Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:18]([C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[C:28](=[O:33])[N:27]([C:34]1[C:42]3[CH2:41][O:40]B(O)[C:38]=3[CH:37]=[CH:36][CH:35]=1)[N:26]=[CH:25]2)([CH3:21])([CH3:20])[CH3:19].N1C=CC=CC=1.[NH4+].[Cl-]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCCl>[C:18]([C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[C:28](=[O:33])[N:27]([C:34]1[C:42]([CH2:41][OH:40])=[C:38]([N:13]3[C:11]4=[N:12][C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)=[CH:8][CH:9]=[C:10]4[C:15]([C:16]#[N:17])=[CH:14]3)[CH:37]=[CH:36][CH:35]=1)[N:26]=[CH:25]2)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Reactant: N#Cc1c[nH]c2nc(N3CCOCC3)ccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(N6CCOCC6)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
In a 25 mL round-bottomed flask, 6-morpholino-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (65 mg, 285 μmol, Eq: 1.00), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (150 mg, 427 μmol, Eq: 1.5) and copper acetate (69.8 mg) were combined with 1,2-dichloroethane (3 ml) to give a blue suspension. Pyridine (45.1 mg, 46.1 μl, 570 μmol, Eq: 2) was added. The reaction mixture was heated to 45° C. and stirred for 2 d. The reaction mixture was poured into 20 mL sat NH4Cl and extracted with EtOAc (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 10% MeOH in DCM, then silica gel, 12 g, 30% to 45% EtOAc in hexanes) gave 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-morpholino-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (157 mg, 50%) as colorless oil which foams upon being dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:20])[N:10]=[N:9]1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:21]([NH:25][C:26]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:10]=[N:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:12]=2[CH3:13])[C:15](=[O:20])[CH2:16]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1c(N2CCNCC2=O)nnn1-c1ccccc1Cl
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1c(N2CCN(C(=O)NC(C)(C)C)CC2=O)nnn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere, 4-[1-(2-chlorophenyl)-5-methyl-1H-[1,2,3]triazol-4-yl]-3-oxopiperazine prepared in 1) of Example 51 was dissolved in 1 ml of chloroform and 0.05 ml of tert-butyl isocyanate and 0.1 ml of triethylamine were added thereto followed by stirring at room temperature for 2 hours. After the solvent was evaporated in vacuo, the resulting residue was purified by a preparative thin-layer silica gel chromatography (chloroform:methanol=9:1) to give 5 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[N:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[N:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Nc1ccc(Cl)nn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)nn3)cccc12
Yield: 32.5 %

Procedure:
A solution of 5-dimethylamino-1-naphthalenesulphonyl chloride (3.98 g), 3-amino-6-chloropyridazine (1.91 g) and 4-dimethylaminopyridine (100 mg) in pyridine (25 ml) was heated at 85° C. for 18 hours. Volatile material was removed by evaporation and dichloromethane (50 ml) was added. Insoluble material was removed by filtration and the filtrate was concentrated by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), and the resulting foam was crystallised from ether to give 5-(dimethylamino)-N-(6-chloro-3-pyridazinyl)-1-naphthalenesulphonamide (1.74 g), m.p. 153-154° C.; mass spectrum (positive chemical ionisation ((+)ve CI)): 363 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH3:36])[S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:24][N:25]([CH3:36])[S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Product: CN(C)S(=O)(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1c from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-aminobenzenesulphonic acid-dimethylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17]OC1=O>ClCCl.[Al+3].[Cl-].[Cl-].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][CH2:18][N:14]([CH2:13][CH2:12][Cl:11])[C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: O=C1OCCN1CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1N(CCCl)CCN1c1cccc(Cl)c1
Temperature: 195 °C
Yield: 78.7 %

Procedure:
A mixture of 3-chlorophenyl isocyanate (7.65 g, 50 mmoles), N-(2-chloroethyl)-2-oxazolidinone (7.5 g, 50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give 10.2 g (78.4 percent) of the desired product, m.p. 64° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:26].CO>>[ClH:26].[NH:8]1[CH2:11][CH:10]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1
Reactant: COc1cccc(-c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2nccnc2C2CNC2)c1
Yield: 99.24 %

