Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.O>O1CCOCC1>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=3)[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:3]=2)=[CH:35][CH:34]=1
Reactant: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCCC3)cc(Cl)n2)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCCC3)cc(-c3ccc(F)cc3)n2)cc1
Yield: 60.5 %

Procedure:
To a solution of 4-(6′-chloro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-ylamino)-N-methyl-benzenesulfonamide (70 mg, 0.18 mmol) in 1,4-dioxane (8 mL) was added sodium carbonate (1N, 80 mg, 0.72 mmol), and tetrakis(triphenyl-phosphine)palladium(0) (21 mg, 0.018 mmol), followed by 4-fluorophenyl boronic acid (49 mg, 0.36 mmol). This reaction was refluxed for 8 hours, after which time water (100 mL) added to the reaction mixture, and the product was extracted with ethyl acetate (100 mL×3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was and concentrated under vacuum. The resulting product was purified through column chromatography using 230-400 mesh silica gel (5% methanol in dichloromethane) to afford the desired compound as A yellow solid (48 mg, Yield 60%). Purity: 98.2%.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([CH2:19][NH:20][OH:21])=[CH:17][CH:16]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.O.Cl>O1CCOCC1>[OH:21][N:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][C:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[CH:23][CH:22]=1)[C:29]([NH2:28])=[O:30]
Reactant: ONCc1ccc(OCCc2noc(-c3ccccc3)n2)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)N(O)Cc1ccc(OCCc2noc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of N-[4-[2-(5-phenyl-[1,2,4]-oxadiazol-3-yl)-ethoxy]-benzyl]-hydroxylamine (1.5 g, 4.82 mmol in dioxane (70 mL) was added trimethylsilylisocyanate (0.84 g, 7.23 mmol). After stirring for 2 hours at room temperature the mixture was poured into H2O, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether (after cooling to 0° C.), gave a white solid (1.2 g, 70% yield, m.p. 135°-136° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7].Br[CH2:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(#N)C>[CH3:54][O:53][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7]
Reactant: COC(=O)CCCBr
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCNCCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-aminopropylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.048 mmol), methyl 4-bromobutanoate (25.9 mg, 0.143 mmol) and potassium carbonate (19.78 mg, 0.143 mmol) in dioxane (1 mL) and Acetonitrile (1 mL) was heated up at 78° C. for 3 hours. LCMS indicated the formation of desired product, the reaction mixture was filtered and the clear solution was purified by prep HPLC to give the title compound as a white solid (10 mg, 29%). LCMS: m/e 729.48 (M+H)+, 2.62 min (method 1).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH:17](=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH:17](=[C:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCC=C1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Solvent: CC#N
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3ccccc32)CC1
Yield: 64.3 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.441 g, 1.33 mmol) and 4-butylidenepiperidine (111MF05) (0.204 g, 1.47 mmol) in MeCN (½ mL) were reacted according to GP14 to give the title compound (108LM33-30) (0.293 g, 64%). 1H NMR (CDCl3) δ 7.19 (bd, J=7.0 Hz, 1H), 7.04-6.97 (m, 3H), 5.13 (t, J=7.9 Hz, CH), 4.60 (ABq, J=14.1 Hz, J=16.2 Hz, CH2), 4.00 (d, J=7.0 Hz, CH2), 2.50-2.38 (m, 2H), 2.35-2.05 (m, 9H), 1.95 (dt, J=7.0 Hz, CH2), 1.50-1.40 (m, 2H), 0.94-0.86 (m, 6H); 13C NMR (CDCl3) δ 165.0, 145.8, 136.3, 128.9, 123.8, 122.8, 122.7, 117.3, 115.7, 67.9, 63.7, 56.5, 55.7, 45.5, 36.4, 29.4, 28.6, 23.4, 17.1, 13.9; HPLC-MS (ammonium acetate) [M+H]+=343.3.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[O-]CC.[Na+].CCO.[S:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[O:10]=[C:4]([CH:20]1[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH2:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C1CCSc2ccccc21
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)C1CSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A solution of diethyloxalate (30.9 mL; 228.34 mmol; 1.5 eq.) in toluene (250 mL) is added dropwise at 0° C. to a solution of sodium ethoxide 21% w/w in EtOH (9.87 g; 182.67 mmol; 2 eq.). A solution of thiochroman-4-one (25 g; 152.23 mmol; 1 eq.) in toluene (250 mL) is added dropwise at 0° C. and the reaction mixture is allowed to warm up to rt. After overnight stirring, the solvent is removed and DCM (200 mL) and water (200 ml) are added. The aqueous phase is washed with DCM then acidified to pH=1-2 with 5N HCl (˜50 mL). The product is extracted with EtOAc (2×200 mL). The organic phases are combined, dried over MgSO4 and the solvent evaporated to afford 39.4 g (98%) of the title compound as an orange oil. MS (ESI+): 265.9.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>CN(C=O)C>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:28][CH:27]=[CH2:26])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCBr
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)n(CCCC)c(=O)n2CCCC
Temperature: 55 °C
Yield: 105.7 %

