Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH3:21][N:22]1[C:26]([CH:27]=[O:28])=[CH:25][CH:24]=[N:23]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:27]([OH:28])[C:26]4[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)ccc1C1CC2C1
Reactant: Cn1nccc1C=O
Product: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1ccc(Br)cc1-2
Yield: 59 %

Procedure:
Methyl 10-bromo-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with 1-methylpyrazole-5-carbaldehyde to afford 385 mg (59% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[Li+].[BH4-].CO>CCOCC>[Cl:1][C:2]1[CH:12]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:13][CH2:14][C:15]([F:16])([F:17])[F:18]
Reactant: CCOC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: OCc1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: 40 °C
Yield: 98.6 %

Procedure:
To a solution of ethyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (7.51 g, 26.5 mmol) in Et2O (200 mL) was added LiBH4 (0.865 g, 39.7 mmol), followed by drop wise addition of methanol (1.611 ml, 39.7 mmol). The reaction was refluxed at 40° C. for one hour. The reaction mixture was then cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3×200 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (6.31 g). LCMS m/z 242.1 (M+H)+, Rt 0.77 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH2:22][CH:21]4[N:23]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N(CC)C(C1C=CC2C(=C3CC4NC(CC4)C3)C3C(OC=2C=1)=CC=CC=3)=O)C.CCOC(C)=O>CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]([CH:16]3[CH2:22][CH:21]4[N:23]([C:24](=[O:29])[C:25]([F:26])([F:28])[F:27])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3cc(Br)ccc31)C2)C(F)(F)F
Agent: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(N1C2CCC1CC(C1c3ccccc3Oc3cc(Br)ccc31)C2)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 9, substituting 1-[3-(3-bromoxanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 1j for 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide, 8a, the title compound 1-[3-(3-bromo-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 2j was obtained after puirification via flash column chromatography (eluent gradient: 5% to 25% EtOAc in heptane). MS m/z (MH+) 465.8.
Reaction SMILES: C(O[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[C:17]3[C:18]([O:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][N:14]=2)[CH2:7][CH2:6]1)C.[C:29]1(=[C:35]([O:41][CH3:42])[O:36][Si](C)(C)C)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.COC(=C1CCOCC1)O[Si](C)(C)C>>[O:26]1[CH2:25][CH2:24][CH:23]([O:22][C:18]2[C:17]3[C:13]([O:12][CH2:11][CH:8]4[CH2:9][CH2:10][N:5]([CH2:4][C:29]5([C:35]([O:41][CH3:42])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[CH2:6][CH2:7]4)=[N:14][O:15][C:16]=3[CH:21]=[CH:20][CH:19]=2)[CH2:28][CH2:27]1
Reactant: COC(O[Si](C)(C)C)=C1CCCCC1
Reactant: CCOCN1CCC(COc2noc3cccc(OC4CCOCC4)c23)CC1
Agent: COC(O[Si](C)(C)C)=C1CCOCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OC5CCOCC5)c34)CC2)CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 7 using 3-{[1-(ethoxymethyl)piperidin-4-yl]methoxy}-4-(tetrahydro-2H-pyran-4-yloxy)-1,2-benzisoxazole (EXAMPLE 30, Step 1) and [cyclohexylidene(methoxy)methoxy](trimethyl)silane (Tetrahedron 2004, 60, 8957-8966) instead of 4-(benzyloxy)-3-{2-[1-(ethoxymethyl)piperidin-4-yl]ethoxy}-1,2-benzisoxazole and [methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH3:13].C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:1][N:2]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH3:13])[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:45])([F:47])[F:46])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: CNC1c2ccccc2CCC1C
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3c4ccccc4CCC3C)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-N,2-dimethyl-1-naphthalenamine (115 mg, 0.66 mmol) and triethylamine (0.12 mL, 0.825 mmol) in 2 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (231 mg, 0.55 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo to give 270 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:17][C:18](=[O:29])[C@H:19]([CH3:28])[NH:20]C(=O)CC(C)CC)[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:29])[C@H:19]([CH3:28])[NH:20][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCC(C)CC(=O)N[C@@H](C)C(=O)OCC(C)C
Reactant: CSc1cccc(CC(=O)O)c1
Product: CSc1cccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)c1

