Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(Cl)c(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
3-(2-Chloro-5-methoxy-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (293 mg) was dissolved in CH2Cl2 (30 mL) and cooled to 0° C. A solution of boron tribromide (1M in CH2Cl2, 3.08 mL) was added dropwise and stirring was continued at 0° C. for 1 hour. The reaction mixture was diluted with CH2Cl2, extracted with sat. NaHCO3 solution and brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane=3:7) to give the title compound as a colorless solid (230 mg, 81%). MS (m/e)=366.0 [MH+].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:11]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:11]([O:20][CH2:21][C:22]([F:23])([F:24])[F:25])[CH:10]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1OCC(F)(F)F
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(O)cc1OCC(F)(F)F
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 4-benzyloxy-2-(2,2,2-trifluoroethoxy)phenylacetate from Step 3 in MeOH was added palladium black (250 mg). The mixture was stirred under an atmosphere of hydrogen gas (1 atm) for 3 h. The hydrogen was removed by bubbling argon through the mixture for 10 min, and the catalyst was removed by filtration. The filtrate solvents were removed inder reduced pressure and the residue was purifed by pressurized silica gel column chromatography using 1:3 EtOAc:hexanes as eluant to give methyl 4-hydroxy-2-(2,2,2-trifluoroethoxy)phenylacetate as a solid (HPLC retention time=18.1 min (method D)).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccccc2F)ncc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (5 g, 28 mmol) in dimethoxyethane (40 mL) was treated with 2-fluorophenylboronic acid (5.3 g, 35 mmol) and 2M K2CO3 (40 mL). The reaction mixture was stirred for 5 minutes and then degassed (argon), treated with tetrakis(triphenylphosphine) palladium (1.7 g, 1.4 mmol) and stirred at 110° C. under argon for 2.4 h. The reaction mixture was cooled, poured into water and extracted into EtOAc. The organic phase washed with brine, dried (Na2SO4), and concentrated in vacuo to yield crude 2-(2-fluoro-phenyl)-4-methyl-5-nitro-pyridine as a hygroscopic solid. The solid was purified by column chromatography (4:2:0.5 CHCl3:hexanes:EtOAc) to yield 2-(2-fluoro-phenyl)-4-methyl-5-nitro-pyridine as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:11]=1.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[OH:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH:9]=[C:8]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[CH:7]=1
Reactant: COC(=O)CCc1cc(-c2ccc(O)cc2)cc(-c2ccc(O)cc2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCCCc1cc(-c2ccc(O)cc2)cc(-c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.90 g (8.32 mmol) 3-(4,4″-dihydroxy-[1,1′;3′,1″]terphenyl-5′-yl)-propionic acid methyl ester are dissolved in THF, and 55 ml (55 mmol) of a 1 M solution of DIBAL-H in toluene are added dropwise under cooling. The cooling is removed and the mixture is stirred overnight at RT. After addition of 3 ml isopropanol the mixture is poured onto ice/water, acidified with 2 M hydrochloric acid and extracted three times with MTB ether. The combined organic layers are washed with sat. aq. sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue is filtered through silica gel with toluene/ethylacetate (2:1). 5′-(3-hydroxy-propyl)-[1,1′;3′,1″]terphenyl-4,4″-diol is obtained as colourless solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([N:10]2[C:18]3[C:13](=[C:14]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=5)[CH2:22][CH2:21]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: COc1cccc(I)c1
Product: COc1cccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 482.3 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[F:3][CH:4]([F:18])[O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=[O:17]>CCO.O>[F:3][CH:4]([F:18])[O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][OH:17]
Reactant: O=Cc1c(OC(F)F)ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1c(OC(F)F)ccc2ccccc12
Yield: 38.4 %

