Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]#[N:29])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[OH-:30].[K+]>CC(O)(C)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:29])=[O:30])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: [OH-]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccc(F)cc4)cc23)CC1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccc(F)cc4)cc23)CC1
Reaction time: 0.02 h
Yield: 47.8 %

Procedure:
The mixture of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-fluorophenyl)-1H-indazole-7-carbonitrile (Intermediate 11) (0.102 mmols) and potassium hydroxide (26 mg, 0.51 mmol) in 2-methyl-2-propanol (4 mL) was heated overnight. The reaction mixture was concentrated and purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 70% B in 3.2 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (21 mg, 48% for 2 steps)
Reaction SMILES: [CH2:1]([N:8]1[CH2:32][C@:31]2([C:33](O)=[O:34])[C@@H:10]([CH2:11][C@H:12]3[CH:25]4[C@@:16]([F:29])([C@:17]5([CH3:28])[C:22]([C@@H:23]([F:26])[CH2:24]4)=[CH:21][C:20](=[O:27])[CH:19]=[CH:18]5)[C@@H:15]([OH:30])[CH2:14][C@@:13]32[CH3:36])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:37][CH:38]1[CH2:42][CH2:41][O:40][C:39]1=[O:43]>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[O:43]=[C:39]1[CH:38]([S:37][C:33]([C@:31]23[C@@:13]4([CH3:36])[CH2:14][C@H:15]([OH:30])[C@@:16]5([F:29])[C@H:25]([C@@H:12]4[CH2:11][C@H:10]2[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:32]3)[CH2:24][C@H:23]([F:26])[C:22]2[C@:17]5([CH3:28])[CH:18]=[CH:19][C:20](=[O:27])[CH:21]=2)=[O:34])[CH2:42][CH2:41][O:40]1
Reactant: O=C1OCCC1S
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)CC1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)O)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)SC4CCOC4=O)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.14 %

Procedure:
A solution of compound 93 and 1,1-carbonyldiimidazole (74.3 mg, 0.458 mmol) in dry DMF (3 ml) is stirred under nitrogen at RT for 1 hour and at 65° C. for 1 hour 30 minutes. The mixture is cooled to RT and 4-dimethylaminopyridine (46.7 mg, 0.382 mmol) and a solution of 3-mercaptodihydrofuran-2(3H)-one (54.1 mg, 0.458 mmol) in dry DMF (1.2 ml) are added. The mixture is stirred at RT for 1 hour then at 70° C. for 48 hours. The mixture is diluted with AcOEt and washed with brine. The organic phase is dried over Na2SO4 and filtered. The solvent is evaporated to give a brown oil which is purified by silica gel chromatography (AcOEt/petroleum ether 45/55) to afford the title compound (30 mg, 0.050 mmol, 13.14% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][OH:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH:21]=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: Cc1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(CO)C2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C=O)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
(R)-(1-(4-Fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol (3.5 g, 7.72 mmol) was dissolved in dichloromethane (80 mL) and Dess-Martin Periodinane (5.24 g, 12.35 mmol) was added. The reaction was stirred at room temperature for 1 hour. A saturated solution of sodium hydrogen carbonate (aqueous, 50 ml) was added and the mixture was stirred for 10 minutes. The phases were separated and solvent removed to give a pale yellow solid. The crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohexane) to afford (R)-1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (2.9 g) as a very pale yellow solid. LCMS (Method F, ES-API): RT 2.46 min, m+H=452.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]=[N:10][NH:9]1.[CH3:14][N:15]([CH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[C:16](Cl)=[O:17]>CN(C)C1C=CN=CC=1>[CH3:14][N:15]([CH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[C:16]([N:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[N:9]=[N:10]1)=[O:17]
Reactant: O=c1nn[nH]n1-c1ccccc1Br
Reactant: CN(C(=O)Cl)C1CCSCC1
Agent: CN(C)c1ccncc1
Product: CN(C(=O)n1nnn(-c2ccccc2Br)c1=O)C1CCSCC1

Procedure:
