Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:12]1=[O:30].[OH-].[Na+]>CO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([N:13]2[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])[C:12]2=[O:30])=[CH:27][CH:26]=1
Reactant: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(OC)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2c(-c3ccccc3)cn(CCCCCCCC(=O)O)c2=O)cc1

Procedure:
The product is produced as described in example 18 from 18.8 g of 8-[3-(4-methoxyphenyl)-2-oxo-4-phenyl-4-imidazolin-1-yl] caprylic acid methyl ester and 2.12 g of NaOH in 100 cc. of methanol. Further purification by chromatography on silicic acid gel using chloroform as eluant.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:10]([C:11]#[N:12])=[C:4]2[NH:3]1.[H-].[Na+].[CH3:21]I.O>CN(C=O)C>[CH3:21][N:3]1[C:2](=[O:1])[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:10]([C:11]#[N:12])=[C:4]12
Reactant: CI
Reactant: N#Cc1c(-c2cccnc2)nn2c1NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCn2nc(-c3cccnc3)c(C#N)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-oxo-2-(pyridin-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (50 mg, 0.21 mmol) in DMF (2 mL) was added NaH (17 mg, 0.42 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 mins, then methyl iodide (30 mg, 0.21 mmol) was added. The mixture was stirred at 0° C. for an additional 30 mins. 1 mL of water was added to quench the reaction which was extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated in vacuo. The residue was purified by HPLC to afford 4-methyl-5-oxo-2-(pyridine-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile: MS (m/z): 254.1 [M+H]+, 1H NMR (CD3OD, 400 MHz): δ8.06 (s, 1 H), 8.60 (d, 1 H, J=1.6 Hz), 8.36 (d, 1H, J=8.0 Hz), 7.59 (dd, 1 H, J=8.0 Hz, J=56 Hz), 4.44 (t, 2 H, J=7.6 Hz), 3.04 (t, 2H, J=7.6 Hz).
Reaction SMILES: C[N:2](C(N=NC(N(C)C)=O)=O)C.[C:13]([OH:22])(=[O:21])/[CH:14]=[CH:15]/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19].[NH3:23]>>[NH2:23][CH:16]([CH:15]([NH2:2])[CH2:14][C:13]([OH:22])=[O:21])[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CN(C)C(=O)N=NC(=O)N(C)C
Reactant: O=C(O)/C=C/C=C/C(=O)O
Reactant: N
Product: NC(CC(=O)O)C(N)CC(=O)O

Procedure:
The bicyclic dilactam of 3,4-diamino-1,6-hexanedioic acid was synthesised via the diamide of muconic acid (2,4-hexadiene-1,6-dioic acid) essentially as outlined by Köhl in Berichte 35, 173 (1903). In a modification of Köhl's procedure, the dimethylester of trans, trans-muconic acid (13.6 g=0.080 mole) was autoclaved for 5 hours at 150° C. with 60 ml 32% aqueous ammonia. The resulting solution on evaporation and cooling yielded 1.40 g of crystalline dilactam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[NH2:13].[CH3:14][O:15][C:16]([N:18]=[C:19]=[S:20])=[O:17]>CC(C)=O>[CH3:14][O:15][C:16]([NH:18][C:19](=[S:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[NH:13][C:19]([NH:18][C:16]([O:15][CH3:14])=[O:17])=[S:20])=[O:17]
Reactant: COC(=O)N=C=S
Reactant: CCCCSc1ccc(N)c(N)c1
Solvent: CC(C)=O
Product: CCCCSc1ccc(NC(=S)NC(=O)OC)c(NC(=S)NC(=O)OC)c1

Procedure:
1.5 G. of 1,2-diamino-4-n-butylthiobenzene in 30 ml. acetone is treated overnight with 4.5 g. methoxy carbonyl isothiocyanate at room temperature. The solution is concentrated, and the residue triturated with methanol and recrystallized from methanol, yielding 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-n-butylthiobenzene.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].C1CCN2C(=NCCC2)CC1.[O:24]=[S:25]1(=[O:50])[C:30]2[CH:31]=[C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43](=[N:45][OH:46])[NH2:44])=[CH:38][CH:37]=3)[CH:33]=[CH:34][C:29]=2[N:28]2[CH2:47][CH2:48][CH2:49][C:27]2=[N:26]1.Cl>CC#N>[O:50]=[S:25]1(=[O:24])[C:30]2[CH:31]=[C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([CH2:42][C:43]4[NH:44][C:1](=[S:2])[O:46][N:45]=4)=[CH:40][CH:41]=3)[CH:33]=[CH:34][C:29]=2[N:28]2[CH2:47][CH2:48][CH2:49][C:27]2=[N:26]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)cc1)=NO
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3ccc(Cc4noc(=S)[nH]4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
348 mg (1.95 mmol) of 1,1′-thiocarbonyldiimidazole and then 530 μl (3.516 mmol) of DBU are added to a suspension of the product obtained in Step A (330 mg, 0.85 mmol) in 8 ml of CH3CN. The reaction solution is stirred at ambient temperature overnight. 20 ml of 1N HCl are added; extraction (CH2Cl2), washing (saturated NaCl), drying (MgSO4) and evaporating to dryness are carried out. The title product is obtained in the form of a yellow wax which is used in the crude state in the following Step.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])(=[O:20])=[O:19]
Reactant: Cc1ncsc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncsc1CCOS(C)(=O)=O
Temperature: 25 °C
Yield: 66.9 %

