Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=O)[C:7](=[CH:19][N:20](C)[CH3:21])[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.C(O)(=O)C.C(N)=[NH:31]>C(N)=N>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:31]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1C[N+]([O-])=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Reactant: N=CN
Solvent: CC(=O)O
Product: [O-][N+]1=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2ncncc2C1

Procedure:
A mixture of 0.4 g (1.1 mmol) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one 2-oxide and 1.0 g (9.6 mmol) of formamidine acetate in 20 ml of formamidine was heated on a steam bath for 7 hr. The mixture was poured over ice and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was triturated with ether to give an off-white solid, mp 215°-217° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=467.0, tR (minutes, Method E)=0.83
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)=[CH:5][CH:4]=1.[I-:16].[Na+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][I:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCCCCBr)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(CCCCCCI)cc1

Procedure:
6-(4-Methoxyphenyl)hexyl iodide [VIa; Ar is 4-CH3OC6H4, R is H] was prepared from 16.3 g. of 6-(4-methoxyphenyl)hexyl bromide (Preparation C11) and 9.93 g. of sodium iodide in 325 ml. of 2-butanone, to give 19.3 g. of product as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH:11]=[CH:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH:11]=[CH:10]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Yield: 69.7 %

Procedure:
A suspension of 1.1 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),6-tetraene in 25 ml of methanol and 2.5 ml of water is refluxed at a bath temperature of 100° C. with 1.1 mg of oxalic acid for 1.5 hours. Then, it is added to water, extracted with dichloromethane, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 0.6 g of 17-difluoromethylene-estra -1,3,5(10),6-tetraen-3-ol is obtained as colorless crystals with a melting point of 132-134° C., [α]D22 =-167.9° (c=0.505% in. pyridine).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2nccc(Oc3cccc4ncccc34)c2cc1OC
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (50 mg) and commercially available 5-hydroxyquinoline (50 mg) were mixed and stirred at 170° C. for 10 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by thin layer chromatography on silica gel eluting first with hexane/ethyl acetate (1/1) and then with chloroform/methanol (50/1) to obtain 47 mg of the title compound (yield: 64%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][CH2:22]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[NH2:29][C:30]1[N:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1>CCCCCCC>[C:15]1([S:12]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:3])[N:29]([C:30]4[N:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)[CH2:22][CH2:21]3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: COc1ccc(N)nn1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: COc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4)CC3)C2=O)nn1
Yield: 14.1 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-Benzenesulfonyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.15 g), dimethylaluminium chloride in heptane (0.9 molar, 0.71 ml) and 3-amino-6-methoxypyridazine (0.069 g) to give the desired 8-benzenesulfonyl-2-(6-methoxy-pyridazin-3-yl)-2,8-diaza-spiro[4.5]decan-1-one (0.024 g) as a white solid. MS (ESI): 403.146 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](#[N:13])[CH:11]=[CH2:12]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:12][CH2:11][C:10]#[N:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C=CC#N
Solvent: CO
Product: COc1ccc(OCCC#N)cc1
Temperature: 78 °C
Yield: 89.48 %

