Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C>O.CN1C(=O)CCC1>[C:30]([C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1)#[N:31]
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cccc(-c2nc(C3CCC(C(=O)O)CC3)cc3cccnc23)c1

Procedure:
A solution of lithium hydroxide (6.5 mg, 0.155 mmol) in water (160 μl) is added to a solution of 4-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexane carboxylic acid ethyl ester (60 mg, 0.155 mmol) in NMP(0.16 ml). Upon completion, the reaction is diluted with water and washed with ethyl acetate (5 ml). The aqueous layer is acidified with 5% citric acid and the product is extracted into ethyl acetate. The organic layer is dried over brine (10 ml) and anhydrous MgSO4, filtered and evaporated. Purification by flash chromatography using Keiselgel 40-63 grade silica and eluting with 1.5% CH3OH:0.5% CH3COOH: dichloromethane affords the title compound. MH+ 357.0. mp 179.8-180.3° C.
Reaction SMILES: Cl[CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][NH:4][C:3]1=[O:10].S([O-])([O-])(=O)=[O:12].[NH4+].[NH4+]>O>[CH3:9][C:6]1([CH3:8])[CH2:5][NH:4][CH:2]([C:3]([OH:10])=[O:12])[CH2:7]1
Reactant: O=S(=O)([O-])[O-]
Reactant: CC1(C)CNC(=O)C(Cl)C1
Agent: [NH4+]
Solvent: O
Product: CC1(C)CNC(C(=O)O)C1
Temperature: 150 °C

Procedure:
A suspension of 20.4 g (0.13 mol) of 3-chloro-5,5-dimethyl-2-piperidone and 45.2 g (0.14 mol) of Ba(OH)3-8H2O in 252 mL of water was heated in a Parr apparatus at 150° C. for 6 h. Then, 18.6 g (0.14 mol) of ammonium sulphate were added. The precipitate was filtered off, and the solution was concentrated under reduced pressure to dryness. Crude 4,4-dimethylpyrrolidine-2-carboxylic acid was obtained as a white solid (37.5 g). (J. Med. Chem., 20, 1176 (1977), EP 0 447 704 A1, page 17)
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][NH:3][CH2:2]1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][N:3]([CH3:22])[CH:4]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CN(C)CCc2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (0.15 g, 0.6 mmol) in DMF (2 mL) was added sodium hydride (60%, 28 mg, 0.7 mmol) at 0° C. and a solution of MeI (38 μL, 0.7 mmol). The mixture was stirred for 30 min at 0° C. Water was added to the reaction mixture, which was then extracted by DCM. The combined organic layer was washed with water and dried over magnesium sulfate. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel eluting with MeOH-DCM (5:95) and then further purified by preparative HPLC to afford the title compound (86 mg); 1H-NMR (CDCl3): δ 10.50 (1H, s), 8.26 (1H, m), 7.77 (1H, s), 7.40 (1H, d), 7.31 (1H, d), 7.05 (2H, m), 5.35 (1H, s), 4.28 (2H, q), 3.54 (2H, t), 3.26 (3H, s), 3.14 (2H, m), 1.36 (3H, t). MS (ES): 271 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:11]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCN1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 0 °C

