Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Se](=O)=[O:12]>O1CCOCC1>[N+:8]([C:7]1[C:2]([CH:1]=[O:12])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[Se]=O
Reactant: Cc1ncccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: O=Cc1ncccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2-Methyl-3-nitropyridine (24 g, 173.91 mmol) was dissolved in 1,4-dioxane (500 mL) and to the mixture was added selenium dioxide (23 g, 208.7 mmol) and the mixture was heated under reflux for 16 h. After completion of reaction, the mixture was cooled to rt and filtered through Celite™ and the filtrate was concentrated under reduced pressure to give thick oily mass. The oily mass was purified by silical gel column chromatography using 20% of ethyl acetate and hexane as eluent to give 3-nitro-2-pyridinecarbaldehyde as an off white solid: 1H-NMR (CDCl3) δ: 7.7 (m, 1H), 8.3 (d, 1H), 9.0 (d, 1H), 10.3 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@@H:18](O)[CH2:17]1)=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@H:18]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:17]1)=[O:15]
Reactant: COC(=O)[C@H]1C[C@@H](O)C1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 75 °C

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (280 mg, 1.00 mmol), cis-3-hydroxycyclobutanecarboxylic acid methyl ester (trans/cis=1:5) (180 mg, 1.38 mmol), and PS-PPh3 (loading 2.02 mmol/g; 951 mg, 2.02 mmol) in dry THF (10 mL), cooled by ice/water, was added DIAD (295 μL, 303 mg, 1.50 mmol), then the cooling bath was removed, and the mixture was vortexed (220 rpm) for 2 d. The resin was filtered off and washed thoroughly with THF (≈80 mL), the filtrate and washings were combined, concentrated, and chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with CH2Cl2 (1-14)→5% EtOAc in CH2Cl2 (15-30)], fractions containing product were combined and chromatographed again under the same conditions. This material was suspended in iPrOH (≈1.5 mL), heated to 75° C. for 10 min and cooled to −20° C. for 2 h. The solid was filtered off, washed with cold (−20° C.) iPrOH, and dried in vacuo, giving the title compound as white solid, trans/cis=5:1. 1H NMR (CDCl3, 400 MHz) δ 2.83-2.97 (m, 4H), 3.23-3.32 (m, 1H), 3.79 (s, 3H), 5.50 (quint, J=8.7 Hz, 1H), 7.51 (s, 1H), 8.61 (s, 1H). MS (ES+): m/z 391.9/393.9 (100/35) [MH+]. HPLC: tR=3.5 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]6)=[CH:21][CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.CS(O[CH2:54][C:55]([F:58])([F:57])[F:56])(=O)=O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][N:29]([CH2:54][C:55]([F:58])([F:57])[F:56])[CH2:28][CH2:27]6)=[CH:21][CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCNCC5)cc4)cnc32)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)CN1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1

Procedure:
3-(1H-indol-5-yl)-5-(4-(piperazin-1-ylmethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (50 mg) was dissolved in THF (1 mL) and treated with triethylamine (13 uL), and 2,2,2-trifluoroethyl methanesulfonate (13 uL); the reaction was allowed to stir for approximately hours, diluted water and extracted with EtOAC and washed with 1 N sodium hydroxide, water and brine and evaporated. The product was suspended in MeOH and (2 mL) detosylated directly by the addition of 0.5 mL sodium hydroxide solution, heated to 50 C for one hour. The reaction was diluted with water, extracted with dichloromethane and purified by MPLC, on silica gel, eluting with methanol in dichloromethane to yield 6 mg of an analytical sample (490 M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([NH2:15])=[N:13][N:14]=3)[N:11]=2)[CH2:3][CH2:2]1.Br[CH2:17][C:18]([C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:23]([O:32][CH3:33])=[C:22]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:21]=1)=[O:19].[ClH:38]>CN(C=O)C>[ClH:38].[C:34]([C:22]1[CH:21]=[C:20]([C:18](=[O:19])[CH2:17][N:13]2[C:12](=[NH:15])[N:10]3[N:11]=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH:7]=[CH:8][C:9]3=[N:14]2)[CH:25]=[C:24]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:23]=1[O:32][CH3:33])([CH3:37])([CH3:35])[CH3:36]
Reactant: COc1c(N2CCOCC2)cc(C(=O)CBr)cc1C(C)(C)C
Reactant: Nc1nnc2ccc(OCC3CC3)nn12
Agent: Cl
Solvent: CN(C)C=O
Product: COc1c(N2CCOCC2)cc(C(=O)Cn2nc3ccc(OCC4CC4)nn3c2=N)cc1C(C)(C)C

