,8,9-tetrahydro-3′H-spiro[benzo[7]annulene-7,2′-benzofuran]-3′-one (0.0607 g, 0.155 mmol) in CH2Cl2 (5 mL) was added 0.7 mL of 1.0 M TiCl4 in CH2Cl2 at room temperature. After 1 h, 0.28 mL of bis(trimethylsilyl)carbodiimide was added to the red solution. The resulting mixture was then stirred at room temperature for 18 h. The mixture was quenched with ice, diluted with CH2Cl2, and dried over Na2SO4. After the solvent was removed under reduced pressure, the crude product was directly used in the next step without further purification.
Reaction SMILES: N[C:2]1[O:7][CH:6]2[C:8]3[C:12](=[CH:13][CH:14]=[C:5]2[CH:4]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([Br:25])[CH:16]=2)[C:3]=1[C:26]#[N:27])[N:11]=[CH:10][CH:9]=3.C(ON=O)(C)(C)C.[BH4-].[Na+]>C1COCC1>[Br:25][C:17]1[CH:16]=[C:15]([CH:4]2[C:3]([C:26]#[N:27])=[CH:2][O:7][CH:6]3[C:8]4[C:12](=[CH:13][CH:14]=[C:5]23)[N:11]=[CH:10][CH:9]=4)[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[O:23][CH3:24]
Reactant: COc1cc(C2C3=CC=C4N=CC=C4C3OC(N)=C2C#N)cc(Br)c1OC
Agent: CC(C)(C)ON=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C2C(C#N)=COC3C4=CC=NC4=CC=C32)cc(Br)c1OC
Temperature: -15 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a solution of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-indolo[4,5-b]pyran (0.998 g, 2.34 mmol) in anhydrous THF (40 mL) kept at −30° C., was added tert-butylnitrite (1.0 mL, 7.58 mmol) via a syringe under argon. The light yellow solution was stirred between −20 to −10° C. for 4 h, then allowed to warm up to 0° C. The reaction mixture was cooled to −10° C. and sodium borohydride (NaBH4, 0.259 g, 6.84 mmol) was added in one portion. The reaction mixture was warmed up to room temperature slowly and stirred overnight (15 h). The THF solvent was evaporated and the residue was dissolved in EtOAc (100 mL). The mixture was washed with saturated NaHCO3 (15 mL) and brine (15 mL), dried over MgSO4, and evaporated to yield a brown residue. The residue was purified by flash column chromatography (silica gel, EtOAc:hexanes/1:2) to yield 0.390 g (40%) of the product as an off-white solid. 1H NMR (CDCl3): 8.30 (brs, 1H), 7.45 (d, J=0.6 Hz, 1H), 7.24 (t, J=2.7 Hz, 1H), 7.13 (dd, J=0.8, 8.6 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 6.70 (J=8.1 Hz, 1H), 6.67 (m, 1H), 4.81 (s, 1H), 3.84 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: [H-].[Na+].ClC1C=C(N)C(I)=CN=1.S(OC[C@@H]1OCCN(C(OC(C)(C)C)=O)C1)(C1C=CC(C)=CC=1)(=O)=O.[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41](I)=[CH:40][N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:66][O:67][C:68]1[CH:73]=[CH:72][C:71](B(O)O)=[CH:70][CH:69]=1>CN(C=O)C.C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41]([C:71]2[CH:72]=[CH:73][C:68]([O:67][CH3:66])=[CH:69][CH:70]=2)=[CH:40][N:39]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2cc(Cl)ncc2I)C1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: Nc1cc(Cl)ncc1I
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(-c2cnc(Cl)cc2NC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
NaH (0.024 g, 0.569 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (0.121 g, 0.474 mmol) in DMF (2.8 mL) at room temperature and stirred for 10 min. The temperature was raised to 80° C. and (R)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate (0.264 g, 0.711 mmol) in DMF (0.6 mL) was added. The reaction mixture was stirred for 2 h before further NaH (0.024 g, 0.569 mmol) was added at room temperature. The reaction mixture was heated at 80° C. for a further 1 h then cooled. Water was added and the mixture was partitioned between ethyl acetate (20 mL) and aq. NaHCO3 (20 mL). The organic phase was washed with brine, dried (MgSO4) and concentrated. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate and hexane (2/4), to give an inseparable mixture of starting material and product. LC-MS (4) Rt=2.66 min; m/z (ESI+) 397 [MH+]. A solution of the crude (R)-tert-butyl 2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate (0.040 g, 0.088 mmol), sodium carbonate (0.5 M, 0.26 mL), 4-methoxyphenyl boronic acid (0.013 g, 0.088 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.011 g, 0.01 mmol) in acetonitrile (2 mL) was heated under microwave irradiation at 100° C. for 20 min. The reaction mixture was concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1/1), to give the title compound as colorless oil (0.036 g, 94%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][C@@H:38]([CH2:41][CH3:42])[CH2:39][NH2:40]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:40][CH2:39][C@@H:38]([CH3:37])[CH2:41][CH3:42])=[O:33])=[CH:35][CH:36]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC[C@H](C)CN
