Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([NH:38][CH:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: CN1CCC(N)CC1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)NC5CCN(C)CC5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 1-methylpiperidin-4-amine. LCMS (M+H)+=544.1/546.1.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[OH-].[K+].CO.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]=[CH:27]OCC)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH:27]=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:3]2[N:4]=[CH:5][NH:6][C:2]=2[CH3:1])(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: CCOC=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1[nH]cnc1CSCCN
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]cnc1CSCCN=CNS(=O)(=O)c1ccc(Cl)cc1
Yield: 61.9 %

Procedure:
To a solution of 2.44 g of 2-[[(5-methyl-1H-imidazole-4-yl)methyl]thio]ethanamine (prepared according to British Pat. No. 1,338,169) in 50 ml of methanol, 13.3 ml of 1.45M methanol potassium hydroxide are added at 0° C. To the resulting solution, 2.47 g of ethyl N-p-chlorobenzene-sulphonylformimidate are added at room temperature and stirring. The mixture is kept under stirring for 1 hour at room temperature, then filtered off and the solvent is removed by distillation at reduced pressure. The formed residue is purified by dissolving in 50 ml of ethyl acetate and 25 ml of water. Then, it is acidulated with 3N hydrochloric acid till pH2. The organic phase is cast aside and the aqueous phase is basified in the presence of 50 ml of ethyl acetate with 1N sodium hydroxide till pH8. The organic phase is washed with water, dried over magnesium sulphate and evaporated to dryness. 2.3 g (oily product) of N-p-chlorobenzene-sulphonyl-N'-[2 -[[(5-methyl-1H-imidazole-4-yl)methyl]thio]ethyl]formamidine are obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[C:26]=1[F:27])(=O)=O.[CH3:30][O:31][C:32]1[CH:41]=[C:40]([CH3:42])[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.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>[F:27][C:26]1[C:11]2[C:12]([C:22](=[O:25])[NH:23][CH3:24])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[C:39]1[C:40]([CH3:42])=[CH:41][C:32]([O:31][CH3:30])=[C:33]([CH:38]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)c(F)c12
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1OC
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)c(F)c12
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A mixture of the above prepared 4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (assumed 0.211 mmol), methyl 2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.078 g, 0.253 mmol), (Ph3P)4Pd (0.024 g, 0.021 mmol) and cesium carbonate (0.103 g, 0.317 mmol) in a mixture of H2O (0.2 mL)/1,4-dioxane (1 mL) was stirred at 95° C. for 2 hours 30 min. The mixture was left standing at r.t. overnight. The mixture was diluted with 3.5 ml 1,4-dioxane, filtered through a Whatman PVDF 0.45 um disk (with 3×1 ml washing). The filtrate was concentrated. The mixture was added with 3.5 ml 1N HCl, and then 6 ml H2O (yellow solid deposited on the wall of the flask). The aqueous was decanted, and the residue washed with 3×2 ml H2O and dried. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH—90% H2O—0.1% TFA, Solvent B=90% MeOH—10% H2O—0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=466.27, HPLC Rt=1.708 min.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[ClH:16]>O>[CH2:1]([Cl:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cl
Reactant: CCCCCCCCCCCCCCO
Solvent: O
Product: CCCCCCCCCCCCCCCl

Procedure:
A 1 l jacketed glass reactor with a glass paddle stirrer, an immersed tube for reactant metering and an attached water separator is initially charged with 200 g of N-n-octylalkylpyridinium chloride (prepared according to Example 2) as catalyst and adjusted to a temperature of 150° C. 243 g of n-tetradecanol are introduced uniformly via the immersed tube within 4.5 h. Over the entire reaction time, gaseous hydrogen chloride in a slight excess is metered in via the immersed tube, while the water of reaction formed is removed distillatively from the reaction mixture. The performance of the reaction and workup are analogous to Example 4a. After a total reaction time of 7.5 h, the conversion based on n-tetradecanol is 99.5%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][N:16]=1>C(Cl)Cl.CC(N(C)C)=O>[Br:12][C:5]1[C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]([NH:1][C:21](=[O:22])[C:18]2[CH:19]=[CH:20][C:15]([F:14])=[N:16][CH:17]=2)=[C:3]([Cl:13])[CH:4]=1
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1Cl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(C(F)(F)F)c(Br)cc1Cl)c1ccc(F)nc1