Procedure:
A 740 g (5.96 mol, 1 eq.) sample of 4-methoxyphenol was charged to a 3 necked 5 L flask under nitrogen. Triton B (50 mL of a 30% wt. solution in methanol) was charged to the flask, and stirring initiated via an overhead stirrer. Acrylonitrile (2365 mL, 35.76 mol, 6 eq.) was then charged to the reaction flask in a single portion, and the reaction mixture heated at 78° C. for 36 h. HPLC analysis indicated that the reaction was complete at this point. Solvents were removed via rotary evaporation, and the resulting oil was chased with toluene to remove excess acrylonitrile. The crude material was recrystallized from TBME (tert-butyl methyl ether) 10 volumes relative to the crude weight), and dried in a vacuum oven to give 945 g of 1 as white crystals (Yield: 89.48%). 1H NMR (450 MHz, CDCl3): δ=2.72 (t, 2H; CH2CN); δ=3.83 (s, 3H; OCH3); δ=4.05 (t, 2H; OCH2); δ=6.70 (m, 4H; Ar—H); 13C NMR (112.5 MHz, CDCl3): d=18.843 (CH2CN); 55.902 (OCH3); 63.699 (OCH2); 114.947 (CH3OCCH); 116.183 (CH2OCCH); 117.716 (CN); 151.983 (CH3OC); 154.775 (CH2OC).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[F:23]
Reactant: O=C(O)c1ccccc1F
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccccc2F)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 2-fluorobenzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(2-fluorobenzoamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 452.3 (M)+
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][N:8]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>O>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:7]2[N:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[CH2:18][CH2:17]1
Reactant: OC1CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N2CCC(O)CC2)nc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a N,N-dimethylformamide (100 mL) solution of 2-chloro-5-cyanopyridine (36.2 g, 262 mmol) and 4-hydroxypiperidine (27.9 g, 275 mmol) was added potassium carbonate (40.1 g, 290 mmol). The reaction mixture was heated to 100° C. and stirred for 3 hours. It was cooled to room temperature, diluted with water (400 mL), and extracted with dichloromethane (3×250 mL). The combined organic extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo to afford the title compound as a solid. This crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J=2.3 Hz, 1H), 7.58 (dd, J=9.1, 2.4 Hz, 1H), 6.62 (d, J=9.1 Hz, 1H), 4.10 (dt, J=13.6, 5.0 Hz, 2H), 4.01 (tt, J=8.3, 3.9 Hz, 1H), 3.37 (ddd, J=13.6, 9.2, 3.4 Hz, 2H), 2.61 (s, 1H), 1.99-1.92 (m, 2H), 1.62-1.53 (m, 2H); LC-MS: m/z 204.2 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[C:9]3[N:10]=[C:11]([C:17]4[N:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=[N:19][N:18]=4)[S:12][C:13]=3[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[CH:22]([N:21]1[CH:20]=[N:19][N:18]=[C:17]1[C:11]1[S:12][C:13]2[CH2:14][CH2:15][O:16][C:7]3[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:26]=[CH:25][C:8]=3[C:9]=2[N:10]=1)([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc2c(c1)OCCc1sc(-c3nncn3C(C)C)nc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C(=O)O)ccc1-2
Reaction time: 65 h
Yield: 95 %

Procedure:
To a suspension of 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid methyl ester in THF (6 mL) and water (1.5 mL) was added an aqueous 1N lithium hydroxide solution (1.0 mL, 1.0 mmol). The reaction mixture was stirred for 65 hours then an aqueous 1N HCl solution (2 mL) was added and the mixture was concentrated in vacuo to remove THF. A small quantity of MeOH was added to the resultant mixture and the solid was collected by filtration to give the title compound as an off-white solid (226 mg, 95%). LCMS: RT=3.88 min, [M+H]+=357
Reaction SMILES: [N:1]1([CH2:7][CH:8]([C:10]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=2)[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CI.[C:32]([O-])(O)=O.[Na+]>C1COCC1>[CH3:32][O:9][CH:8]([C:10]1[C:19]2[C:14](=[C:15]([C:20]([F:21])([F:22])[F:23])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:24]([F:27])([F:25])[F:26])[CH:11]=1)[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: OC(CN1CCCCC1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(CN1CCCCC1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To an ice-cold solution of α-piperidinomethyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol (60 mg, 0.15 mmol) in THF (1.5 mL) was added NaH (6 mg, 60% dispersion in oil, 0.15 mmol), the mixture stirred at 0° C. for 30 min, treated with methyl iodide (10 μL, 0.16 mmol), allowed to warm to room temperature and stirred for 1 h. The reaction mixture was poured into saturated NaHCO3, extracted with EtOAc (2×20 mL), the combined extracts dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2, EtOAc] to give the title compound (62 mg, 100%) as a pale yellow oil: IR νmax (Nujol)/cm−1 2937, 2855, 2824, 1603, 1585, 1309, 1188, 1147, 1108 and 769; NMR δH (400 MHz, CDCl3) 1.40-1.45 (2H, m), 1.52-1.66 (4H, m), 2.44-2.61 (5H, m), 2.84 (1H, dd, J 13.9, 7.8 Hz), 5.14 (1H, dd, J 7.8, 3.3), 7.74 (1H, t, J 7.7 Hz), 7.92 (1H, s), 8.17 (1H, d, J 6.9 Hz) and 8.45 (1H, d, J 8.5 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][NH2:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(O)C>[Br:1][C:2]1[C:3]([NH:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Reaction time: 20 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine 3.2 g (0.0135 mole) in ethanol 80 mL was added Hunig's base 3.0 mL followed by the addition of a solution of N-(tert-butoxy carbonyl)-1,2-diaminoethane 2.5 g (0.0156 mole) in 20 mL ethanol. The contents were stirred overnight for 20 hrs. The solvent was evaporated under vacuum. Ethyl acetate (200 mL) and water (100 mL) was added and the layers separated. The organic layer was dried with magnesium sulfate and then concentrated under vacuum. Column chromatography on silica gel using hexane/ethyl acetate (0-60%) afforded tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. 1HNMR (d6-DMSO) 8.21 (s, 1H), 7.62 (brs, 1H), 7.27 (brs, 1H), 3.39 (m, 2H), 3.12 (m, 2H), 1.34 (s, 9H). LCMS (ESI) 351 (M+H)
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([CH3:16])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([S:7][C:8]1[N:9]=[C:10]([CH3:16])[CH:11]=[C:12]([CH2:14][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCNC1
Reactant: CCCCCCSc1nc(C)cc(C=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCSc1nc(C)cc(CN2CCCC2)n1
Reaction time: 24 h
Yield: 28.2 %