Procedure:
A solution of (33) (341 mg, 1.0 mmol) in 4N HCl/MeOH (20 mL) was stirred at RT for 30 min. The reaction mixture was concentrated to give (34) (260 mg, 0.99 mmol, yield 99.24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]2[C:16](=[O:17])OC(C)(C)OC2=O)=[CH:5][CH:4]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:10]=[CH:11][C:16]2=[O:17]
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cn1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2[nH]ccc(=O)c2n1
Temperature: 250 °C

Procedure:
A suspension of 5-((6-methoxypyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (51.3 g, 0.185 mol) in diphenylether (1275 mL) was heated to 250° C. under nitrogen atmosphere for 20 min. The reaction mixture was cooled to RT and diluted with hexane. The gummy solid was then triturated with hexane to obtain 6-methoxy-1,5-naphthyridin-4(1H)-one as a pale brown color solid.
Reaction SMILES: [CH3:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][C:43]=1[N:44]1[CH2:48][C@H:47]([OH:49])[C@@H:46]([OH:50])[CH2:45]1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([Cl:40])([F:39])[F:38])=[CH:32][CH:31]=1)=[O:28]>CN(C=O)C.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>[Cl:40][C:37]([F:38])([F:39])[O:36][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:43]([N:44]3[CH2:45][C@H:46]([OH:50])[C@@H:47]([OH:49])[CH2:48]3)=[C:42]([C:7]3[C:2]([CH3:1])=[N:3][CH:4]=[N:5][CH:6]=3)[CH:41]=2)=[CH:35][CH:34]=1
Reactant: Cc1ncncc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncncc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)ccc1N1C[C@H](O)[C@@H](O)C1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
4-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (Stage 297.1, 94 mg, 0.429 mmol), K2CO3 (118 mg, 0.857 mmol) and Pd(PPh3)4 (33.0 mg, 0.029 mmol) were added to a solution of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 244.1, 150 mg, 0.286 mmol) in DMF (2.5 mL). at RT in a vial. The vial was evacuated/purged with argon, sealed and stirred at 130° C. for 2 h. The RM was diluted in EtOAc (80 mL), washed with water (3×30 mL), dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure. The residue was dissolved in methanol (3 mL) and filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) and by preparative HPLC. The obtained residue was treated with a aq. solution of Na2CO3 (3 mL) and extracted twice with EtOAc (2×30 mL). The combined organic phases were washed with water (2×15 mL), dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure to afford the title product as a beige solid. HPLC (Condition 10) tR=6.091 min, UPLC-MS (Condition 11) tR=0.93 min, m/z=491.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.19/2.40 (s, 3H) 2.65-2.78 (m, 2H) 3.06-3.22 (m, 2H) 3.80-3.90 (m, 2H) 5.01-5.12 (m, 2H) 6.93 (d, J=8.99 Hz, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.70-7.80 (m, 1H) 7.83-7.89 (d, J=8.60 Hz, 2H) 7.91-7.98 (m, 1H) 8.82 (s, 1H) 9.05 (s, 1H) 10.01-10.12 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:39]>COCCOC.C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O-:32])=[O:31])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:39]
Reactant: CCOC(=O)COc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: COCCOC
Product: O=C([O-])COc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1