Procedure:
2-(4-methylthiazol-5-yl)ethanol (5.01 g) was dissolved in dichloromethane (100 ml) and to the solution was added triethylamine (5.06 g), followed by adjusting the temperature of reactor to 0° C. To the obtained solution was added dropwise methanesulfonyl chloride (4.58 g), and the mixture was stirred for 21. hours while allowed to warm up to room temperature. The reaction solution was washed with water, concentrated under reduced pressure, and then purified by column-chromatography (hexane/ethyl acetate=1/3) to yield 5-(2-methylsulfonyloxyethyl)-4-methylthiazole (5.18 g, 67%) as a pale yellow liquid.
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])C(=O)[O-])(C)C.Cl>CO.O1CCOCC1>[NH2:5][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:30])[F:31])[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reaction time: 12 h
Yield: 109.2 %

Procedure:
To a solution of 1,1-dimethylethyl((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)carbamate (3.2 g, 7.1 mmol) in MeOH (35 mL) at RT was added 4M HCl in dioxane (18 mL). After 12 h, the solution was concentrated affording the title compound (2.7 g, quant.) as the HCl salt: LCMS (ES) m/z 349 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[C:26](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[C:31]([F:34])([F:33])[F:32])=[CH:24][CH:23]=2)[CH:29]=[N:28]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccc(OCC(F)(F)C(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 36.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.94 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.16 g of 4-[4-(2,2,3,3,3pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.68 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:14])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Reactant: NCCCN1CCOCC1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCCCN2CCOCC2)c1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (200 mg, 0.59 mmol) and N-(aminopropyl)morpholine (0.17 ml, 1.18 mmol) in DMF 3.0 mL was added EDC (168.7 mg, 0.88 mmol), HOBt (118.9 mg, 0.88 mmol) and DIPEA (0.15 ml, 0.88 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=15:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-(3-morpholine-4-yl-propyl)-benzamide as a yellow solid (56.7 mg, 20% yield).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[OH:36].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=4[OH:36])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 13 mmol), NaHCO3 (1.1 g), several crystals of KI, 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone, and acetonitrile (100 ml) was refluxed for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 5.7 g of a thick yellow oil. The oil was chromatographed on a Waters Prep 500 LC on silica gel, eluting with 7% methanol/methylene chloride. Concentration of the appropriate fraction afforded a yellow oil, which upon standing yielded 3.5 g of the compound as a pale, yellow solid. The solid was recrystallized from ethyl alcohol to afford 2.7 g (50%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-1-piperidinyl]-propoxy]-3-hydroxyphenyl]ethanone as a pale yellow solid, m.p.=122°-124° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[CH2:5][N:6]([C:13](=[O:15])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[CH3:19][I:20]>C(O)C>[I-:20].[CH3:19][N+:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]([C:13](=[O:15])[CH3:14])[CH2:5][CH:4]([O:16][CH2:17][CH3:18])[O:3][CH2:1][CH3:2]
Reactant: CI
Reactant: CCOC(CN(C(C)=O)c1ccccn1)OCC
Solvent: CCO
Product: CCOC(CN(C(C)=O)c1cccc[n+]1C)OCC
Product: [I-]
Temperature: 60 °C
Yield: 96 %

Procedure:
A mixture of N-acetyl-N-(2-pyridyl)-aminoacetaldehyde diethyl acetal (6.0 g.), methyl iodide (25 g.) and ethanol (30 ml.) was heated for 15 hours at 60° C in a sealed tube. The reaction mixture was concentrated and water was added to the residual oil. The mixture was washed twice with ether and the aqueous layer was concentrated under reduced pressure to give oil of 1-methyl-2-[N-acetyl-N-(2,2-diethoxyethyl)-amino]-pyridinium iodide (9.0 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[F:21][C:22]([F:36])([F:35])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][C:27]=1[I:34])=[O:24]>CCO>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:32]2[C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[C:22]([F:35])([F:21])[F:36])=[C:27]([I:34])[CH:28]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=Cc1ccc(NC(=O)C(F)(F)F)c(I)c1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(NC(=O)C(F)(F)F)c(I)c3)nc3ccccc3c2=O)cc1
Yield: 66 %