Procedure:
Following General Procedure I above, and using 3-methylthiophenylacetic acid (CAS# 18698-73-2) and alanine iso-butyl ester (prepared following General Procedure 3 above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]>C1(C)C=CC=CC=1.[OH-].[Na+].[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][CH2:14][CH2:2][CH:3]=[CH2:4])([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:4]=2[CH:3]=1
Reactant: C=CCCCCBr
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCCCCC1(CCCCC=C)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
2,7-dibromofluorene (5 g, 15.4 mmol) was combined with 1-bromo-5-hexene (7.5 g, 46.0 mmol) in toluene (50 mL), NaOH (50 mL, 50%, aq) and Bu4NBr (0.1 g) as a phase transfer catalyst. The mixture was heated at ca. 100° C. with stirring for 5 h. The organic layer was separated from the aqueous layer and then treated with 10% HCl and then water and then stirred the MgSO4 and carbon black. The solution was filtered and all solvents were removed in vacuo to give a brown oil, 7.83 g.
Reaction SMILES: [N:1]([C@@H:4]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][C@H:5]1N1C=CC(=O)NC1=O)=[N+:2]=[N-:3].C(=[O:27])C1C=CC=CC=1>O.NN.O>[N:1]([C@H:4]([C@@H:8]([C@@H:7]([CH2:10][OH:11])[OH:6])[OH:9])[CH:5]=[O:27])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: O=Cc1ccccc1
Agent: NN
Solvent: O
Product: [N-]=[N+]=N[C@@H](C=O)[C@H](O)[C@H](O)CO
Temperature: 110 °C
Yield: 64 %

Procedure:
2.54 g of 2'-azido-2'-deoxyuridine was dissolved in 250 ml of a 15% hydrazine hydrate solution and heated in an oil bath while stirring for a period of one hour to 65° C. Upon expiration of this time, the thin-layer chromatogram of the solvent System A indicated the total disappearance of the starting material. The solution was evaporated in a vacuum and yielded an orange-colored resin which was dissolved in 100 ml of water. 10 ml of benzaldehyde was added and the mixture heated during constant stirring for a period of 8 minutes in a boiling water bath. The solution was then rapidly cooled to below room temperature and a glutinous precipitate was filtered off, consisting mainly of benzaldehydeazine. The filtrate was then extracted with three times 100 ml of ether. The aqueous solution was evaporated and the residue was dissolved in a minimal amount of methanol. The solution was then applied to a silica gel column (2.3 × 32 cm) prepared with chloroform. The column was eluted with 100 ml fractions of chloroform (200 ml), 700 ml of a 5% solution of methanol in chloroform and with 600 ml of a 10% solution of methanol in chloroform. The desired product was found in the fractions 9 to 13 and was identified by examining each fraction by means of thin-layer chromatography, by the solvent System A, and sprayed on plates with a solution of aniline phosphate (17 ml of n-butanol, 6 ml of water, 0.36 ml of aniline and 0.28 ml of 85% phosphoric acid), and, finally, heated for a period of ten minutes in a drier at 110° C. The 2-azido-2-deoxyribose emerged as a reddish-brown stain with an Rf value of 0.5. The fractions containing the product were combined and evaporated to a colorless resin (1.053 g, yield = 64%), which did not crystallize.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C>COCCOC>[OH:16][CH:15]([CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:14][O:13][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:3]=1[O:2][CH3:1])[C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: COc1cc2c(cc1OCC1CO1)CCC2=O
Reactant: C1CCNC1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OCC(O)CN1CCCC1)CCC2=O

