Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].NC1C=CC=CC=1C(F)(F)F>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:23])([F:24])[F:25])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccccc1C(F)(F)F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cc2ncnc(Nc3ccccc3C(F)(F)F)c2cn1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (300 mg, 1.56 mmol), 2-aminobenzotrifluoride hydrochloride (1.00 g, 5.06 mmol) and 2-aminobenzotrifluoride (2.00 g, 12.4 mmol) is stirred at 160° C. for 10 min. The resulting product is neutralized with excess NaHCl, dissolved in MeOH/CHCl3, dried onto silica gel and chromatographed over silica gel (6-7% MeOH/CH2Cl2) to give 7-amino-4-(2-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (194 mg, 41%) as a cream solid, mp (MeOH/CHCl3 /light petroleum) 126°-130° C. (dec.). 1H NMR (DMSO) δ 10.60 (1H, brs), 9.17 (1H, brs), 8.13 (1H, brs), 7.76, 7.69 (1H, 1H, m, m), 7.45 (2H, m), 6.66 (2H, brs), 6.36 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.NN>[Ni].CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cccc2ccc(Cl)nc12
Yield: 81.6 %

Procedure:
In the similar fashion using route 6 general procedure 14, 2-chloro-8-nitroquinoline (Intermediate 24) (100 mg, 0.48 mmol), Raney nickel (20 mg, 20% wt), hydrazine hydrate (96 mg, 1.92 mmol) and MeOH (10 ml) gave the crude title compound (70 mg, 82%) which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Yield: 53.1 %

Procedure:
A solution of 4-methyl-3-nitrobenzonitrile (30 g), N-bromosuccinimide (37 g) and azobisisobutyronitrile (3.1 g) in carbon tetrachloride (300 ml) was refluxed under heating for 8 hr. To the reaction mixture was added water (100 ml) and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:4) and recrystallized from ethyl acetate-hexane to give the title compound (23.7 g) as pale-yellow crystals, m.p.=85-89° C.
Reaction SMILES: [N:1]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:2]=1[CH2:3][C:4]([OH:6])=O.C1C(=O)N(O)C(=O)C1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:38][CH:39]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>C(OCC)(=O)C>[C:48]1([CH:39]([NH:38][C:4]([CH2:3][C:2]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:1]=2)=[O:6])[CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: NC(CCN1CCCCC1)c1ccccc1
Reactant: O=C(O)Cc1ccc2ccccc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc2ccccc2n1)NC(CCN1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a suspension of 866 mg (5.0 mmol.) of quinaldinic acid and 576 mg (5.0 mmol.) of 1-hydroxysuccinimide in 20 ml of ethyl acetate was dropwise added over a period of 5-10 min. under chilling with ice a solution of 1.09 g (5.0 mmol.) of N,N'-dicyclohexylcarbodiimide. After the addition was complete, the mixture was stirred for 2 hours at room temperature. To this mixture was dropwise added a solution of 1.09 g (5.0 mmol.) of 1-(3-amino-3-phenylpropyl)piperidine in 5 ml of ethyl acetate. After the addition was complete, the mixture was stirred overnight at room temperature. Precipitated insolubles were filtered off and then the insolubles were washed with ethyl acetate. The filtrate and the washings were combined and washed twice with a saturated aqueous sodium hydrogencarbonate solution and once with a saturated aqueous sodium chloride solution. The mixture was then dried over sodium sulfate, and was evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (silica gel: 20 g, CHCl3 and CHCl3 /CH3OH (30:1)) to obtain 1.72 g (yield: 92%) of the subject compound as a pale yellow crystalline product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.O.[OH-].[K+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 95 %

