Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:12](=[O:13])/[C:11](=[CH:14]/[C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[C:32]([F:35])([F:34])[F:33])[N:19]=[CH:18]4)/[S:10][C:9]2=[O:36])[N:6]=1.[F:37][C:38]([F:44])([F:43])[S:39](Cl)(=[O:41])=[O:40]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:20]2[C:21]3[C:17](=[CH:16][C:15](/[CH:14]=[C:11]4/[C:12](=[O:13])[N:8]([CH2:7][C:5]5[N:6]=[C:2]([NH:1][S:39]([C:38]([F:44])([F:43])[F:37])(=[O:41])=[O:40])[S:3][CH:4]=5)[C:9](=[O:36])[S:10]/4)=[CH:23][CH:22]=3)[CH:18]=[N:19]2)=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:27]=1
Reactant: Nc1nc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)cs1
Reactant: O=S(=O)(Cl)C(F)(F)F
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1csc(NS(=O)(=O)C(F)(F)F)n1

Procedure:
N-(4-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}-1,3-thiazol-2-yl)-1,1,1-trifluoromethanesulfonamide was prepared from (5Z)-3-[(2-amino-1,3-thiazol-4-yl)methyl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 400) and trifluoromethanesulfonyl chloride following General Procedure U.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Fc1ccccc1CBr
Reactant: Ic1n[nH]c2ncccc12
Product: Fc1ccccc1Cn1nc(I)c2cccnc21
Yield: 95.7 %

Procedure:
In analogy to example 24A, 25.00 g (102.031 mmol) of 3-iodo-1H-pyrazolo[3,4-b]pyridine (synthesis described in WO 2006/130673, scheme D) were reacted with 21.21 g (112.234 mmol) of 2-fluorobenzyl bromide. 34.49 g of the title compound were obtained (95% of theory).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:20])([CH3:19])[CH2:11][C:10]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:20])([CH3:19])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Reactant: CC(C)[Mg]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: COc1cc2c(cc1Br)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 6.1 mL, 21.3 mmol) was added to a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 700 mg, 2.46 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:52][CH:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48]C(O)=O)[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1S(C)(=O)=O.CN1C=CC(N)=N1.N1C(C)=CC=CC=1C.C(Cl)[Cl:74]>>[CH:53]1([CH2:52][C@H:39]([C:31]2[CH:32]=[CH:33][C:34]([Cl:74])=[C:29]([Cl:28])[CH:30]=2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: ClCCl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Agent: Cn1ccc(N)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Product: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
In a round bottom flask under argon was placed triphenylphosphine (120 mg, 0.46 mmol) and methylene chloride (10 mL) and it was cooled to 0° C. in an ice bath. To this was added N-bromosuccinimide (81 mg, 0.46 mmol) and it was stirred for 15 minutes at 0° C. To this was then added 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in PCT WO 2002/046173 A1, Example 3, 100 mg, 0.35 mmol) and it was stirred for an additional 5 minutes at 0° C. and then warmed to 25° C. and stirred for 10 minutes. The solution was recooled to 0° C. and then 1-methyl-1H-pyrazol-3-ylamine (68 mg, 0.70 mmol) in methylene chloride (500 μL) and 2,6-lutidine (160 μL, 1.4 mmol) were added to the flask and it was stirred at 0° C. and then warmed to 25° C. and stirred for 2.5 h. After this time the reaction was diluted with methylene chloride and then washed with an aqueous 1 N hydrochloric acid solution and saturated aqueous brine solution. Flash chromatography using Biotage system (40S column, Silica gel, 50% ethyl acetate/hexanes) provided a white foam, this material was then lyophilized to afford 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(1-methyl-1H-pyrazol-3-yl)-propionamide (62 mg, 48%) as a white powder: [α]27589=−15.6° (c=0.27, methanol); ES-HRMS m/e calcd for C18H21N30Cl2 (M+H)+ 366.1135, observed 366.1135; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.19 (m, 2H, CH2), 1.34-1.80 (m, 8H, 4×CH2), 1.95-2.14 (m, 1H, CH), 3.70 (s, 3H, NCH3), 3.79 (dd, J=8.6, 6.0 Hz, 1H, ArCH), 6.30-6.44 (m, 1H, Ar), 7.34 (dd, Jo=8.4 Hz, Jm=1.3 Hz, 1H, Ar), 7.51 (d, Jm=1.3 Hz, 1H, Ar), 7.54-7.65 (m, 2H, Ar), 10.66 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[NH:22][C:21]2[C:23]([F:36])=[C:24]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:25]([C:27](O)=[O:28])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[F:68][C:69]([F:78])([F:77])[C@H:70]1[CH2:75][CH2:74][C@H:73]([NH2:76])[CH2:72][CH2:71]1>CN(C=O)C>[F:68][C:69]([F:77])([F:78])[C@H:70]1[CH2:71][CH2:72][C@H:73]([NH:76][C:27]([C:25]2[C:24]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[C:23]([F:36])[C:21]3[NH:22][C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:26]=2)=[O:28])[CH2:74][CH2:75]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c(OCC(F)(F)F)c(F)c3[nH]2)c1Cl
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)(F)F)c(F)c3[nH]2)c1Cl
Reaction time: 0.5 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]phenylamino}-6-(2,2,2-trifluoroethoxy)-7-fluoro-1H-benzimidazole-5-carboxylic acid (60 mg, 0.109 mmol), TBTU (36.7 mg, 0.114 mmol), DIPEA (66 μl, 0.38 mmol) and DMF (1 mL) is stirred for 30 min, then trans-4-trifluoromethyl-cyclohexylamine (24 mg, HCl salt) is added and it is stirred for 1 h.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([S:19][CH3:20])[CH:16]=[C:15]([CH3:21])[C:3]=1[O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].[Cl:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:22][CH2:20][S:19][C:17]1[CH:18]=[C:2]([CH3:1])[C:3]([O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:6]([CH3:7])[CH3:8])[CH:9]([CH3:10])[CH3:11])=[C:15]([CH3:21])[CH:16]=1
Reactant: CSc1cc(C)c(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(SCCl)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a stirring solution of (2,6-dimethyl-4-methylsulfanylphenoxy)triisopropylsilane (2.18 g, 6.72 mmol) in CCl4 (25 mL) at room temperature was added N-chlorosuccinimide (0.99 g, 7.39 mmol). The reaction mixture was stirred at room temperature for 16 hrs and filtered through a Celite plug. The solvent was removed under reduced pressure to afford crude (4-chloromethylsulfanyl-2,6-dimethylphenoxy)triisopropylsilane as an oil (2.4 g, 100%). This crude oil was dissolved into phosphorous acid triethyl ester (1.5 mL). It was heated at 180° C. for 30 min by microwave. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1) to afford diethyl (3,5-dimethyl-4-triisopropylsilanyloxy-phenylsulfanyl)methylphosphonate as a yellow oil (1.6 g, 52%): 1H NMR (200 MHz, DMSO-d6): δ 7.09 (s, 2 H), 4.98 (m, 4 H), 3.31 (d, J=13.8 Hz, 2 H), 2.17 (s, 6 H), 1.25 (m, 9 H), 1.09 (d, J=7.0 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate/Hexanes (2:3); Rf=0.45.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[C:28]3[O:37][CH2:38][O:39][C:27]=13)=[CH:22][C:21]([O:40][CH3:41])=[C:20]([O:42][CH3:43])[CH:19]=2)#[N:14].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:36])=[C:28]3[O:37][CH2:38][O:39][C:27]=13)=[CH:22][C:21]([O:40][CH3:41])=[C:20]([O:42][CH3:43])[CH:19]=2)#[N:14]
