Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[C:6]([C:17]([O:19]CC)=[O:18])[C:5]2=[O:22].[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1>>[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][N:30]([C:11]3[CH:10]=[C:9]4[C:4]([C:5](=[O:22])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]4[C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:3][C:2]=3[F:1])[CH2:29]2)[CH2:25][CH2:24]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2cc(F)c(F)cc2c1=O
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)cc21
Yield: 21.8 %

Procedure:
Using ethyl 6,7-difluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-3-quinolinecarboxylate (309 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 40 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (91.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:9]=[C:10]1[CH2:15][C:14](=O)[CH2:13][CH2:12][NH:11]1>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:14]1[CH2:13][CH2:12][NH:11][C:10](=[O:9])[CH:15]=1
Reactant: O=C1CCNC(=O)C1
Reactant: Nc1ccccc1F
Product: O=C1C=C(Nc2ccccc2F)CCN1
Yield: 82.2 %

Procedure:
A mixture of 2-fluoroaniline (0.98 g) and 2,4-dioxopiperidine (1.0 g) was heated at 120° for 2 h. The cooled mixture was triturated with dry ether (5×40 ml) and the solvent was decanted to leave the title compound (1.495 g), m.p. 98°-100°.
Reaction SMILES: [CH3:1][C:2]([O:7][SiH2:8][O:9][C:10]([CH3:15])([CH2:12][CH:13]=[CH2:14])[CH3:11])([CH2:4][CH:5]=[CH2:6])[CH3:3].B(C1C(F)=C(F)C(F)=C(F)C=1F)(C1C(F)=C(F)C(F)=C(F)C=1F)C1C(F)=C(F)C(F)=C(F)C=1F>ClCCl>[CH3:3][C:2]1([CH3:1])[CH2:4][CH2:5][CH2:6][Si:8]2([CH2:14][CH2:13][CH2:12][C:10]([CH3:15])([CH3:11])[O:9]2)[O:7]1
Reactant: C=CCC(C)(C)O[SiH2]OC(C)(C)CC=C
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: ClCCl
Product: CC1(C)CCC[Si]2(CCCC(C)(C)O2)O1
Temperature: 25 °C

Procedure:
A heat-dried Schlenk flask is charged with 23.8 g (104 mmol) of bis((2-methylpent-4-en-2-yl)oxy)silane (example 1) in 400 mL of dried dichloromethane, and 1.06 g (2.07 mmol, 2 mol %) of the catalyst B(C6F5)3 are added with stirring at room temperature. The reaction mixture is then stirred at room temperature for 16 hours and purified by fractional condensation.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][OH:30])[CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][OH:30])[CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(CO)c2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2cccc(CO)c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(3-(hydroxymethyl)phenyl)benzoate and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile 0.1% trifluoroacetic acid aqueous solution] to obtain 12 mg of 2-(benzamido)-4-(3-(hydroxymethyl)phenyl)benzoic acid as white solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:16])[C:10](=[O:15])[N:11]2[OH:14])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>P([O-])(O)(O)=O.[K+].C(O)C>[CH2:17]([O:14][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:13]=2)[NH:8][C:9](=[O:16])[C:10]1=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]c(=O)c(=O)n(O)c2c1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
7-Carboxy-1-hydroxyquinoxaline-2,3(1H,4H)-dione (2.22 g, 10 mmol) was dissolved in a mixture of 50 ml of 1M potassium dihydrogen phosphate buffer (pH 7.4) and 25 ml of ethanol by gently heating. To the cooled mixture was added 1.19 ml (10 mmol) of benzylbromide and the mixture was stirred overnight at room temperature. The precipitate was isolated by filtration and washed with ethanol. The crude product was triturated with 4M hydrochloric acid and washed with water and dried in vacuo to give 1.56 g (50%) of the title compound.1H-NMR (DMSO-d6): 5.22 (s, 2H, CH2), 7.2-7.9 (m, 8H, ArH), 12.35 (s, 1H, exchangeable), 13.05 (br.s, 1H, exchangeable).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][C:9]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:21]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:15]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:16]=3)[C:11]=2[CH:10]=1>N1C=CC=CC=1.C(OCC)C>[C:1]([O:8][C:9]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:21]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:15]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:16]=3)[C:11]=2[CH:10]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCCCCOc1cc2c(cc1O)c1cc(OCCCCC)c(OCCCCC)cc1c1cc(OCCCCC)c(OCCCCC)cc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCOc1cc2c3cc(OCCCCC)c(OCCCCC)cc3c3cc(OC(=O)C(C)(C)C)c(OCCCCC)cc3c2cc1OCCCCC
Temperature: 80 °C