Procedure:
2-amino-N-(4-sec-butylphenyl)benzamide (0.275 g, 1.00 mmol) and anhydrous CuCl2 (0.275 g, 2.00 mmol) were added to a solution of 2,2,2-trifluoro-N-(4-formyl-2-iodophenyl)acetamide in anhydrous EtOH (15 mL) and heated to reflux temperature for 3 hours. After concentrating in vacuo, the residue was dissolved in EtOAc, washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 60% EtOAc in heptane, afforded N-(4-(3-(4-sec-butylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-iodophenyl)-2,2,2-trifluoroacetamide (0.390 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:30]=[C:31]([CH3:39])[C:32]3[O:36][C:35]([CH3:37])=[N:34][C:33]=3[CH:38]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][C:35]1[O:36][C:32]2[C:31]([CH3:39])=[CH:30][C:29]([NH:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:38][C:33]=2[N:34]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2o1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5oc(C)nc5c4)ncn3)CC1)C(=O)N2
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
70 mg (0.25 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 55 mg (0.20 mmol) (6-chloro-pyrimidin-4-yl)-(2,7-dimethyl-benzoxazol-5-yl)-amine and 0.15 mL (0.87 mmol) DIPEA were combined in 1.5 mL DMF and stirred for 2.5 h at 150° C. The reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and freeze-dried. The residue was stirred with MeOH and DMF, left to stand for 1 h and filtered. The precipitate was washed with MeOH and dried.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1)#N.[SH:19][CH2:20][CH2:21][NH2:22].[CH2:23](O)C>>[S:19]1[CH:20]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH:7]=[C:6]3[C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=2)[CH2:21][N:22]=[CH:23]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Reactant: NCCS
Reactant: CCO
Product: CN1CC=C(c2c[nH]c3ccc(C4CN=CS4)cc23)CC1
Temperature: 25 °C
Yield: 51 %

Procedure:
A mixture of 1.0 gm (4.2 mMol) 5-cyano-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.90 gm (11.7 mMol) 2-mercaptoethylamine in 20 mL ethanol was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and a colorless crystalline solid formed. The solid was isolated by filtration, washed with ethanol and dried under reduced pressure to provide 0.64 gm (51%) of the title compound.
Reaction SMILES: [CH:1]([N:4]([CH:30]([CH3:32])[CH3:31])[C:5](=O)[CH2:6][CH:7]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O1CCCC1>[CH2:22]([O:21][C:15]1[CH:16]=[CH:17][C:18]([Br:20])=[CH:19][C:14]=1[CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:30]([CH3:32])[CH3:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)N(C(=O)CC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(CCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Yield: 70.6 %

Procedure:
To a stirred solution of (±)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide (11.8 g) in 40 ml of dry tetrahydrofuran was added 1 M lithium aluminium hydride/tetrahydrofuran (36 ml). The reaction was refluxed for 4 hrs and then quenched with the dropwise addition of water. After removal of the precipitate the solvent was evaporated and the oily residue dissolved in diluted sulphuric acid. The aqueous phase was washed several times with diethyl ether, adjusted to pH 10-12 (aqueous NaOH), and extracted with diethyl ether. The extract was dried (sodium sulphate), filtered and evaporated to dryness in vacuum to leave 8.1 g (76.7%) of the title compound as a viscous colourless oil, tlc: (4) 0.86. The NMR spectrum corresponds to the product, obtained from the tosylate precursor (see above).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].Cl([O-])(=O)(=O)=O.[Li+]>>[N:15]([C@@H:12]1[CH2:13][CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C@H:10]1[OH:11])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(CN2CCC3OC3C2)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: [N-]=[N+]=N[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Yield: 67 %

