Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([C:20]([OH:22])=[O:21])=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N12CCCN=C1CCCC[CH2:30]2.IC>C1COCC1>[CH3:30][O:21][C:20]([C:11]1[CH:10]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)=[O:22]
Reactant: COCCOCOc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: C1CCOC1
Product: COCCOCOc1c(-c2ccccc2)cc(C(=O)OC)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
At 0° C., to a stirred solution of 2'-(2-methoxyethoxymethoxy)-[1,1';3',1"]terphenyl-5'-carboxylic acid (1.72 g, 4.55 mmol) in THF (4.55 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene. After 0.5 h, to the reaction was added iodomethane and the reaction was stirred for 16 h, eventually warming to ambient temperature. The reaction was filtered and the filtrate concentrated. The crude product was dissolved in EtOAc, washed sequentially with sat. aq. NaHCO3 (3×), with 1 N HCl (3×), brine (3×), dried (K2CO3) and concentrated. Purification on Biotage KP-Sil eluting with 20% acetone/hexane gave 1.641 g (92%) of the title compound as a yellow oil. 1H NMR (DMSO-d6) δ 2.77-2.80 (m, 2 H), 2.88-2.91 (m, 2 H), 3.01 (s, 3 H), 3.87 (s, 3 H), 4.40 (s, 2 H), 7.40-7.53 (m, 6 H), 7.60-7.62 (m, 4 H), 7.90 (s, 2 H).
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8]([S:20][CH3:21])=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:28][N:29](C)[C:30](C(OCC)=O)=CC=[N+](C)C.CC[O-].[Na+]>C(O)C>[CH3:19][N:17]([CH3:18])[C:11](=[CH:10][CH:9]=[C:8]([S:20][CH3:21])[C:7]([C:1]1[CH:2]=[CH:3][C:4]([N:29]([CH3:30])[CH3:28])=[CH:5][CH:6]=1)=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CC[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(N(C)C)cc1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino-2,4-hexadienoate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (8.6 g), a 2M ethanolic solution of sodium ethylate (15 cc) and α-methylthio-4-dimethylaminoacetophenone (5.8 g) in ethanol (60 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-6-(4-dimethylaminophenyl)-5-methylthio-6-oxo-2,4-hexadienoate (5.5 g) is obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:6]([CH3:23])=[C:5]2[C:24]([OH:26])=[O:25].[C:27](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=1)[C:6]([CH3:23])=[C:5]2[C:24]([O:26][CH3:27])=[O:25]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(F)cc2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-fluoro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (9.0 g, 24.64 mmol) in dichloromethane (120 mL) at 0° C. was added 5 drops of DMF. Oxalyl chloride (3.24 mL, 37.0 mmol) was added slowly. The mixture was stirred at 0° C. for 1 h. The mixture was warmed to room temperature, and an additional portion of oxalyl chloride (3.24 mL, 37.0 mmol) was added. The reaction mixture was stirred overnight. Methanol (50 mL) was added and the mixture was stirred overnight. The solvent was removed under reduced pressure to afford methyl 6-fluoro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification in the next step. MS (m/z) 380.1 (M+H+).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[C:13](O)=[O:14].[BH4-].[Na+]>CCOCC.CO>[F:16][C:12]([F:17])([C:11]([F:19])([F:18])[F:10])[CH:13]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)[OH:14]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Mg]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(C(O)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
In a three neck flask purged with nitrogen were charged magnesium (12.2 g, 502 mmol) and ether (100 ml). A solution of 4-bromotoluene (56.1 ml, 456 mmol) in ether (200 ml) was added dropwise, and the mixture was heated under reflux for 1.5 hrs. The reaction vessel was cooled in a dry ice-acetone bath. A solution of pentafluoropropionic acid (25 g, 152 mmol) in ether (100 ml) was added dropwise, and the temperature was slowly raised to room temperature. The mixture was heated under reflux for 3 hrs, and stirred overnight at room temperature. The reaction mixture was ice-cooled, and quenched with 3N hydrochloric acid. The mixture was diluted with ethyl acetate, and the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0, 30:1) to give a colorless transparent oil. This was dissolved in methanol, and sodium borohydride was added under ice-cooling. The temperature was raised to, room temperature, and the mixture was stirred for 1 hr. After completion of the reaction, the reaction was quenched with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1, 5:1) to give 2,2,3,3,3-pentafluoro-1-(4-methylphenyl)propan-1-ol (20.28 g, 56%) as a colorless transparent oil.
