Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:33]([CH3:35])[CH3:34])[CH3:15])=[CH:8][C:7]=1[CH3:36].[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[CH:33]([C:17]1[N:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[S:20][C:16]=1[CH:14]([CH3:15])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]([CH3:36])[CH:8]=1)([CH3:34])[CH3:35]
Reactant: COC(=O)CCc1ccc(OCC(C)c2sc(-c3ccc(-c4cccnc4)cc3)nc2C(C)C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OCC(C)c2sc(-c3ccc(-c4cccnc4)cc3)nc2C(C)C)ccc1CCC(=O)O
Yield: 27 %

Procedure:
3-(4-{2-[4-Isopropyl-2-(4-pyridin-3-yl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid methyl ester from step A is dissolved in tetrahydrofuran (1 mL) and 5N sodium hydroxide (1 mL) solution is added at room temperature. The reaction is heated to reflux and monitored by HPLC. Upon complete conversion, the reaction is allowed to cool to room temperature and neutralized with 5N hydrochloric acid (1 mL), diluted with ethyl acetate, and extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(4-{2-[4-Isopropyl-2-(4-pyridin-3-yl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid (86 mg, 0.172 mmol, 27% yield) may also be obtained by recrystalization from ethyl acetate. MS (ES): 501.1 (M++1-HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([NH:19][C:20]3[CH:21]=[N:22][N:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:24]=3)[N:11]=2)=[CH:5][CH:4]=1>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([NH:19][C:20]3[CH:21]=[N:22][N:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:24]=3)[N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2nc(Nc3cnn(-c4ccccc4)c3)ncc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(Nc3cnn(-c4ccccc4)c3)ncc2N)cc1

Procedure:
A solution of 800 mg (1.98 mmol) N4-(4-Methoxy-phenyl)-5-nitro-N2-(1-phenyl-1H-pyrazol-4-yl)-pyrimidine-2,4-diamine in 20 ml THF is hydrogenated with 200 mg palladium on charcoal as catalyst at room temperature and under atmospheric pressure. The catalyst is filtered off; the filtrate is evaporated and dried under vacuum giving N4-(4-methoxy-phenyl)-N2-(1-phenyl-1H-pyrazol-4-yl)-pyrimidine-2,4,5-triamine as greenish crystals; HPLC/MS (A): 1.45 min, [M+H] 374;
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[Cl-].O[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH3+:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl>ClCCl.O>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:30][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)[C@@H]([NH3+])Cc1ccc(O)cc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.6 %

Procedure:
A solution of triflic anhydride (0.934 g, 3.3.1 mmol) in dichloromethane (3.31 mL) was added dropwise to a solution of (2S)-3-(4-hydroxyphenyl)-1-methoxy-1-oxopropan-2-aminium chloride (0.767 g, 3.31 mmol) and triethylamine (1.005 g, 9.93 mmol) in dichloromethane (12.79 mL) at −78° C. The mixture was stirred for 24 h at room temperature. Water (5 mL) was added and the pH was adjusted to pH=5 using 32% hydrochloric acid. The aqueous layer was extracted with diethyl ether. The organics extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (diethyl ether) afforded the title compound as yellow solid (0.704 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-])=O.Cl>C(O)(C)C.O.[Fe]>[NH2:13][C:4]1[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(C(F)(F)F)cc1N
Temperature: 50 °C
Yield: 82.8 %