Procedure:
A solution of 1,3-di-N-butyl xanthine (10 g, 38 mmol) in anhydrous DMF (80 ml) was treated with K2CO3 (5.2 g, 38 mmol) followed by allyl bromide (3.6 ml, 42 mmol). The mixture was heated at 55° C. under nitrogen for 18 hours. After cooling to rt the mixture was partitioned between water and EtOAc. A few mls of 2M HCl(aq) was added to aid separation. The organic layer was separated and the aqueous extracted once more with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated to afford the title compound as an off-white solid (12.23 g, 106%). m/z 305.3 [MH+].
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
To a suspension of sodium hydride (934 mg, 0.0358 mol) in DMF (57 mL) was added dropwise under N2, a solution of 1H-pyrrolo[2,3-b]pyridine (3.00 g, 0.0254 mol) in DMF (20 mL). The mixture was stirred at r.t. for 45 min. then cooled to 0° C. and treated dropwise with [2-(trimethylsilyl)ethoxy]methyl chloride (6.32 mL, 0.0357 mol). The mixture was stirred at rt for 12 h. then poured into water (10 mL), stirred for 30 min. and extracted with Et2O (4×10 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product which was chromatographed over silica gel eluting with hexane→1:9 Et2O: hexane to afford 6 g desired product.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH3:31][CH:32]1[NH:37][CH2:36][CH2:35][NH:34][C:33]1=[O:38]>CN1CCCC1=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:37]3[CH2:36][CH2:35][NH:34][C:33](=[O:38])[CH:32]3[CH3:31])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: CC1NCCNC1=O
Solvent: CN1CCCC1=O
Product: CC1C(=O)NCCN1c1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1C(C)(C)C(=O)N2
Temperature: 220 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 550 mg (4.82 mmol) of 3-methylpiperazin-2-one was added. The mixture was heated in the microwave for 3 h at 150° C. and for 3 h at 220° C. After cooling, the reaction mixture was purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→100:0). 61 mg (purity 100%, 50% of theor.) of the target compound was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1N)#[N:2].[S:10]([NH2:14])([NH2:13])(=[O:12])=[O:11].C1CCN2C(=NCCC2)CC1>O>[NH:13]1[C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:1]([NH2:2])=[N:14][S:10]1(=[O:12])=[O:11]
Reactant: NS(N)(=O)=O
Reactant: N#Cc1ccccc1N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: NC1=NS(=O)(=O)Nc2ccccc21
Temperature: 160 °C