Procedure:
To a solution of N-(4-bromo-2-nitrophenyl)acetamide obtained in step H above (1.0 eq) in MeOH and water was added KOH (1.5 eq) at room temperature and stirred for 5 hrs. Water was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired 4-bromo-2-nitroaniline. (Yield=95%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH:14]([CH3:16])[CH3:15]>O1CCCC1>[OH:11][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)C[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A solution of 4-formyl-benzoic acid methyl ester (1.56 g, 9.50 mmol) in tetrahydrofuran (53 mL) was cooled to 0° C. Isobutylmagnesium chloride (4.75 mL, 2M in THF) was then added dropwise over 15 minutes. The reaction was stirred at 0° C. for 1 hour. The ice bath was removed and the reaction was allowed to warm to room temperature and stir for 1 hour. The reaction was quenched by carefully adding 1N HCl. The reaction was diluted with water and diethylether and the layers were separated. The aqueous was extracted three more times with diethyl ether. The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification by column chromatography (0-40% ethyl acetate in heptane) gave (+/−)-methyl 4-(1-hydroxy-3-methylbutyl)benzoate (404.6 mg, 19%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3, δ): 7.99 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 4.79 (br. s., 1H), 3.89 (s, 3H), 1.94 (d, J=2.73, 1H), 1.65-1.78 (m, 2H), 1.42-1.52 (m, 1H), 0.91-0.97 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C)C=O.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: CN(C)C=O
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.72 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), dimethylformamide (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 12 to 13 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.72 to 0.75%].
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1)#[N:2]>N.C(O)C.[Rh]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCN(CCCC#N)CC1
Agent: [Rh]
Agent: N
Solvent: CCO
Product: CCOC(=O)N1CCN(CCCCN)CC1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
60 g of ethyl 4-(3-cyanopropyl)-piperazine-1-carboxylate were dissolved in a 10% w/w solution of ammonia in ethanol and 6 g of 5% rhodium on alumina were added thereto. The mixture was cooled to room temperature and filtered. The filtrate was evaporated to dryness under vacuum and the residual oil was distilled under reduced pressure to obtain 20 g of ethyl 4-(4-aminobutyl)-piperazine-1-carboxylate with a boiling point of 126°-130° C. at 0.15 to 0.2 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:26])[N:6]2[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=1.[H-].[Al+3].[H-].[H-].C1C[O:34]CC1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:26])[N:6]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[O:34])=[CH:23][CH:24]=1
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C#N)cc3)c2n1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Product: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C=O)cc3)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-[6-amino-8-methoxy-2-(2-methoxyethoxy)purin-9-ylmethyl]benzonitrile (100 mg) is dissolved in dry THF (3 mL) and cooled to 0° C. under argon. The aluminum hydride reagent generated above (0.72 mL) is added to the reaction flask and the mixture is stirred at 0-5° C. for 1 hour and then quenched by addition of 3 M HCl. The mixture is then extracted with ethyl acetate and then dichloromethane and concentrated in vacuo to yield 85 mg. NMR is consistent with structure assignment.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Mg]>>[CH2:11]([OH:12])[C@H:9]1[O:10][C@:3]([OH:4])([CH2:2][OH:1])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Mg]
Product: OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O

Procedure:
These rods (25 g) are introduced into a tube for endurance testing, and an initial feed rate of 120 cc/hour of a solution containing 450 g of glucose per liter and no magnesium makes it possible to obtain a degree of conversion into levulose of 42%. The feed rate is still 60 cc/hour after 600 hours of operation.
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9](Cl)(=[O:11])[CH3:10].CN1CCOCC1>C(OCC)(=O)C>[C:9]([N:3]1[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]1=[O:8])(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1NC(=O)OC1=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(=O)N1C(=O)OC(=O)[C@@H]1C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
(S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of acetyl chloride (306 mg, 3.9 mmol) under ice cooling. Further, a solution of N-methyl-morpholine (394 mg, 3.9 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in chloroform (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound (350 mg, 74%) as a colorless clear syrup.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[C:8]([CH3:14])=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([F:6])[C:8]=1[CH3:14])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1c(N)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(F)cccc1NC(=O)CCl
Temperature: 0 °C