Procedure:
To a solution of 5-amino-2-bromo-4-chlorobenzotrifluoride (466 mg, 1.70 mmol) dissolved in DCM (1 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (270 mg, 1.70 mmol) in DCM (1 mL). A few drops of DMA were added and the reaction mixture was concentrated to form N-(4-bromo-2-chloro-5-trifluoromethyl-phenyl)-6-fluoro-nicotinamide as a purple solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>[Pd].CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(=C[C@@H]2CCCCO2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 2.7 %

Procedure:
A mixture of 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-2(S)-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (220 mg, 5.7 mmol) and 10% palladium on activated carbon (66 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) and kept for 16 h. The mixture was cooled to 25° C., the catalyst was removed by filtration and then washed with ethyl acetate and the filtrate concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-2-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (60 mg, 27%) as a mixture of two diastereoisomers: LC/MS m/e calcd for C21H24N2O3S [M+H]+ 385.50, observed 385.2; 1H NMR (400 MHz, CDCl3) δ ppm 1.34-1.67 (m, 5H), 1.82 (m, 1H), 2.15 (m, 1H), 2.36 (m, 1H), 3.05, 3.09 (2×s, 3H), 3.21-3.40 (m, 2H), 4.13, 4.18 (2×m, 1H), 4.61, 4.67 (2×dd, 1H), 6.33, 6.42 (2×s, 1H), 7.18, 7.26 (2×m, 1H), 7.52, 7.59 (d, J=8.5 Hz, 2H), 7.89, 7.94 (2×m, 3H), 8.16 (m, 1H), 11.47 (br, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][N:13]([Si](C(C)(C)C)(C)C)[C:12](=[O:22])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[C:28]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.O>O1CCCC1.CCCCCC>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH:10]2[CH2:14][NH:13][C:12](=[O:22])[CH2:11]2)=[CH:3][C:2]=1[C:28]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C1CCCC1
Reactant: COc1ccc(C2CC(=O)N([Si](C)(C)C(C)(C)C)C2)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C2CNC(=O)C2)cc1C1(O)CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
2.2 g (0.7 mmol) of 4-(3-bromo-4-methoxy-phenyl)-1-tert-butyldimethylsilylpyrrolidin-2-one in 30 ml of absolute tetrahydrofuran is combined at -70° C. with 8.2 ml (0.7 ml) of a butyllithium solution in hexane. The mixture is allowed to warm up to 0° C., agitated at this temperature for 10 minutes, and again cooled to -70° C. Then a solution of 0.48 g of cyclopentanone in 10 ml of tetrahydrofuran is added dropwise thereto, the mixture is allowed to warm gradually to 0° C., and stirred at this temperature for one hour. After addition of 0.1 ml of water, the mixture is evaporated and chromatographed over silica gel with methylene chloride:acetone=1:1 as the eluent. After repeating chromatography of the corresponding fractions over silica gel with methylene chloride:ethanol=10:1 as the eluent, 110 mg of 4-[4-methoxy-3-(1-hydroxycyclopent-1-yl)phenyl]pyrrolidin-2-one is obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
p-Toluic acid (100 g, 0.734 mol) (Tokyo Chemical Industry Co., Ltd.) and toluene (500 mL) (Wako Pure Chemical Industries, Ltd.) were placed into a sufficiently dried recovery flask (egg plant flask), and p-toluic acid was dissolved. Thionyl chloride (132.4 mL, 1.84 mol) (Wako Pure Chemical Industries, Ltd.) was added dropwise to this solution for 1 hour. After the dropwise addition, the solution was heated and refluxed for 2 hours. After the reaction, the temperature was cooled to room temperature, and then remaining thionyl chloride and remaining toluene were evaporated by using a rotary evaporator. Toluene (200 mL) was added to an obtained concentrate, and the concentrating operation was repeated twice. A finally obtained residue was dissolved in tetrahydrofuran (200 mL) (Wako Pure Chemical Industries, Ltd.), which was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C([O:12][C:13](=O)[CH2:14][C:15]([CH3:17])=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:12])[CH2:14][C:15]([CH3:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CC1=NN(c2ccc(Cl)cc2)C(=O)C1