Procedure:
A stirred mixture of 2-cyanoaniline (236 mg, 2.0 mmol), sulfamide (192 mg, 2.0 mmol) and DBU (304 mg, 2.0 mmol) was heated at 160° C. under nitrogen for 3 days. After cooling to room temperature, the reaction mixture was diluted with water and extracted three times with EtOAc. The aqueous layer was removed under vacuum and the residue was purified by chromatography on silica gel eluting with 10% MeOH in dichloromethane to give the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.03 (dd, J=0.8, 8.0 Hz, 1H), 7.12 (dt, J=0.8, 8.0 Hz, 1H), 7.56 (dt, J=0.8, 8.0 Hz, 1H), 7.85 (dd, J=0.8, 8.0 Hz, 1H). MS 198 (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7])=O.Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[O:13][C:4]3[C:5]([C:6]([OH:8])=[O:7])=[CH:10][CH:11]=[CH:12][C:3]=3[CH:1]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1cccc(C=O)c1O
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc2cc(-c3ccc(Cl)cc3)oc12
Temperature: 100 °C
Yield: 60.8 %

Procedure:
A mixture of 2.0 g of methyl 3-formyl-2-hydroxybenzoate, 3.51 g of methyl α-bromo-p-chlorophenylacetate, 5.55 g of potassium carbonate and 60 ml of dimethylformamide is heated at 70°-80° C. for 15 minutes and further heated at 100° C. for 10 minutes. The reaction mixture is filtered and washed with ethyl acetate. The washings and the filtrate are combined and water is added to the mixture. The mixture is acidified with 10% hydrochloric acid. The organic layer is collected and the aqueous layer is extracted with ethyl acetate. The organic layer and the extract are combined, washed with water, dried and evaporated to remove solvent. The residue is dissolved in 30 ml of ethanol and 3.25 g of potassium hydroxide are added to the solution. The mixture is refluxed for 1 hour. The reaction mixture is evaporated to remove solvent, and water is added to the residue. The aqueous mixture is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. 100 ml of xylene and 150 mg of p-toluenesulfonic acid are added to the residue and the mixture is refluxed for 1 hour. After cooling, ethyl acetate is added to the reaction mixture. The mixture is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate to give 1.84 g of 2-(4-chlorophenyl)benzofuran-7-carboxylic acid as colorless needles.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])([CH3:36])[CH3:35]>C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[C:7]1[CH:13]=[CH:14][C:4]([C:1]2[O:3][C:45](=[O:46])[C:44]([S:43][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH:34]([CH3:35])[CH3:36])=[C:48]([OH:49])[CH:2]=2)=[CH:5][CH:6]=1)[CH3:12]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using ethyl 4-acetylbenzoate (2.93 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0 mmol) m.p. 201-203° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 1.35 (t, 3H), 3.42 (m, 1H), 4.35 (q, 2H), 6.94 (m, 1H), 7.00 (s, 1H), 7.10 (m, 2H), 7.28 (m, 1H), 7.99 (m, 2H), 8.11 (m, 2H).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:25][C:24]([C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:14]2[CH:15]=[N:16][C:17]3[NH:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:23]=1)([CH3:26])[C:27]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:29]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C(C)(C)C(=O)O)c3)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C(=O)N1CCOCC1)c1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.3 %