Procedure:
A solution of chloroacetyl chloride (38.4 ml, 480 mmol) in ethyl acetate (100 ml) was slowly added to a vigorously-stirred mixture of 3-fluoro-2-methylaniline (60 g, 480 mmol), saturated aqueous sodium bicarbonate (400 ml), ice (ca 100 g) and ethyl acetate (400 ml). Some solid formed then dissolved. After 1 hour the mixture was evaporated to removing the ethyl acetate) and filtered, washing with water. The resulting product was dried in vacuo (94.4 g, 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>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.C1(C)C=CC=CC=1>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][C:10]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:13][CH:14]=2)=[CH:9][CH:8]=4)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Product: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Yield: 73 %

Procedure:
As depicted in Reaction 5, 15 g (46 mmol) of 3,6-dibromocarbazole, 14 g (92 mmol) of phenylboronic acid, K2CO3 (2 mol), Pd(PPh3)4 and toluene were refluxed for 10 hours. The reaction mixture was extracted with methylene chloride. The solvent was removed, and then the residue was purified by column chromatography (eluent:hexane) to give the title compound. Yield: 73%. MS (EI) (Calcd. for C24H17N, 319.14. Found: 319).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([N:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1Cc2ccccc2C1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Under N2, at 0° C., trichloroacetyl chloride (0.57 mL, 5.0 mmol) was added dropwise to a stirring solution of isoindoline (1.0 g, 5.0 mmol), Et3N (0.7 mL, 0.51 g, 5.0 mmol) and CH2Cl2 (20 mL). The solution was allowed to warm to room temperature and stirred for 1 h. After evaporating the solvents in vacuo, the mixture was purified via silica gel chromatography using 8:2 hexanes/EtOAc to obtain the desired amide (1.2 g, 4.6 mmol, 91% yield). LC/MS (10-99% CH3CN), M/Z: M+1 obs=265.9; tR=3.51 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.NN.C(Cl)(Cl)Cl>C(O)(C)C.[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ccc2c1
Agent: [Pd]
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Nc1cc(Br)c2[nH]ccc2c1
Yield: 71.4 %

Procedure:
A solution of 7-bromo-5-nitroindole (0.68 g, 2.8 mmol), hydrazine (1.0 mL, 31 mmol) and 10% Pd/C (50 mg) in 50 mL of isopropanol was stirred at reflux for 2 h. The reaction mixture was filtered and concentrated in vacuo, yielding oily residue which was subjected to column chromatography (CHCl3, neat) to produce 0.41 g (2.0 mmol, 70%) of the desired product.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@@H:12]3[CH2:14][C@H:13]3[CH2:15][NH2:16])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@@H:12]3[CH2:14][C@H:13]3[CH2:15][NH:16][C:25](=[O:27])[CH3:26])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To a suspension of 1-[(1R,2R)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine dihydrochloride (750 mg, 2.74 mmol) and triethylamine (1.52 mL, 10.9 mmol) in tetrahydrofuran (27 mL) was added acetic anhydride (388 μL, 4.10 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (600 mg, yield 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[CH:14]([C:16]1[CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19](=[O:26])[N:20]2[C:25]=1[CH:24]=[CH:23][CH:22]=[CH:21]2)=[O:15].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([OH:15])[C:16]2[CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19](=[O:26])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)=[N:3][CH:4]=1
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(O)c2ccc(Br)cn2)c2ccccn2c1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dibromopyridine (1.00 g, 4.22 mmol) in 50 mL of toluene at −78° C. was added n-BuLi (2.0 mL, 5.0 mol, 2.5 M in THF) dropwise. After 2 h, ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (1.35 g, 5.5 mmol) was added. The reaction was stirred at −78° C. for another 1 h, then transferred to a 0° C. ice water bath. After an additional 1 h at 0° C., saturated aqueous ammonium chloride (10 mL) was added. The mixture was warmed to rt and filtered to remove an insoluble brown solid. The filtrate was separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was subjected to purification via silica gel chromatography from 0-5% MeOH in CH2Cl2 to yield crude ethyl 1-[(5-bromopyridin-2-yl)(hydroxy)methyl]-4-oxo-4H-quinolizine-3-carboxylate that gave a mass ion (ES+) of 402.9 (79Br) for M+H+.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:8][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccccc1C
Temperature: 70 °C

