Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:8][C:7]=1[C:18]#[C:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO.[C].[Pd]>[C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:7]2[CH:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][C:3]([OH:29])=[O:2])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CCc1ccc(Cn2cccn2)cc1C#CCCCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1ccc(Cn2cccn2)cc1CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of the compound prepared in Example 36 (300 mg) in methanol (3 ml) was added 10% palladium carbon (30 mg) and the mixture was stirred at room temperature overnight under an atmosphere of hydrogen. The reaction mixture was filtered through cellite (trade mark) and then the filtrate was concentrated. To a solution of the residue in THF were added 1N aqueous solution of sodium hydroxide (2 ml) and methanol (2 ml) and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (220 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[CH:10]=[CH:11][N:12]=[C:4]2[CH:3]=1.[OH-:13].[K+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([OH:13])[N:5]2[CH:10]=[CH:11][N:12]=[C:4]2[CH:3]=1
Reactant: [OH-]
Reactant: CSc1nc(Cl)cc2nccn12
Agent: [K+]
Solvent: CO
Product: Oc1nc(Cl)cc2nccn12

Procedure:
A solution of 73.25 g (366.87 mmol) of 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine are dissolved in 732 ml of methanol, and 1275 ml of a 2 molar aqueous potassium hydroxide solution are added. The mixture is heated under reflux for 3 h. After the reaction is complete, the methanol is removed in vacuo, the mixture is neutralized with half-concentrated hydrochloric acid, and the crystals which have separated out are filtered off with suction. They are washed with methanol and water and then dried under high vacuum. 40.0 g (64% of theory) of the product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24](O)=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[N:4][C:3]=1[CH2:24][OH:25]
Reactant: CC(C)n1cc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2)ccc1=O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2nc(CO)c(N)nc2-c2ccccc2)ccc1=O
Reaction time: 1.5 h
Yield: 35.7 %

Procedure:
To a mixture of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic acid (70 mg) and NEt3 (40.4 mg) in THF (0.7 ml), was added isobutyl chloroformate (32.7 mg) under ice-bath cooling. After 1.5 hours stirring at the same temperature, the mixture was poured into a mixture of sodium borohydride (30.2 mg) in a mixture of THF (0.7 ml) and water (1.4 ml) under ice-bath cooling. After 2.5 hours stirring at the same temperature, the mixture was diluted with water and EtOAc, and then the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography (CH2:Cl2:MeOH=25:1-10:1). A desired fraction was triturated with IPE to give 5-[5-amino-6-(hydroxymethyl)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (24 mg).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][CH:4]([OH:6])[CH3:5].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S([O-])(O)=O.[Na+]>[Cr+6].CC(C)=O>[CH3:1][C@@H:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: CC(C)=CCC[C@H](C)CC(C)O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(=O)C[C@@H](C)CCC=C(C)C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Acetone (2,000 ml) and the (4S)-4,8-dimethyl-7-nonen-2-ol (240 g) synthesized in Reference Example 1 were placed in a 5-liter, 4-necked flask equipped with a dropping funnel, thermometer, condenser and stirrer. Jones reagent (prepared from water (520 ml), conc. sulfuric acid (165 g) and chromium trioxide (112 g)) placed in the dropping funnel was dropped in over the course of 4 hours while cooling with ice. After the dropwise addition, the mixture was stirred for 2 hours. The sodium hydrogen sulfite was added little by little until the orange color of chromium (VI) disappeared. The liquid was then separated and the bottom layer was extracted with petroleum ether (1,000 ml). Since the liquid was again separated into two layers when the extract was combined with the top layer, that bottom layer was added to the previous bottom layer and additionally extracted three times with 500 ml of petroleum ether. After combining the extracts and washing with a saturated brine, a saturated aqueous sodium hydrogencarbonate solution and again with a saturated brine, the solvent was distilled off and the resulting concentrated oil was distilled with a Widmer distiller to obtain 194 g of (4S)-4,8-dimethyl-7-nonen-2-one: (4S)-(14) (b.p.: 63° C./133 Pa (1.0 torr)).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:10][CH:9]([CH2:11][CH3:12])[CH:8]=[N:7]1)=[S:5])[CH3:2].I[CH3:14]>CO>[CH3:14][S:5][C:4]([N:6]1[CH2:10][CH:9]([CH2:11][CH3:12])[CH:8]=[N:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CCNC(=S)N1CC(CC)C=N1
Reactant: CI
Solvent: CO
Product: CCN=C(SC)N1CC(CC)C=N1
Temperature: 50 °C
Yield: 0.8 %

