Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:59]=[CH:58][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)[C:48](=[O:49])[NH:47][C:46](=[O:50])[NH:45][C:44]3=[O:51])=[O:40])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH:60](=O)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH2:60]([N:55]1[CH2:54][CH2:53][N:52]([C:43]2([CH2:42][NH:41][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:59][CH:58]=3)[C:44](=[O:51])[NH:45][C:46](=[O:50])[NH:47][C:48]2=[O:49])[CH2:57][CH2:56]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(=O)NCC3(N4CCN(Cc5ccccc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 62 %

Procedure:
Following a procedure analogous to that used in reaction (9), the material from example 8 was reacted with benzaldehyde for 2 days to provide the title compound (18 mg, 62%). MS found: (M+H)+=607.5.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:28]=[CH:27]2.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[C:36]([O:35][C:33]([N:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:1][C:2]3[CH:14]=[C:13]([CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:32][CH:31]=2)[CH:27]=[CH:28]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
To toluene 4.0 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.20 g were added tert-butyl 5-bromo-1H-indol-1-carboxylate 0.29 g, cesium carbonate 0.55 g, tris(dibenzylideneacetone)dipalladium(0) 6 mg, palladium acetate 3 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 16 mg at room temperature, and it was heated and refluxed under nitrogen atmosphere for 8 hours. After the reaction mixture was cooled to room temperature, tris(dibenzylideneacetone)dipalladium(0) 6 mg, palladium acetate 3 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 16 mg were added to it, and it was heated and refluxed under nitrogen atmosphere for 10 hours. After the reaction mixture was cooled to room temperature, water was added, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((1-(tert-butoxycarbonyl)-1H-indol-5-yl)amino)-4-phenethylbenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10]=1[C:20]([O:22]CC)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.Cl>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]=1[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2)nc1C(=O)O
Temperature: 52.5 °C
Yield: 68.7 %

Procedure:
To a solution of compound ethyl 5-(tert-butoxycarbonylamino)-2-phenylthiazole-4-carboxylate (348 mg, 1 mmol) in MeOH/H2O (10 mL, 1:1) was added LiOH.H2O (20 mg, 5 mmol). The reaction mixture was heated at 50-55° C. until starting material disappeared from TLC. It was cooled at ˜0-4° C. and conc. HCl added dropwise until pH ˜5. The resulted mixture was then extracted with DCM (3×20 mL). Combined organic layers were washed with brine (2×20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (50:1 DCM:MeOH) to give the desired product 5-(tert-butoxycarbonylamino)-2-phenylthiazole-4-carboxylic acid (0.22 g, 68%) as white solid: 1H-NMR (CDCl3, 500 MHz) δ (ppm): 9.69 (s, 1H), 7.89-7.91 (m, 2H), 7.46-7.47 (m, 3H), 1.57 (s, 9H); MS (ESI) m/z: 321 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(CC#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCN)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
Under ice cooling, 17.0 g of 2-(3-methoxy-4-nitrophenyl)acetonitrile in 50 ml of tetrahydrofuran is combined with 180 ml of 1-molar borane-tetrahydrofuran complex in tetrahydrofuran, stirred for 16 hours at room temperature, and mixed with water. The mixture is agitated at 0° C. for 0.5 hour, 200 ml of 2N hydrochloric acid is added dropwise, and the mixture is again stirred for 2 hours at 0° C. and for 2 hours at room temperature. A pH of 9.5°-10.5 is set with sodium hydroxide solution, and the mixture is extracted four times with ethyl acetate/butanol 10:1. The product is chromatographed on silica gel with methanol/dichloromethane 1:1, thus obtaining 9.0 g of 2-(3-methoxy-4-nitrophenyl)ethylamine as an oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[N:17]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(OCC)C>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(CN2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 0.2 g (0.60 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione in 2 mL of N,N′-dimethylformamide is added 4-piperidin-1-ylmethyl-phenylamine (0.127 mL, 0.67 mmol). The reaction mixture is heated at 120° C. under N2 for 1.5 h. After cooling, ethyl ether is added and left in refrigerator overnight to give dark brown crystal. The crystal is collected and dissolved in 4 mL of dimethyl sulfoxide, followed by addition of 6 mL of 65% MeOH/H2O solution to give a precipitate. The solid is collected and washed thoroughly with water, MeOH, Et2O and hexane, and air-dried to give 0.143 g (48.3% yield) of tan solid: mp 202-203° C., MS (ESI) m/z 488.1 (M+H)+1
Reaction SMILES: [OH-].[Na+].[CH:3]1([C@H:9]([NH:12][C:13](=[O:18])[C:14]([O:16]C)=[O:15])[CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>>[CH:3]1([C@H:9]([NH:12][C:13](=[O:18])[C:14]([OH:16])=[O:15])[CH2:10][OH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)C(=O)N[C@H](CO)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(=O)N[C@H](CO)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
Sodium hydroxide 1M (8.7 mL; 8.7 mmol) was added to (S)-methyl 2-(1-cyclohexyl-2-hydroxyethylamino)-2-oxoacetate (0.660 g; 2.88 mmol) and the mixture was stirred at room temperature for 2 hours. The solution was acidified to pH 0-1 by addition of concentrated hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, and dried to afford 0.350 g (56%) of (S)-2-(1-cyclohexyl-2-hydroxyethylamino)-2-oxoacetic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.CCOCC>C1COCC1>[CH3:1][C:2]1[C:3]([CH:16]([OH:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc2c(cc1C(C)O)C(C)(C)CCC2(C)C
Reaction time: 3 h