Procedure:
6-Cyclopropylmethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W1.009; 350 mg) was initially charged in DMF (5 ml) at RT while stirring, and 2-bromo-1-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)ethanone (O1.003; 631 mg) predissolved in DMF (5 ml) was added dropwise. The reaction mixture was stirred at RT for 14 h. Then the solvent was removed under reduced pressure and the residue was purified using silica gel (40 g cartridge, dichloromethane/ethanol gradient of 0-40% in 60 min). The product was taken up with a little acetonitrile, diluted with water and, after addition of 2 eq. of HCl, freeze-dried. 500 mg of the title compound were obtained. LC-MS rt: 1.37 min [M+H]+: 495.2 (met. a)
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:31]#[N:32])=[N:14][C:15]=2[NH:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.N.[H][H]>C(O)C.[Pd]>[NH3:10].[NH2:32][CH2:31][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[CH:18][N:10]2[C@H:3]2[C@H:2]([OH:1])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4]2)=[C:15]([NH:19][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[N:14]=1
Reactant: N#Cc1nc(NCc2cccc3ccccc23)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CCO
Product: NCc1nc(NCc2cccc3ccccc23)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 42 h
Yield: 47.4 %

Procedure:
A solution of 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(1-naphthylmethyl)amino]-9H-purine-2-carbonitrile (0.75 g, 1.74 mmol) (Preparation 14) in ethanol (30 ml) was saturated with ammonia gas, treated with 5% w/w palladium on charcoal (0.50 g), pressurised to 1034 kPa (150 psi) with hydrogen in a sealed vessel and stirred at room temperature for 42 hours. TLC analysis indicated that some starting material still remained and therefore further 5% w/w palladium on charcoal (0.30 g) and ethanol (10 ml) saturated with ammonia gas were added. The mixture was re-pressurised to 1034 kPa (150 psi) with hydrogen in a sealed vessel and stirred at room temperature for 24 hours. The mixture was filtered through a pad of Arbocel (trade mark) and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:0.88 ammonia (90:10:0.5 by volume) gradually changing to dichloromethane:methanol:0.88 ammonia (85:15:0.75 by volume) to afford the title compound (0.18 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.[CH3:10][NH:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH3:10])=[O:9]
Reactant: O=C(O)CCCCCBr
Reactant: CCCCNC
Product: CCCCN(C)C(=O)CCCCCBr

Procedure:
Using the procedure of Step A of Example 3, 4.88 g of 6-bromohexanoic acid and 4.36 ml of N-methylbutylamine were reacted to obtain 7.0 g of the expected product which was used as is for the following step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[N:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1>>[F:8][C:6]1[CH:7]=[C:2]([C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:3]=[N:4][CH:5]=1
Reactant: OB(O)c1ccncc1
Reactant: Fc1cncc(Br)c1
Product: Fc1cncc(-c2ccncc2)c1

Procedure:
Prepared from 3-bromo-5-fluoropyridine (439.0 mg, 2.50 mmol) and pyridin-4-ylboronic acid (509.9 mg, 3.73 mmol) according to Method K, except the product was purified by silica gel chromatography (ethyl acetate, Rf=0.21) instead of preparative HPLC: 1H NMR (300 MHz, chloroform-D) δ ppm 7.50-7.51 (m, 2H), 7.65 (dt, J=9.1, 2.4 Hz, 1H), 8.56 (d, J=2.8 Hz, 1H), 8.73-8.76 (m, 3H). MS (DCI/NH3) m/z=175 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[C:3]=1[OH:11].Cl[CH2:13][C:14](Cl)=[O:15].C([O-])([O-])=O.[K+].[K+]>>[CH:8]([C:4]1[C:3]2[O:11][CH2:13][C:14](=[O:15])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1)([CH3:9])[CH3:10]
Reactant: O=C(Cl)CCl
Reactant: CC(C)c1cccc(N)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1cccc2c1OCC(=O)N2