Reaction SMILES: [N:1]([C@@:4]1([CH2:35][O:36][C:37](=[O:45])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[C@@H:8]([O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:7]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:6]([N:27]2[CH:32]=[CH:31][C:30](=O)[NH:29][C:28]2=[O:34])[O:5]1)=[N+:2]=[N-:3].[NH:46]1[CH:50]=[CH:49][N:48]=[CH:47]1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>CC1OCCC1.O>[N:1]([C@@:4]1([CH2:35][O:36][C:37](=[O:45])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[C@@H:8]([O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:7]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:6]([N:27]2[CH:32]=[CH:31][C:30]([N:46]3[CH:50]=[CH:49][N:48]=[CH:47]3)=[N:29][C:28]2=[O:34])[O:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@]1(COC(=O)c2cccc(Cl)c2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Solvent: O
Product: [N-]=[N+]=N[C@]1(COC(=O)c2cccc(Cl)c2)O[C@@H](n2ccc(-n3ccnc3)nc2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
A suspension of 30.0 g (47.5 mmol) 3-chlorobenzoic acid (2R,3S,4R,5R)-2-azido-3,4-bis-benzoyloxy-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethyl ester and 26.0 g (380 mmol) imidazole in 110 ml MeTHF was treated at room temperature with 19.2 g (189 mmol) triethylamine. The resulting mixture was treated at 10 to 20° C. within 30 minutes with 11.03 g (71.2 mmol) phosphorous oxychloride. The mixture was heated to 60° C. and stirred at this temperature for 5 hours. The mixture was then cooled to 15° C. and treated at this temperature with 125 ml water. The layers were separated and the aqueous layer was extracted with MeTHF (1×30 ml). From the organic layer MeTHF was completely removed by distillation and replaced by 250 ml acetonitrile. Water (50 ml) and methylene chloride (100 ml) were added and the layers were separated. The aqueous layer was extracted with methylene chloride (1×100 ml). The organic layer was filtered, the solvent was evaporated and the residue (34.2 g) dried in vacuo (<30 mbar) at 40° C. for 16 hours to afford 29.7 g (90.8%) of 3-chlorobenzoic acid (2R,3S,4R,5R)-2-azido-3,4-bis-benzoyloxy-5-(4-imidazol-1-yl-2-oxo-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethyl ester with an assay of 99.3% (area).
Reaction SMILES: [N:1]1([C:7]2[C:8]([C:15]([F:18])([F:17])[F:16])=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28].Cl>C(#N)C>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8]([C:15]([F:16])([F:18])[F:17])=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:2][CH2:3]1)[CH2:27][CH3:28]
Reactant: N#Cc1cccc(N2CCNCC2)c1C(F)(F)F
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(C#N)c2C(F)(F)F)CC1

Procedure:
Preparation according to Example 1: 3-piperazin-1-yl-2-(trifluoromethyl)benzonitrile (0.83 g, 3.25 mmol), acetonitrile (40 ml), potassium carbonate (0.88 g, 8.1 mmol) and 1-iodopropane (0.255 ml, 3.25 mmol). Yield: 0.74 g (77%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 234-236° C. MS m/z (relative intensity, 70 eV) 297 (M+, 15), 269 (14), 268 (bp), 225 (26), 177 (8).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=5)[N:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:38](O)(=O)[CH2:39][CH2:40]CC>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:36])([F:35])[F:37])=[N:32][N:33]=5)[N:30]=4)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH2:8][CH2:9]1)(=[O:3])[CH2:2][CH2:38][CH2:39][CH3:40]
Reactant: CCCCC(=O)O
Reactant: CC(=O)N1CCN(CCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Product: CCCCC(=O)N1CCN(CCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 77 %

Procedure:
Obtained in 77% yield by an analogous method to Example 4.1, starting from 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 32, preparation of starting materials) and pentanoic acid.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:56]\[H])/[C:50]1[CH:55]=[CH:54][CH:53]=[N:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:7]1([C:6]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:21][N:56]=[C:49]([C:50]4[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=4)[N:48]=3)[C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1cccnc1
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3cccnc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxynicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 9.23 (d, J=1.7, 1H), 8.76 (dd, J=1.7, 4.9, 1H), 8.27 (dt, J=1.9, 8.0, 1H), 7.50-7.25 (m, 11H), 4.91 (s, 2H), 3.59 (t, J=6.5, 2H), 2.90 (t, J=6.5, 2H); MS (DCI) m/z 397.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CN1CCCN(C)C1=O.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C1(C)C=CC=CC=1>[CH2:31]([C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:22][C:14]=2[NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[N:17]=1)[CH3:32]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: C1CNCCN1