Procedure:
1.80 g (1 mol equiv.) 4-Ethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide was dissolved in 36 mL methanol; 6.1 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 4 hours. Volatiles were removed under reduced pressure, and the residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to yield 1.68 g (87%) 4,N-diethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J=7.5 Hz, 3H), 1.16 (t, J=7.3 Hz, 3H), 1.45-1.70 (m, 2H), 2.45 (s, 3H), 2.97-3.07 (m, 1H), 3.44 (dd, J=11.0, 8.3 Hz, 1H), 3.51-3.58 (m, 2H), 3.83 (t, J=11.0 Hz, 1H), 6.81 (s, 1H).
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[Br:8][CH2:9][CH2:10][CH2:11][NH2:12]>C1(C)C=CC=CC=1>[Br:8][CH2:9][CH2:10][CH2:11][NH:12][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4]
Reactant: NCCCBr
Reactant: COCC(Cl)C=O
Solvent: Cc1ccccc1
Product: COCC(C=O)NCCCBr
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. γ-Bromopropylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-γ-bromopropylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:21][C:15]3[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26]>CS(C)=O>[OH:26][CH2:25][C:24]([NH:23][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:21][C:15]3[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:28])[CH3:27]
Reactant: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1F
Reactant: CC(C)(N)CO
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1NC(C)(C)CO
Yield: 10.8 %

Procedure:
Prepared similarly to that described in Example 260 using 6-(3-fluoro-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (Example 264; 60 mg, 0.203 mmol) and 2-amino-2-methylpropanol (81 μl, 0.847 mmol, Sigma-Aldrich) in DMSO (2 mL) at 50° C. for 20 min. The mixture was purified by rpHPLC (Phenomenex Gemini C18 column (100×50 mm, 10 μm), 90 mL/min, 5-30% ACN in water with 0.1% TFA) to give 6-(3-((1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (8.0 mg, 0.022 mmol, 13% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 365.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.44 (1H, s), 11.86 (1H, br. s.), 8.00 (1H, dd, J=7.5, 1.3 Hz), 7.90 (1H, d, J=3.7 Hz), 7.70 (1H, d, J=8.0 Hz), 7.41 (1H, t, J=7.8 Hz), 7.28 (1H, d, J=2.2 Hz), 5.94 (1H, s), 5.12 (1H, t, J=5.9 Hz), 3.65 (2H, d, J=5.7 Hz), 2.57 (3H, s), 1.54 (6H, s)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH3:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[Br:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH3:15])[CH:9]=3)[CH:5]=[C:4]([CH3:16])[N:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidine (example A.47) (3.84 g, 15.2 mmol) and commercially available 3-bromo-benzene-boronic acid (3.2 g, 15.9 mmol) according to the general procedure IVb. Obtained as a white solid (2.87 g, 51%). MS (ISP) 375.1 [(M+H)+]; mp 108° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([O:26][CH2:27][CH:28]1[CH2:30][O:29]1)[CH:23]([CH3:25])[CH3:24]>>[OH:29][CH:28]([CH2:27][O:26][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:30][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: CC(C)COCC1CO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)COCC(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 174 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(isobutoxymethyl)oxirane and conditions outlined in procedure X. LCMS: 432 [M+H]; Rt=0.97 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CCN(CC)CC>C(O)C>[CH:11]([N:8]1[C:6]2[N:7]=[CH:2][CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]=2[CH:10]=[N:9]1)([CH3:13])[CH3:12]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Cl)nc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)n1ncc2c(C(=O)O)ccnc21