Procedure:
From the reaction of 4-chlorphenylhydrazine and ethylacetoacetate, 2-(4-chlorphenyl)-2,4-dihydro-5-methyl-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 2-(4chlorphenyl)-4-(2-ethylanilinomethylene)-2,4-dihydro-5-methyl-3H-pyrazol-3-one
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4C[CH2:23]4)=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(COC3C(CC)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.CS(N)(=O)=O.[N:55]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57][CH2:56]1>>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH2:22][CH3:23])=[CH:20][C:16]([C:17]([NH:62][S:59]([N:55]4[CH2:58][CH2:57][CH2:56]4)(=[O:61])=[O:60])=[O:19])=[C:15]([F:25])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CCc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: CS(N)(=O)=O
Product: CCc1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-ethyl-2-fluorobenzoic acid and methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.16 g, 59%): 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.94 (d, J=13.0 Hz, 1H), 4.08-4.01 (m, 4H), 3.62 (s, 2H), 2.59 (q, J=7.5 Hz, 2H), 2.22-2.12 (m, 2H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H), 1.15 (t, J=7.5 Hz, 3H); MS (ES+) m/z 451.2 (M+1); MS (ES−) m/z 449.3 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]2)[CH:20]=[N:19][CH:18]=1.[F:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:25][CH2:24]3)[CH:20]=[N:19][CH:18]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cccc(F)c5)cc34)n2)CC1
Temperature: 140 °C
Yield: 57.9 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.200 g, 0.359 mmol), 3-fluorophenylboronic acid (0.072 g, 0.515 mmol, Aldrich), Na2CO3 (0.210 g, 1.981 mmol, J. T. Baker) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.022 g, 0.031 mmol, Strem). Dioxane (3 mL) and water (1 mL) were added and the reaction mixture was sealed under argon and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 15 min. The mixture was partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (40 gram)) eluting with 2M NH3 in MeOH:DCM (0:1→1:49) to give 119 mg of tert-Butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 573.2 (M+1). A solution of tert-butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.119 g, 0.208 mmol) in HCl, 5-6 N in IPA (5.00 mL, 25.00 mmol) and water (0.5 mL) was heated at 80° C. for 2.5 h. The reaction mixture was cooled to RT and the solid was filtered and washed with IPA. The material was dissolved in DMSO and purified by reverse-phase HPLC (Gilson; Gemini-NX 10μ C18 110 A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA ACN (9:1→1:9). The fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX II cartridge eluting with MeOH then 2M NH3 in MeOH to give the title compound as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 389.1 (M+1).
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9](I)=[CH:10][C:4]=2[O:3]1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C.[NH4+].[Cl-].[Na+].[Cl-]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([B:26]3[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1cc2c(cc1I)OC(F)(F)O2
Agent: CC(C)[Mg+]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)OC(F)(F)O2
Temperature: 2.5 °C
Reaction time: 0.83 h