Reactant: C1COCCN1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(/C=C/C(=O)O)c4c3OCO4)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cc2ncc(C#N)c(Nc3ccc(/C=C/C(=O)N4CCOCC4)c4c3OCO4)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.196 g) was added to a mixture of (2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylic acid (0.35 g), morpholine (0.36 ml), N-methylmorpholine (0.112 ml), 1-hydroxybenzotriazole (0.112 ml), DMF (2 ml) and methylene chloride (10 ml) and the reaction mixture was stirred at ambient temperature for 12 hours. The resultant mixture was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulphate and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a solid (0.031 g); NMR Spectrum: (DMSOd6) 3.66 (s, 8H), 3.96 (s, 6H), 6.09 (s, 2H), 6.87 (d, 1H), 7.19 (d, 1H), 7.28 (d, 1H), 7.34 (s, 1H), 7.49 (d, 1H), 7.77 (s, 1H), 8.48 (s, 1H), 9.63 (s, 1H); Mass Spectrum: M+H+ 489.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][N+:13]([CH3:16])=[CH:14]Cl.[Cl-]>>[CH3:12][N:13]([CH3:16])[CH:14]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]=[O:11]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Product: CN(C)C=C(C=O)c1ccc(F)cc1

Procedure:
In a manner similar to Example 1, p-fluorophenyl acetic acid is treated with Vilsmeier reagent to produce 3-(dimethylamino)-2-(4-fluorophenyl)-2-propenal. Treatment of this product with cyanoacetamide and sodium methoxide provides 1,2-dihydro-5-(4-fluorophenyl)-2-oxo-3-pyridinecarbonitrile. Hydrolysis of this product with acid gives 1,2-dihydro-5-(4-fluorophenyl)-2-oxo-3-pyridinecarboxylic acid. Treatment of this product with quinoline affords 5-(4-fluorophenyl)-2(1H)-pyridone, which is reacted with phosphorus oxychloride to give 2-chloro-5-(4-fluorophenyl)pyridine. Treatment of the above product with hydrazine produces 2-hydrazino-5-(4-fluorophenyl)pyridine. Treatment of this product with ethyl orthoacetate produces 6-(4-fluorophenyl)-3-methyl-1,2,4-triazolor[4,3-a]pyridine which yields the product of the Example on hydrogenation.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:13]/[C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[O:12])[NH:6]2.[CH:21]1[CH:25]=[C:24]([C:26]([C:28]([C:30]2[O:34][CH:33]=[CH:32][CH:31]=2)=O)=O)[O:23][CH:22]=1>C(O)C>[O:23]1[CH:22]=[CH:21][CH:25]=[C:24]1[C:26]1[C:28]([C:30]2[O:34][CH:33]=[CH:32][CH:31]=2)=[N:11][C:10]2[CH:9]=[CH:8][C:7]3[NH:6][C:5](=[O:12])/[C:4](=[CH:13]\[C:14]4[NH:15][CH:16]=[CH:17][C:18]=4[O:19][CH3:20])/[C:3]=3[C:2]=2[N:1]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21
Reactant: O=C(C(=O)c1ccco1)c1ccco1
Solvent: CCO
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3nc(-c4ccco4)c(-c4ccco4)nc3c21
Yield: 86 %

Procedure:
Using Method A above, (Z)-4,5-diamino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.22 mmol) (Starting Material 5) was condensed with furil (200 mg) (Aldrich) in ethanol (3 mL) at reflux to give (Z)-7,9-dihydro-2,3-di-(2-furanyl)-9-[(3-methoxy-1H-pyrrol-2-yl)methylene]-8H-pyrrolo[3,2-f]quinoxalin-8-one in 86% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:23][O:24][CH3:25])=[C:11]([C:20](O)=[O:21])[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:40]([NH2:43])([CH3:42])[CH3:41].O>CN(C)C=O>[CH:40]([NH:43][C:20]([C:11]1[N:12]=[CH:13][C:14]2[NH:15][C:16]3[C:8]([C:9]=2[C:10]=1[CH2:23][O:24][CH3:25])=[C:7]([O:6][C:5]1[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:19]=[CH:18][CH:17]=3)=[O:21])([CH3:42])[CH3:41]
Reactant: COCc1c(C(=O)O)ncc2[nH]c3cccc(Oc4ccc(Cl)cc4)c3c12
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COCc1c(C(=O)NC(C)C)ncc2[nH]c3cccc(Oc4ccc(Cl)cc4)c3c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
382 mg of 5-(4-chlorophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid in 10 ml of dimethylformamide is mixed with 380 mg of carbonyldiimidazole. After 2 hours stirring at room temperature, 1 ml of isopropylamine is added and stirred overnight. After mixing with water, it is extracted with ethyl acetate. The ethyl acetate phase is dried, filtered and concentrated. The residue is chromatographed over silica gel with methylene chloride: acetone=1:1 as eluant. 90 mg of 5-(4-chlorophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid isopropylamide with a melting point of 255° C. is obtained.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].C(=O)(O)[O-].[Na+].O>FC(F)(F)S(O)(=O)=O>[C:9]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)O