Procedure:
2-Hexylsulfanyl-6-methyl-pyrimidine-4-carbaldehyde (0.1 g, 0.42 mmol) was dissolved in ethanol (1 mL) and acetic acid (0.1 mL). Then pyrrolidine (0.07 mL, 1 mmol) and sodium cyanoborohydride (26 mg, 0.4 mmol) were added slowly at 20° C. and stirring continued for 24 h. The reaction mixture was evaporated to dryness and dissolved in a minimal amount of DMF (0.8 mL) and directly purified by preparative HPLC chromatography on a YMC combiprep ODS-AQ column (75×20 mm iD, S-5 μM, 12 nm) with an acetonitrile-water gradient. One obtained 34.7 mg (28%) of a yellow liquid. MS: m/z=294 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[C:5](O)=[O:6].C([N:20](CC)CC)C.ClC(OCC(C)C)=O.N>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[C:5]([NH2:20])=[O:6]
Reactant: CCN(CC)CC
Reactant: CN1CCN(c2ccc(C(=O)O)cc2F)CC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(N)=O)cc2F)CC1
Reaction time: 3 h
Yield: 12 %

Procedure:
To 3-fluoro-4-(4-methylpiperazin-1-yl)benzoic acid (250 mg, 1.05 mmol) in THF (10 ml) was added triethylamine (221 μl, 1.58 mmol) and isobutyl chloroformate (145 μl, 1.10 mmol). The mixture was stirred at 0° C. for 1 hour, at which time concentrated aqueous ammonia (3 ml) was added. The reaction mixture was stirred for 3 hours then the volume was reduced in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated to afford (30.0 mg, 12%) of 3-fluoro-4-(4-methylpiperazin-1-yl)benzamide, which was used without further purification. MS (EI) for C12H16FN3O: 238 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:42])([CH3:41])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32]1=[O:40].FC(F)(F)C([O-])=O>>[CH3:42][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:41])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32]1=[O:40]
Reactant: CC(C)(N)CCn1c(=O)oc2ccccc21
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(CCn1c(=O)oc2ccccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
This is prepared according to General Method 1 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 220 mg (1 mmol) 3-(3-amino-3-methyl-butyl)-3H-benzoxazol-2-one. Yield: 227 mg (42%, trifluoroacetate); mass spectroscopy: [M+H]+=428.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[OH:16][C:17]1[C:18](=[O:28])[C:19]2[C:24]([C:25](=[O:27])[CH:26]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>C1C=CC=CC=1.[Ag]>[O:28]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:26][C:17]1=[O:16]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: O=C(CCCCBr)OCc1ccccc1
Agent: [Ag]
Solvent: c1ccccc1
Product: O=C(CCCCOC1=CC(=O)C(=O)c2ccccc21)OCc1ccccc1

