Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9](C#N)[CH2:10][CH2:11][C:12]([CH3:20])([CH3:19])[CH2:13][C:14]([O:16]CC)=O.Cl.C(O)(=[O:26])C.O>C(OCC)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10](=[O:26])[CH2:11][C:12]([CH3:19])([CH3:20])[CH2:13][C:14]1=[O:16]
Reactant: CCOC(=O)CC(C)(C)CCC(C#N)c1ccc(C)cc1C
Reactant: CC(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)c(C)c1
Reaction time: 12 h
Yield: 32 %

Procedure:
A one-neck round bottom flask was charged with 52.50 g (0.17 mol) of ethyl 6-(2',4'-dimethylphenyl)-6-cyano-3,3-dimethylhexanoate, 250 ml of concentrated hydrochloric acid, 250 ml of glacial acetic acid, and 100 ml of water. The reaction mixture was stirred and refluxed for 48 hours. After 12 hours and 24 hrs. of refluxing, an additional 100 ml of conc. HCl and 100 ml glacial HOAC were added. After 48 hours, the mixture was stripped to dryness under reduced pressure. To the residue were added 150 ml of water and 150 ml of ethyl ether, and the mixture shaken vigorously. A white, crystalline precipitate formed, and this was removed by suction filtration to give 13.20 g (32%) of 2-(2',4'-Dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione as a white, crystalline solid, m.p. 167°-168.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][C:19]1[CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[CH:22]=[CH:21][N:20]=1.CN(C=O)C>C(OCC)(=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>[C:16]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[C:23]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[CH:24]=1)#[N:17]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Cl)c(C#N)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(CC(=O)OC(C)(C)C)cc2C#N)ccn1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of tert-butyl 2-(4-chloro-3-cyanophenyl)acetate 111-7 (572 mg, 2.28 mmol), 2-methyl-4-(tributylstannyl)pyridine 111-8 (870 mg, 2.28 mmol) and Pd(PPh3)4 (220 mg, 0.2 mmol) and DMF (9 mL) was stirred at 120° C. for 10 hours under argon. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated aqueous Na2S2O3 solution, water and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give tert-butyl 2-(3-cyano-4-(2-methylpyridin-4-yl)phenyl)acetate 111-9 as a yellow oil. MS m/z 309.2 (M+1).
Reaction SMILES: C([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)CCCCCCC.[CH2:49]([O:56]C1C=NC(C2C=CC(O)=CC=2)=NC=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CN(C)C=O>[CH2:49]([O:56][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:38])[F:39])([F:29])[F:28])=[CH:19][CH:20]=2)=[N:13][CH:14]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: CN(C)C=O
Product: CCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The title compound was prepared essentially as in Example I by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy) 1-chloropropane (5.5 g, 15.0 mmol, Example 24) with 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.5 mmol) in dimethylformamide and stirring at 120° C. overnight to provide product boiling at 195°-210° C. at 0.3 torr (yield of 5.6 g).
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.N1C2C(=CC=CC=2)C=C1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([O:35]C)=O)=[CH:25]1>>[S:11]1[CH:12]=[CH:13][N:14]=[C:10]1[NH:9][C:33]([C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:24]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:25]=1)=[O:35]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Nc1nccs1
Reactant: BrCC1CCCCC1
Agent: c1ccc2[nH]ccc2c1
Product: O=C(Nc1nccs1)c1cn(CC2CCCCC2)c2ccccc12

Procedure:
R5Br=Cyclohexylmethylbromide; NH2A=2-aminothiazole; Indole starting material=methyl indole 3-carboxylate
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1>N1CCC(O)CC1>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:42](=[O:43])[C:41]2[CH:40]=[CH:39][C:38]([S:35]([N:32]3[CH2:31][CH2:30][CH:29]([OH:28])[CH2:34][CH2:33]3)(=[O:37])=[O:36])=[CH:46][CH:45]=2)=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: OC1CCNCC1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)N2CCC(O)CC2)cc1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 506 μL of piperidin-4-ol via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 114 mg of 4-(4-hydroxypiperidin-1-ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-hydroxypiperidin-1-ylsulfonyl)benzamide. MS (Q1) 472.3 (M)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1>>[ClH:22].[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:35][C:33]5[CH:32]=[CH:31][C:28]6[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=6[N:34]=5)[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)C[C@H]1O
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Product: Cl
Product: O=C1CSc2ccc(CN[C@H]3CCN(CC4Cn5c(=O)ccc6ncc(Cl)c4c65)C[C@H]3O)nc2N1
Yield: 49 %