Procedure:
Crude 2-Amino-6-isopropylphenol (95MF80(2240) (0.16 g, 1.1 mmol), 2-chloroacetyl chloride (0.14 g, 1.2 mmol) and K2CO3 (0.32 g, 2.3 mmol) were mixed according to GP1 to give the title compound as a crude (95MF83) (0.115 g).
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C(O)=O)(=O)=[O:21])CC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1[C:44](=[O:73])[CH:45]([CH2:49][S:50]([N:53]1[CH2:58][CH2:57][CH:56]([O:59][C:60]2[CH:65]=[CH:64][C:63]([C:66]3[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=3)=[CH:62][N:61]=2)[CH2:55][CH2:54]1)(=[O:52])=[O:51])[CH:46]([CH3:48])[CH3:47])C1C=CC=CC=1>>[F:72][C:69]1[CH:68]=[CH:67][C:66]([C:63]2[CH:64]=[CH:65][C:60]([O:59][CH:56]3[CH2:57][CH2:58][N:53]([S:50]([CH2:49][C@H:45]([CH:46]([CH3:47])[CH3:48])[C:44]([OH:73])=[O:21])(=[O:51])=[O:52])[CH2:54][CH2:55]3)=[N:61][CH:62]=2)=[CH:71][CH:70]=1
Reactant: CC(C)C(CS(=O)(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Yield: 47 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-{4-[5-(4-fluorophenyl)pyridin-2-yloxy]piperidine-1-sulfonyl methyl}-3-methyl-butyryl)oxazolidin-2-one (0.70 g) to yield the title compound as a cream solid (0.24 g, 47%).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: OB(O)c1ccncc1
Reactant: Cn1c(-c2ccc(OC(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2ccc(OC(F)(F)F)cc2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 66) was reacted with pyridine-4-yl-boronic acid to give the title compound as light brown solid. MS: 500.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@:24]([CH3:30])([C:26](OC)=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:44]>>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@:24]([CH3:30])([C:26]([NH2:44])=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:43])([F:1])[F:42])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@]1(C)CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(C(N)=O)N2
Yield: 371.9 %

Procedure:
In a sealed tube a solution of methyl (2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-methyl-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 45, 75 mg, 0.121 mmol) in 7 N methanolic ammonia (5 ml, 35.0 mmol) was shaken at 40° C. for 5 days by PLS. Volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel using a SNAP 10 g as column and Dichloromethane/Methanol 98:2 as eluent affording the title compound (27 mg, 0.45 mmol, y=37.2%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[Br:22])[CH3:8].[C:24](OCC)(=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CCOCC>[CH2:28]([O:27][C:25](=[O:26])[C:24](=[O:30])[CH:11]([C:10]([O:9][CH2:7][CH3:8])=[O:23])[CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[Br:22])[CH3:29]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CCCc1cc(OC)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(=O)C(CCc1cc(OC)ccc1Br)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
Potassium t-butoxide (26.94 g) was suspended in 130 ml of anhydrous ether and cooled to 0° C. A solution of 60.24 g ethyl -4-(2-bromo-5-methoxy phenyl)butyrate and 43.84 g diethyl oxalate in 60 ml ether was added dropwise over 20 min. After 2 h at 25° C., the reaction was poured into 400 ml H2O and the aqueous layer was separated, acidified to pH 1 and extracted with ether. The ether layer was dried (MgSO4) and the solvent was evaporated to yield 71.26 g of the desired product as a colorless oil (89%). NMR (CDCl3) δ 1.25 (t, 3H), 1.4 (t, 3H), 2.25 (m, 2H), 2.75 (m, 2H), 3.78 (s, 3H), 4.0-4.5 (m, 5H), 6.64 (dd, 1H), 6.79 (d, 1H), 7.40 (d, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.Cl.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1ccc2ccccc2c1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc2ccccc2c1