Procedure:
A mixture of 33.2 g. of p-fluoroacetophenone, 48.3 g. of N-propylpiperazine and 99.5 g. of potassium carbonate in 100 ml. of dimethyl sulfoxide is stirred and heated at 95° for 4.5 hours, then cooled and poured into ice water. The precipitate of p-(4-propyl-1-piperazinyl)-acetophenone is collected by filtration, washed with water and dried; m.p. 68°-70° after crystallization from hexane.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[Si:18]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
20.0 g (115 mmol) of tert-butyl 3-hydroxyazetidine-1-carboxylate and 9.43 g (139 mmol) of imidazole were initially charged in 200 ml of anhydrous DMF, and 34.91 g (127 mmol) of tert-butyl(diphenyl)silyl chloride were added at RT. After the reaction mixture had been stirred at RT for 18 h, it was poured into 3.2 liters of water and then extracted three times with approx. 1 liter each time of diethyl ether. The combined organic extracts were washed successively with saturated sodium hydrogencarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The remaining residue was stirred with 100 ml of pentane for a few minutes. Subsequently, the solid was filtered off with suction and dried under high vacuum. 29.18 g (61% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C>[F:17][C:18]1[CH:19]=[C:20]([F:24])[CH:21]=[CH:22][C:23]=1[C:10]([CH:7]1[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]1)=[O:12]
Reactant: Fc1cccc(F)c1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
A stirred solution of 10 g (58.5 mmol) of 1-acetylpiperidine-4-carboxylic acid in anhydrous dichloroethane (35 mL) was treated with 5.1 mL (70.2 mmol) of thionyl chloride in 7 mL of dichloroethane and then heated to 60° C. for 30 min. Another flask containing a suspension of 8.02 mL (81.8 mmol) of 1,3-difluorobenzene and 17.9 g (134 mmol) of aluminum chloride in 55 mL of dichloroethane was prepared, to this was added the previously prepared acid chloride suspension in portions. The resulting suspension was refluxed for 4 h, cooled and then poured over ice and HCl. The acidic solution was extracted with CH2Cl2 (3×300 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The crude product was recrystallized from hexanes to afford 9.5 g (61%) of the desired product as a white solid. MS (electrospray): exact mass calculated for C14H15F2NO2, 267.11; m/z found, 268.1 [M+H]+, 1H NMR (CDCl3, 400 MHz): 7.87 (dt, J=8.41, 6.65 Hz 1H), 6.98 (m, 1H), 6.88 (ddd, J=10.96, 8.61, 2.35 Hz, 1H), 4.55 (m, 1H), 3.87 (m, 1H), 3.32 (dtt, J=10.76, 3.91, 1.37 Hz, 1H), 3.19 (ddd, J=13.89, 11.93, 2.93 Hz, 1H), 2.79 (ddd, J=13.89, 12.24, 2.93 Hz, 1H), 2.10 (s, 3H), 1.95 (br d, J=12.91 Hz, 2H), 1.72 (br m, 1H), 1.56 (br m, 1H).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[CH2:13]([N:15]1[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][C:19]=2C(=O)[O:17][C:16]1=O)[CH3:14].Cl>O.C(O)C>[CH2:13]([N:15]1[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][N:21]=2)[C:4]([OH:6])=[C:3]([C:2]([O:10][CH2:11][CH3:12])=[O:9])[C:16]1=[O:17])[CH3:14]
Reactant: CCn1c(=O)oc(=O)c2cccnc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cccnc2n(CC)c1=O
Reaction time: 0.08 h

Procedure:
To a solution of 0.115 g. (0.005 g. atom) of sodium in 20 ml. of ethanol was added 1.6 g. (0.01 mole) of diethyl malonate. After stirring for 5 minutes the solution was evaporated in a rotary evaporator. The residue was dissolved in 15 ml. of N,N-dimethylformamide and 0.96 g. (0.005 mole) of 1-ethyl-2H-pyrido[2,3-d]-[1,3]oxazine-2,4[1H]dione was added. The mixture was heated under reflux for 1.5 hours. The mixture was cooled, diluted with a little water and was acidified with concentrated hydrochloric acid. The precipitate which formed was collected, air dried and was recrystallized from heptane to give 0.2 g. of the title product, m.p. 120°-2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH:17]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)[CH2:19][CH2:18]1
Reactant: OB(O)C1CC1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2ccncc2C2CC2)CC1
Yield: 19 %

Procedure:
General procedure D was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol), cyclopropyl boronic acid (9.4 mg, 0.44 mmol), tetrakis (triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 50 min. The crude product was purified by preparative tlc on silica (CH2Cl2, MeOH 10:1) to furnish the title compound as a white solid (4 mg, 19%), LC-MS (ESI, 3.5 min) Rt 0.97 min, m/z 246 (100%, [M+H]+); m/z (ESI) C14H19N3O requires 246.1601 found [M+H]+ 246.1596.
Reaction SMILES: Br[CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)([O:24][CH3:25])[CH2:22][CH3:23])=[CH:17][C:16]=1[O:31][CH3:32]>>[CH3:25][O:24][C:21]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:2][C:3]2[C:4](=[O:13])[NH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[C:16]([O:31][CH3:32])[CH:17]=1)[CH2:22][CH3:23]
Reactant: CCC(OC)(c1ccc(O)c(OC)c1)c1nccs1
Reactant: O=c1[nH]c2ccccc2cc1CBr
Product: CCC(OC)(c1ccc(OCc2cc3ccccc3[nH]c2=O)c(OC)c1)c1nccs1
Yield: 28 %

