Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:19]2[O:20][CH:21]=[N:22][N:23]=2)[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:7]=1C(O)=O.O>C(O)COCCO>[CH3:24][C:4]1[NH:3][C:2]([CH3:1])=[CH:7][CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:5]=1[C:19]1[O:20][CH:21]=[N:22][N:23]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2Cl)C(c2nnco2)=C(C)N1
Solvent: O
Solvent: OCCOCCO
Product: CC1=CC(c2cccc(Cl)c2Cl)C(c2nnco2)=C(C)N1
Temperature: 25 °C

Procedure:
20 g of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridine-3-carboxylic acid in 100 ml of diethylene glycol are heated at 180° C. for 10 minutes. The mixture is then cooled to room temperature, 500 ml of water are added and the mixture is extracted by shaking with four times 200 ml of ethyl acetate. The organic phase is dried over sodium sulphate and concentrated and the residue is recrystallised from ethyl acetate with the addition of active charcoal. This gives 12.2 g (corresponding to 61% of theory) of 1,4-dihydro-2,6-dimethyl-3-(1,3,4-oxadiazol-2-yl)-4-(2,3-dichlorophenyl)-pyridine, melting point 235° C. with decomposition.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[C:24](N1C=CN=C1)([N:26]1C=CN=[CH:27]1)=O.CNC>O1CCCC1>[CH3:24][N:26]([CH3:27])[C:19](=[O:21])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (10 g, 0.031 mole), 1,1'-carbonyldiimidazole (6.0 g, 0.037 mole), and dry tetrahydrofuran (200 ml) was stirred at room temperature for 2 hr. with a stream of nitrogen bubbling through it. The suspension was heated at 50° C. under nitrogen for 2 hr, cooled in ice and treated with a solution of dimethylamine in tetrahydrofuran (4.22 g of dimethylamine in 40 ml of tetrahydrofuran.) The solution was stirred at room temperature overnight, more dimethylamine (0.71 mole in 30 ml of tetrahydrofuran) was added, and the reaction mixture was heated at 45° C. for 3 hr. The reaction mixture was concentrated under reduced pressure; the resulting solid was triturated in water, filtered, rinsed twice with water, twice with 5% potassium hydroxide solution and then twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, and cooled. Water was added and the solid filtered and dried at 80° C. under vacuum to yield 3.55 g (33%) of white solid, mp 181°-183° C.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15]4[C:16]5[N:24]=[CH:23][S:22][C:17]=5[N:18]=[C:19](Cl)[N:20]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:5]2)[CH2:3][O:2]1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=2)[C:36]([O:38][CH3:39])=[O:37])O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15]4[C:16]5[N:24]=[CH:23][S:22][C:17]=5[N:18]=[C:19]([C:33]5[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=5)[C:36]([O:38][CH3:39])=[O:37])[N:20]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:5]2)[CH2:3][O:2]1
Reactant: Clc1nc(Nc2cccc(N3CC4(COC4)C3)c2)c2ncsc2n1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(N4CC5(COC5)C4)c3)c3ncsc3n2)c1
Yield: 30.5 %

Procedure:
To a solution of N-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-5-chlorothiazolo[5,4-d]pyrimidin-7-amine (160 mg, 0.5 mmol) and methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (145 mg, 0.55 mmol) in 9 mL of 1,4-dioxane and 1 mL of water was added Na2CO3 (159 mg, 1.5 mmol) followed by Pd(PPh3)4 (58 mg) under nitrogen with stirring. The mixture was refluxed for 15 hours under nitrogen. After cooled, the solvent was evaporated by rotary evaporation. The residue was poured into water and extracted with EtOAc (3×10 mL). The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with (petroleum ether EtOAc=1:1) to give methyl 3-(7-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (70 mg, 30%). LC-MS: 460 [M+H]+, tR=1.74 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[C:14]([CH2:16]C(OC)=O)#[N:15].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[C:10]([OH:12])[C:16]([C:14]#[N:15])=[C:7]2[OH:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: COC(=O)CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(O)nc2ccc(Cl)cc2c1O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 300 ml, three neck flask, equipped as described in Example 1, was charged with 39.5 g 5-chloroisatoic anhydride (molecular weight 198.5:assay 95 percent), 21.8 g methyl cyanoacetate, 150 ml triethylamine and four drops of DMF. Agitation was commenced, and continued until reaction was discontinued. A slight exotherm caused the temperature of the reaction mixture to increase from 20° C. to about 38° C., and to remain at about 38° C. for approximately one hour, during which time there was a steady and vigorous evolution of gas. At the end of one hour the temperature began to drop, and the rate of gas evolution slowed as the consistency of the reaction mixture became jelly-like. The reaction mixture was then heated to a temperature of 90° C. and maintained at a temperature within the range of 85° to 90° C. for one-half hour. The heating to 90° C. occurred over a period of one-half hour. The temperature of the reaction mixture was then raised to approximately 100° C., and maintained at about such temperature for an additional 30 minutes. Gas evolution reached a maximum during the time that the reaction mixture was at a temperature between 85° and 100° C. and then gradually decreased and stopped. The reaction mixture became jelly-like and gummy during the time that the temperature was being maintained between 85° and 90° C.; to facilitate stirring a 20 ml addition of DMF was made when this occurred. After the reaction mixture had been maintained at approximately 100° C. for one-half hour, agitation was stopped and the reaction mixture separated into an upper colorless layer consisting mainly of triethylamine and a lower layer of a tan oil. The excess of triethylamine was recovered by distillation, after which the oily remainder was dissolved in 700 ml water and treated with 3 g activated charcoal at reflux. Concentrated hydrochloric acid at a temperature of 60° to 70° C. was then added to the beaker to bring the pH to 1.0 and to form a precipitate. The precipitate was recovered by filtration; the filter cake was washed with water, was reslurried in warm water, refiltered, and finally dried at 60° C. The yield was 39.34 g (93.9 percent of theory based upon the pure 5-chloro-isatoic anhydride charged) 6-chloro-3-cyano-2,4-dihydroxyquinoline, melting point 275°-277° C. Examination of the product by infrared spectroscopy and nuclear magnetic resonance indicated that it was of high purity.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].[OH-].[Na+].Cl>CO>[CH3:16][O:15][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COCCOc1ccc(OC)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCOc1ccc(OC)c(C(=O)O)c1
Yield: 100.7 %