Solvent: CN1CCCN(C)C1=O
Solvent: Cc1ccccc1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(N5CCNCC5)ccn34)c12
Temperature: 105 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
N-(3-Ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (12 mg, 0.03 mmol; Example 74, Step A) was dissolved in toluene (0.2 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (0.1 mL) and piperazine (24 mg, 0.28 mmol) was added in one portion. The mixture was heated to 105° C. and stirred for 16 hours. The crude mixture was loaded onto a Biotage 12+ C-18 samplet and purified using a gradient of 10-65% acetonitrile/water to give N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(piperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxamide as a white solid (12 mg). MS m/z 495.3 (M+1, APCI+)
Reaction SMILES: C[N+]1([O-])[CH2:7][CH2:6][O:5]CC1.N1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H]1C(O)=O>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:11]1[C:12]2[C:17](=[CH:18][C:7]([CH:6]=[O:5])=[CH:14][CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCC2
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of the alcohol (370 mg, 2.5 mmol) in dichloromethane (10 mL) was stirred at room temperature. N-Methylmorpholine-N-oxide (307 mg, 2.62 mmol) and powdered 4 Å molecular sieves (˜1 g) were added and the mixture was stirred under Ar for 30 minutes. Tetrapropylammonium perruthenate (44 mg, 0.12 mmol) was added in one portion and stirring was continued for 30 minutes. Tic indicated some starting material remaining, so further N-methylmorpholine-N-oxide (100 mg, 0.85 mmol) was added and stirring continued for an additional 30 minutes. The mixture was evaporated onto SiO2 (˜2 g) and purified by flash column chromatography (SiO2, 10% EtOH/Hexane eluent) to afford the aldehyde as a pale yellow oil (299 mg, 82%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[NH:17]1[CH2:22][CH2:21][CH:20]([C@H:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]3[C:40]4[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=4)[N:34]([S:45]([C:48]4[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=4)(=[O:47])=[O:46])[CH:33]=3)[C:29]([C:55]#[N:56])=[CH:28][N:27]=2)[CH3:24])[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:79](O)(=[O:82])[CH2:80][OH:81]>O1CCCC1>[OH:82][CH2:79][C:80]([N:17]1[CH2:18][CH2:19][CH:20]([C@H:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]3[C:40]4[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:43])([F:44])[F:42])[CH:39]=4)[N:34]([S:45]([C:48]4[CH:49]=[CH:50][C:51]([CH3:52])=[CH:53][CH:54]=4)(=[O:46])=[O:47])[CH:33]=3)[C:29]([C:55]#[N:56])=[CH:28][N:27]=2)[CH3:24])[CH2:21][CH2:22]1)=[O:81]
Reactant: O=C(O)CO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCNCC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCN(C(=O)CO)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
Diisopropylethylamine (179 μl, 1.025 mmol) was added to a mixture of 2-((R)-1-(piperidin-4-yl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 2,2,2-trifluoroacetate (140 mg, 0.205 mmol), TBTU (131.7 mg, 0.14 mmol) and glycolic acid (15.6 mg, 0.205 mmol) in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The crude mixture was concentrated to dryness and redissolved in ethyl acetate. The organic phase was washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound (60 mg, 47% yield). Also obtained was 20 mg (21% yield) of the detosylated compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:26][NH:27][S:28](=[O:31])(=[O:30])[NH2:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.Cl>[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:29][S:28](=[O:31])(=[O:30])[NH:27][CH3:26])=[O:8]
Reactant: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2O1
Reactant: CNS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNS(=O)(=O)NC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