Procedure:
Using a similar procedure to that described in Example 1, 3-bromomethyl-1,2-dihydroquinolin-2-one was reacted with 2-[1-(4-hydroxy-3-methoxyphenyl)-1-methoxypropyl]thiazole to give 2-[1-methoxy-1-[3-methoxy-4-(1,2-dihydro-2-oxoquinolin-3-ylmethoxy)phenyl]propyl]thiazole in 28% yield, m.p. 170°-171° C. (recrystallised from a mixture of hexane and ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]1([CH2:44][CH2:45][NH2:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NCCN1CCCCC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCN3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-piperidin-1-yl-ethylamine according to conditions described in general procedure C. Mp: 98-100° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.42 (bs, 6 H), 2.06 (s, 2 H), 2.33 (s, 4 H), 2.55-2.94 (m, 2 H), 3.26 (t, J=4.4 Hz, 4 H), 3.77 (t, J=4.8 Hz, 4 H), 6.20-6.35 (bd, 1 H), 6.95 (s, 1 H), 7.04 (d, J=12.0 Hz, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.48 (s, 1 H), 7.55-7.61 (m, 3H), 7.81-7.83 (m, 1 H), 8.00 (d, J=8.4 Hz, 1 H), 8.23 (s, 1 H), 10.45 (s, 1 H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: C1CCCNCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and hexahydro-1H-azepine but with sequential purifications by MDAPs using Method A followed by Method E.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:10][C:4]3[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=3[N:2]=2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Oc1ccc2nc(-c3ccc(F)cc3)oc2c1
Yield: 81 %

Procedure:
4-Aminoresorcinol HCl salt (1.61 g) is dissolved in 10 ml of NMP under nitrogen atmosphere. 4-Fluorobenzoyl chloride (1.91 g) is added all at once and the mixture is heated under reflux for approximately 2 hours. After reflux, the mixture is allowed to cool and is diluted with 60 ml of water. Potassium carbonate (3.5 g) is added and the mixture is stirred. The resulting precipitate is filtered and recrystallized from ethanol and water to yield 1.85 g of the above-named product. The product melts at 225° C.-227° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C:10]([CH3:29])([CH3:28])[CH2:9]1)=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH3:29][C:10]1([CH3:28])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C)(C)C1
Product: CC1(C)CNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 141 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H3O+ of 436. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.72 (s, 1H) 8.34 (d, 2H) 7.95 (d, 1H) 7.68 (m, 2H) 7.17 (d, 2H) 6.72 (d, 2H) 4.54 (s, 2H) 3.96 (t, 2H) 3.71 (s, 2H) 3.35 (m, 4H) 2.96 (t, 2H) 1.76 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(OCC)(=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: C#Cc1ccccc1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Nc1cc(C#Cc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A flame-dried flask was charged with the 5-bromo-2-nitroaniline (2, 300 mg, 1.38 mmol) (scheme 1, Example 1), phenylacetylene (155 mg, 1.52 mmol) and ethyl acetate (13.8 mL). The solution was degassed under vacuum and put under N2 atmosphere. Then, dichlorobis(triphenylphosphine)palladium (48 mg, 0.069 mmol) and copper iodide (26 mg, 0.138 mmol) were added. The yellow solution was degassed again (3 cycles) N,N-diisopropylamine (231 μl, 1.68 mmol) was added and the solution rapidly turned dark. It was degassed twice again and allowed to stir under N2 atmosphere at r.t. over 16 h. Then it was passed through celite and the filtrate was successively washed with dilute aqueous ammonia (NH4OH), saturated NaHCO3, saturated NH4Cl, brine, dried over MgSO4, filtered and concentrated. The resulting dark solid was purified by flash chromatography on silica gel using EtOAc/hexanes as the eluent with increasing polarity (10:90 to 15:85) affording the title compound 124 (242 mg, 74% yield) as a deep yellow solid. 1H NMR: (400 MHz, CD3OD) δ(ppm): 8.04 (dd, J=8.8, 0.4 Hz, 1H), 7.54-7.51 (m, 2H), 7.40-7.37 (m, 3H), 7.11 (dd, J=1.8, 0.4 Hz, 1H), 6.73 (dd, J=8.8, 1.8 Hz, 1H). LRMS: (m/z): 239.3 (MH+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][SH:12].B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[C:2]1([CH:1]2[S:13][CH2:9][CH2:10][CH2:11][S:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: SCCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: c1ccc(C2SCCCS2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of benzaldehyde (15.0 g, 141 mmol) in chloroform (150 mL), propane-1,3-dithiol (16.9 g, 155 mmol) and boron trifluoride etherate (26.1 g, 183 mmol) were added. The reaction mixture was stirred at ambient temperature for 24 h, and was then poured into ice-cold aqueous sodium hydroxide (10%) and extracted with chloroform. The combined chloroform extracts were washed with water, dried over sodium sulfate, concentrated and purified by flash column chromatography using 1% ethyl acetate in hexane as eluent. Yield: 21.2 g, 77%.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1.[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][C:31]=1[Br:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[OH:35])=[CH:32][C:31]=1[Br:38])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Br)c1
Reactant: CCOc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(C(O)c2ccc(OCc3ccccc3)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Then, 1.6 M n-butyllithium hexane solution (22.9 mL) was added to a mixture of 4-bromophenetole (7.3 g, 0.037 mol) and tetrahydrofuran (70 mL) at −78° C. After stirred for 0.5 hours, 4-benzyloxy-3-bromobenzaldehyde (7.0 g, 0.024 mol) in a tetrahydrofuran (70 mL) solution was added and further stirred for 15 minutes, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain colorless oily [4-(benzyloxy)-3-bromophenyl](4-ethoxyphenyl)methanol (8.7 g, 86%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]([CH3:14])C(O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C[CH2:23][O:24]CC>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH2:10][CH2:14][CH2:23][OH:24]
Reactant: CCOCC
Reactant: CC(C(=O)O)C1Cc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: OCCCC1Cc2ccccc2O1