Procedure:
NaBH4 (255 mg, 6.73 mmol) was added to a suspension of 2-(difluoromethoxy)-1-naphthaldehyde (0.997 g, 4.49 mmol) in EtOH (29.9 mL). After 3 h the mixture was diluted with H2O, extracted with EtOAc, the combined extracts were washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate concentrated to give a residue that was purified by silica gel chromatography to provide (2-(difluoromethoxy)naphthalen-1-yl)methanol (387 mg, 39%) as an orange solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]1([N:7]([CH:34]2[CH2:36][CH2:35]2)[C:8]([C:10]2[N:31]([CH2:32][CH3:33])[C:13]3=[N:14][C:15]([NH:22][C:23]4[S:24][C:25]([C:28]([OH:30])=O)=[CH:26][N:27]=4)=[C:16]4[N:20]=[CH:19][N:18]([CH3:21])[C:17]4=[C:12]3[CH:11]=2)=[O:9])[CH2:6][CH2:5]1>>[CH:4]1([N:7]([CH:34]2[CH2:35][CH2:36]2)[C:8]([C:10]2[N:31]([CH2:32][CH3:33])[C:13]3=[N:14][C:15]([NH:22][C:23]4[S:24][C:25]([C:28]([N:2]([CH3:3])[CH3:1])=[O:30])=[CH:26][N:27]=4)=[C:16]4[N:20]=[CH:19][N:18]([CH3:21])[C:17]4=[C:12]3[CH:11]=2)=[O:9])[CH2:6][CH2:5]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Reactant: CNC
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)N(C)C)s3)nc21

Procedure:
This compound was prepared according to Example 20 using N,N-dimethylamine and 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid (example 20A) to give 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-N,N-dimethylthiazole-5-carboxamide.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC1(O)CCCC1
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(C#CC3(O)CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (73) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 1-ethynylcyclopentanol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.56 (m, 3H), 7.39 (d, J=8 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.26 (s, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.93 (m, 4H), 1.78 (m, 4H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.56.
Reaction SMILES: C[O:2]C1C=CC(S(C(C)(CC2C=CC(OCCN3CCCCC3)=CC=2)C(O)=O)(=O)=O)=CC=1.O[CH:34]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]2)=[CH:53][CH:52]=1)[C:35]([S:40]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)(=[O:42])=[O:41])([CH3:39])[C:36]([NH2:38])=[O:37]>>[OH:2][NH:38][C:36](=[O:37])[C:35]([S:40]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)(=[O:42])=[O:41])([CH3:39])[CH2:34][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]2)=[CH:53][CH:52]=1
Reactant: COc1ccc(S(=O)(=O)C(C)(Cc2ccc(OCCN3CCCCC3)cc2)C(=O)O)cc1
Reactant: COc1ccc(S(=O)(=O)C(C)(C(N)=O)C(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Product: COc1ccc(S(=O)(=O)C(C)(Cc2ccc(OCCN3CCCCC3)cc2)C(=O)NO)cc1

Procedure:
Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-piperidin-1-yl-ethoxy) phenyl]-propionic acid (2.0 g, 4.2 mmol) and following the procedure as outlined in example 1, -1 g of 1N-hydroxy- 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)phenyl]-propionamide was isolated as colorless solid. Yield: 1 g, 48%; mp 98° C.; MS: 477 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.2 (s, 3H), 3.5-1.5 (m, 16 H), 3.9 (s, 3H), 4.4 (m, 1H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=2)=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[C:29]([NH:32][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:30][N:31]=2)=[CH:25][CH:26]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: COc1ccc(-c2cc(N)[nH]n2)cc1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)cc1

Procedure:
The named compound is prepared by substituting 5-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2392 gms. of 5-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].C(OC(C1C=CC=CC=1P(=CC(=O)C=NOC)(C1C=CC=CC=1)C1C=CC=CC=1)=O)C>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:21][C:10]1([CH3:22])[S:9][CH:15]2[N:12]([C:13](=[O:17])[CH2:14]2)[CH:11]1[C:18]([OH:20])=[O:19]
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Agent: CC(C)(C)C(=O)O
Agent: CCOC(=O)c1ccccc1P(=CC(=O)C=NOC)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC1(C)SC2CC(=O)N2C1C(=O)O
Reaction time: 0.17 h