Procedure:
A mixture of 6-methoxy-5-oxiranylmethoxy-indan-1-one (Intermediate M, 2.5 g, 0.0106 mole) and pyrrolidine (0.9 mL, 0.011 mole) was stirred in 50 mL of DME at 50° C. for 5 hrs under Argon. Then, 150 mL of ethyl acetate was added and the solution washed with water (2×). Following extraction with 2N HCl, the aqueous acidic layer was made basic with 3N NaOH and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was triturated with diethyl ether to yield the title compound. MS m/z 306 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:4]([C:6]2[N:7]=[C:8]([C:15]3[C:16]([O:23][CH3:24])=[CH:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:28][CH:27]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(-c2c(OC)cccc2OC)n(C)c(=O)c1O
Product: COc1cccc(OC)c1-c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 4-fluorobenzylamine (125 mg, 1.0 mmol). The title product was obtained as a pink solid (48.7 mg, 79% yield). 1HNMR (500 MHz, CDCl3) δ: 12.10 (1H, s), 7.92 (1H, t, J=5.50 Hz), 7.39 (1H, t, J=8.54 Hz), 7.30 (1H, d, J=5.19 Hz), 7.28 (1H, d, J=5.19 Hz), 7.00 (2H, t, J=8.54 Hz), 6.62 (2H, d, J=8.24 Hz), 4.52 (2H, d, J=6.40 Hz), +3.75 (6H, s), 3.28 (3H, s). HRMS (ESI) calcd for C21H21FN3O5 (M+H): 414.1465; found: 414.1454.
Reaction SMILES: C(NC1C=CC([C:16]2[CH:24]=[C:23]3[C:19](C[N:21]([C@@H:26]([CH:31]([CH3:33])C)[C:27](OC)=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([CH:51]4[CH2:56][CH2:55][CH2:54][CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.CC1OC(C2C=CC=CC=2)=NC=1C(Cl)=O>>[CH3:33][C:31]1[O:25][C:22]([C:23]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:24]=2)=[N:21][C:26]=1[C:27]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([CH:51]4[CH2:56][CH2:55][CH2:54][CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:28]
Reactant: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)C1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: Cc1oc(-c2ccccc2)nc1C(=O)Cl
Product: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(NC(=O)c5nc(-c6ccccc6)oc5C)cc4)cc3C2=O)C1
Yield: 65 %

Procedure:
The compound of example 552 was prepared analogous to compound of example 97 by reaction of compound of example 543 with 5-methyl-2-phenyloxazole-4-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH2:9]([NH2:13])[CH2:10][CH2:11][NH2:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][CH2:11][CH2:10][CH2:9][NH2:13])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1ccc(Cl)nn1
Yield: 66.1 %

Procedure:
A mixture of 3,6-dichloropyridazine (25 g), 1,3-propanediamine (62 g) and sodium carbonate (18 g) in ethanol (500 mL) was stirred and refluxed overnight. The reaction mixture was filtered over dicalite and the filtrate was evaporated. The residue was crystallized from acetonitrile. The crystals were filtered off and dried, yielding 20.7 g of N-(6-chloro-3-pyridazinyl)-1,3-propanediamine; mp. 124.9° C. (intermediate 2).
Reaction SMILES: [Li+].[OH-].[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]3[C:13]=2[CH2:14][CH2:15][C@H:16]3[O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([O:33]C)=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)=[C:7]([CH3:37])[CH:6]=1)#[N:4]>O1CCCC1.O.CO>[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]3[C:13]=2[CH2:14][CH2:15][C@H:16]3[O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)=[C:7]([CH3:37])[CH:6]=1)#[N:4]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C#N)cc5C)ccc(F)c43)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
LiOH×H2O (38 mg) is added to a solution of methyl 2-((S)-6-((R)-4-(4-cyano-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (85 mg) in tetrahydrofuran (1 mL), water (1 mL) and methanol (1 mL) at room temperature. The mixture is stirred at room temperature for 12 hours. The mixture is concentrated, cooled to 0° C., diluted with water and acidified with 4 M aqueous HCl solution. The resulting mixture is extracted with dichloromethane. The organic phase is dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol/acetic acid 9:0.05:0.05) to give the title compound. Yield: 41 mg; LC (method 20): tR=6.91 min; Mass spectrum (ESI−): m/z=456 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH3:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][CH:33]([F:36])[CH2:34]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH3:1][N:2]1[C:6]([O:7][CH2:34][CH:33]([F:36])[F:32])=[C:5]([CH3:8])[C:4]([C:9]([F:11])([F:10])[F:12])=[N:3]1
Reactant: OCC(F)F
Reactant: Cc1c(C(F)(F)F)nn(C)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(F)(F)F)nn(C)c1OCC(F)F
Yield: 55.7 %