Procedure:
The free base of the title compound was synthesised from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 301(d)) according to the general method of Example 2(h), in 49% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:30][CH2:29][N:28]([C:26]5[CH:25]=[CH:24][CH:23]=[C:22]6[C:27]=5[N:18]=[CH:19][CH:20]=[CH:21]6)[CH2:33][CH2:32]4)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Fc1cc(N2CCNCC2)c2ncccc2c1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1cc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 0.247 g of 6-fluoro-8-piperazino-quinoline (Step 3) in 10 mL of dichloroethane, was added 0.226 g of 1-quinolin-8-yl-piperidin-4-one (Example A, Step 6, above) followed by 0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product crystallized and filtered to give 0.200 g of the desired product. Mp: 211° C.; MS (ES) m/z (relative intensity): 442 (M++−H, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][CH:60]=[C:61]([C:63]2[CH:68]=[CH:67][C:66]([S:69](Cl)(=[O:71])=[O:70])=[CH:65][CH:64]=2)[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:69]([C:66]1[CH:67]=[CH:68][C:63]([C:61]2[N:62]=[C:58]([NH:57][C:54](=[O:56])[CH3:55])[S:59][CH:60]=2)=[CH:64][CH:65]=1)(=[O:71])=[O:70])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)Cl)cc2)cs1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(-c2csc(NC(C)=O)n2)cc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester was treated with 4-(2-acetylamino-thiazol-4-yl)-benzenesulfonyl chloride according to General Procedure E to give (S)-2-({(S)-7-[4-(2-acetylamino-thiazol-4-yl)-benzenesulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:20]3[CH:35]=[CH:34][C:23]([O:24][CH2:25][C@@H:26]([N:28]4[CH2:32][CH2:31][C@@H:30]([CH3:33])[CH2:29]4)[CH3:27])=[CH:22][CH:21]=3)=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:9]2)=[CH:5][CH:4]=1.C(OCC)(=O)C>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[CH:7]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C@@H:26]([N:28]3[CH2:32][CH2:31][C@@H:30]([CH3:33])[CH2:29]3)[CH3:27])=[CH:34][CH:35]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:9]2
Reactant: COc1ccc(C2=C(c3ccc(OC[C@H](C)N4CC[C@@H](C)C4)cc3)c3ccc(OC)cc3C2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C2Cc3cc(OC)ccc3C2c2ccc(OC[C@H](C)N3CC[C@@H](C)C3)cc2)cc1
Reaction time: 25 h
Yield: 85.6 %

Procedure:
A mixture of (R)-1-((S)-1-(4-(6-methoxy-2-(4-methoxyphenyl)-1H-inden-3-yl)phenoxy)propan-2-yl)-3-methylpyrrolidine (400 mg, 0.85 mmol), 10% Pd/C (350 mg, 0.33 mmol), ethyl acetate (8 mL), and ethanol (8 mL) was shaken at 65 psi of H2 for 25 h. The sides of the reaction vessel were rinsed (4 mL, 1:1 EtOAc/EtOH), and the mixture was shaken at 65 psi of H2 for an additional 22.5 h. The reaction was filtered through Celite. The Celite was washed (200 mL, 1:1 EtOAc/EtOH), and the filtrate was concentrated and purified by silica gel chromatography (1:0→17:3; dichloromethane:methanol) to give 343 mg of (3R)-1-((2S)-1-(4-(5-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)phenoxy)propan-2-yl)-3-methylpyrrolidine: 1H NMR (400 MHz, DMSO-d6): δ 6.99 (d, 1H), 6.92 (d, 1H), 6.80 (d, 2H), 6.74 (dd, 1H), 6.66-6.57 (m, 4H), 6.50 (d, 2H), 4.51 (d, 1H), 3.96-3.87 (m, 2H), 3.77 (s, 3H), 3.63 (s, 3H), 3.70-3.60 (br, 1H), 3.26 (dd, 1H), 3.12 (dd, 1H), 2.81 (br, 1H), 2.70-2.50 (br, 3H), 2.07 (br, 2H), 1.88 (br, 1H), 1.24 (br, 1H), 1.07 (br d, 3H), 0.96 (d, 3H); LCMS: 472.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18]Cl.CN(C)C=O>O>[Cl:16][CH2:17][CH2:18][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: ClCCCl
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(CCCl)C1=O

Procedure:
A mixture of 1,664 g of 5,5-dimethyl-hydantoin (13.0 mols), 897 g of anhydrous potassium carbonate (6.5 mols), 5,148 g of 1,2-dichloroethane (52 mols) and 1,485 ml of dimethylformamide is reacted for 18 hours and 20 minutes at 90° C to 100° C internal temperature (external temperature 155° C), the water of reaction produced being removed continuously by azeotropic circulatory distillation. Water of reaction split off: 110 g (94.0% of theory). Thereafter, the reaction mixture, whilst still hot, is separated by filtration from the potassium chloride produced, the filtrate is concentrated on a rotary evaporator at 100° C in a water pump vacuum and the residue is dried to constant weight at 100° C and 10-1 mm Hg.
Reaction SMILES: [C:1]([CH:5]1[NH:19][C:18](=[O:20])[CH:17]([CH2:21][N:22]([O:25]CC2C=CC=CC=2)[CH:23]=[O:24])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1=[O:33])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([CH:5]1[NH:19][C:18](=[O:20])[CH:17]([CH2:21][N:22]([OH:25])[CH:23]=[O:24])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)C1NC(=O)C(CN(C=O)OCc2ccccc2)CCCC=CCCCCNC1=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)C1NC(=O)C(CN(O)C=O)CCCCCCCCCNC1=O

Procedure:
The cyclic compound 14 (50.0 mg) was dissolved in ethyl acetate and methanol (1:1, 10 mL) and 20 mg of 10% Pd/C as added. The mixture was exposed to 1 atm of hydrogen until all the starting material was consumed. The charcoal was removed by filtration and the filtrate was concentrated to give the desired compound quantitatively. 1H NMR (250 MHz, CDCl3) δ 9.39 (brs, 1H), 8.37 (brs, 0.27H),7.86 (brs, 0.73H), 7.40 (d, J=8.7 Hz, 0.27H), 6.94 (brs, 1H), 6.57 (brs, 0.73H), 4.33 (m, 1H) 3.81 (m, 2H), 3.43 (m, 1H), 2.87 (m, 2H), 1.64 (brs, 2H), 1.45–1.23 (m, 16H), 0.96 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 175.0, 173.3, 171.2, 170.9, 157.2, 61.1, 60.4, 52.7, 44.5, 38.5, 34.6, 29.8, 28.0, 27.8, 27.5, 26.8, 26.5, 25.2, 21.1, 14.2. HRESI-MS: C19H35N3O4Na+ ([M+Na])+calc'd 392.2520, found 392.2504. HPLC analysis showed a purity of ˜96% (FIG. 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:29])[N:16]4[C@H:19]4[CH2:24][CH2:23][C@H:22]([C:25](OC)=[O:26])[CH2:21][CH2:20]4)=[CH:12][N:11]=3)[C:6]=2[CH:30]=1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:29])[N:16]4[C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][OH:26])[CH2:23][CH2:24]4)=[CH:12][N:11]=3)[C:6]=2[CH:30]=1
Reactant: COC(=O)[C@H]1CC[C@H](n2c(=O)[nH]c3cnc(-n4cnc5ccc(F)cc54)nc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1[nH]c2cnc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of trans-methyl 4-(2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-7,8-dihydropurin-9-yl)cyclohexanecarboxylate (6 mg) in DCM was treated with 10 equivalents of a 1 M THF solution of LiAlH4 at −10° C. The mixture was stirred at −10° C. for 12 hours and 0° C. for 2 more hours. The mixture was quenched with aqueous sodium bicarbonate and extracted with EtOAc. Silica gel chromatography provided 3.0 mg of the title compound. 1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.3 (dd, 1H), 8.1 (s, 1H), 7.7 (dd, 1H), 7.1 (td, 1H), 4.3 (m, 1H), 3.3 (d, 2H), 2.4 (m, 2H), 1.9 (m, 4H), 1.6 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Cl.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:27][CH:28]=3)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of 4.8 mmol of 2-(4-((5-chloro-3-fluoro-2-pyridinyl)oxy)phenoxy)propanoyl chloride (previously prepared from the corresponding acid) in 15 ml of methylene chloride was added, under N2, to an ice-cooled mixture of 1.03 g (4.8 mmol) of 4-(trifluoromethoxy)aniline hydrochloride, 0.95 g (12 mmol) of pyridine and 25 ml of methylene chloride. The resulting mixture was stirred at ambient temperature overnight and then poured into dilute aqueous HCl. The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate, treated with charcoal and MgSO4 and filtered. The filtrates were evaporated to dryness and the residue recrystallized from methylcyclohexane to give 0.34 g of the above-named product as colorless crystals, m.p. 92°-93.5° C. (Compound 37)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.[CH3:52][N:53]([CH3:60])[CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:52][N:53]([CH3:60])[CH:54]1[CH2:59][CH2:58][N:57]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=5)=[O:49])[CH2:38][CH2:39]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:56][CH2:55]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70.3 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) were added N,N-dimethyl-N-(piperidin-4-yl)amine dihydrochloride (79.4 mg), triethylamine (0.157 ml) and water (0.10 ml), followed by stirring at room temperature for 10 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol=20:1, then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (30.6 mg, 70.5%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:20]C(=O)OC(C)(C)C)([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[ClH:28].O1CCOCC1>>[Cl-:28].[C:1]([O:4][CH2:5][C:6]([CH2:15][O:16][C:17](=[O:19])[CH3:18])([NH3+:20])[C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)OCC(COC(C)=O)(NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCC([NH3+])(COC(C)=O)C(=O)c1ccccc1
Product: [Cl-]
Reaction time: 0.42 h
Yield: 51.8 %