Procedure:
To a solution of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (500 mg; 2.0 mmol) in dry THF (5 ml) was added slowly LiAlH4 (80 mg; 2.0 mmol) at 0° C. The reaction mixture was stirred for 3 hours, and then water (20 ml) was added. Ether (50 ml) was added and the mixture was filtered through filter aid. The organic phase was separated and the water phase was extracted with ether. The combined organic phases were dried and evaporated to give the title compound in 504 mg (100%) yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.[C:16]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[CH:21]=[C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:20]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C2CCCCC2=O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCCCC1c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 99.8 %

Procedure:
Combine 2-(3-methoxyphenyl)-cyclohexanone (5.0 g, 24.5 mmol), carbethoxymethylene triphenylphosphorane (15.4 g, 44.1 mmol), and toluene (150 mL), stir and heat at reflux. After 22 hours, cool to ambient temperature and concentrate under vacuum. Add ether and filter off the triphenylphosphine oxide precipitate and concentrate the ether filtrate. Flash chromatograph with 0% to 10% ethyl acetate/hexanes to yield the titled compound (6.71 g, 99%) as a clear oil. TLC Rf=0.58 in 8:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.25 (m, 1H), 6.81-6.79 (m, 3H), 6.73 (s, 1H), 5.14 (s, 1H), 4.07 (q, J=14.4, 7.2, 2H), 3.80 (s, 3H), 3.80-3.69 (m, 1H), 3.39-3.36 (m, 1H), 2.20-2.16 (m, 1H), 2.06-2.03 (m, 1H), 1.96-1.87 (m, 3H), 1.65-1.54 (m, 2H), 1.2 (t, J=1.2, 8, 3H).
Reaction SMILES: CS([O:5][CH:6]([C:26]([NH:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:27])[CH2:7][CH2:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)(=[O:11])=[O:10])(=O)=O.[C:37]([O-])(=[S:39])[CH3:38].[K+]>CN(C=O)C>[C:37](=[S:39])([O:5][CH:6]([C:26]([NH:28][CH2:29][CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:27])[CH2:7][CH2:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)(=[O:10])=[O:11])[CH3:38]
Reactant: CS(=O)(=O)OC(CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)NCCN1CCOCC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=S)OC(CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)NCCN1CCOCC1
Reaction time: 1 h
Yield: 69.1 %

Procedure:
Part I: A solution of 2.5 g (5 mmol) of 1-[(2-morpholinoethyl)amino]carbonyl-3-[(3-phenoxybenzyl)sulfonyl]propyl methanesulfonate from Part H in 20 mL of anhydrous DMF was treated with 0.8 g (7 mM) of potassium thioacetate. After 1 hour, the reaction was partitioned between ethyl acetate and sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine (3×), dried (MgSo4) and concentrated to yield 2.4 g of crude product. This was chromatographed on silica gel using 1-3% methanol/ethyl acetate to yield 1.8 g of 1-[(2-morpholinoethyl)amino]carbonyl-3-[(3-phenoxybenzyl)sulfonyl]propyl ethanethioate suitable for the next reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH:13]([OH:15])[CH3:14])[CH:10]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[CH:11]([CH:13]([O:15][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=2)[CH3:14])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C#N)cn1)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a stirred solution of 4-[(3SR,4RS)-1-benzyl-4-((SR)-1-hydroxy-ethyl)-pyrrolidin-3-yl]-benzonitrile (V-A-5) (0.65 g, 2.12 mmol) in DMF (40 mL) at RT was added NaH (55% purity, 0.10 g, 4.1 mmol). After 10 minutes, 6-chloro-nicotinonitrile (0.32 g, 2.33 mmol) was added. The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NH4Cl sat, followed by column chromatography (SiO2, EtOAc/H, 1:1) yielded 0.39 g (45%) of the title compound as a colorless oil. ES-MS m/e: 409.3 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[N:7](CC2C=CC3NC4C=CC=CC=4CCC=3C=2)[C:6]2[CH:24]=[C:25](C)[CH:26]=[C:27]([CH3:28])[C:5]=2[N:4]=1)[CH3:2].C(C1[NH:33]C2C(C)=CC(C)=CC=2N=1)C>>[CH2:1]([C:3]1[NH:7][C:6]2=[N:33][C:25]([CH3:24])=[CH:26][C:27]([CH3:28])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2cc(C)cc(C)c2[nH]1
Reactant: CCc1nc2c(C)cc(C)cc2n1Cc1ccc2c(c1)CCc1ccccc1N2
Product: CCc1nc2c(C)cc(C)nc2[nH]1

Procedure:
[step 1] 2-(2-Ethyl-4,6-dimethylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (422 mg, 75%) was obtained in the same manner as in step 1 of Example 1, using 2-ethyl-4,6-dimethylbenzimidazole (256 mg, 1.47 mmol), obtained in Reference Example 1, instead of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([F:25])[CH:12]=1.[OH-:26].[K+].Cl>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)C>[F:25][C:13]1[CH:12]=[C:11]([N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[C:2]([OH:26])[C:3]=3[CH:4]=[N:5]2)[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Fc1cc(-n2ncc3c(Br)cccc32)ccc1OCc1ccccc1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Oc1cccc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 90 °C
Yield: 86.1 %

Procedure:
To a solution of 4-bromo-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazole (D38) (5.25 g, 13.2 mmol) in dioxane (50 mL) and water (50 mL) was added potassium hydroxide (2.95 g, 52.7 mmol). The reaction mixture was degassed with argon and then treated with bis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)-2-biphenylyl]phosphane (336 mg, 0.79 mmol) and tris(dibenzylideneacetone)dipalladium (0) (242 mg, 0.26 mmol). After heating at 90° C. for 1 hour under argon, the mixture was allowed to cool to room temperature and then diluted with ethyl acetate and water. The pH was adjusted to ˜7 by the addition of 1M hydrochloric acid. After separation of the layers, the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5-70% ethyl acetate in hexane to yield the title compound (D39) (3.80 g).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1>CN(C=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]=[C:26]([N:3]2[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]2=[O:1])[CH:27]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2cc(Cl)ncn2)c2ccccc21
Temperature: 140 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate (130 mg, 0.52 mmol, described in Intermediate 4), in DMF (0.7 mL) was added sodium hydride (15 mg of a 60% dispersion in mineral oil, 0.38 mmol). The mixture was stirred for 5 min, then 4,6-dichloropyrimidine (234 mg, 1.57 mmol) was added and argon was bubbled through the mixture for 5 min. The reaction mixture was heated at 140° C. for 10 min in a microwave reactor. The cooled mixture was partitioned between CHCl3 (10 mL) and saturated aqueous NaHCO3 (5 mL). The aqueous phase was extracted further with CHCl3 (10 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane::EtOAc—95:5 to 75:25, to give the title compound. MS: m/z=361 (M+1).
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ce+3].[Cl-].[Cl-].[C:7]([O:15][C@@H:16]1[CH2:24][C@@H:19]2[O:20][C:21](=[O:23])[CH2:22][C@@H:18]2[C@H:17]1/[CH:25]=[CH:26]/[C:27](=[O:34])[CH:28]([CH3:33])[CH2:29][CH2:30][CH2:31][CH3:32])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>C(Cl)Cl.CO.C(OCC)(=O)C.O>[C:7]([O:15][C@@H:16]1[CH2:24][C@@H:19]2[O:20][C:21](=[O:23])[CH2:22][C@@H:18]2[C@H:17]1/[CH:25]=[CH:26]/[C@@H:27]([OH:34])[CH:28]([CH3:33])[CH2:29][CH2:30][CH2:31][CH3:32])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCC(C)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A slurry of sodium borohydride (1.8 g, 48 mmol) and cerium chloride (9 g, 24 mmol) in a mixture of methylene chloride (300 mL) and methanol (600 mL) was stirred at room temperature as a solution of (3aR,4R,5R,6aS)-5-(benzoyloxy)hexahydro-4-[(1E)-4-methyl-3-oxo-1-octenyl]-2H-cyclopenta[b]furan-2-one (9.3 g, 24 mmol) in 100 mL of methylene chloride was added. After 30 min, the reaction was treated with water, a saturated ammonium chloride solution, and ethyl acetate. The combined organic layers were dried and concentrated. Purification by normal phase chromatography using a gradient of ethyl acetate in hexane gave (3aR,4R,5R,6aS)-5-(benzoyloxy)hexahydro-4-[(1E,3S)-3-hydroxy-4-methyl-1-octenyl]-2H-cyclopenta[b]furan-2-one and 3.2 g of the second eluted compound which is the corresponding 3R-isomer, (3aR,4R,5R,6aS)-5-(benzoyloxy)hexahydro-4-[(1E,3R)-3-hydroxy-4-methyl-1-octenyl]-2H-cyclopenta[b]furan-2-one.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[CH3:22])=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[CH:46]1([S:49]([NH2:52])(=[O:51])=[O:50])[CH2:48][CH2:47]1.Cl>O1CCCC1>[CH:1]1([C:4]2[C:5]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[CH3:22])=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([NH:52][S:49]([CH:46]2[CH2:48][CH2:47]2)(=[O:51])=[O:50])=[O:11])[CH2:2][CH2:3]1
Reactant: CC1CCCCC1COc1cc(F)c(C(=O)O)cc1C1CC1
Reactant: NS(=O)(=O)C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CCCCC1COc1cc(F)c(C(=O)NS(=O)(=O)C2CC2)cc1C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred solution of 5-cyclopropyl-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzoic acid (0.093 g, 0.305 mmol) in tetrahydrofuran (2 mL) under an atmosphere of nitrogen was added carbonyldiimidazole (0.074 g, 0.457 mmol) and the reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled to room temperature and 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.07 mL, 0.45 mmol) was added followed by cyclopropanesulfonamide (0.06 mg, 0.52 mmol). Stirring was continued at ambient temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and directly purified by column chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.05 g, 43%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.79-8.58 (m, 1H), 7.56 (d, J=9.1 Hz, 1H), 6.57 (d, J=14.5 Hz, 1H), 3.87 (dd, J=7.0, 2.7 Hz, 2H), 3.08 (tt, J=8.1, 8.1, 4.8, 4.8 Hz, 1H), 2.21-1.93 (m, 3H), 1.76-1.35 (m, 9H), 1.13 (dq, J=6.20, 6.08, 1.31 Hz, 2H), 0.98-0.86 (m, 5H), 0.68-0.59 (m, 2H); MS (ES+) m/z 410.1 (M+1); MS (ES−) m/z 408.2 (M−1).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(P(N(C)C)(N(C)C)=O)C.C1OC1C>CCN(CC)CC>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: BrCCCCCCCCCc1ccccc1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Reaction time: 6 h
Yield: 32.1 %