Procedure:
Stir a mixture of 2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid methyl ester (0.87 g, 3.6 mmol), methanol (20 mL) and 1N NaOH solution (20 mL) for two hours at room temperature. Acidify the reaction with 1N HCl and extract with dichloromethane. Dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Vacuum dry the residue at room temperature over 48 hours to afford 0.82 g of 2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid as an oil, Rf=0.84 (silica gel, dichloromethane:methanol:acetic acid, 85:10:5).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])(=O)=O>CN(C)C=O>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[C:8]([O:10][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)cc1
Reactant: COC(OC)c1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(OC)c1cc(OCCCNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
5-Hydroxy-2-nitrobenzaldehyde dimethyl acetal (3.0 g) is dissolved in dry dimethylformamide (50 ml), and thereto are added sodium iodide (3.15 g), potassium carbonate (1.93 g) and 3-(t-butoxycarbonylamino)propyl tosylate (6.95 g). The mixture is stirred at 50° C. for three hours, and cooled to room temperature. The mixture is extracted with ethyl acetate, and the extract is washed with a saturated aqueous sodium chloride solution, and dried over sodium sulfate. The resultant is concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography to give the title compound (5.22 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:19](=[O:20])[C:18]4[S:21][C:22]([CH2:24][OH:25])=[CH:23][C:17]=4[N:16]=[CH:15]3)=[CH:10][CH:9]=2)[CH2:4]1.[H-].[Na+].CN(C=O)C.Br[CH2:35][CH2:36][CH3:37]>C(OCC)(=O)C.O>[CH3:1][N:2]([CH3:26])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[C:19](=[O:20])[C:18]4[S:21][C:22]([CH2:24][O:25][CH2:35][CH2:36][CH3:37])=[CH:23][C:17]=4[N:16]=[CH:15]3)=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CCCBr
Reactant: CN(C)C1CCN(c2ccc(-n3cnc4cc(CO)sc4c3=O)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOCc1cc2ncn(-c3ccc(N4CCC(N(C)C)C4)cc3)c(=O)c2s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-6-hydroxymethyl-3H-thieno[3,2-d]pyrimidin-4-one (50.0 mg), sodium hydride (5.24 mg) and DMF (1 mL) was stirred at 0° C. for 15 min. Then 1-bromopropane (22.0 mg) was added, the solution was warmed to room temperature and stirred for 2 h. Water and ethyl acetate were added and the aqueous phase was extracted with ethyl acetate several times. The combined organic phase was dried over sodium sulfate and the solvent removed in vacuo. The crude product was purified by preparative HPLC. The product with the molecular weight of 412.55 (C22H28N4O2S) was obtained in this way; MS (ESI): 413 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=O)[CH:9]=[CH:8]2.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=c1ccc2cccc(C(F)(F)F)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc2ccc(Cl)nc12
Reaction time: 0.25 h
Yield: 33 %