Procedure:
To a suspension 6-[5-(1-carboxy-1-methyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (50 mg, 0.13 mmol) in DMF (1 mL) is added HATU (57 mg, 0.15 mmol), morpholine (11 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.81 mmol). The mixture is stirred at room temperature for 16 h. The reaction mixture is purified by reverse phase HPLC (mobile phase contains 1% TFA) to afford 53 mg of 2-methyl-1-morpholin-4-yl-2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-propan-1-one.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:24][CH2:23][C:13]3([CH2:22][CH2:21][C:16]4(OCC[O:17]4)[CH2:15][CH2:14]3)[C:12]2=[O:25])=[CH:7][CH:6]=1)[OH:4].Cl>O1CCCC1>[F:27][C:2]([F:1])([F:26])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:24][CH2:23][C:13]3([CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]3)[C:12]2=[O:25])=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)CCN(c1ccc(C(O)C(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
10-[4-(2,2,2-Trifluoro-1-hydroxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (402 mg, obtained in example 133, step 4) was dissolved in tetrahydrofuran (10 mL). Then, hydrochloric acid (2M, 5.22 mL) was added dropwise over a period of 10 minutes to the reaction mixture. The mixture was stirred for 3 hours at RT. The reaction mixture was poured into ice/water and was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (265 mg, 73%). MS (m/e): 342.1 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C@@H:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])[CH3:2]
Reactant: COC(=O)[C@@H](C)O
Reactant: CCc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cccc(O[C@@H](C)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-ethylphenol (3.42 g, 28 mmol) in THF (20 mL) at ice bath was added triphenylphosphine (9.5 g, 36.4 mmol) and then (R)-methyl 2-hydroxypropanoate (2.94 mL, 31 mmol). And then DIAD (8.2 mL, 42 mmol) was added dropwise to the above cole solution. The mixture was stirred at room temperature for 16 hr. The solvent was removed and the residue was purified by silica gel to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1C2C(=CC=CC=2[N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)C=CC=1>>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([N:23]3[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Clc1cc(Br)c2ncccc2c1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Product: O=C1CCN(c2cc(Cl)cc3cccnc23)CC1

Procedure:
This compound was prepared from the known 8-bromo-6-chloroquinoline (Lachowicz et al., Rocz. Chem., 40:1848 (1966)) using a synthetic sequence and reagents identical to those described for the synthesis of 1-quinolin-8-yl-piperidin-4-one (Step 5, Example A, above). The compound was obtained as an off-white solid; MP: 223-225° C.; MS (ES) m/z (relative intensity): 261 (M+H)+ (100).
Reaction SMILES: [N:1]1([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:21][CH2:20]2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(O)(=O)C>C(O)C.[Pd]>[N:1]1([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21][CH2:20]2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: C1=CC2(CCN(CCCCN3CCC4(C=Cc5ccccc54)CC3)CC2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCC21CCN(CCCCN2CCC3(CCc4ccccc43)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1,4-Bis-spiro[ind-2-en-1,4'-piperidin-1'-yl]butane (compound 4a) (3 g) in ethanol (90 ml) were added acetic acid (5 ml) and 5% palladium on carbon (0.9 g). The mixture was hydrogenated in a Parr apparatus for 2 hours ar 3 atm. The catalyst was filtered off and the solvent evaporated. The remaining oil was dissolved in diluted aqueous NH4OH (200 ml, pH>9). The title compound 5a was extracted with ethyl acetate and worked-up as above and finally crystallized from ethyl acetate. Yield 1.6 g. Mp 113-115° C. 1H NMR (CDCl3) δ 1.55-1.65 (m,8H), 1.95-2.10 (m,8H), 2.15 (t,4H), 2.45 (broad s,4H), 2.95 (t,8H), 7.10-7.30 (m,8H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)=[CH:21][CH:20]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=c1ccc2cc(OCCCCCl)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCSc3ccc(Cl)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-chlorobutoxy)-carbostyril (m.p. 206°-208° C.) and 4-chlorothiophenol.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH:8]([CH3:11])[CH2:9][OH:10])=[CH:5][N:6]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O.O>[Si:17]([O:10][CH2:9][CH:8]([S:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1)[CH3:11])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(CO)Sc1cnc(N)s1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(CO[Si](C)(C)C(C)(C)C)Sc1cnc(N)s1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 87.4 %

Procedure:
2-((2-Aminothiazol-5-yl)thio)propan-1-ol (101 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (5 mL). Thereafter, imidazole (72 mg, 1.06 mmol) and t-butyldimethylsilyl chloride (100 mg, 0.64 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 14.5 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with water and brine, and was then dried over anhydrous magnesium sulfate, followed by concentration in vacuo. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain 5-((1-((t-butyldimethylsilyl)oxy)propan-2-yl)thio) thiazole-2-amine (141 mg, 87%) in the form of a yellow oily product.