Procedure:
2,2-Difluoro-5-iodo-6-methoxybenzo[d][1,3]dioxole (1.6 g, 5.0 mmol) was dissolved in dry tetrahydrofuran (15 mL), cooled to 0-5° C. and treated in portions with isopropylmagnesium lithium chloride (1.3 M; 4.1 mL, 5.3 mmol). After 50 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.4 mmol) was added and stirring was continued for 40 min at 15-20° C. The mixture was treated with saturated NH4Cl (10 mL) and then mixed with saturated NaCl (10 mL) and ethyl acetate (20 mL). The organic phase was washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give title compound as a thick oil which was used without further purification (1.4 g, 89%): 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 6.65 (s, 1H), 3.81 (s, 3H), 1.34 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −50.17 (s); EIMS m/z 314.
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=NC=1.[NH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:51]=[C:50]3[C:46]([CH2:47][N:48]([C@@H:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])[C:49]3=[O:52])=[CH:45][CH:44]=2)=[N:41][CH:42]=1.[F:61][C:62]1[CH:63]=[C:64]([N:69]=[C:70]=[O:71])[CH:65]=[CH:66][C:67]=1[F:68]>>[F:61][C:62]1[CH:63]=[C:64]([NH:69][C:70](=[O:71])[NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:51]=[C:50]4[C:46]([CH2:47][N:48]([C@@H:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])[C:49]4=[O:52])=[CH:45][CH:44]=3)=[N:41][CH:42]=2)[CH:65]=[CH:66][C:67]=1[F:68]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Reactant: O=C=Nc1ccc(F)c(F)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cn3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 399 was prepared analogous to the compound of example 393 by reaction of the compound of example 392 with 3,4-difluoro phenyl isocyanate.
Reaction SMILES: O=[C:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH3:19])[CH2:17][OH:18])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2>C(O)C>[CH:14]1[C:15]2[CH2:2][C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:9][C:10]=2[CH:11]=[CH:12][C:13]=1[CH:16]([CH3:19])[CH2:17][OH:18]
Reactant: CC(CO)c1ccc2oc3ccccc3c(=O)c2c1
Solvent: CCO
Product: CC(CO)c1ccc2c(c1)Cc1ccccc1O2

Procedure:
10 g. of 2-(9-oxo-2-xanthenyl)-propanol is hydrogenated in 300 ml. of ethanol in the presence of 0.5 g. of 5% Pd-C under a pressure of 3 atmospheres and at 20° until absorption of the theoretical amount of H. After filtration and concentration, 2-(2-xanthenyl)-propanol is obtained, m.p. 86°-89°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[N:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:24][CH:25]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CN1CCC(O)CC1
Reactant: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Product: CN1CCC(n2ncc(-c3ccnc(Nc4ccc(CN5CCN(C)CC5)cc4)n3)c2-c2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared as described in Example 54 starting from {4-[3-(4-chloro-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine (Example 32) and 1-methyl-piperidin-4-ol.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH:23]1([CH:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:6]=2)[C:3]([OH:28])=[O:2])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Temperature: 50 °C

Procedure:
To a solution of the 2-cyclopentyl-2-(4-(2-quinolylmethoxy)phenyl)acetic acid methyl ester prepared in step 1 in methanol (100 ml) was added dropwise 1N sodium hydroxide (25 ml) and the resulting mixture was refluxed at 50° C. for 16 hours. The reaction mixture was then cooled to room temperature, and the methanol was removed in vacuo. The residue was acidified with 10% citric acid and the resulting solid was filtered, washed with water and dried in vacuo to provide 4.8 g of 2-cyclopentyl-2-(4-(2-quinolylmethoxy)phenyl)acetic acid.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:28])C.[Li+].[OH-]>>[CH2:30]([O:29][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:28])[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][OH:13])[CH2:6]2.Br>>[OH:13][CH2:12][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=2)[CH2:8]1
Reactant: COc1ccc2c(c1)CC(CO)C2
Agent: Br
Product: OCC1Cc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
Combine (5-Methoxy-indan-2-yl)-methanol (117.0 mg, 0.65 mmol), and 48% HBr (aq). After the reaction refluxes for 30 minutes, cool to room temperature and extract the product with ethyl acetate. Wash with brine and dry over Na2SO4. After concentrating the organic layer under reduced pressure, flash chromatograph using 2/1 Hexanes/Ethyl acetate eluent to afford 67.3 mg, 0.41 mmol (63% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.6-2.8 (3H, m), 2.9-3.1 (2H, m), 3.6-3.8 (2H, m), 6.6-6.8 (2H, m), 7.0-7.1 (1H, m); TLC 1:1 Hexanes:Ethyl acetate Rf:=0.3.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1)=[N+:13]=[N-:14]
Reactant: ClCc1ccc2[nH]nnc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2[nH]nnc2c1
Reaction time: 16 h

Procedure:
To a solution of 5-chloromethyl-1,2,3-benzotriazole (2.2 g, 12.2 mmol, Katritzky et al. Synth. Commun. 1993, 23, 2019) dissolved in DMF (25 mL) was added sodium azide (2.4 g, 36.5 mmol). The resulting mixture was stirred under Ar for 16 h and the precipitated product was filtered and air dried to afford the title compound: