Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:27]=2[Cl:36])[CH2:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:6]=1.[Li+].[OH-].C(O)(=O)C.C(OCC)(=O)C>C1COCC1.O>[Cl:36][C:27]1[C:28]([C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:15]([CH2:16][C@H:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:18])[CH2:14][CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:37])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)C[C@@H](C)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](CN(CCCOc1cccc(CC(=O)O)c1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A solution of (S)-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)acetic acid methyl ester (0.6 g, 1.1 mmol) in THF (9 ml) and water (6 ml) was treated with aqueous LiOH (1.0 N, 1.0 ml, 1.0 mmol). After stirring at RT for 2 h, additional LiOH (1.0 ml, 11.0 mmol) was added and stirring was continued for 2 h. The reaction was neutralized with acetic acid and poured into water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified by HPLC to give the title compound as an oil (0.4 g, 75%). MS (ESI) 520.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(=O)C.[C:32]([O-])([O-])([O-])[O:33][CH2:34][CH3:35]>>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]2[C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=[C:32]2[O:33][CH2:34][CH3:35])=[CH:15][CH:16]=1)#[N:27]
Reactant: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC([O-])([O-])[O-]
Solvent: CC(=O)O
Product: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate (2.03 g) in ethyl orthocarbonate (5 ml) was added acetic acid (0.37 g), and the mixture was stirred for one hour at 80° C. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogencarbonate and water. The solvent was evaporated to dryness to give crystals. Recrystallization of the crystals from ethyl acetate-hexane afforded colorless crystals (2.01 g, 86%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[N:45]=[C:44]([CH3:46])[CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:41]=[CH:42][CH:43]=[C:44]([CH3:46])[N:45]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: Cc1cccc(Br)n1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)n1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 6-bromo-2-picoline (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (425 mg, 82%) as a yellow oily substance.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)(=[O:33])=[O:34])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-(4-bromo-benzenesulfonyl)-morpholine (example B.26) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (420 mg, 74%). MS (ISP) 563.4 [(M+H)+]; mp 227–228° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[C:9]([O:27][C:28]([F:31])([F:30])[F:29])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:14]1([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:8][C:9]=2[O:27][C:28]([F:30])([F:31])[F:29])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2OC(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1cc(N2CCOCC2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A 50 mL round-bottom flask was charged with a solution of tert-butyl 4-[[4-(morpholin-4-yl)-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate (590 mg, 1.32 mmol, 1.00 equiv) in dichloromethane (15 mL). Trifluoroacetic acid (262 mg, 2.30 mmol, 1.74 equiv) was added dropwise at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to provide 445 mg (crude) of 4-[4-(piperazin-1-ylmethyl)-3-(trifluoromethoxy)phenyl]morpholine as light yellow oil. LCMS (ESI, m/z): 346 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:32]2[CH:37]=[CH:36][C:35]([O:38]CC3C=CC=CC=3)=[CH:34][CH:33]=2)[C:16]2[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=2[CH2:18][NH:19][CH:20]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H].C(=O)([O-])O.[Na+]>>[CH:20]1([NH:19][CH2:18][C:17]2[CH:28]=[CH:29][CH:30]=[CH:31][C:16]=2[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:32]2[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: c1ccc(COc2ccc(C(c3ccc(OCc4ccccc4)cc3)c3ccccc3CNC3CCCCCCC3)cc2)cc1
Reactant: [H][H]
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(C(c2ccc(O)cc2)c2ccccc2CNC2CCCCCCC2)cc1
Reaction time: 2 h
Yield: 54.5 %

Procedure:
Two grams of 2-[bis(4-benzyloxyphenyl)methyl]-N-(cyclooctyl)benzylamine obtained by Example 82 was dissolved in 120 ml of a mixture of ice-cooled hydrogen bromideacetic acid solution. The solution was stirred for 2 hours, and the mixture was added to a mixture of ice and a saturated aqueous sodium hydrogencarbonate, stirred and then neutralized with sodium hydrogencarbonate. Thereafter, it was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to recrystallization to afford 0.76 g of the desired compound (Compound 85).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([C:16]2[C:17]([Cl:32])=[C:18]([NH:24]C(=O)OC(C)(C)C)[CH:19]=[C:20]([C:22]#[N:23])[CH:21]=2)[CH2:13][CH2:12][O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:24][C:18]1[CH:19]=[C:20]([CH:21]=[C:16]([N:14]2[CH2:13][CH2:12][O:11][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:15]2)[C:17]=1[Cl:32])[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCOC(CO[Si](C)(C)C(C)(C)C)C2)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CN(c2cc(C#N)cc(N)c2Cl)CCO1
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a round bottom flask charged with (+/−)-tert-butyl (3-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-2-chloro-5-cyanophenyl)carbamate (1.2321 g, 2.56 mmol) in Dichloromethane (12.78 ml) and cooled to 0° C. was added 2,6-lutidine (0.595 ml, 5.11 mmol). Trimethyl trifluoromethanesulfonate (0.924 ml, 5.11 mmol) was added drop wise over several minutes. The reaction mixture was stirred at 0° C. 2 h and warmed to room temperature ON. The reaction mixture was poured into a separatory funnel containing 1:1 dichloromethane: saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane (2×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on the ISCO system (40 g, 0-50% EtOAc/CH2Cl2). (+/−)-3-Amino-5-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-4-chlorobenzonitrile (0.860 g) was isolated as a yellow sticky solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[OH-].[Na+]>O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: BrCCCCCCBr
Reactant: OCCOCCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCOCCc1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
A mixture of 2-[2-(2-pyridinyl)ethoxy]ethanol hydrochloride (1.55 g), 1,6-dibromohexane (5.94 g), TAB (0.5 g) and 50% sodium hydroxide (15 ml) was stirred at room temperature under nitrogen for 5 h. The mixture was diluted with water (100 ml), extracted with diethyl ether (2×150 ml) and evaporated in vacuo to give an oil. The residual oil was partitioned between 2N hydrochloric acid (100 ml) and hexane (2×100 ml). The aqueous phase was basified to pH12 with 50% sodium hydroxide, extracted with diethyl ether (2×150 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System F (2:1→1:1) gave the title compound (1.62 g) as a colourless oil. T.l.c. (diethyl ether) Rf 0.40
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: COc1cccc(N)c1N
Reaction time: 1 h

Procedure:
To a solution of 2-amino-3-nitroanisole (465 mg, 2.94 mmol) in methanol (50 mL) was added palladium on carbon (10% Pd, 100 mg). The mixture was then placed under an atmosphere of hydrogen gas (1 atm) and was stirred for one hour. The mixture was then filtered through celite and concentrated to give 2,3-diaminoanisole as a yellow foam in a yield of 400 mg (98%). 1H NMR (CDCl3) δ 3.45 (br s, 4H(NH)), 3.84 (s, 3H), 6.40 (m, 2H), 6.67 (t, 1H, J=7.8 Hz)
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[CH:5][CH:4]=1)=[O:2].P([O-])([O-])([O-])=[O:19].[Na+].[Na+].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.C1COCC1.O>[C:14]([NH:13][C:11]1[S:12][C:8]([C:6]2[O:7][C:3]([C:1]([OH:19])=[O:2])=[CH:4][CH:5]=2)=[C:9]([CH3:17])[N:10]=1)(=[O:16])[CH3:15]
Reactant: O=P([O-])([O-])[O-]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C=O)o2)s1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)O)o2)s1
Temperature: 0 °C

Procedure:
To a solution of 1.2 g of N-(5-(5-formylfuran-2-yl)-4-methylthiazol-2-yl)acetamide in 100 mL of tert-butanol was added 5 mL of water and 20 mL of 2N monobasic sodium phosphate. The resulting suspension was cooled to 0° C. while being stirred. To the chilled suspension was added 20 mL of a 2M solution of 2-methyl-2-butene in THF followed by 3 g of sodium chlorite in 10 mL of water. The reaction was allowed to warm to room temperature overnight and the upper organic layer was separated and dried over sodium sulfate and used as is in the subsequent reactions. LC/MS: 267.04 (M+H)/2.04 min.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[N:1]1([C:7]2[N:8]=[C:9]3[N:17]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C@H:16]([C:18]([F:20])([F:21])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Ic1ccncc1
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1ccncc1

Procedure:
The product is prepared according to the procedure described in Example 12, using 200 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 380 mg of 4-iodopyridine. After purification by silica chromatography (elution gradient from CH2Cl2 to CH2Cl2/MeOH 96/04), 26 mg of (S)-2-morpholin-4-yl-9-pyridin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)[C:12]([C:16]#[N:17])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:13]1[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:11][C:12]=1[C:16]#[N:17]
Reactant: Cc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(Cl)cc2Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C

Procedure:
To an oven-dried round bottom flask fitted with a condenser was added the product of Step C (0.350 g; 0.986 mmol) and excess phosphorous oxychloride (1 mL). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was allowed to cool to room temperature, and the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 solution (2×), water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-10% ethyl acetate:hexane) to afford 0.283 g of the desired product: m/e=375 (M+2) Rt=4.36 min on LCMS.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: COCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.37 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. 2Methoxyethylamine (1.71 g, 0.023 mole) was added and the reaction mixture was allowed to stir at room temperature overnight.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][C@@H:20]([CH3:22])[N:11]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cu][C:24]#[N:25]>O1CCOCC1.[C-]#N.C([N+](CC)(CC)CC)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:21][C@@H:20]([CH3:22])[N:11]2[C:12]3[CH:13]=[C:14]([C:24]#[N:25])[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)cc3N21
Agent: [Fe+2]
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C#N)cc3N21

Procedure:
(4R,10aR)-7-Bromo-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (0.1 g) was dissolved in dioxane (2 mL) and copper(I)cyanide (0.1 g), tris-(dibenzylideneacetone)dipalladium chloroform complex (12 mg), 1,1′-bis(diphenylphosphino)ferrocene (24 mg) and tetraethylammonium cyanide (43 mg) were added. The mixture was heated to reflux for 18 h, cooled, filtered and the filter cake was washed with ethyl acetate. Saturated sodium bicarbonate solution (30 mL) was added to the filtrate, the phases were separated, the water phase was extracted with ethyl acetate (2-×20 mL) and the organic phases washed twice with saturated bicarbonate solution. Organic phases were pooled, dried with MgSO4 and the solvent removed in vacuo. Chromatography on silica gel (n-hexane/ethyl acetate 6:1) yielded the title compound as light yellow wax (34 mg; 40%). ISP-MS: m/e=314.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1([O:10][CH3:11])[CH2:8][CH2:7]N(C)[CH2:5][CH2:4]1)#[CH:2].[CH:12]1(N2CCC(C#C)(OC)CC2)CCCC1>>[C:1]([C:3]1([O:10][CH3:11])[CH2:8][CH2:7][CH2:12][CH2:5][CH2:4]1)#[CH:2]
Reactant: C#CC1(OC)CCN(C2CCCC2)CC1
Reactant: C#CC1(OC)CCN(C)CC1
Product: C#CC1(OC)CCCCC1