Similarly to the process described in Example 1, 2.5 g (10 mmol) of 1-(2-bromophenyl)-1,2-dihydro-5H-tetrazol-5-one, 2 g (10 mmol) of N-methyl-N-(tetrahydro-2H-thiopyran-4-yl)carbamoyl chloride and 1.5 g (12 mmol) of 4-dimethylaminopyridine were reacted. Yield 2.5 g.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:4]Br.[CH3:13][S-:14].[Na+]>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:4][S:14][CH3:13]
Reactant: O=[N+]([O-])c1cccc(F)c1CBr
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1c(F)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
16.36 g (69.9 mmol) of 2-fluoro-6-nitrobenzyl bromide were introduced into 410 ml of THF, 5.88 g (83.9 mmol) of sodium methanethiolate were added in portions, and the mixture was stirred at RT for 24 h. The solid was filtered off and the filtrate was freed of solvent in a rotary evaporator. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10/1) to result in 11.43 g (81% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C@H:13]1[CH2:12][NH:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Yield: 101.1 %

Procedure:
A mixture of benzyl (3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidine-1-carboxylate (3.86 g, 9.59 mmol) in MeOH (50 mL) was hydrogenated in the presence of 10% Pd on carbon (0.30 g) under 25 psi of hydrogen for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the sub-title compound (2.6 g, 100%). LCMS calc. for C11H20F3N2O2(M+H)+: m/z=269.1. found: 269.2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][CH:24]=1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:27][CH:28]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: O=C1CCC(c2ccc(OCCNCC(O)COc3ccc(CCOCC4CC4)cc3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:30]([NH:32][C:33]([CH3:44])([CH3:43])[CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[O:31])=[CH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[F:45][C:46]1[CH:54]=[C:53]2[C:49]([C:50]([Sn](CCCC)(CCCC)CCCC)=[N:51][NH:52]2)=[CH:48][CH:47]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Si:36]([O:35][CH2:34][C:33]([NH:32][C:30]([C:8]1[C:6]2=[N:7][C:2]([C:50]3[C:49]4[C:53](=[CH:54][C:46]([F:45])=[CH:47][CH:48]=4)[NH:52][N:51]=3)=[CH:3][N:4]=[C:5]2[N:10]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1)=[O:31])([CH3:43])[CH3:44])([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:38])[CH3:37]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 85 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
2-Bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (287 mg, 0.674 mmol) and 6-fluoro-3-(tributylstannyl)-1H-indazole (450 mg, 0.674 mmol) were dissolved in DMF (8 mL) under nitrogen. Pd(PPh3)4 (39 mg, 0.034 mmol) and CuI (26 mg, 0.136 mmol) were added and the mixture was sonicated for 5 min while bubbling nitrogen through it. The reaction mixture was then stirred at 85° C. for 4 h. The mixture was cooled, concentrated in vacuo and then purified by chromatography (silica, petroleum ether:EtOAC 5:1 v/v) to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 20%) as a white solid. 1H NMR (300 MHz, CD3C1): δ 8.55 (s, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 8.32 (s, 1H), 7.49-7.47 (m, 3H), 7.29-7.01 (m, 15H), 3.87 (s, 2H), 1.55 (s, 6H), 0.78 (s, 9H), 0.02 (s, 6H). LC-MS: 725.3 [M+H]+.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:30])[C:13]([CH2:28][OH:29])([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:33]I>O1CCCC1>[C:1]12([NH:11][C:12](=[O:30])[C:13]([CH2:28][O:29][CH3:33])([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)C(CO)(Cc1ccncc1)Cc1ccncc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
To a well-stirred suspension of N-adamantan-1-yl-2-hydroxymethyl-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionamide (40 mg, 0.1 mmol) in anhydrous tetrahydrofuran (0.50 ml), sodium hydride (7.8 mg of 60% mineral oil dispersion; 0.2 mmol of sodium hydride) was added. After stirring at ambient temperature for 30 minutes, methyl iodide (12.5 μl, 0.2 mmol) was added. After stirring for 2 hours at ambient temperature, the reaction was quenched by the addition of water/methylene chloride (10 ml of each). The mixture was then extracted twice with 10 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to an oil (60 mg). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with methanol/ethyl acetate=1:9 in volume) afforded the title compound (free base) as an amorphous solid (16 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[S:20])#[N:5]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N#Cc1ccccc1N