Procedure:
2-(2,3-Dihydrobenzofuranyl)-propanoic acid (10 g) was dissolved in ether (60 mls) added dropwise to a stirred suspension of lithium aluminum hydride (2.0 g) in ether (90 mls). The reaction temperature was maintained below 30° C. whilst under an atmosphere of nitrogen. After 3 hours water was added to destroy excess hydride. The mixture was filtered and the ether layer separated and dried over anhydrous magnesium sulphate. Removal of solvent gave an oil (8.0 g). M/e 178.0984 NMR (CDCl3) (60 MHz) δ1.65 (4H, m); 2.30-3.30 (2H, m); 3.50 (2H, t, J=6 Hz); 3.90 (1H, s), 4.65 (1H, m); 6.40-7.20 (4H, m).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:12]Br>CO>[Br:12][C:5]1[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[C:2]([OH:1])=[N:3][CH:4]=1
Reactant: Oc1ncccc1C(F)(F)F
Reactant: BrBr
Solvent: CO
Product: Oc1ncc(Br)cc1C(F)(F)F
Yield: 94.2 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine (10.0 g) and bromine (3.08 ml, 9.60 g) in methanol (50 ml) was stirred at 20° C. for 22 h. The solution was concentrated and the residue partitioned between ethyl acetate (400 ml) and water (100 ml). The layers were separated and the organic layer was washed with 5% Na2S2O3aq. (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated. Purified by Biotage SNAP cartridge KP-Sil column twice (100 g, heptane:ethyl acetate=1:0, 3:1 to 2:1) to give 13.69 g light yellow solid as 5-bromo-2-hydroxy-3-(trifluoromethyl)pyridine (95%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:17]3[CH2:18][CH2:19][N:20]4[C:25]([C:16]=3[NH:15][C:12]2=[CH:13][CH:14]=1)=[C:24]([CH2:26][CH3:27])[CH2:23][CH2:22][C:21]4=[S:28].O.Cl>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:17]3[CH:18]=[CH:19][N:20]4[C:25]([C:16]=3[NH:15][C:12]2=[CH:13][CH:14]=1)=[C:24]([CH2:26][CH3:27])[CH2:23][CH2:22][C:21]4=[S:28]
Reactant: CCC1=C2c3[nH]c4ccc(OC)cc4c3CCN2C(=S)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1=C2c3[nH]c4ccc(OC)cc4c3C=CN2C(=S)CC1
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (665 mg, 5.9 mmol) is added to a solution of 9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinolizine-4-thione (500 mg, 1.6 mmol) in DMF (42 ml). After placing the reaction assembly under vacuum, the mixture is stirred under normal oxygen pressure overnight. Water (15 ml) and concentrated hydrochloric acid (3 ml) are then successively added. The solution is stored in a refrigerator for 4 hours. After filtration, 9-methoxy-1-ethyl-2,3,4,12-tetrahydroindolo[2,3-a]quinolizine-4-thione is obtained (150 mg, Y=30%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CCCC(O)c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(O)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
N,N-dimethylformamide (8.60 mL) was added to a vial containing 4-(1-hydroxybutyl)benzoic acid (250 mg, 1.29 mmol), ethyl 3-aminopropanoate hydrochloride (395 mg, 2.57 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (979 mg, 2.57 mmol). Diisopropylethylamine (1.12 mL, 6.44 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (350 mg, 93% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.84 (br.s., 1H), 4.74 (t, J=6.5 Hz, 1H), 4.23-4.07 (m, 2H), 3.72 (q, J=5.9 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 1.85-1.72 (m, 1H), 1.72-1.58 (m, 1H), 1.52-1.37 (m, 1H), 1.37-1.30 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1) 294.3.