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: CC[C@H](C)CNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 98.6 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-2-methylbutylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 56 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]+.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[C:7]([F:15])=[C:8]([CH2:13]O)[C:9]([Cl:12])=[CH:10][CH:11]=1.O>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH2:13][Br:2])[C:7]=1[F:15]
Reactant: OCc1c(Cl)ccc(Br)c1F
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: Fc1c(Br)ccc(Cl)c1CBr
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
Add phosphorous tribromide (1.8 mL, 19.2 mmol) to (3-bromo-6-chloro-2-fluoro-phenyl)methanol (Preparation 8) (4.6 g, 19 mmol) in dichloromethane (50 mL) at 0° C. Stir for 20 minutes. Add the reaction mixture into ice and water. Extract with dichloromethane (100 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure. Purify the residue by biotage chromatography to yield the product to give 1.7 g (30%) of the title compound as a white solid. 1HNMR (CDCl3) 7.48-7.44 (m, 1H), 7.14-7.11 (m, 1H), 4.62-4.61(m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: COc1cccc(CCl)c1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1cccc(CN2N=C(c3ccc(OC)c(OC)c3)[C@@H]3CCCC[C@@H]3C2=O)c1

Procedure:
Prepared from compound 1 and 3-methoxybenzylchloride as described for compound 78. Crystallized from methanol. M.p. 115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:19])[CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1cncc(Br)c1
Solvent: ClCCl
Product: CCOc1cc(Br)c[n+]([O-])c1
Reaction time: 15 h
Yield: 63 %

Procedure:
To a solution of 3-bromo-5-ethoxypyridine (53 g, 262 mmol) in DCM (200 mL) at 0° C. was slowly added m-CPBA (67.9 g, 393 mmol) over 30 min. After the resulting solution was stirred for 15 h, the mixture was washed with NaS2O3 solution and extracted with DCM (2×300 mL), dried over Na2SO4 and the organic phase was concentrated to give 3-bromo-5-ethoxypyridine 1-oxide (40 g, 165 mmol, 62.9% yield): 1H NMR (400 MHz, CD3OD) δ 8.19-8.18 (m, 1H), 8.08-8.07 (m, 1H), 7.50-7.49 (m, 1H), 4.17-4.15 (d, J=8.8 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H); ES-LCMS m/z 217 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[NH2:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([C:43]=1[N:44]1[CH2:49][CH2:48][CH2:47][C@H:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:45]1)=[CH:41][CH:40]=[CH:39][CH:38]=2.N1C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([C:43]=1[N:44]1[CH2:49][CH2:48][CH2:47][C@H:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])[CH2:45]1)=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:24])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccccc23)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccccc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
To a solution of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (81.1 mg, 0.228 mmol) in THF (0.5 mL), a solution of 1-chloro-N,N,2-trimethylpropenylamine (Aldrich, 80.5 mg, 0.602 mmol) in THF (1.0 mL) was added. The mixture was stirred at room temperature for 5 h. To the above mixture was added a solution of tert-butyl [(3S)-1-(3-aminoquinolin-4-yl)piperidin-3-yl]carbamate (63.8 mg, 0.186 mmol) in THF (2.0 mL) followed by pyridine (146.4 mg, 1.851 mmol). The mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (115.8 mg, 91%). LCMS calc. for C34H39F2N6O5S (M+H)+: m/z=681.3. found 681.3.