Procedure:
181 mg (1.5 mmol) pivaloyl chloride was added to a solution of 673 mg (1 mmol) 2-hydroxy-3,6,7,10,11-pentapentyloxytriphenylene (see Henderson et al., Liquid Crystals 18 (1995) 191) in 1 mL pyridine. The mixture was heated for one hour at 80° C., diluted with diethyl ether and extracted repeatedly with dilute HCl and sodium carbonate solution. Purification was performed by crystallization from ethanol.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:18](=[O:19])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:8]=3[O:9][C:10](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:20][NH2:21]>C(Cl)(Cl)Cl>[NH2:20][N:21]1[C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:19])[C:7]=2[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[C:10]1=[O:9]
Reactant: NN
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Solvent: ClC(Cl)Cl
Product: Nn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Benz[d]indeno[1,2-b]pyran-5,11-dione (4d) (0.150 g, 0.604 mmol) was treated with hydrazine (0.255 g, 7.964 mmol) in CHCl3 (50 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, diluted with CHCl3 (150 mL), and washed with sat NaHCO3 (2×50 mL). The solution was dried over sodium sulfate and concentrated to provide a red-orange solid (0.120 g, 76%): mp 272-274° C. IR (film) 3448, 3305, 1686, 1663, 1610, 1507, 1312, 762 cm−1; 1H NMR (CDCl3) δ 8.54 (d, J=7.8 Hz, 1H), 8.51 (d, J=7.2 Hz, 1H), 8.24 (d, J=7.4 Hz, 1H), 7.85 (m, 1H), 7.60-7.45 (m, 4H), 6.19 (s, 2H); EIMS m/z (rel intensity) 262 (M+, 100). Anal. (C16H10N2O2.0.25H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](C(O)=O)[CH:3]=1.C([N:13](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl>C(O)(C)(C)C.O1CCOCC1.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:13])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)ccn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-pyridinecarboxylic acid (5.95 g) in tert-butanol (89.25 mL) were added triethylamine (6.32 mL) and diphenylphosphoryl azide (8.95 mL). The mixture was stirred at 100° C. for overnight. To the solution was added water and the mixture was extracted with EtOAc and washed with water and brine. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized with EtOAc to give a white solid. The solid was dissolved in dioxane (50 mL). To the solution was added 4M HCl in dioxane (90 mL) and the mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure to give 4-chloro-2-pyridinamine hydrochloride (3.02 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.I(C1C=CC=CC=1C(O)=O)(=O)=O.O.C(OCC)(=O)C>CS(C)=O>[F:1][C:2]([F:11])([F:12])[CH:3]1[CH2:4][CH2:5][CH:6]([CH:9]=[O:10])[CH2:7][CH2:8]1
Reactant: OC[C@H]1CC[C@@H](C(F)(F)F)CC1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=CC1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.2 %

Procedure:
After dissolving [cis-4-(trifluoromethyl)cyclohexyl]methanol (2.04 g, 10.2 mmol) in dimethylsulfoxide (30 ml), 2-iodoxybenzoic acid (4.00 g, 14.3 mmol) was added thereto and stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, the insoluble matter was removed by filtration, and then the filtrate was separated into layers. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated to afford the title compound as a colorless oil (2.3 g, 100%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[CH2:7]>C(#N)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.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([C:10]1[CH:11]=[C:2]2[C:3](=[CH:8][CH:9]=1)[NH:4][CH:5]=[C:6]2[CH3:7])([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=CCNc1ccc(C(=O)OCC)cc1Br
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCOC(=O)c1ccc2[nH]cc(C)c2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of 2-bromo-4-carboethoxy-N-allylaniline (J. Org. Chem., 45, 2710(1980)) (650 mg, 2.29 mmol) in acetonitrile (10 ml), tetrakis(triphenylphosphine)palladium(0) (132 mg, 0.114 mmol), palladium (II) acetate (25.7 mg, 0.114 mmol) and TEA (0.413 ml, 2.98 mmol) were added and stirred overnight in a sealed tube at 100° C. After filtering the reaction mixture, the filtrate was evaporated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:2) to give the titled compound (340 mg, 73%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[OH2:22].[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:16][CH2:17][S:18](=[O:22])[CH2:19][CH2:20]1
Reactant: CN1CCN(C)C1=Nc1ccccc1N1CCSCC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCN(C)C1=Nc1ccccc1N1CCS(=O)CC1