Procedure:
8-Trifluoromethyl-1H-quinolin-2-one (8.35 g, 39.2 mmol) was taken in a 25 mL RB POCl3 (10 mL) was added, and then refluxed for 1 h. The excess POCl3 was distilled off and ice was added to the reaction mixture. This was stirred for 15 min, the precipitate was filtered off and then dried under vacuum to afford the title compound (3 g, yield: 33%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([NH2:17])=[CH:15][C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13]2)=[CH:8][CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31].O>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([NH:17][C:30]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:31])=[CH:15][C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a suspension of ethyl[4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl]acetate (10 g, 33.2 mmol) and K2CO3 (9.17 g, 66.4 mmol) in THF (300 mL) was added phenyl chloroformate (8.61 mL, 66.4 mmol), and the resulting reaction mixture was stirred at room temperature overnight. The mixture was poured into a mixture of water and EtOAc and the organic phase was separated and dried over Na2SO4, concentrated at reduced pressure to afford a brown syrup, which was purified by MPLC (0% to 20% EtOAc in hexane). The desired product was obtained as a white solid (10.6 g) in 76% yield. 1H-NMR (CD2Cl2-d2) δ 7.51-7.10 (m, 10H), 6.47 (s, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.71 (s, 2H), 1.37 (s, 9H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:41]=[C:42]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:43][NH:44][C:45](=[O:59])[C:46]1[CH:51]=[CH:50][C:49]([O:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:48][CH:47]=1>CN(C=O)C.O>[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:63]1[CH2:64][CH2:65][N:60]([C:42](=[O:41])[CH2:43][NH:44][C:45](=[O:59])[C:46]2[CH:47]=[CH:48][C:49]([O:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[CH:50][CH:51]=2)[CH2:61][CH2:62]1)=[O:15]
Reactant: Cc1ccccc1C(=O)O
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
DIPEA (0.091 mL, 0.53 mmol) was added drop wise to 2-Methyl benzoic acid (23 mg, 0.2123 mmol) in DMF (5 mL). EDCI (84 mg, 0.44 mmol) and HOBT (28 mg, 0.21 mmol) were added consecutively and, after 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide (60 mg, 0.18 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the resulting solid was filtered under reduced pressure. The residue was dissolved in methylene chloride and filtered to afford N-{2-[4-(2-Methyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide in 36% yield. LC-MS purity: 98%, 1H NMR (DMSO-D6): δ 8.5 (d, 1H), 7.9 (d, 2H), 7.4 (t, 2H), 7.2 (m, 5H), 7.1 (q, 4H), 4.2 (2d, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H), 2.2 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17](O)=[O:18])=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CC[N:23]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([NH2:23])=[O:18])=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1cc(C(N)=O)c(Nc2ccc(Br)cc2F)cc1=O
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.069 g, 0.202 mmol), EDCl (0.1.2 g, 0.61 mmol), and HOBt (0.082 g, 0.61 mmol) in DMF (5 mL) was stirred for 30 minutes. NH4Cl (0.033 g, 0.61 mmol) was added followed by Et3N (0.085 mL, 0.61 mmol). After 1 hour, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 52 mg (76%) clean desired product as an off-white solid. MS APCI (+) m/z 340, 342 (M+, Br pattern) detected: 1H NMR (400 mHz, DMSO-d6) 10.39 (s, 1H), 8.34 (s, 1H), 7.67 Odd, 1H), 7.43 (m, 2H), 3.36 (s, 3H).
Reaction SMILES: C([N:8]1[CH:14]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:16])[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH:18]1([NH:17][C:15]([CH:14]2[CH2:13][C:10]3([CH2:11][CH2:12]3)[CH2:9][NH:8]2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(NC1CCCCC1)C1CC2(CC2)CN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NC1CCCCC1)C1CC2(CC2)CN1
Reaction time: 8 h
Yield: 103.4 %

Procedure:
5-Benzyl-N-cyclohexyl-5-azaspiro[2.4]heptane-6-carboxamide (prepared according to Example 30, 14 mg, 0.0000448 mol) was dissolved in methanol (1 mL). To this solution was added Pd/C (3 mg) and the resulting mixture was stirred under an atmosphere of hydrogen overnight. The catalyst was filtered off and the volatiles were removed in vacuo to afford the desired product (10.3 mg), which was used in the next step without further purification. LC/MS: 223.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:16]C1C=C(C=CC=1)CBr.[Mg].C(OCC)(=O)C(OCC)=O>>[CH3:16][C:7]1[CH:2]=[C:3]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(CBr)c1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1cccc(C)c1
Yield: 72 %