Procedure:
4-Ethynyl-4-methoxy-1-methyl-piperidine and 1-cyclopentyl-4-ethynyl-4-methoxypiperidine may be prepared analogously.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:16])(=O)=O>C(OC(C)C)(C)C>[Cl:16][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(C)OC(C)C
Product: O=C(CCl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
3′-Nitroacetophenone (2.00 g) was dissolved in diisopropyl ether (12.1 ml) and sulfuryl chloride (6.70 g) was added all at once thereto at 22° C. and refluxed for 6.5 hours. The reaction mixture was allowed to cool to room temperature while stirring, and the precipitated solids were filtered and washed with diisopropyl ether. Drying under reduced pressure yielded the desired 2-chloro-3′-nitroacetophenone (2.01 g; 83.1%).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[C:7]3[N:8]([C:11]([CH3:14])=[N:12][N:13]=3)C=[N:10][C:5]=2[S:4][CH:3]=1.CNCCN>CO.[Cl-].[NH4+]>[Cl:1][C:2]1[C:6]([C:7]2[NH:13][N:12]=[C:11]([CH3:14])[N:8]=2)=[C:5]([NH2:10])[S:4][CH:3]=1
Reactant: Cc1nnc2c3c(Cl)csc3ncn12
Agent: CNCCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1n[nH]c(-c2c(Cl)csc2N)n1
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
9-Chloro-3-methylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (82 mg, 365 umol) and N-methylethane-1,2-diamine (0.30 ml, 3.40 mmol) in methanol (2 ml) was placed into a preheated oil bath at 60° C. After stirring for 15 min, the solution was diluted with saturated ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 69 mg (88% yield) of 4-chloro-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine as a yellow solid. Method [1] Retention time 0.61 min by HPLC (M+=215 and 217).
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:22](=O)([O-])[O-].[Na+].[Na+]>CO>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2([C:7]([O:9][CH3:22])=[O:8])[CH2:4][CH2:5][CH2:6][CH2:2]2)=[CH:11][CH:12]=1
Reactant: CC1CCCC1(C(=O)O)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccc(F)cc2)CCCC1

Procedure:
To a solution of methyl 1-(4-fluorophenyl)cyclopentanecarboxylic acid (5.0 g, 24.01 mmol) in anhydrous methanol was added 1 mL of the concentration of sulfuric acid. The mixture was refluxed for overnight. The mixture was neutralized to pH 4-5 with sodium carbonate. The solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (3×10 mL), dried over MgSO4. The crude product was used for the next reaction without further purification.
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7]Br)=O.[CH3:10][C:11]([NH:16][C:17]([NH2:19])=[O:18])([CH3:15])[CH2:12][CH2:13][CH3:14].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][C:11]([NH:16][C:17]([NH:19][C:5]1[CH2:7][O:2][C:3](=[O:9])[CH:4]=1)=[O:18])([CH3:15])[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CC(=O)CBr
Reactant: CCCC(C)(C)NC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCC(C)(C)NC(=O)NC1=CC(=O)OC1
Yield: 8 %

Procedure:
To a solution of 22 g of methyl-4-bromoacetoacetate in 200 ml benzene is added 14.4 g of 1,1-dimethylbutylurea and 100 mg of p-toluenesulfonic acid. The solution is heated at reflux under nitrogen for 4 hours with water removal. At the end of this period the solution is cooled and concentrated. The residual material is chromatographed on 400 g of silicic acid. Elution with a solution of benzene (60%), ethyl acetate (30%) and methanol (10%) gives crystalline material. Recrystallization of this material from ethyl acetate gives 1.8 g of 1-(1,1-dimethylbutyl)-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 130°-132°C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7](C=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([Cl:15])([Cl:14])=O>C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:12]([Cl:15])[Cl:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Cl
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=[N+]([O-])c1ccc(C(Cl)Cl)cc1
Yield: 107.4 %

Procedure:
151 g (1 mol) of p-nitrobenzaldehyde and 5 g (0.018 mol) of triphenylphosphine oxide are treated, in the tube reactor described above, at a temperature of 120° to 140° C, for 6 hours with 80 g (0.8 mol) of phosgene gas per hour. At the end of the reaction time the increased in weight was 53 g (calculated 55 g). Vacuum distillation of the resulting crude product gave, in a boiling range of 100° to 110° C/1.5 mm Hg, 177 g (86% of theory) of p-nitrobenzal chloride with a melting point of 44° to 46° C.