Procedure:
To a 100 mL round bottom flask was charged 10% Pd/C(degussa) (0.213 g, 0.100 mmol), under N2 followed by addition of ca. 5 mL EtOH. The slurry was stirred followed by addition of 6-chloro-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.48 g, 2.003 mmol) and ethanol (22 mL). Next added Et3N (0.837 mL, 6.01 mmol) and stirred for 5 min under nitrogen. The contents were then stirred under an atmosphere of hydrogen (1 atm) for 6 h at RT. The vessel was then flushed with nitrogen and the contents diluted with DCM (10 mL) and a small amount of celite. The contents were stirred for 10 min., filtered through analytical grade celite and washed with 10% MeOH/DCM, EtOH, then DCM. The filtrate was concentrated in vacuo to a residue and dried on hi-vacuum overnight. The solid was treated with water and adjusted to pH 3 with 1M HCl. The contents were filtered, air-dried and then dried in hi-vacuum oven at 45° C. for 18 h. The title compound was collected as 0.326 g (78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.82 Hz, 6 H) 5.28 (quin, J=6.69 Hz, 1 H) 7.70 (d, J=4.55 Hz, 1 H) 8.39 (s, 1 H) 8.73 (d, J=4.55 Hz, 1 H) 13.91 (br. s., 1 H). LCMS(ES) [M+H]+ 205.9
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[C:30]2=[CH:31][CH:32]=[C:27]([CH:28]=[CH:29]2)[CH:26]=[CH:25][CH2:24][CH2:23][O:22][C:21](=[O:33])[C@H:20]2[NH:34][N:16]([CH2:17][CH2:18][CH2:19]2)[C:15](=[O:35])[C@H:14]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][Si](C(C)(C)C)(C)C)[CH:38]=2)[NH:13][C:12](=[O:51])[C@H:11]([CH:52]([CH3:54])[CH3:53])[NH:10][C:9](=[O:55])[C@@H:8]1[CH3:56])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:6][C@@H:7]1[C:30]2=[CH:29][CH:28]=[C:27]([CH:32]=[CH:31]2)[CH:26]=[CH:25][CH2:24][CH2:23][O:22][C:21](=[O:33])[C@H:20]2[NH:34][N:16]([CH2:17][CH2:18][CH2:19]2)[C:15](=[O:35])[C@H:14]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([OH:43])[CH:38]=2)[NH:13][C:12](=[O:51])[C@H:11]([CH:52]([CH3:53])[CH3:54])[NH:10][C:9](=[O:55])[C@@H:8]1[CH3:56]
Reactant: CC(C)[C@@H]1NC(=O)[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(cc2)C=CCCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC1=O
Agent: CC(C)[C@@H]1NC(=O)[C@H](C)[C@H](O)c2ccc(cc2)/C=C/CCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC1=O
Agent: CC(C)[C@@H]1NC(=O)[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(cc2)/C=C/CCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)[C@@H]1NC(=O)[C@H](C)[C@H](O)c2ccc(cc2)C=CCCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 8d (90 mg, 0.108 mmol.) in anhydrous tetrahydrofuran (30 ml) was cooled over an ice bath before adding a solution of tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 1.08 ml, 1.08 mmol.). The reaction was warmed to room temperature and stirred for 1 hour before adding saturated sodium bicarbonate solution (25 ml). The mixture was extracted with ethylacetate (2×25 ml). The extract was dried over anhydrous sodium sulfate, filtered and evaporated to give a brown gum. The gum was purified on a silica column eluting with ethyl acetate to yield 8 as a white solid (27 mg) LCMS. (m/z) 607.27 [M+H] Tr=4.21 min 1H NMR δ (300 MHz NMR, CDCl3) 1.12-1.28 (m, 6H), 1.31-1.39 (d, 3H, J=7.1 Hz), 1.44-1.60 (m, 3H), 1.71-2.13 (m, 3H) 2.14-2.28 (m, 1H), 2.38-2.70 (m, 4H), 2.81-2.91 (m, 1H), 2.91-3.08 (m, 1H), 3.61-3.70 (d, 1H), 4.12-4.21 (m, 1H), 4.32-4.46 (m, 2H), 4.81-4.89 (s, 1H) 5.07-5.18 (q, 1H, J=6.5 Hz), 5.90-6.05 (m, 1H) 6.15-6.33 (m, 3H) 6.37-6.44 (d, 1H) 6.61-6.70 (m, 1H) 6.95-7.72 (m, 7H) 7.80-8.05 (bs, 1H).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][CH2:10][CH3:11].C(OC)(OC)OC.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH2:9]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)[CH2:10][CH3:11]
Reactant: CCC
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(OC)OC
Solvent: O
Product: CCCOC1=CC(=O)CCC1