Procedure:
A solution of ethyl [3-[[2-(4,5-diphenyl-2-oxazolyl)-2-cyclohexen-1-yl]methyl]phenoxy]acetate (355 mg) and 1N sodium hydroxide aqueous solution (0.71 ml) in 1,2-dimethoxyethane (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours and evaporated in vacuo. The solid residue was washed with diethyl ether to afford sodium [3-[[2-(4,5-diphenyl-2-oxazolyl)-2-cyclohexen-1-yl]methyl]phenoxy]acetate (308 mg) as a pale yellow powder.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][CH:22]([NH2:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:31][CH:22]([CH3:21])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CC(N)CCc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NC(C)CCc2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-methyl-3-phenyl-propylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H27NO5 [M−H]−: 384.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.Br[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([Br:19])[N:11]=1.C(N(CC)CC)C>CC(O)C>[Br:19][C:12]1[N:11]=[C:10]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Reactant: Nc1ccnc(Cl)c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Br)nc1Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-pyridin-4-ylamine (1 eq, 6.6 mmol, 850 mg) and 2,6-dibromo-3-nitro pyridine (2 eq, 13.2 mmol, 3.85 g) are dissolved in IPA (15 ml) and heated using microwave radiation at 150° C. for 6 hours. After cooling to room temperature, triethylamine (1 eq) is added and reaction mixture is stirred for 1 hour. The majority of solvent is removed in vacuo and the residue is diluted using 6% DCM in iso-hexane (75 ml). The solvent is decanted off and the process repeated 3 times. The resulting brown solid is dissolved in DCM and excess amine is scavenged using SCX-2 resin (6 g) and discarded. The solid is triturated in hexane, DCM and IPA (50 ml of a 58:40:2 mixture) and the resulting yellow solid is collected by filtration. The solid is dissolved in DCM and washed with water. The organic portion is dried (MgSO4) and concentrated in vacuo to afford the title compound; [M+H]+ 330.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][O:14][CH:15]3[CH:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[O:39][CH3:40])=[CH:23][CH:22]=4)[CH2:19][CH2:18][N:17]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:16]3)[CH:11]=2)[C:6]([CH3:49])([CH3:48])[CH2:5]1.[C:50](Cl)(=[O:52])[CH3:51]>C(N(CC)CC)C.ClCCl>[C:50]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][O:14][CH:15]3[CH:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[O:39][CH3:40])=[CH:23][CH:22]=4)[CH2:19][CH2:18][N:17]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:16]3)[CH:11]=2)[C:6]([CH3:49])([CH3:48])[CH2:5]1)(=[O:52])[CH3:51]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCN)CC3(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCNC(C)=O)CC3(C)C)cc1
Reaction time: 0.5 h

Procedure:
The solution of 0.268 g of tert-butyl 3-[1-(2-aminoethyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 0.061 ml of triethylamine and 9.0 ml of dichloromethane is cooled to 0° C. and admixed slowly with the solution of 0.033 ml of acetyl chloride in 1.0 ml of dichloromethane. The reaction solution is stirred over a further 30 minutes, poured onto ice-water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed successively with water (20 ml) and brine (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.73 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=5.82.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:16][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Yield: 117.5 %

Procedure:
The product from Example 6b (8.65 g, 31.3 mmol) was reduced with SnCl2 following the procedure from Example 5I giving the title compound as a white solid (8.51 g, 100%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].CCOCC>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:1][N:2]=[C:3]([NH2:7])[CH:4]([OH:6])[CH3:5])=[O:13]
Reactant: CC(O)C(N)=NO
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)C(N)=NOC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.45 g crude N′,2-dihydroxypropanimidamide was cooled on an ice-bath with 23.5 mL DEA in THF (200 mL). To this slurry 21.94 g 3-chlorobenzoyl chloride was added. The mixture was warmed to r.t. and stirred for 2 h. Addition of Et2O (200 mL), washing with sat. aq. NH4Cl and re-extraction of the aq. layer gave after combining and concentration of the org. layers followed by drying in vacuo 27.24 g of crude title compound, which was directly used in the next step. LC-MS (M++1): 243.
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)C(Cl)=O.[NH:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[S:14]C1=S.C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:11][C:6]1[S:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: S=c1[nH]c2ccncc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Clc1nc2ccncc2s1
Temperature: 25 °C
Yield: 87 %