Procedure:
tert-butyl 3-acetoxy-2-(acetoxymethyl)-1-oxo-1-phenylpropan-2-ylcarbamate (2) (420 mg, 1.1 mmol, 1.0 equiv.) was added to a 100 mL RBF and a 4.0 N HCl-Dioxane solution (8.3 mL, 33.0 mmol, 30.0 equiv) was added. The solution was stirred for 25 min and the solvent was evaporated with a steady stream of N2 (g). The resulting residue was taken up in Et2O (40 mL) giving a sticky solid. The mixture was cooled by partial evaporation and the solid was triturated and stirred for 10 min. The precipitate was filtered, washed with Et2O (2×50 mL), and dried under vacuum to give 180 mg (53%) of 4 as a white solid. mp=122-123° C.; 1H NMR (500 MHz, DMSO) δ 9.01 (br s, 3H, C—NH3), 7.97 (d, J=7.0 Hz, 2H, Ph-H), 7.72 (t, J=7.5 Hz, 1H, Ph-H), 7.58 (t, J=7.5 Hz, 2H, Ph-H), 4.78 (AB, J=12.5 Hz, 2H, CCH2), 4.66 (AB, J=12.5 Hz, 2H, C—CH2), 1.97 (s, 6H, (O═C—CH3)2); 13C NMR (125 MHz, DMSO) δ 193.8, 169.4, 133.7, 133.6, 129.0, 128.2, 67.2, 62.8, 20.4; LRMS (ESI-MS m/z): Mass calcd for C14H18NO5 [M]+, 280.30. Found 280.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Reactant: C1CCNC1
Product: Fc1ccc(-c2csc3cc(OCCCN4CCCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and pyrrolidine were converted to yield 1-{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-pyrrolidine as colorless oil, MS: 356 (MH+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CO>[CH2:1]([CH:8]1[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCC3(CC2)OCCO3)cc1
Solvent: O
Solvent: CO
Product: O=C1CCC(Cc2ccccc2)CC1
Yield: 105.8 %

Procedure:
A mixture of 28 g of 8-benzyl-1,4-dioxa-spiro[4.5]decane, 100 mL of water, 10 mL of methanol and 20 g of Amberlite™ IR-120+ was heated to reflux for 5 h. After cooling, removal of solvents under reduced pressure gave 24 g of 4-benzyl-cyclohexanone as an oil.