Product: N#Cc1ccccc1NC(=S)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 1a from 2-aminobenzonitrile and benzoyl isothiocyanate as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.35-7.56 (m 3H), 7.67 (t, 1H), 7.75-7.76 (d, J=5.2 Hz, 2H), 7.89-7.91 (d, J=7.2 Hz, 2H), 7.98-8.01 (dd, J1=1.6 Hz, J2=8.2 Hz, 2H), 11.90 (s, 1H), 12.54 (s, 1H). MS 282 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:30]=[CH:29][C:15]3[N:16]=[C:17]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=4[CH3:28])[NH:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[N-:31]=[N+:32]=[N-:33].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:30]=[CH:29][C:15]3[N:16]=[C:17]([C:19]4[C:20]([CH3:28])=[CH:21][C:22]([C:26]5[N:31]=[N:32][NH:33][N:27]=5)=[CH:23][C:24]=4[CH3:25])[NH:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(C#N)cc4C)[nH]c3c2)cc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(-c5nn[nH]n5)cc4C)[nH]c3c2)cc1C
Temperature: 120 °C

Procedure:
A mixture of 2-(4-Cyano-2,6-dimethyl-phenyl)-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide (40 mg), NaN3 (65 mg) and NH4Cl (54 mg) in DMF (1 mL) was heated at 120° C. under microwave radiation for 60 min. The mixture was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (C18, H2O:CH3CN=100:0 to 70:30) to give 2-[2,6-dimethyl-4-(2H-tetrazol-5-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide as a white solid: MS (m/z) 438 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)#[CH:23]>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.C(N(CC)CC)C>[N+:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:23]#[C:22][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:3][N:4]2[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc([N+](=O)[O-])cc21
Reactant: C#Cc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1nc(C#Cc2ccccn2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-Iodo-6-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (838 mg, 2.0 mmol), 2-ethynyl-pyridine (242 μL, 2.4 mmol), and triethylamine (6.0 mL), were degassed and flushed with argon, then treated with Cul (8 mg, 0.042 mmol), and Pd(PPh3)2Cl2 (16 mg, 0.023 mmol). The resulting mixture was stirred overnight at room temperature, at which time HPLC indicated all starting material had been consumed. The mixture was purified by stripping of volatiles under high vacuum, then passing through a plug of silica eluted with ethyl acetate. The resulting product was used in the next step without further purification. ESIMS (M+H+): 395.1.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Br:11]Br.CCCCCC>C(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:2][Br:1]
Reactant: BrBr
Reactant: COc1cccc(CBr)c1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of above-described crude 1-(bromomethyl)-3-methoxybenzene (152.5 g) in 1 L of chloroform a solution of 134 g (0.841 mol) of bromine in 200 ml of chloroform was added dropwise by vigorous stirring at room temperature. The reaction mixture was stirred overnight at ambient temperature and then evaporated to dryness. The residue was triturated with 1000 ml of n-hexane, and the precipitate was filtered off, washed with 100 ml of n-hexane, and then dried in vacuum. An additional amount of the product was obtained by evaporation of mother liquor followed by treatment of the residue with 200 ml of n-hexane. In total, this procedure gave 153 g (55% overall yield for two stages) of 1-bromo-2-(bromomethyl)-4-methoxybenzene. (average of two runs)
Reaction SMILES: BrC1C=CC=CC=1[O:8]C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:16]1([P:22]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[O:37][CH3:38])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.NN>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.CO.O1CCOCC1>[CH:39]1([P:22]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[O:37][CH3:38])=[O:8])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COc1ccccc1Br