Procedure:
To a solution of 9.0 g (50.0 mmol) of 1,4-dimethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 50 ml of tetrahydrofuran were added 14.4 g (55.0 mmol) of triphenylphosphine and 4.5 g (55.0 mmol) of 2,2-difluoroethanol at room temperature, followed by stirring. Furthermore, 12.3 g (60.0 mmol) of diisopropyl azodicarboxylate was added thereto under ice-cooling, followed by stirring at room temperature overnight. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 6.8 g (yield: 55.7%) of 1,4-dimethyl-5-(2,2-difluoroethoxy)-3-trifluoromethyl-1H-pyrazole as a pale yellow liquid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)O1.[C:26]([C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1OS(C(F)(F)F)(=O)=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])#[N:27].C(Cl)Cl.CC([O-])=O.[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCO>[C:26]([C:28]1[CH:29]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:36]=[CH:37][C:38]=1[C:9]1[CH:10]=[CH:11][C:12]([C@H:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])=[CH:13][CH:14]=1)#[N:27]
Reactant: CC(C)S(=O)(=O)NC[C@H](C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc([C@H](C)CNS(=O)(=O)C(C)C)cc2)c(C#N)c1
Temperature: 0 °C
Yield: 74 %

Procedure:
Stir a solution of (2R)-propane-2-sulfonic acid {2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-amide (50 g, 136.2 mmol), Ethyl 3-Cyano-4-trifluoromethanesulfonyloxy-benzoate (40 g, 123.8 mmol), PdCl2(dppf).DCM (3.03 g, 3.71 mmol) and KOAc (36.43 g, 371.4 mmol) in DME:EtOH:H2O (200 mL/200 mL/200 mL) under nitrogen at 80° C. for 50 minutes. Pour the reaction mixture into ice-water and extract it with EtOAc. Wash the organic layer with water and saturated aq. sodium chloride solution, dry over MgSO4, filter and concentrate it in vacuo. Subject residue to silica gel chromatography eluting with hexane/EtOAc 4:1 to 3:1. Triturate the product in hexane, filter and dry, to yield 37.95 g of 1-(S)-Ethyl 2-Cyano-4′-[1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylate (74%). MS(ES): m/z=413.1 [M-H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[C:6]=2[CH:21]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:12]1[CH2:13][CH:10]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cnc3ccc(Br)cc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc2ncn(C3CNC3)c2c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylate (crude) in DCM (9 mL) was added TFA (3 mL). After stirred for 2 h, the solution was concentrated to give desired product and used directly in the next step.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[N:11]=[C:10]2I)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:25]([Sn:29]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:31][CH2:32][CH2:33][CH3:34])Cl)[CH2:26][CH2:27][CH3:28]>C1COCC1>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[N:11]=[C:10]2[Sn:29]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:25][CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
In a round-bottomed flask, 5-(tert-butyl-dimethyl-silanyloxy)-3-iodo-1-methyl-1H-indazole (140 mg, 0.36 mmol) was dissolved in THF (2 ml). The solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.22 ml, 0.44 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (0.11 ml, 0.41 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature over 1.5 h then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to provide 5-(tert-butyl-dimethyl-silanyloxy)-1-methyl-3-tributylstannanyl-1H-indazole as a light yellow oil which was used without further purification.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]=[C:22]1[C:27]2=[CH:28][NH:29][C:30]([CH:31]=O)=[C:26]2[CH2:25][CH2:24][O:23]1>>[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[CH:31][C:30]2[NH:29][CH:28]=[C:27]3[C:22](=[O:21])[O:23][CH2:24][CH2:25][C:26]=23)(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3ccccc3)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(S(=O)(=O)Nc3ccccc3)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid phenylamide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]([CH2:7][CH:8]([NH:16][C:17](=[O:40])[CH2:18][CH:19]([NH:26][S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:29])=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9](=[O:15])[N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1)#N.C(O)=[O:44]>[Al].[Ni]>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([NH:16][C:17](=[O:40])[CH2:18][CH:19]([NH:26][S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:28])=[O:29])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9](=[O:15])[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:41][CH:42]=1)=[O:44]
Reactant: N#Cc1ccc(CC(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)C(=O)N2CCCC2)cc1
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Product: O=Cc1ccc(CC(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)C(=O)N2CCCC2)cc1

Procedure:
3 g of aluminium/nickel alloy are added to a mixture of 3 g of the compound obtained in step A of Example 1 and 40 ml of 75% formic acid, and the mixture is refluxed for 2 hours. The insoluble material is filtered off by suction while hot and washed with MeOH, and the filtrate is concentrated under vacuum. The residue is taken up in chloroform, the insoluble material is filtered off by suction and washed with an MeOH/chloroform mixture, and the filtrate is concentrated under vacuum. The residue is taken up in chloroform and filtered, the filtrate is washed with saturated NaHCO3 solution and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 2.4 g of the expected product are obtained.