Procedure:
4-Methoxy-3-nitrobenzotrifluoride (95 g) in isopropanol (1.0 liter) and water (250 ml) was mixed with concentrated hydrochloric acid (15 ml). Iron powder (180 g) was added and the mixture was heated and stirred under reflux. After 90 minutes the mixture was cooled to 50° C. and filtered. The residue was washed with isopropanol and the combined filtrates evaporated. The residue was dissolved in toluene and the solution dried (MgSO4) and evaporated. The residue was triturated with light petroleum (b.p. 30°-40°) to give the 3-amino-4-methoxybenzotrifluoride as a colourless solid (68 g).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH:10]=[CH:9][C:8]=1[C:24]1[NH:28][C:27]2[CH:29]=[CH:30][C:31]([F:34])=[C:32]([CH3:33])[C:26]=2[N:25]=1.BrC1C=CC(OCCCC2CCN(C)CC2)=CC=1C1OCCCO1.C([Li])CCC.C([O-])(O)=O.[Na+].O1CCCOC1C1C=C(OCCCC2CCN(C)CC2)C=CC=1C=O.FC1C(C)=C(N)C(N)=CC=1>C1COCC1.CN(C=O)C.O>[F:34][C:31]1[CH:30]=[CH:29][C:27]2[NH:28][C:24]([C:8]3[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:12][C:7]=3[CH2:2][OH:1])=[N:25][C:26]=2[C:32]=1[CH3:33]
Reactant: Cc1c(F)ccc2[nH]c(-c3ccc(OCCCC4CCN(C)CC4)cc3C3OCCCO3)nc12
Agent: CN1CCC(CCCOc2ccc(Br)c(C3OCCCO3)c2)CC1
Agent: CN1CCC(CCCOc2ccc(C=O)c(C3OCCCO3)c2)CC1
Agent: Cc1c(F)ccc(N)c1N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)ccc2[nH]c(-c3ccc(OCCCC4CCN(C)CC4)cc3CO)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
2-{2-[1,3]Dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-5-fluoro-4-methyl-1H-benzoimidazole. To a stirred solution of 4-[3-(4-bromo-3-[1,3]dioxan-2-yl-phenoxy)-propyl]-1-methyl-piperidine (4.82 g, 12.4 mmol, 1.0 equiv) in THF (62 mL) at −78° C. was added 2.5 M n-butyllithium in hexanes (22 mL, 55 mmol, 4.4 equiv). The resulting orange solution was stirred for 30 min then DMF (9.6 mL, 124 mmol, 10.0 equiv) was added. The solution was warmed to rt and stirred for 1.0 h then re-cooled to −78° C. and satd. aq. NaHCO3 was added. The mixture was warmed to rt, poured into water, and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude residue was partially purified by Method 2. The resultant 2-[1,3]dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde (491 mg, 1.41 mmol, 1.0 equiv) was stirred with 4-fluoro-3-methyl-benzene-1,2-diamine (198 mg, 1.41 mmol, 1.0 equiv) and Na2S2O5 (350 mg, 1.84 mmol, 1.3 equiv) in DMF (7.0 mL) at 90° C. for 2 h. The mixture was loaded onto silica gel and purified by Method 2 to afford 509 mg (77%) of the title compound. MS (electrospray): mass calculated for C27H34FN3O3, 467.26; m/z found, 468.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.62 (d, J=8.5 Hz, 1H), 7.44-7.37 (m, 1H), 7.35 (d, J=2.7 Hz, 1H), 7.09-6.99 (m, 2H), 5.97 (s, 1H), 4.19-4.13 (m, 2H), 4.09 (t, J=6.4 Hz, 2H), 3.95-3.86 (m, 2H), 2.95-2.87 (m, 2H), 2.53 (s, 3H), 2.30 (s, 3H), 2.22-1.99 (m, 3H), 1.93-1.76 (m, 4H), 1.51-1.22 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:30]([NH:32][CH2:33][CH3:34])=[O:31])[CH:23]=2)=[C:18]([OH:35])[CH:17]=1)([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:33]([NH:32][C:30]([NH:29][CH2:28][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:2]([CH3:15])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH3:1])=[CH:17][C:18]=2[OH:35])[CH:27]=[CH:26][CH:25]=1)=[O:31])[CH3:34]
Reactant: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCCC(=O)N3CCOCC3)cc2O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCCCN3CCOCC3)cc2O)c1
Temperature: 25 °C

Procedure:
To a solution of 20 (0.2 g, 0.416 mmol, 1.0 eq) in tetrahydrofuran (10 mL) under nitrogen atmosphere at 0° C. was added lithium aluminum hydride (1.0 M in THF, 1.6 mL, 1.60 mmol, 4.0 eq). The mixture was slowly warmed up to room temperature over 2.5 hours, and LC/MS showed the reaction was complete. The reaction was quenched with ice chips, and then water/ethyl acetate was added. The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layer was washed with water (20 mL), brine (20 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (neutral aluminum gel, 2% methanol in dichloromethane).
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[CH2:16]([C:18]1[N:19]([CH3:43])[C:20]2[C:25]([N:26]=1)=[C:24]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[N:23]=[C:22]([S:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[N:21]=2)[CH3:17].[N+:44](C1C=C(C=CC=1OC)CBr)([O-:46])=[O:45]>CC(C)=O>[CH2:16]([C:18]1[N:19]([CH3:43])[C:20]2[C:25]([N:26]=1)=[C:24]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[N:23]=[C:22]([S:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([N+:44]([O-:46])=[O:45])[CH:36]=1)[N:21]=2)[CH3:17]
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Reactant: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)cc3)nc2n1C
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)c([N+](=O)[O-])c3)nc2n1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Trifluoroacetic acid (40 ml) and anisole (2.7 ml, 15 mmol) were added to 8-ethyl-2-(4-methoxybenzylsulfanyl)-9-methyl-6-morpholino-9H-purine (5.0 g, 12.5 mmol), and heated and stirred at 80° C. overnight. After distilling away trifluoroacetic acid under reduced pressure, neutralization was performed by adding excess triethylamine under ice cooling. After distilling away triethylamine under reduced pressure, the residue was dissolved in acetone (50 ml) and 3-nitro-4-methoxybenzyl bromide (3.69 g, 15 mmol) dissolved in acetone (10 ml) was added. After stirring at room temperature for 2.5 hours, the reaction solution was concentrated under reduced pressure, the residue was made to have a pH of approximately 7.0 by 2N—NaOH solution, and the precipitated crystals were collected by filtration. The obtained crystals were washed sequentially with hexane and ether to obtain 3.93 g (71% yield) of 8-ethyl-9-methyl-6-morpholino-2-(3-nitro-4-methoxybenzylsulfanyl)-9H-purine.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CC([O-])(C)C.[K+].C1COCC1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25]Br>CN(C=O)C.O>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: c1ccc2[nH]nnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2nnc3ccccc32)cc1F
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of benzotriazole (1.2 g, 10.1 mmol) in DMF (40 mL) at r.t. was added a solution of 1M t-BuOK in THF (11 mL, 11 mmol). After stirring for 30 min., 3,4-difluorobenzyl bromide (2.4 g, 11.6 mmol) was added. The mixture was further stirred for 1 h, diluted with H2O, extracted with EtOAc. The EtOAc extract was washed H2O (3×), dried (MgSO4) and concentrated. The residue was chromatographed over silica gel and eluted with hexanes:EtOAc (3:1), then (2:1) to afford 1.6 g (65%) of title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].O[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(P(CCCC)CCCC)CCC.N(C(N(C)C)=O)=NC(N(C)C)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: OC1CCNCC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)c1oc2cccc(OC3CCNCC3)c2c1C
Temperature: 60 °C
Yield: 17.4 %