Procedure:
To an ice-cold mixture of dimethylformamide (DMF, 1.1 mL) and DCE (8 mL) was added dropwise a solution of oxalyl chloride (1.73 mL) in DCE (4 mL). A white precipitate formed, and the reaction mixture was stirred at rt for 5 min. [1,3]Thiazolo[5,4-c]pyridine-2(1H)-thione (1 g, 6 mmol) was added in portions, and the reaction mixture was stirred at reflux for 3 h. After cooling to rt, the reaction mixture was treated with water (20 mL) and saturated (satd.) aqueous (aq.) NaHCO3 (100 mL) and then extracted with ethyl acetate (EtOAc) (2×100 mL). The combined organic layers were dried, filtered and concentrated to provide the desired product as a brown solid (1 g, 87%). 1H NMR (400 MHz, CDCl3): 9.11 (d, J=0.8, 1H), 8.68 (d, J=5.6, 1H), 7.85 (dd, J=5.6, 0.8, 1H). MS (ESI): mass calcd. for C6H3ClN2S, 169.97; m/z found, 171.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]([CH2:13][C:14]([O:16]CC)=[O:15])[C:7](=[O:19])[CH:6]=[N:5]2.[OH:20]O.Cl>[OH-].[Na+]>[C:14]([CH2:13][N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=2)[NH:5][C:6](=[O:20])[C:7]1=[O:19])([OH:16])=[O:15]
Reactant: OO
Reactant: CCOC(=O)Cn1c(=O)cnc2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(Cl)c(Cl)cc21
Yield: 81 %

Procedure:
The above ester (1.5 g, 5 mmol) was suspended in 70 ml of 2.5% NaOH and 30% H2O2 (1.95 ml) was added. The mixture was warmed at 70°-80° C. for 5 h, cooled and acidified (pH=1) with concentrated hydrochloric acid. The precipitate was filtered off and recrystallized from DMF-water to afford 1.17 g (81%) of the title compound. M.p. 317°-19° C. 1H-NMR (DMSO-d6):δ4.95 (s, 2H), 7.36 (s, 1H), 7.72 (s, 1H), 12.13 (s, 1H), 13.32 (br.s, 1H).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>>[F:1][C:2]([F:41])([F:42])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]([OH:31])=[O:30])=[CH:23][CH:22]=3)=[O:16])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 81.2 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-(4′-trifluoromethylbiphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionate (1.10 g), which is the product of Example 81, was reacted with aqueous sodium hydroxide solution (1N, 5.00 ml) and the reaction mixture was treated to give the title compound (850 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[C:10]([OH:9])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccccc1-c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
1-Bromo-4-iodobenzene (Aldrich, 2 g, 7.07 mmol), (2-hydroxyphenyl)boronic acid (Aldrich, 1.073 g, 7.78 mmol), Pd(Ph3P)4 (0.204 g, 0.177 mmol) were dissolved in 1,4-dioxane (30 mL) and water (10 mL), K3PO4 (2.251 g, 10.60 mmol) was added. The reaction mixture was stirred at 100° C. overnight. Solvents were removed under reduced pressure and DCM was added, mixture was washed with water, dried over anhydrous sodium sulfate. Then solvent was removed under reduced pressure to give the title product 4′-bromo-2-biphenylol (1.85 g, 6.54 mmol, 92% yield) as brown oil. LCMS: (M+H)+=247-249; Rt=3.52 min.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH:5]1[C:9]2=[C:10]([S:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:11]3[C:12]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:13][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[Li+].[OH-].CC(O)=O>C1COCC1.CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:10]2[C:11]3[C:12]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:13][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:15][C:16]=3[N:8]3[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:33])=[O:2])[C:9]=23)=[CH:27][CH:28]=1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(OC(C)C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1cc(S(C)(=O)=O)c2c(Sc3ccc(Cl)cc3)c3n(c2c1)CCC3CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of the ester of Step 2 (70 mg) in THF/MeOH (3:1) mixture at r.t. was added 1 M LiOH aqueous solution (1 mL). The reaction mixture was stirred at r.t. for 1 hour. Then AcOH was added. The aqueous layer was extracted with EtOAC and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with 1% AcOH in EtOAc to give 60 mg of the title compound.