Procedure:
In a 21 three-necked flask, 100 g (0.89 mol) of cyclohexane-1,3-dione are initially charged and dissolved in 166.6 ml (2.23 mol) of n-propane and 600 ml of toluene and 97.6 ml (892 mmol) of trimethyl orthoformate, 5 g of p-toluenesulphonic acid dihydrate are added and the mixture is stirred under reflux on a water separator for 5 h until no more water separates off. The solution is then concentrated under reduced pressure on a rotary evaporator and the residue is taken up in 400 ml of MTBE and washed three times with 100 ml of 10% strength NaOH and saturated NaCl solution. The organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. This gives 124.8 g yield of a yellow oil which is used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[C:4]([CH3:15])[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:25]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[S:25])=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(N)ccc1N1CCCCC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(N)ccc1N1CCCCC1=S
Reaction time: 0.67 h
Yield: 171.5 %

Procedure:
10 g (48.95 mmol) of 1-(4-amino-2-methylphenyl)piperidin-2-one are heated to the boil in 70 ml of anhydrous toluene together with 9.9 g (24.48 mmol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent). After 40 minutes, the solvent is removed, and the residue is taken up in dichloromethane (DCM)/1 M aqueous hydrochloric acid. After repeated washing with DCM, a pH of 12 is set using conc. sodium hydroxide solution. Extraction with DCM, drying over Na2SO4 and evaporation of the solvent give 9.25 g (41.98 mmol) of 1-(4-amino-2-methylphenyl)piperidine-2-thione.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][S:7][C:8]23[CH:17]=[CH:16][CH:15]=[CH:14][C:9]2=[N:10][CH:11]=[CH:12][C:13]=13)=[O:4].[OH-].[Na+]>CO>[S:7]1[C:8]23[CH:17]=[CH:16][CH:15]=[CH:14][C:9]2=[N:10][CH:11]=[CH:12][C:13]3=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: COC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1=C2C=CN=C3C=CC=CC32SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
In 200 ml of methanol was dissolved 12.16 g of benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid methyl ester and after adding thereto 55 ml of a methanol solution of 1N sodium hydroxide, the mixture was refluxed for 30 minutes. After allowing the temperature to lower to room temperature, the mixture was allowed to stand overnight in a refrigerator and crystals thus deposited were collected by filtration. The crystals were suspended in water and after adjusting the pH thereof to from 2 to 3 with 1N hydrochloric acid, the suspension was stirred for a whole day and night at room temperature. Precipitates thus formed were collected by filtration to provide 10.2 g (yield of 88%) of benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>>[CH3:19][C:8]1([CH3:20])[C:7]2[CH:6]=[C:5]3[NH:21][C:2]([NH:1][C:22](=[O:25])[CH2:23][CH3:24])=[N:3][C:4]3=[CH:12][C:11]=2[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]1=[O:18]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Reactant: CCC(=O)Cl
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)CC)nc3cc21
Yield: 30.9 %

Procedure:
N-(7,7-Dimethyl-6-oxo-5-pentyl-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-propionamide (37 mg) is prepared from D5 (100 mg) and propionyl chloride (71 mg; 0.77 mmol) as described in Example 173.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14](I)([F:16])[F:15].OO>CS(C)=O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:6][C:7]1[N:12]=[CH:11][C:10]([C:14]([F:16])([F:15])[F:13])=[CH:9][N:8]=1
Reactant: FC(F)(F)I
Reactant: Nc1ncccn1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncc(C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 13.1 %

Procedure:
A 2-L flask fitted with a dry ice condenser and addition funnel was charged with dimethylsulfoxide (500 mL) and a 0.5 M solution of sulfuric acid in dimethylsulfoxide (400 mL), followed by the addition of 2-aminopyrimidine (20.0 g, 211 mmol). The reaction mixture was stirred vigorously for 5 minutes, and then a 1 M solution of iron(II) sulfate in water (60 mL) was added. Trifluoromethyl iodide (200 g, 1.02 moles) was added below the surface of the reaction mixture at room temperature. The reaction mixture was then cooled to 0° C., and 50% aqueous hydrogen peroxide (20 mL, 294 mmol) was added dropwise over one hour. The ice bath was then removed, and the reaction mixture was allowed to warm to room temperature over three hours. The reaction mixture was then carefully neutralized to pH 6.5 with aqueous sodium carbonate. The reaction mixture was then extracted with ethyl acetate (3×300 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel eluting with a hexane/ethyl acetate gradient to afford 4.51 g of the title compound as an off white solid. 1H NMR (CDCl3) δ 8.51 (s, 2H), 5.55 (br s, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH2:7][O:8][CH2:9][CH2:10]P(OCC)(OCC)=O)[CH3:4].[CH2:20]([O:22][CH:23]([O:34][CH2:35][CH3:36])[CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)[CH3:21]>C1COCC1>[CH2:9]([O:8][C:7](=[CH:30][C:29]1[CH:32]=[CH:33][C:26]([O:25][CH2:24][CH:23]([O:34][CH2:35][CH3:36])[O:22][CH2:20][CH3:21])=[CH:27][CH:28]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:19])[CH3:10]
Reactant: CCOC(=O)COCCP(=O)(OCC)OCC
Reactant: CCOC(COc1ccc(C=O)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc(OCC(OCC)OCC)cc1)OCC
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a stirred suspension of sodium hydride (756 mg, 32 mmol, 95%) in dry THF (60 mL) was added a solution of ethyl(diethylphosphono)ethoxyacetate (6.20 g, 23.1 mmol) in THF (20 mL) at 0-5° C. dropwise and stirred for 30 min at 5-25° C. To the reaction mixture was added a solution of 4-[(2,2-diethoxy)ethoxy]benzaldehyde (5.0 g, 21.0 mmol) in THF (10 mL) at 25° C. and stirred further for 30 min. After completion of the reaction (TLC monitored), THF was removed and the resultant residue was diluted with water (100 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the title compound (6.5 g, 88%) as a mixture of E/Z isomers.
Reaction SMILES: C(OC([N:8]1[CH2:37][CH2:36][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:33][CH2:32][CH2:31][C@@H:30]5[CH3:34])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:35])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38]>CO.O1CCOCC1>[ClH:38].[F:35][C:18]1[CH:19]=[C:20]([CH:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:33][CH2:32][CH2:31][C@@H:30]3[CH3:34])[CH2:25][CH2:24]2)[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:13][CH2:12][C:11]2([CH2:10][CH2:9][NH:8][CH2:37][CH2:36]2)[C:15]1=[O:16]
Reactant: C[C@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCNCC4)C3=O)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{2-Fluoro-4-[4-((S)-2-methyl-pyrrolidin-1-yl)-cyclohexyl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester was dissolved in 0.5 mL of methanol and cooled to ice-water bath. To this solution was added 0.5 mL of 4M HCl in dioxane (excess). The clear solution was stirred at r.t. overnight. The solvent was evaporated and the residue was further dried under reduced pressure to obtain the title compound as a gummy semi-solid.