Procedure:
A mixture of 10.8 g (0.1 mol) of o-cresol, 18.1 g (0.1 mol) of ethyl 2-bromopropionate, and 14.5 g of K2CO3 in 50 ml of DMF is heated at 70° C. for 3 days. The reaction mixture is poured into H2O, and extracted with ethyl acetate. The organic solution is dried and evaporated to give ethyl 2-(2-methylphenoxy)propionate which is used directly in the next step.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>C(Cl)Cl>[C:19]([Si:16]([CH3:18])([CH3:17])[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)([CH3:22])([CH3:21])[CH3:20]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Imidazole (15.3 g, 225 mmol) was added to a solution of 4-hydroxyindole (20 g, 150 mmol) in 300 mL of anhydrous methylene chloride at ambient temperature. The resulting mixture was treated with tert-butyldimethylsilyl chloride (25 g, 165 mmol). After stirring overnight at ambient temperature, the reaction mixture was poured into 300 mL of water. The layers were separated, and the aqueous phase was extracted with methylene (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to a black oil. The crude residue was purified on a Prep 500 (silica gel; 0% to 5% ethyl acetate/hexanes) to give the title compound as a light purple waxy solid in quantitative yield. MS (ion spray, NH4OAc) m/e [M+1]+ 248, [M−1]− 246.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([Cu])#[N:11]>CN(C=O)C.CCOC(C)=O.[Cu]I>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][C:2]=1[F:1]
Reactant: N#C[Cu]
Reactant: Nc1ccc(I)cc1F
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c(F)c1
Yield: 101.4 %

Procedure:
2-Fluoro-4-iodoaniline (5.0 g, 21 mmol) was dissolved in 20 mL dry DMF. To it were added CuCN (3.8 g, 42 mmol) and catalytic amount of CuI (200 mg). The slurry was refluxed for 1 hour. Diluted with EtOAc. Filtered through celite. Concentrated in vacuuo to yield solid 4-amino-3-fluorobenzonitrile (2.9 g, 100%). ES-MS: (M+H)+ 137.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+]>C(O)C>[N+:13]([CH:16]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, step 1, naphthalene-2-carbaldehyde (3 g, 19.20 mmol) in ethanol (35 mL) was reacted with nitro methane (1.17 g, 19.49 mmol) and 10N NaOH (0.807 g, 20.17 mmol). The resulting mixture was stirred at 0° C. for 1 hour to afford 3.2 g of the product (84.21% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CN)CO
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CC(C)(CO)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
50.0 g of N-(benzyloxycarbonyloxy)succinimide (200 mmol) was added to a solution of 13.8 g of 3-amino-2,2-dimethylpropanol (134 mmol) in tetrahydrofuran (140 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/ethyl acetate=9/1-3/1) to obtain 29.52 g of the title compound (yield: 93%).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[N-:10]=[N+:11]=[N-:12].[Na+].Cl>CN(C=O)C>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:12][N:11]=[N:10][N:8]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 135 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A solution of 10.0 grams (0.085 mole) of para-toluonitrile in 160 mL of DMF was stirred and 5.6 grams (0.085 mole) of sodium azide was added. Upon completion of addition, the reaction mixture was warmed to 135° C. where it stirred for three hours. The reaction mixture was then cooled and poured into 200 mL of stirred, cold aqueous 1N hydrochloric acid. Upon completion of addition, the mixture was stirred for five minutes and filtered to collect a white solid. The solid was dried for 16 hours in a vacuum oven at 35-40° C., yielding 7.1 grams of the subject compound. The reaction was repeated.