Procedure:
A solution of 6.6 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 150 ml of benzene is treated at room temperature with 11 g of ethoxycarbonyl(methoxyimino)acetylmethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (6:4). There is obtained methylene-(2S,5R)-6-[3-ethoxycarbonyl)-2-(Z)-(methoxyimino)acetonylidene]-3,3-dimethyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate pivalate as an orange oil [Rf: 0.51; cyclohexane/ethyl acetate (6:4); NMR (CDCl3), δ (ppm): 1.23 (9H); 1.37 (m, 3H); 1.53 (3H); 1.62 (3H); 4.21 (3H, --OCH3); 4.42 (m, 2H); 4.65 (1H3); 5.9 (m, 2H); 6.11 (1H); 6.66 (1H)].
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:13]1(=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.Cl.C(O)C.O>C(O)C>[CH:2]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:15]3[C:16]4[C:21]([CH2:13][C:14]=3[C:7]=2[CH:6]=1)=[CH:20][CH:19]=[CH:18][CH:17]=4)([CH3:4])[CH3:3]
Reactant: O=C1CCc2ccccc21
Reactant: CC(C)c1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-isopropylphenylhydrazine hydrochloride (6.3 g, 34 mmol) and 1-indanone (4.5 g, 34 mmol) were heated to reflux in ethanol (40 cm3) containing concentrated hydrochloric acid (2 cm3). Heating was continued for 4 hours, and then the reaction mixture was cooled to room temperature during which time the product crystallised out of solution as colourless crystals. This compound was filtered off, dried in a vacuum oven, and recrystallised from ethanol/water to yield colourless prisms. Yield: 6.59 g, (79%). M.p. 193° C. (from ethanol/water). 1H NMR (DMSO-d6) δ: 1.27 (6H, d,), 2.96 (1H, septet,), 3.65 (2H, s,), 6.9-7.6 (7H, m,), 11.2 (1H, br,).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)c2cc(F)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a solution of 6-fluoro-4-hydroxy-naphthalene-2-carboxylic acid methyl ester (3.7 g, 16.8 mmol) in dry DMF (40 mL) was added K2CO3 (3.25 g, 23.5 mmol), benzyl bromide (3.44 g, 20.2 mmol) and Bu4NI (0.02 g) simultaneously at room temperature under nitrogen. The reaction mixture was stirred for 3 hours at room temperature. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Silica gel column chromatography (2%-5% ethyl acetate in hexanes) afforded 4-benzyloxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester (4.6 g, 88%) as an off-white solid. MS cald. for C19H16FO3 [(M+H)+]: 311, obsd. 311.0.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([C:10]1[CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([O:20][CH3:21])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7]>C(#N)C>[C:6]([C:10]1[CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([O:20][CH3:21])=[C:14]([S:16]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:17])=[O:18])[CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)N
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(=O)(=O)Cl
Solvent: CC#N
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butylamine (9 ml) was added to a cooled solution of 5-t-butyl-2-methoxy-3-nitrophenyl sulfonyl chloride (7.4 g) in acetonitrile (40 ml). The mixture was stirred at ambient temperature for 1 hour and then the solvent was removed under vacuum. The residue was shaken with ethyl acetate (100 ml) and 4% citric acid (100 ml). The organic phase was separated and dried over sodium sulphate. Evaporation of solvent gave a solid residue which was recrystallized from aqueous ethanol to give the title compound (6.0 g);
Reaction SMILES: [C:1]([C@H:4]([O:34][CH3:35])[CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([N:25](C)[C:26](=O)OC(C)(C)C)[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2)(=[O:3])[NH2:2].[ClH:36]>ClCCl>[ClH:36].[CH3:35][O:34][C@H:4]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([NH:25][CH3:26])[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2)[C:1]([NH2:2])=[O:3]
Reactant: CO[C@H](C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21)C(N)=O
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](OC)C(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 25-mL round-bottom flask, a solution of tert-butyl N-(4-[[(3R)-3-[(2R)-2-carbamoyl-2-methoxyethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (140 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (10 mL) was added hydrochloric acid (2 M, 1.0 mL) at 0° C. and the resulting mixture was stirred at room temperature for 5 h. After completion, the resulting mixture was concentrated under vacuum to afford (2R)-2-methoxy-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1 (8),2 (6),9,11-tetraen-3-yl]propanamide hydrochloride (110 mg) as a light yellow solid. The residue hydrochloride (110 mg) was dissolved in 5 mL of methanol, HCHO (37%, 0.5 mL) was added and the solution stirred for 30 min at room temperature. Then NaBH3CN (65 mg) was added and the resulting solution was allowed to react, with stirring, for an additional 2 hr at ambient temperature. After completion, the resulting solution was diluted with 20 mL of water, extracted with 3×50 mL of DCM and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.1% HCOOH and CH3CN (6.0% CH3CN up to 75% in 20 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired (2R)-3-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-2-methoxypropanamide formate (47.5 mg, 45%) as an off-white solid. MS (ES): m/z 419 [M−HCOOH+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (m, 2H), 5.28 (s, 1H), 3.59-3.52 (m, 2H), 3.34-3.27 (m, 4H), 3.08-2.82 (m, 8H), 2.65-2.62 (m, 1H), 2.45-2.18 (m, 6H), 1.85-1.82 (m, 5H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:12])[NH:4][NH:3]1.[C:13]([OH:20])(=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH3:18]>C(#N)C>[C:13]([CH:14]1[CH:15]=[CH:16][CH:17]([CH3:18])[N:4]2[C:5](=[O:12])[N:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:2](=[O:1])[N:3]12)([OH:20])=[O:19]
Reactant: O=C(O)CCn1c(=O)[nH][nH]c1=O
Reactant: CC=CC=CC(=O)O
Solvent: CC#N
Product: CC1C=CC(C(=O)O)n2c(=O)n(CCC(=O)O)c(=O)n21
Yield: 76 %