Procedure:
A mixture of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (100 mg), 4-hydroxypiperidine (46 mg), tributylphosphine (170 μl) and 1,1′-azobis(N,N-dimethylformamide) (120 mg) in benzene (2 ml) was heated at 60° C. for one hour. The suspension was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was separated by silica gel column chromatography developed by dichloromethane-methanol to give 3-methyl-4-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester (24 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:33]4[CH:32]=[N:31][C:30]([NH2:29])=[CH:35][CH:34]=4)[CH:7]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.50) (0.15 g, 0.36 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.103 g, 0.47 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.144 g, 84%). MS (ISP) 476.0 [(M+H)+]; mp 223° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13]1.C(N(CC)CC)C>ClCCl>[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C:12](=[O:11])[CH2:13]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
To a solution of 1.7 mL (24 mmol) of DMSO in 30 mL of dichloromethane at −50° C. was added dropwise 5.5 mL (11.0 mmol) of 2.0 M oxalyl chloride solution in dichloromethane. After 10 min, a solution of 3.85 g (10.0 mmol) of 3-hydroxy-1-(triphenylmethyl)piperidine from Step A in 15 mL of dichloromethane was added dropwise. After 15 min, 7.0 mL (50 mmol) of triethylamine was added dropwise. The reaction mixture was allowed to warm to ambient temperature over 0.5 h. The mixture was diluted with dichloromethane, washed sequentially with water, 5% aqueous citric acid solution, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography (silica gel, 6% ethyl acetate/hexane) gave 1.95 g (57%) of the title compound as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11](O)[CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+].C(=O)(OC(C)(C)C)OC(C)(C)C>C(Cl)Cl.C1COCC1>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc3c(N)ncnn23)C1
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(Cc2ccc3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.1 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl]azetidine-1-carboxylate (1.35 g, 4.25 mmol) in CH2Cl2 (12 mL) was added TFA (3.7 mL, 47.54 mmol) followed by triethylsilane (3.80 mL, 23.77 mmol), dropwise. The mixture was stirred at rt for 17 h. Additional TFA (1.8 mL) and triethylsilane (1.9 mL) were added and the mixture continued to stir at rt for 22 h. The reaction was concentrated to dryness. To a solution of the residue in THF (10 mL) was added 2M aqueous Na2CO3 (36 mL, 71.32 mmol) and di-tert-butyl carbonate (713 mg, 3.27 mmol). The mixture was stirred at rt for 17 h. The mixture was partitioned between EtOAc (50 mL) and H2O (25 mL) and the solid was removed by filtration. The layers of the filtrate were separated and the aqueous was further extracted with EtOAc (2×50 mL). The combined organics were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude residue was purified by ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 259 mg (29%) of the desired product. ES-MS m/z 304.02 [M+H]+, HPLC RT (min) 2.35.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]3[C:14](=[C:15]([C:21](OC)=[O:22])[C:16]=2[C:17](OC)=[O:18])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]3[C:14](=[C:15]([CH2:21][OH:22])[C:16]=2[CH2:17][OH:18])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(Cl)c(Cl)c2)n2c1CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: OCc1c(CO)c(-c2ccc(Cl)c(Cl)c2)n2c1CCC2
Yield: 19.8 %

Procedure:
A solution of dimethyl 2,3-dihydro-5-(3,4-dichlorophenyl)-1H-pyrrolizine-6,7-dicarboxylate (57.8 g, 0.157 mol) in dry dichloromethane (250 mL) was added dropwise, over a 30-min period, to a mechanically stirred mixture of lithium aluminum hydride (14.04 g, 2.35 equiv) in anhydrous ether (400 ml) heated under reflux. The stirred mixture was heated at reflux for 1 h after the addition was completed and cooled in an ice bath. The excess hydride was decomposed with wet ether and then with water until the salts were white. The mixture was filtered (through sintered glass) and the inorganic residue was washed with several portions (ca. 100 mL) of hot dichloromethane until the total filtrate volume was 1.2 L. The filtrate was concentrated in vacuo to a volume of 500 mL, warmed to boiling, and diluted with slow addition of 350 mL of petroleum ether. Compound 2,3-Dihydro-5-(3',4'-dichlorophenyl)-6,7-bis(hydroxy-methyl)-1H-pyrrolizine precipitated as clear, white, chunky prisms (33.8 g); the concentrated mother liquor, after similar treatment, gave an additional 9.71 g of 2,3-dihydro-5-(3',4'-dichlorophenyl)-6,7-bis(hydroxymethyl)-1H-pyrrolizine to a total yield of 89%.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19]2[C:27](=[O:31])[CH2:28][C:29]#[N:30])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19]2[C:27]([C:28](=[CH:3][N:4]([CH3:5])[CH3:6])[C:29]#[N:30])=[O:31])(=[O:16])=[O:17])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CCC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=C(C#N)C(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1