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: NN
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(OC)c1-c1ccccc1P(=O)(C1CCCCC1)C1CCCCC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To the mixture of 2-bromoanisole (0.020 ml, 0.16 mmol) and 1,4-dioxane (2 ml), water (0.2 ml), cesium carbonate (0.32 g, 0.97 mmol), sodium 1,3-dioxo-1,3-dihydro-isoindole-2-ylmethyl trifluoroborate (81 mg, 0.32 mmol), palladium(II) acetate (3.6 mg, 0.016 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (13 mg, 0.032 mmol) were added, and then the obtained reaction mixture was stirred at 95° C. (an outer temperature) overnight. The reaction mixture was cooled to room temperature, and then hydrazine hydrate (0.039 ml, 0.81 mmol) and methanol (2 ml) were added thereto, followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the reaction mixture, followed by filtration with celite. The organic layer of the filtrate was separated and washed with saline. The solvents were evaporated under reduced pressure from the organic layer, and then the obtained residue was purified with NH-silica gel column chromatography (heptane:ethyl acetate=1:4), thereby obtaining the entitled compound (4.1 mg, 19%) as the mixture with 2′-(dicyclohexyl-phosphinoyl)-2,6-dimethoxy-biphenyl (6.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1cccc(OCc2c(Cl)cccc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC(=O)c1cccc(OCc2c(Cl)cccc2Cl)c1
Reaction time: 3 h

Procedure:
A solution of Ethyl 4-(3-(2,6-Dichlorobenzyloxy)phenyl)-4-oxobutanoate (Step B, 14.86 g, 39 mmol) in abs ethanol (100 ml) was treated with 1N NaOH (60 ml) at room temperature. The reaction mixture was stirred for 3 hours, or until all the starting material is gone, concentrated and diluted with chloroform and washed with 1M HCl to bring the pH to 3.5-4. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound as white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](Cl)=[N:5][OH:6].[CH3:12][O:13][C:14](=[O:19])[CH2:15][C:16]([CH3:18])=O.C[O-].[Na+]>CO>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])=[N:5][O:6][C:16]=1[CH3:18])=[O:19]
Reactant: COC(=O)CC(C)=O
Reactant: ON=C(Cl)c1ccccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2F)noc1C
Yield: 72.3 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 2-fluoro-N-hydroxybenzimidoyl chloride (8.00 g, 46.09 mmol), methylacetoacetate (10.07 g, 92.18 mmol) and sodium methoxide (7.47 g, 138.27 mmol), a white solid required compound (7.84 g, 33.33 mmol, 72%) was obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:42][C:18]3=[N:19][C:20]([CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[C:21]([C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=[O:27])[CH:22]=[C:17]3[C:16]=2[C:43](=[O:46])[NH:44][CH3:45])=[CH:11][CH:10]=1>ClC(Cl)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:42][C:18]3=[N:19][C:20]([CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[C:21]([C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])[CH:22]=[C:17]3[C:16]=2[C:43](=[O:46])[NH:44][CH3:45])=[CH:11][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(CCC(F)(F)F)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(CCC(F)(F)F)c(-c3cccc(C(=O)O)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
TFA (2.24 ml, 29.0 mmol) was added to a stirring solution of tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)benzoate (315 mg, 0.581 mmol) in dichloroethane (5.81 ml) at rt. The reaction was allowed to stir for 1 h at rt and then was concentrated to dryness azeotroping with toluene to give the expected product 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)benzoic acid (189 mg, 0.389 mmol, 67% yield) consistent by LCMS and NMR. LC-MS retention time: 2.89 min; m/z (MH+): 487. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 13.16 (br. s, 1H), 8.55-8.47 (m, 1H), 8.10-8.02 (m, 3H), 8.00-7.96 (m, 2H), 7.74 (d, J=7.8 Hz, 1H), 7.69-7.62 (m, 1H), 7.42 (t, J=8.9 Hz, 2H), 3.05-2.96 (m, 2H), 2.85-2.70 (m, 5H).