Procedure:
A mixture of benzyl 5-bromovalerate (2.27 g, 8.4 mmol) and the silver salt of 2-hydroxy-1,4-naphthoquinone (1.63 g, 5.81 mmol) in benzene (8 mL) was stirred for 48 h at 55° C. and filtered through celite. The filtrate was diluted with diethyl ether, extracted with a 20% aqueous solution of NaHSO3 then basified to pH 10-11 with Na2CO3, and extracted with CH2Cl2. Yellow solid (1.334 g, 63%). 1H NMR (CDCl3) 8.12 (d, J=7.5 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.68 (t, J=7.5, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.25-7.50 (m, 5H), 5.93 (s, 1H), 5.14 (s, 2H), 4.15 (t, J=5.7 Hz, 2H), 2.50 (t, J=7.0 Hz, 2H), 1.8-2.2 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:48]([C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[N:52][CH:51]=1)=[CH2:49]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([CH:49]=[CH:48][C:50]4[C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH:53]=[N:52][CH:51]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: C=Cc1cncc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(C=Cc4cncc5ccccc45)cc3CC[C@@H]12
Reaction time: 20 h

Procedure:
A 508 mg portion of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one, 4 mg of palladium acetate, 20 mg of tri-o-tolylphosphine, 0.34 mL of triethylamine and 5 mL of dimethylformamide were combined in a sealable tube with a stir bar, and the mixture was warmed to 50 under argon. An 0.26 g portion of 4-ethenylisoquinoline was added. Then the vessel was blanketed with argon and sealed and the mixture was heated with stirring at 120° for 20 hours. It was then cooled, and concentrated under vacuum and the residue was purified by chromatography on silica gel, eluting with 5% isopropanol in chloroform. An 0.29 g portion of an oil was obtained, which was recrystallized from ethyl acetate/hexane to obtain the desired product in crystalline form. mp 183°-185°; FDMS 382 M+.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].[C:21](#[N:24])[CH:22]=[CH2:23].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:1]([C:3]1[C:7](/[CH:23]=[CH:22]/[C:21]#[N:24])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: C=CC#N
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#C/C=C/c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.864 g), acrylonitrile (0.264 g), triethylamine (0.4 ml), palladium acetate (0.04 g) and dimethylformamide (10 ml) were stirred under an atmosphere of nitogen at 70° C. for 24 hours. The reaction mixture was evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with water, brine, then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid m.p. 144-145° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8](=[O:12])/[CH:9]=[CH:10]/[CH3:11].[C:13]1([Si:19]([CH3:22])([CH3:21])Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH:8]([O:12][Si:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:22])[CH3:21])=[CH:9][CH:10]=[CH2:11]
Reactant: C/C=C/C=O
Reactant: C[Si](C)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC=CO[Si](C)(C)c1ccccc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A 250 mL flask, fitted with a magnetic stirrer, a reflux condenser and an addition funnel, was charged with zinc chloride (0.25 g, 1.83 mmol, anhydrous), triethylamine (36.2 mL, 0.260M, distilled from CaH2), crotonaldehyde (21.0 mL, 0.257M, dried over MgSO4 and distilled), and toluene (35 mL, distilled from sodium). 42 mL of phenyldimethyl chlorosilane (0.254M) were added dropwise via the addition funnel over one hour with stirring. The resulting mixture was heated slowly to about 65° and maintained at 65°-75° for a total of 6.5 hours with stirring. The mixture was cooled to ambient temperature and filtered to remove precipitated triethylamine hydrochloride (32 g, 92%) which was rinsed on the filter with 35 mL of dry toluene. The resulting filtrate and rinse were combined and distilled on a water pump at about 110 mm to remove solvent and unreacted starting materials. The resulting residue was distilled on an oil pump to give (1,3-butadienyloxy)phenyldimethylsilane (30.9 g, 59%) as a colorless liquid boiling at 57.8°-59.0°/0.10 mm (13 Pa).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.[ClH:22]>CCOC(C)=O.O>[ClH:22].[ClH:22].[CH3:1][O:2][C:3]1([C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=2)[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: COC1(c2nccn2C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC1(c2nccn2C)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (182 mg) in EtOAc (0.7 ml) and water (0.09 ml) was added 4N hydrogen chloride in EtOAc (0.7 ml) and the mixture was stirred at room temperature for 2 hours. Solvent was removed in vacuo to give 4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidine dihydrochloride (122 mg) as a colorless powder. The obtained crude product was used in next reaction without further purification.