Reactant: C=CCCCCCC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)OCCCCCCCC
Temperature: 90 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To 30.0 g (267 mmoles, 3 eq) of 1-octene was added 0.802 g (5.35 mmoles, 0.06 eq) of trifluoromethanesulfonic acid followed by 7.67 g (89.1 mmoles, 1 eq) of methacrylic acid. This mixture was heated to 90° C. for 6 hours. By NMR, the yield was 81% based on acrylic acid consumed. To the reaction mixture was added 36.16 g of a saturated solution of sodium bicarbonate in water (8.28 wt-%, 35.6 mmoles, 0.4 eq) and the mixture was stirred at room temperature for 1 hour. The aqueous phase was removed and the residue was distilled at 25° C./10-20 torr. The receiver was cooled with dry ice to trap the octene. This gave 14 grams of recovered octene. The product was distilled at 103° C./1.0 torr to give 14.7 g of octyl methacrylate (83.2% yield based on acrylic acid consumed).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([CH:21]3[CH2:23][CH2:22]3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)O)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](\[CH:21]3[CH2:22][CH2:23]3)/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccc(F)cc2)C2CC2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CN1CCc2c(c3cc(Cl)ccc3n2/C=C(/c2ccc(F)cc2)C2CC2)C1
Temperature: 0 °C

Procedure:
2-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-cyclopropyl-1-(4-fluorophenyl)ethanol (1 g, 2.51 mmol, 1 equiv) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.50 (m, 2H), 7.40 (d, 1H), 7.20 (m, 3H), 7.05 (m, 1H), 6.80 (d, 1H), 4.75 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.30 (m, 3H), 3.12 (s, 3H), 2.80 (m, 1H), 2.0 (m, 1H), 1.80 (m, 1H), 1.15 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:23][CH2:24][CH3:25])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17].C(N=C=NC(C)C)(C)C>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:16]2([OH:17])[CH:18]=[CH:19][CH:20]=[CH:21][CH:15]2[C:14]([O:23][CH2:24][CH3:25])=[O:22])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccccc1O
Reactant: O=C(O)CCCCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCOC(=O)C1C=CC=CC1(O)C(=O)CCCCc1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of 1.07 g of 5-phenylvaleric acid and 60 mg of N,N-dimethylaminopyridine in 20 ml of dichloromethane is added 0.75 ml of ethyl salicylate, followed by 0.95 ml of diisopropyl carbodiimide. After 18 hours, the mixture is concentrated under reduced pressure, and the residue triturated with ether. The organic phase is washed with aq. sodium bicarbonate and brine, dried (magnesium sulfate), and concentrated under reduced pressure. Flash chromatography on silica with 10% ethyl acetate in hexane affords 1.60 g of the title product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:14])[C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:5][OH:6]>ClCCl.[O-2].[Mn+4].[O-2]>[Cl:14][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[O:6]
Reactant: CS(=O)(=O)c1c(Cl)cc(CO)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CS(=O)(=O)c1c(Cl)cc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
3,5-Dichloro-4-(methylsulfonyl)benzyl alcohol (1.7 g) was dissolved in dichloromethane (35 mL) and then active manganese(IV) oxide (7.0 g) was added and the mixture was stirred for 25 min at 22-28° C. The solid was removed by filtration and the filtrate was evaporated to dryness (yield 1.5 g). 1H-NMR (400 MHz, DMSO-d6 d=3.53 (s, 3H), 8.12 (s, 2H), 10.02 (s, 1H).