Procedure:
Reaction of 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]thiamorpholine (1.5 g prepared as described in Example 144) in methanol (20 ml) and sodium metaperiodate (1.4 g) in water (4 ml) for 4 hours at 10° C. yielded 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]thiamorpholine-1-oxide monohydrate (m.p. 103°-105° C.) which was recrystallised from a 1:1 mixture of 1,2-dimethoxyethane and hexane.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH2:16](O)[CH3:17]>>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCO
Reactant: O=C(O)Cc1ccc2ccccc2c1
Agent: Cl
Product: CCOC(=O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A steady stream of anhydrous hydrochloric acid was bubbled subsurface into a solution of 2-naphthylacetic acid (251.38 grams, 1.35 mmol) dissolved in ethanol (1760 mL) over a period of 10 minutes. The resulting solution was stirred at ambient temperature until complete as determined by hplc (2 hours). The reaction mixture was concentrated to dryness. The resulting oil was dissolved in ethyl acetate (200 mL) and filtered through silica gel (300 grams) eluting the product with ethyl acetate (1400 mL). The filtrate was concentrated to give 286.33 grams (99%) of ethyl 2-(2-naphthyl)acetate as a colorless oil. MS (FIA) m/z 215.3 [(M+H)+]. 1H nmr (DMSO-d6): δ 1.15-1.24 (t, 3H), 3.81-3.86 (d, 2H), 4.07-4.15 (q, 2H), 7.41-7.55 (m, 3H), 7.80-7.92 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][NH:15][CH2:16][CH:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:27]C)=[CH:22][CH:23]=4)[O:18]3)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[BrH:29]>>[BrH:29].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][NH:15][CH2:16][CH:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][C:21]([OH:27])=[CH:22][CH:23]=4)[O:18]3)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)OC(CNCc1cncc(-c3ccc(F)cc3)c1)CC2
Agent: Br
Product: Oc1ccc2c(c1)OC(CNCc1cncc(-c3ccc(F)cc3)c1)CC2

Procedure:
300 mg of (2R/S)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-7-methoxychroman is treated with 25 ml hydrobromic acid (48% in water) at 130 degrees C. The obtained red solution is neutralized and worked up as described in example 1. 130 mg of (2R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-ol hydrobromide is obtained;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:9])[S:5][C:6]=1[Cl:7].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)OC1>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>[Cl:7][C:6]1[S:5][C:4]([C:8]([NH:10][C@@H:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:9])=[CH:3][C:2]=1[C:45]1[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1C(F)(F)F)NC(=O)c1cc(Br)c(Cl)s1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
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: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reaction time: 12 h
Yield: 25.9 %