Procedure:
The title compound was prepared as described for B4 using 3-methylbenzyl bromide (1.250 g, 6.75 mmol), magnesium (0.181 g, 7.43 mmol) and diethyl oxalate (1.974 g, 13.51 mmol). The resulting compound was isolated in the form of colorless oil in 72% yield and use instantly in next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[S:7][CH:6]2[CH2:8][CH2:9][CH2:10][CH2:11][N:5]2[C:4](=[O:12])[C@H:3]1[NH:13]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2.N1CCCCC1>C(Cl)Cl>[NH2:13][C@H:3]1[C:2]([CH3:1])([CH3:31])[S:7][CH:6]2[CH2:8][CH2:9][CH2:10][CH2:11][N:5]2[C:4]1=[O:12]
Reactant: CC1(C)SC2CCCCN2C(=O)[C@H]1NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC1(C)SC2CCCCN2C(=O)[C@H]1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a round bottom flask was added (9H-fluoren-9-yl)methyl (3R)-2,2-dimethyl-4-oxooctahydropyrido[2,1-b][1,3]thiazin-3-ylcarbamate (37 mg, 0.085 mmol), DCM (1 mL) and piperidine (0.017 mL, 0.17 mmol). The reaction was stirred at rt for 3 hr. The solvent was removed and the residue was dried over vacuum pump overnight to give (3R)-3-amino-2,2-dimethylhexahydropyrido[2,1-b][1,3]thiazin-4(6H)-one (17 mg, 0.080 mmol, 94% yield).
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[O:20])[CH:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:19]
Reactant: CCCCCCCCCCCC#N
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(C#N)C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 Moles of n-undecyl cyanide and 0.5 moles of diethyl oxalate are mixed in 1,000 ml of dimethylformamide. To this solution is added with ice cooling 0.52 moles of potassium t-butoxide. The mixture is allowed to stir overnight at room temperature. Following evaporation (rotary evaporator under vacuum) of most of the dimethylformamide the residue is mixed with 3 liters of diethyl ether followed by the addition of 1 liter water. The mixture is acidified with concentrated hydrochloric acid to a pH of 3 and then the ether phase is separated. After washing the ether with water and drying the ether over magnesium sulfate evaporation of the ether affords 3-cyano-2-oxotridecanoic acid ethyl ester. Recrystallization from petroleum ether at 30°-60° C. provides pure material.
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1
Reactant: [H][H]
Reactant: O=C(NCC1Cc2ccccc2C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCC1Cc2ccccc2C1
Yield: 90.8 %

Procedure:
10.6 g (37.7 mmol) of 2-(benzyloxycarbonylaminomethyl)indan was dissolved in 100 ml of methanol, to which 1.3 g of palladium on carbon was added and stirred for 4 hours in the stream of hydrogen. The catalyst was removed by filtration, the solvent was evaporated, and 5.04 g of 2-(aminomethyl)indan was obtained. The obtained compound was immediately dissolved in 150 ml of methylene chloride, to which 100 ml of water and 6.2 g of potassium carbonate were added, and the mixture was vigorously stirred. 8.02 g (38.0 mmol) of 4-chlorobenzenesulfonyl chloride was added thereto portionwise under ice-cooling, followed by stirring for 30 minutes. The organic phase was collected, dried and the solvent was removed by distillation. The crystalline residue was recrystallized from a solvent mixture of ethyl acetate and hexane to obtain 9.82 g of 2-[(4-chlorophenyl)sulfonylaminomethyl]indan as colorless needles. Yield: 76%
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][N:25]2[S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)(=[O:32])=[O:31])=[O:23])[C:18](O)=[O:19])=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C@H:17]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][N:25]2[S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)(=[O:32])=[O:31])=[O:23])[C:18](=[O:19])[NH:1][CH:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)O)cc1
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.3 %

Procedure:
To a solution of 0.094 g (0.94 mmol) of 4-aminotetrahydropyran and 0.48 g (0.94 mmol) of (S)-3-(4-methoxy-phenyl)-2-{[(S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-propionic acid in 50 ml of dichloromethane was added 0.079 g (0.94 mmol) of sodium bicarbonate followed by 0.128 g (0.94 mmol) of HOAT and 0.179 g (0.94 mmol) of EDCI. The mixture was stirred at room temperature for 17 hours after which it was washed with brine and purified by flash chromatography on silica gel, eluting with 50-100% ethyl acetate/heptane to give 0.50 g (0.83 mmol) of the title compound. 1H NMR (300 MHz, CDCl3): 1.00-1.21 (m, 3H); 1.32-1.43 (m, 4H); 1.80 (b, 2H); 2.14 (bd, 1H); 2.69 (t, 1H); 2.99 (dd, 1H); 3.13 (dd, 1H); 3.45 (s, 2H); 3.65 (bd, 1H); 3.78 (s, 3H); 3.87-4.00 (m, 3H); 4.39 (b, 1H); 4.58 (q, 1H); 5.88 (d, 1H); 6.78 (d, 1H); 6.85 (d, 2H); 7.13 (d, 2H); 7.70 (t, 1H); 7.88 (d, 1H); 8.00 (d, 1H); 8.08 (s, 1H).