A mixture of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (50 mg, 0.14 mmol), methyl(sulfamoyl)amine (23 mg, 0.21 mmol), 1-ethyl-(3-dimethylamino-propyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) and 4-dimethylaminopyridine (26 mg, 0.21 mmol) in DCM (20 mL) was stirred at room temperature for 16 hrs. The mixture was diluted with HCl (2.0 N, 20 mL) and extracted with EtOAc (50×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase Combiflash (18%-25% MeCN in 0.5% NH4HCO3) to give target product (35.4 mg, 56%) as a pale yellow solid. LCMS (ESI) Method A: RT=5.78 min, m/z: 456.7 [M+H]+; 1H-NMR (500 MHz, MeOH-d4,): δ 7.77 (d, J=6.0 Hz, 1H), 7.42 (d, J=10.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.52 (dd, J=9.0, 2.5 Hz, 1H), 6.36 (d, J=2.5 Hz, 1H), 5.14 (s, 2H), 2.74 (t, J=6.5 Hz, 2H), 2.71 (s, 3H), 1.80 (t, J=6.5 Hz, 2H), 1.32 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH2:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][C:39]4=[O:43])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: NCCCN1CCCC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(3-aminopropyl)-2-pyrrolidinone using conditions similar to those employed in Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.28 (1H, t, J=6 Hz), 8.55 (1H, s), 8.10 (1H, s), 7.40 (2H, dd, J=6, 9 Hz), 7.13 (2H, t, J=9 Hz), 4.37 (2H, t, J=6 Hz), 4.15 (2H, s), 3.43 (2H, t, J=6 Hz), 3.31-3.39 (6H, m), 3.22 (2H, t, J=7 Hz), 2.22 (2H, t, J=8 Hz), 1.87-2.00 (4H, m), 1.70-1.78 (4H, m); ES+ MS: 550 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:20]([O-])=O)[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[H][H].C([O-])(O)=O.[Na+]>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:20])[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
6-chloro-7-cyclopropylmethoxy-8-nitro-9H-β-carboline (510 mg, 1.61 mmol) was suspended in 12 ml of methanol and 100 mg of Pd/C(10%) was added. The flask was fitted with a balloon of hydrogen and the reaction mixture was stirred overnight at RT. Upon filtration through a pad of celite and evaporation of the methanol, a dark brown solid was obtained. This residue was suspended in methanol (10 ml) and added, with vigorous stirring, to a solution of saturated NaHCO3 (100 ml). The light brown solid that precipitated out was collected by filtration and dried thoroughly in vacuo to give the desired 6-chloro-7-cyclopropylmethoxy-9H-β-carbolin-8-ylamine (371 mgs, 80% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21]C)[CH:19]=4)[CH2:14][CH2:13][N:12]3[C:25]=2[CH3:26])=[CH:4][C:3]=1[CH3:32].Cl.N1C=CC=CC=1>C(OCC)(=O)C.Cl>[CH3:24][O:23][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][C:18]=1[OH:21])[C:11]1=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:9]([C:5]3[CH:6]=[C:7]([CH3:8])[C:2]([OH:1])=[C:3]([CH3:32])[CH:4]=3)=[C:25]([CH3:26])[N:12]1[CH2:13][CH2:14]2
Reactant: CCOC(=O)c1c(-c2cc(C)c(O)c(C)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2cc(C)c(O)c(C)c2)c(C)n2c1-c1cc(O)c(OC)cc1CC2
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
1 g (2.3 mmol) of ethyl 2-(4hydroxy-3,5-dimethylphenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate (Example 1) was intimately mixed with 4 g of pyridine hydrochloride and heated to fusion at 150° C. The mixture was stirred at 150° C. for 20 min., then cooled to room temperature and dissolved in a mixture of ethyl acetate and dilute hydrochloric acid. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with water, dried over Na2SO4, and the solvent was evaporated under reduced pressure. Column chromatography on silica gel using a dichloromethane/ethyl acetate 10:1 mixture as eluant afforded the title compounds ethyl 8-methoxy-9-hydroxy-2-(3,5-dimethyl-4-hydroxyphenyl)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylate (Example 26):
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][CH:5]([C:7]2[C:8]([F:18])=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH2:4][O:3]1.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:19])[O:6][CH:5]([C:7]2[C:8]([F:18])=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([OH:12])=[O:11])[CH2:4][O:3]1
Reactant: CCOC(=O)c1cccc(C2COC(C)(C)O2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)OCC(c2cccc(C(=O)O)c2F)O1
Temperature: 0 °C
Reaction time: 17 h
Yield: 95 %

Procedure:
A 5.46 g portion of ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorobenzoate was dissolved in 100 ml of THF and cooled to 0° C., and then 40.8 ml of 1 N sodium hydroxide aqueous solution was slowly added thereto. This was risen to room temperature and further stirred for 17 hours. After evaporation of THF, the residue was cooled to 0° C. and acetic acid was slowly added thereto until the pH value became 3 to 4. This was extracted with diethyl ether, dried with sodium sulfate and concentrated, and then subjected to azeotropic treatment three times with Tol, thereby obtaining 4.66 g (95%) of 3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorobenzoic acid (Reference Example 11-1). FN: 239