Procedure:
To a solution of 1,1-dimethylethyl {(2S)-2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (750 mg, 1.38 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (762 mg, 5.52 mmol), tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol), and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (373 mg, 1.8 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h where additional tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (373 mg, 1.8 mmol) were added. After 12 h, the solution was poured onto H2O (100 mL) and extracted with DCM. The organics were dried (Na2SO4), concentrated under vacuum, and purified on silica gel (hexanes/EtOAc, 1:1) to give the title compound (194 mg, 26%) as a white solid: LC-MS (ES) m/z=544.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:13]=3[C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=3[CH3:30])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-:31].[Na+].OO.Cl>CS(C)=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:13]=3[C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:31])[NH2:29])=[CH:24][C:23]=3[CH3:30])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [OH-]
Reactant: Cc1cc(C#N)ccc1-c1c(-c2ccc(-n3ccnc3)cc2)ccn1CCC(=O)O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C(N)=O)ccc1-c1c(-c2ccc(-n3ccnc3)cc2)ccn1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
To a mixture of compound 3-(3-(4-(1H-imidazol-1-yl)phenyl)-2-(4-cyano-2-methylphenyl)-1H-pyrrol-1-yl)propanoic acid (180 mg, 0.98 mmol) and sodium hydroxide (80 mg, 2.0 mol) in DMSO (5 mL) was added 0.1 mL of 30% hydrogen peroxide, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized by 1N HCl to PH=5-6, concentrated, and purified by preparative HPLC to give 3-(3-(4-(1H-imidazol-1-yl)phenyl)-2-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-1-yl)propanoic acid (29 mg, yield 15.4%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2Cl.C(O)(=O)C.C(O)(=O)C.[CH3:25][N:26]([CH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1)[CH3:27].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([CH2:28][N:26]([CH3:27])[CH3:25])[CH2:30][CH2:31]1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a suspension of 1-(6-bromo-4-chloroquinolin-3-yl)propan-1-one (500 mg, 1.67 mmol) in dioxane (10 mL) and DMF (4 mL) was added trans-4-((dimethylamino)methyl)cyclohexanamine diacetic acid salt (583 mg, 2.11 mmol) and Cs2CO3 (3.27 g, 10.0 mmol). The resultant suspension was then heated to 90° C. and stirred for 5.5 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was then washed with saturated sodium bicarbonate, water and then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (silica, 0-10% methanol/dichloromethane) afforded the desired product (403 mg, 58%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 10.79 (d, J=8.4 Hz, 1H), 9.00 (s, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.83-7.67 (m, 2H), 4.01-3.88 (m, 1H), 3.08 (q, J=7.2 Hz, 2H), 2.24 (s, 6H), 2.21-2.12 (m, 2H), 1.98 (d, J=13.4 Hz, 2H), 1.61-1.42 (m, 3H), 1.25 (t, J=7.3 Hz, 3H), 1.19-1.00 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][O:3]1.Cl([O-])(=O)(=O)=O.[Li+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH2:26][C:27]2[S:31][C:30]([Cl:32])=[N:29][C:28]=2[Cl:33])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH2:26][C:27]2[S:31][C:30]([Cl:32])=[N:29][C:28]=2[Cl:33])[CH2:1][C:2]([OH:3])([CH3:5])[CH3:4])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC1(C)CO1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2sc(Cl)nc2Cl)CC1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(O)CN(Cc1sc(Cl)nc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
Add 2,2-dimethyl-oxirane (3.0 mL, 33.3 mmol) to a stirred suspension of lithium perchlorate (3.39 g, 31.9 mmol) in anhydrous acetonitrile (40 mL). Stir for one hour under nitrogen at room temperature. Add 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.1337 g, 3.10 mmol) in anhydrous acetonitrile (15 mL). Heat the reaction at reflux for 72 hours under nitrogen. Pour the reaction into saturated sodium bicarbonate (100 mL) and extract with ethyl acetate (3×100 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 30% ethyl acetate/hexanes to yield 0.4527 g (33%) of 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-(2-hydroxy-2-methyl-propyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=438.2 (M+1); 1H NMR (CDCl3): δ=4.22 (br s, 2H), 3.97 (s, 2H), 2.67-2.59 (m, 3H), 2.50 (s, 2H), 1.77-1.74 (m, 2H), 1.60 (s, 2H), 1.49 (s, 9H), 1.47-1.35 (m, 1H), 1.23 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCOC(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid ethyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and ethyl chloroformate (84 μl, 0.89 mmol). The title compound was obtained as brown powder (100 mg, 32%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:47])=[N:17][C:18]([CH3:46])=[C:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:32][CH:31]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][C:24]([CH2:28][CH3:29])([CH3:27])[CH2:23][CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:47])=[N:17][C:18]([CH3:46])=[C:19]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:34][CH:35]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][C:24]([CH2:28][CH3:29])([CH3:27])[CH2:23][CH2:22]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCC1(C)CCN(c2c(-c3ccc(OCCc4ccc(F)cc4)cc3)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)OC(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC1(C)CCN(c2c(-c3ccc(OCCc4ccc(F)cc4)cc3)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)O)CC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
The 1.86 mL of 1M sodium hydroxide (74 mg, 1.86 mmol) was added to a solution (S)-isopropyl 2-(tert-butoxy)-2-(4-(4-ethyl-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (128 mg, 0.207 mmol) in ethanol (2 mL) and stirred for 24 h at 90° C. An additional 0.8 mL sodium hydroxide was added and the reaction was continued for 24 h. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to give (S)-2-(tert-butoxy)-2-(4-(4-ethyl-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid 116 mg (97%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.38-7.35 (m, 2H), 7.20-7.18 (m, 1H), 7.13 (t, J=9.1 Hz, 2H), 7.03-7.00 (m, 3H), 5.85 (s, 1H), 4.27-4.18 (m, 2H), 3.52 (br. s, 2H), 3.27-3.21 (m, 1H), 3.04 (t, J=6.6 Hz, 2H), 2.84-2.97 (m, 1H), 2.43 (s, 3H), 2.19-2.14 (br. s, 1H), 2.05 (s, 3H), 1.96-1.91 (m, 1H), 1.49-1.38 (m, 1H), 1.29-1.23 (m, 1H), 1.17-1.12 (m, 1H), 1.12 (br. s, 9H), 1.01-0.99 (m, 1H), 0.75-0.72 (m, 3H), 0.54 (br. s, 3H). UPLC (M+H)=577.5.