Procedure:
N,N-Dimethylformamide dimethylacetal (620 μl) was added at room temperature to a tetrahydrofuran (THF) solution (8.5 ml) of 3-(1-benzenesulfonyl-1H-indol-2-yl)-3-oxo-propionitrile (1.0 g, 3.08 mmol), and stirred for ten minutes. The reaction mixture was then concentrated under reduced pressure to give crude 2-(1-benzenesulfonyl-1H-indole-2-carbonyl)-3-dimethylamino-acrylonitrile as yellow amorphous material. The obtained crude product was used in subsequent reactions without purification.
Reaction SMILES: [CH2:1]([C:6]1([CH:17]=[O:18])[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[BH4-].[Na+]>C(O)(C)C>[CH2:1]([C:6]12[O:7][CH:8]([O:18][CH2:17]1)[CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1=COC(C=O)(CCCCC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCCC1CCC2(CCCCC)COC1O2
Temperature: 35 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2,5-dipentyl-3,4-dihydro-2H-pyran-2-carbaldehyde (165 g, synthesized as above) was loaded in a 3-liter round bottom flask and dissolved in 500 mL of isopropanol. Sodium Borohydride (6.1 g, commercially available from Sigma-Aldrich Inc) was added and the reaction exothermed up to about 58° C. The reaction was then stirred for about 2 hours. The reaction mixture was periodically sampled and analyzed by GC to monitor the reaction progress. After GC indicated the consumption of about all the starting material, sulfuric acid (500 mL, 10% solution in water) was then added and the temperature was increased to 35° C. The reaction mixture was further stirred for about 30 minutes and then cooled. The organic layer was separated and washed with 500 mL 10% aqueous sodium hydroxide solution. The solvents were removed to yield the crude product, which was purified by distillation to provide 1,4-dipentyl-6,8-dioxa-bicyclo[3.2.1]octane (128 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]=[CH:5][C:6]1[CH:17]=[CH:16][C:15]2[CH2:14][CH:13]3[CH:18]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]([CH2:11][CH2:12]3)[CH2:9][C:8]=2[CH:7]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:17]=[CH:16][C:15]2[CH2:14][CH:13]3[CH:18]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH:10]([CH2:11][CH2:12]3)[CH2:9][C:8]=2[CH:7]=1
Reactant: COC(=O)C=Cc1ccc2c(c1)CC1CCC(C2)C1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)CCc1ccc2c(c1)CC1CCC(C2)C1NC(=O)OC(C)(C)C
Yield: 94.3 %

Procedure:
3-(13-tert-Butoxycarbonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-acrylic acid methyl ester (300 mg, 0.809 mmol, prepared in Example 32 Step 3) and 20% palladium hydroxide on carbon (30 mg) in ethanol (30 ml) were stirred under 1 atm. of hydrogen at room temperature for 18 hours. The mixture was filtered through Celite and the filtrate concentrated to give a colourless oil 285 mg (94%). 1H NMR (CDCl3, 400 MHz) δ 7.00 (1H, d, J=8.2 Hz), 6.90 (2H, m), 4.97 (1H, m), 4.03 (1H, m), 3.67 (3H, s), 2.99 (2H, m), 2.89 (2H, m), 2.55–2.62 (4H, m), 2.48 (2H, m), 1.71 (2H, m), 1.47 (9H, s), 1.19 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16]([CH3:18])=O)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH2:18][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1cc(Br)co1

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 404 (M{81Br}+H+, 85), 402 (M{79Br}+H+, 100).