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[CH3:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:36]=1[CH:37]=O.Cl>O1CCCC1.O>[CH3:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:36]=1[CH:37]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C)c1C=O
Reactant: O=C(O)CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1C=CCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.65 g, 16 mmol) was added portionwise at room temperature to a stirred solution of (8-carboxy-octyl)-triphenyl-phosphonium bromide (2.8 g, 5.6 mmol) in tetrahydrofuran (30 mL) at room temperature, then after 1 hour 2,6-dimethylbenzaldehyde (757 mg, 5.64 mmol) was added portionwise to the reaction mixture and the solution stirred for 2 days at room temperature. On reaction completion, water (10 ml) was added and the solution acidified to pH 3 with concentrated hydrochloric acid. The product was extracted with ethyl acetate, the organic layer dried over magnesium sulfate, filtered and evaporated. Chromatography (SiO2, heptane-ethyl acetate 4:1) afforded 10-(2,6-dimethyl-phenyl)-dec-9-enoic acid as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(O)ccc21
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A solution of 740 mg of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester, of 328 mg of ammonium formate and of 234 mg of 10% palladium-on-charcoal in 56 ml of ethanol is heated at 70° C. for 35 minutes. The reaction mixture is then cooled to ambient temperature. The catalyst is filtered through paper and washed abundantly with ethanol to obtain 533 mg of the crude compound 3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-5-hydroxyindazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]([O:3][C:4](=[O:19])[O:5][CH2:6][CH:7]1[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)=[CH2:2].Cl[C:21]([O:23][CH:24]=[CH2:25])=[O:22]>ClCCCl>[CH:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][CH:7]([CH2:6][O:5][C:4]([O:3][CH:1]=[CH2:2])=[O:19])[CH2:8]1)=[O:22])=[CH2:25]
Reactant: C=COC(=O)OCC1CCN(Cc2ccccc2)C1
Reactant: C=COC(=O)Cl
Solvent: ClCCCl
Product: C=COC(=O)OCC1CCN(C(=O)OC=C)C1
Yield: 82.7 %

Procedure:
A solution of carbonic acid 1-benzyl-pyrrolidin-3-ylmethyl ester vinyl ester (440 mg, 1.68 mmol) and vinyl chloroformate (0.30 mL, 3.5 mmol) in 1,2-dichloroethane (10 mL) was heated to reflux for 6 h then concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (20% EtOAc/hexanes) gave a yellow oil (335 mg, 83%). 1H NMR (CDCl3) δ 1.68-1.85 (m, 1H), 2.03-2.16 (m, 1H), 2.59-2.71 (m, 1H), 3.26 (m, 1H), 3.41-3.52 (m, 1H), 3.55-3.72 (m, 2H), 4.11-4.28 (m, 2H), 4.45 (dd, 1H, J=6.3, 1.5 Hz), 4.61 (m, 1H), 4.78 (dd, 1H, J=14, 1.5 Hz), 4.94 (m, 1H), 7.08 (m, 1H), 7.22 (dd, 1H, J=14, 6.3 Hz).
Reaction SMILES: [CH2:1]1[N:11]2[C@@H:5]([CH2:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[CH2:4][NH:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][F:25].O>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C>[F:25][CH2:24][CH2:23][N:3]1[CH2:2][CH2:1][N:11]2[C@@H:5]([CH2:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[CH2:4]1
Reactant: c1ccc2c(c1)OCC[C@H]1CNCCN21
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: FCCN1CCN2c3ccccc3OCC[C@H]2C1

Procedure:
To a solution of Example 169 (430 mg 2.1 mmol) in N,N-dimethylformamide (10 mL) was added K2CO3 (582 mg, 4.21 mmol) followed by 1-bromo-2-fluoroethane (267 mg, 2.1 mmol). The reaction stirred at room temperature for 16 hours before addition of water, brine and ethyl acetate. The organic layer was collected and concentrated. Purification via flash chromatography (0-100% ethyl acetate/hexanes) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.69-7.00 (m, 4H), 4.64 (t, J=4.96 Hz, 1H), 4.48 (t, J=4.76 Hz, 1H), 4.28-4.43 (m, 1H), 4.03-4.15 (m, 1H), 2.97-3.21 (m, 3H), 2.57-2.86 (m, 4H), 2.33-2.46 (m, 1H), 2.19-2.33 (m, 1H), 1.80-2.08 (m, 2H); MS (ESI+) m/z 251 (M+H)+.