Procedure:
A solution of 1.2 g of 3-benzyl-7-oxa-3-azabicyclo[4.1.0]heptane (6.3 mmol) was refluxed in the presence of 0.62 g of sodium azide (9.5 mmol) and 3 g of lithium perchlorate (19 mmol) for 4 hs. After completion reaction mixture was evaporated and the residue was extracted with dichloromethane, washed with water and combined organic fractions were dried over sodium sulfate and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate 4:1 as eluent affording 980 mg of trans-4-azido-1-benzylpiperidin-3-ol.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:15])[O-])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.N12CCCN=C1CCCCC2.O>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([C:13]([NH:12][C:9]2[C:10]3[CH2:11][CH:2]([OH:1])[CH2:3][CH2:4][C:5]=3[CH:6]=[CH:7][CH:8]=2)=[O:15])[CH2:26][CH2:25]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=C([O-])Nc1cccc2c1CC(O)CC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c1CC(O)CC2)N1CCN(c2ccccc2Cl)CC1
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
To a mixture of (7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (141 mg, 0.50 mmol) and 2-chlorophenyl piperazine hydrochloride (155 mg, 0.66 mmol) in tetrahydrofuran (15 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (228 mg, 1.50 mmol) at room temperature, and the mixture was stirred for 30 minutes. Water was added and the mixture was extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/1) to provide 4-(2-chlorophenyl)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)piperazine-1-carboxamide (103 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:13]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.N(C(OC(C)C)=O)=NC([O-])=O>C1(C)C=CC=CC=1.O1CCCC1.C(O)C>[CH2:12]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([NH2:11])=[C:2]([NH2:1])[CH:3]=1)[CH3:13]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)[O-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3,4-Diaminobenzoic acid (2.003 g, 13.17 mmol) and triphenylphosphine (4.248 g, 16.20 mmol) were suspended in toluene (20 ml) and tetrahydrofuran (10 ml). Ethanol (2 ml) was then added, diisopropyl azodicarboxylate (2.5 ml, 9.96 mmol) was added dropwise to the obtained light brown suspension, and the mixture was stirred at room temperature for 3.5 hours. Isopropyl azodicarboxylate (1.5 ml, 5.98 mmol) was further added dropwise, the mixture was stirred at room temperature for 1 hour, and the obtained reaction mixture was extracted with 1N hydrochloric acid (100 ml×2 times), after which the aqueous layer was washed with 50 ml of ethyl acetate. After adding 2N aqueous sodium hydroxide to the aqueous layer to raise the pH to 11 or higher, the precipitate was extracted with ethyl acetate (100 ml×2 times). The organic layer was washed with saturated brine (50 ml) and dried overnight over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated to obtain 3,4-diaminobenzoic acid ethyl ester as a faint yellow solid. The compound was identified by LC-MS.
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1.[Cl:10]N1C(=O)CCC1=O>CS(C)=O.C(OCC)(=O)C>[Cl:10][C:7]1[N:3]2[CH:4]=[CH:5][N:6]=[CH:1][C:2]2=[CH:9][CH:8]=1.[Cl:10][C:9]1[CH:8]=[CH:7][N:3]2[CH:4]=[CH:5][N:6]=[CH:1][C:2]=12
Reactant: c1cc2cnccn2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1ccc2cnccn12
Product: Clc1ccn2ccncc12
Temperature: 60 °C
Reaction time: 6 h

Procedure:
3.6 g of pyrrolo[1,2-a]pyrazine prepared in Preparation Example 1 was dissolved in a mixture of 20 ml of dimethyl sulfoxide and 20 ml of ethyl acetate; and 4.8 g of N-chloro succinimide was added thereto. The reaction mixture was stirred at 60° C. for 6 hours, poured into ice-water, extracted with ethyl acetate(100 ml×3), and then concentrated under a reduced pressure. The residue was chromatographed over silica gel to obtain 0.6 g of 6-chloropyrrolo[1,2-a]pyrazine and 0.4 g of 8-chloropyrrolo[1,2-a]pyrazine, respectively.
Reaction SMILES: [OH:1][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[CH3:18]I>C1COCC1.[Ag]=O>[CH:14]([C:6]1[C:5]([C:3](=[O:4])[CH:2]([O:1][CH3:18])[CH3:17])=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: CC(O)C(=O)c1c(C(C)C)nn2ccccc12
Reactant: CI
Agent: O=[Ag]
Solvent: C1CCOC1
Product: COC(C)C(=O)c1c(C(C)C)nn2ccccc12

Procedure:
A solution of 2-hydroxy-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (0.6 g, 1 equivalent), silver oxide (5 g, 8 equivalents), and methyl iodide (2.5 mL, 15 equivalents) in 2 mL of THF was stirred in a sealed tube at room temperature for 26 hours. The mixture was filtered to remove precipitated solids. The filtrate was worked up with ethyl acetate and saturated NaHCO3. The crude oil obtained was purified by silica gel flash column chromatography to give 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methoxypropan-1-one as an oil. Compound 1069.