Procedure:
Following General Procedure BB and using 2-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 128-129° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:16][CH2:17][C:18]2([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:12](OC)=[O:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:7]=2)[CH:3]=1.[BH4-].[Li+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:16][CH2:17][C:18]2([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:12][OH:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:43])[CH3:44])[N:7]=2)[CH:3]=1
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (850 mg, 1.28 mmol) in tetrahydrofuran (7.4 mL) and methanol (0.37 mL) at 0° C. was added lithium borohydride (55.9 mg, 2.57 mmol). The ice bath was removed and stirring continued for 30 min. The reaction was diluted with diethyl ether and quenched by addition of saturated ammonium chloride. The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→50% ethyl acetate/n-hexane) gave 794 mg (98%) as a foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.33 (dd, J=8.6, 5.2 Hz, 2H), 7.05 (dd, J=8.6, 8.5 Hz, 2H), 6.75 (s, 1H), 5.65 (d, J=10.7 Hz, 1H), 5.62 (d, J=10.7 Hz, 1H), 4.95 (dd, J=7.0, 3.4 Hz, 1H), 3.55-3.85 (m, 6H), 3.52 (d, J=8.9 Hz, 1H), 3.41 (d, J=8.9 Hz, 1H), 3.06 (m, 2H), 2.10-2.35 (m, 3H), 1.88 (m, 2H), 1.43 (s, 9H), 0.90 (t, J=8.2 Hz, 2H), −0.06 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=246 Hz), 155.0, 145.7, 138.6, 130.2, 128.8 (d, J=7.7 Hz), 128.1, 124.2, 122.8, 122.5, 118.5, 115.4 (d, J=21 Hz), 81.9, 79.5, 79.1, 78.6, 67.7, 66.2, 41.5, 40.0, 32.3, 32.2, 28.6, 17.9, −1.4. Mass spec.: 634.38 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@@:12]([CH2:23][CH:24]([OH:27])CO)([CH3:22])[C:11]1=[O:28])=[O:4].O.I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@@:12]([CH2:23][CH2:24][OH:27])([CH3:22])[C:11]1=[O:28])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@](C)(CC(O)CO)OC[C@H]1C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@](C)(CCO)OC[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester from Example 7 Step 3 was dissolved in 4 ml THF, and 3.7 mL solution was taken out for the reaction. To the stirred solution was added THF (2.3 mL), water (2.0 mL), and then sodium periodate (0.28 g, 1.31 mmol, 1.6 equiv) at 0° C. The resulting solution was stirred at room temperature for 30 minutes. And then at 0° C. another portion of sodium periodate (0.09 g, 0.44 mmol, 0.5 equiv) was added to the mixture and stirred for another 30 minutes at room temperature. The reaction was quenched by adding brine solution (0.5 mL) and EtOAc (10 mL). The organic layer was separated, dried (over Na2SO4) and concentrated. The residue was dissolved in ethanol (6.0 mL) and to the resulting solution at 0° C. was added sodium borohydride (0.27 g, 7.0 mmol, 8.8 equiv). The mixture was stirred at 0° C. for 15 minutes after which the reaction was quenched by adding water (2.0 mL) and EtOAc (10 mL). The organic layer was separated, dried (over Na2SO4) and concentrated to give product 128 mg (yield 35%). The crude product was continued to the next step with no further purification. MS: 462 [M−H+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][CH:21](CS([O-])(=O)=O)[CH2:20][CH2:19]2)=[N:16][CH:17]=1)[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH2:9]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([O:1][C:2]3[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=3)[CH2:20][CH2:19]2)=[N:16][CH:17]=1)[CH2:10][CH3:11]
Reactant: CCCc1cnc(N2CCC(CS(=O)(=O)[O-])CC2)nc1
Reactant: O=c1cc(O)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Temperature: 100 °C
Yield: 40.6 %

Procedure:
A stirring suspension of 4-hydroxypyridin-2(1H)-one (5.23 g, 47.1 mmol, Aldrich), 1-(5-propylpyrimidin-2-yl)piperidin-4-ylmethanesulfonate (11.7 g, 39.2 mmol), potassium carbonate (12.5 g, 90.0 mmol, EMD) and DMSO (48 mL) was heated at 100° C. for 3 hours and then cooled to room temperature. The resulting mixture was diluted with H2O and extracted with EtOAc (2×). The organic layers were combined and concentrated in vacuo to a brown solid. The solid was purified by flash chromatography (SiO2, 100% EtOAc and then SiO2, 10% MeOH in CH2Cl2) to yield 5.00 g of desired product as an off-white solid. MS (ESI) 315 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][C:15]([NH2:24])([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:16]>ClCCl.C(OCC)(=O)C>[CH3:16][C:15]([NH:24][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])([CH3:14])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(N)Cc1ccccc1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Quinoxaloyl chloride (207 mg, 1.07 mmol) in dichloromethane (1 mL) was added to a solution of phentermine (160 mg, 1.07 mmol) in dichloromethane (3 mL) cooled to 0° C. The reaction was allowed to warm to 25° C. After 5 min, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with 1 M sodium hydroxide (2×40 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through silica gel, and rotary evaporated. This provided 51 mg (16%) of (108):
Reaction SMILES: P(Cl)(Cl)(Cl)=[O:2].Cl[C:7]1[C:12]2[CH:13]=[N:14][N:15]([CH2:16][CH3:17])[C:11]=2[N:10]=[C:9]2[C:18](=[O:27])[C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH2:21][CH2:22][C:8]=12>C(O)C>[CH2:16]([N:15]1[C:11]2[N:10]=[C:9]3[C:18](=[O:27])[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[CH2:21][CH2:22][C:8]3=[C:7]([OH:2])[C:12]=2[CH:13]=[N:14]1)[CH3:17]
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCn1ncc2c(O)c3c(nc21)C(=O)c1ccccc1CC3

Procedure:
41 g. of 1-ethyl-5,6-dihydro-4-hydroxybenzo[5,6-cyclophepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.14 mol.) and 350 ml. of phosphorus oxychloride are refluxed for 4.5 hours. After cooling, the solution is filtered, the excess phosphorus oxychloride is removed in vacuo and the residue treated with water and extracted with chloroform. The chloroform extract is washed with water, dried with Na2SO4, treated with charcoal and then evaporated in vacuo to give 38 g. (87%) of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one; m.p. 156°-159° (ethanol; refrigerator).