Procedure:
In a manner analogous to that described in Example 1(D), from 3,5-dioxo-1,2,4-triazolidine-4-propionic acid, prepared as described in Example 2(C) and hexa-2,4-dienoic acid, there was obtained in 76% yield 5-carboxy-2,3,5,8-tetrahydro-8-methyl-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-2-propionic acid of melting point 184°-186° C. (from acetonitrile).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[N:16]=[C:7]2[CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=[CH:11][N:6]2[N:5]=1>CO>[Br:3][C:4]1[N:16]=[C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: COC(=O)c1ccn2nc(Br)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccn2nc(Br)nc2c1
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A 1 N sodium hydroxide aqueous solution (150 ml) was added to a methanol (150 ml) suspension of the methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (10 g) obtained in (Example 3.15) <Step 2>, and the obtained mixture was then stirred for 30 minutes. Thereafter, about half of the solvent was distilled away under reduced pressure, and the residue was then adjusted to pH 4 by addition of 3 N hydrochloric acid (50 ml). The precipitated solid was collected by filtration, and was then successively washed with water (50 ml) and methyl tert-butyl ether (20 ml). The obtained solid was, subjected to azeotropy with toluene to obtain the title compound (9.0 g) in the form of a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1.[CH3:31][C:32]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][C:33]=1[C:34](O)=[O:35]>>[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:34]([C:33]4[CH:37]=[C:38]([O:41][C:42]([F:43])([F:44])[F:45])[CH:39]=[CH:40][C:32]=4[CH3:31])=[O:35])[CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2
Reactant: Cc1ccc(OC(F)(F)F)cc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OC(F)(F)F)ccc4C)CC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B6) and 2-methyl-5-(trifluoromethoxy)benzoic acid (compound F5) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: I[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[O:13][CH:14]=2)=[CH:6][CH:7]=1.[CH2:27]([N:31]1[CH:35]=[CH:34][N:33]=[N:32]1)[CH2:28][C:29]#[CH:30].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.[Cu](I)I.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>[N:31]1([CH2:27][CH2:28][C:29]#[C:30][C:2]2[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]3[N:11]=[C:12]([CH:15]=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[O:13][CH:14]=3)=[CH:6][CH:7]=2)[CH:35]=[CH:34][N:33]=[N:32]1
Reactant: C#CCCn1ccnn1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(COc3ccc(I)nn3)co2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3ccc(C#CCCn4ccnn4)nn3)co2)cc1
Reaction time: 3 h

Procedure:
3-Iodo-6-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyridazine (0.114 g, 0.25 mmol), 1-but-3-ynyl-1H-[1,2,3]triazole (0.040 g, 0.30 mmol) and triethyl amine (NEt3) (0.125 ml) are dissolved in THF (1 ml) and copper iodide (CuI) (0.0048 g, 0.025 mmol) is added under stirring. After passing a stream of argon through the mixture for 10 min bis(triphenylphosphine)palladium(II) dichloride (0.088 g, 0.0125 mmol) is added and stirring is continued for 3 h at r.t. Ethyl acetate (30 ml) is added; the mixture is washed with saturated ammonium chloride (NH4Cl) and brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 1:3->ethyl acetate (100%)) yielding 3-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-6-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyridazine as a colorless solid. Yield 93 mg (64%).