Procedure:
To a stirred mixture of 5-hydroxy-6methoxy-4methyl-8nitroquinoline (4.7 g, 0.02 mol), 1 bromo-9-phenylnonane (4.2 g, 0.015 mol) and HMPA (10 ml), at 125- 130° C., was added dropwise, during 0.5 h, a mixture of propylene oxide (6 ml) and Et3N (1 ml). The reaction was continued for 6 h, allowed to cool and extracted successively with pet ether, Et2O and Me2CO leaving 1.9 g of insoluble starting material, 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline. The combined pet ether and Et2O extracts were washed (H2O, dil NaOH, H2O) dried (Na2SO4) and concentrated. The residual oil was dissolved in CHCl3, placed on a silica gel column (100 g) and eluted with CHCl3. The eluates were concentrated, triturated with pet ether and crystallized from Et2O (Darco) to give 2.1 g of 6-methoxy-4-methyl-8-nitro-5 -(9-phenylnonoxy) quinoline as yellow crystals, mp 56°-56.5° C. This material was used without further purification.
Reaction SMILES: N12CCC(CC1)CN2.[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>>[OH:16][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:18](=[CH2:19])[C:17]([O:21][CH3:22])=[O:20]
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccccc1
Agent: C1CN2CCC1CN2
Product: C=C(C(=O)OC)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 70.7 %

Procedure:
Diazabicyclo[2.2.2]octane (5.2 g, 0.046 mol, 0.15 eq) was added to a mixture of benzaldehyde (31.5 mL, 0.309 mol, 1 eq) and methyl acrylate (42 mL, 0.464 mol, 1.5 eq). The reaction mixture was then allowed to stir at room temperature for 7 days. The reaction mixture was purified by column chromatography (eluent: hexane/ethyl acetate=95:5) to give the desired product as colorless oil (42 g, 77%). Rf 0.5 (hexane/ethyl acetate=7:3). 1H NMR δ (DMSO-d6) 3.6 (s, 3H), 5.43 (m, 1H), 5.73 (m, 1H), 5.98 (s, 1H), 6.19 (s, 1H), 7.29 (m, 5H).