Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:13][CH2:12][C:11]([CH3:14])=[CH:10][CH2:9][CH2:8][C:7]([CH3:15])=[CH:6][CH2:5][CH2:4][CH:3]=1.[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][CH2:13]1)[CH3:17]
Reactant: CC1=CCCC=C(C)CCC(C)=CCC1
Reactant: CCO
Product: CCOC1(C)CCCC=C(C)CCC=C(C)CC1
Yield: 63 %

Procedure:
550 g (2.7M) of 2,5,9-trimethyl-cyclododeca-1,5,9-triene and 380 g of acidic diatomaceous earth in 6250 ml of anhydrous ethanol were refluxed for 72 h to give, after the same treatment as that described in Example 1 above, 532 g of a product having b.p. 70°-110°/0.01 Torr. On fractional distillation, there were recovered 495 g of starting 2,5,9-trimethyl-cyclododeca-1,5,9-triene (b.p. 43°-52°/0.1 Torr) and 42.5 g of the desired product (b.p. 90°-105°/0.01 Torr); yield 63% based on the converted starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH:30]3[CH2:32][CH2:31]3)(=[O:29])=[O:28])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:33])[CH:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH:30]3[CH2:31][CH2:32]3)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[CH2:9]/[C:10](=[N:35]\[OH:36])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(NS(=O)(=O)C2CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(NS(=O)(=O)C2CC2)cc1

Procedure:
In analogy to example 151, step 3, cyclopropanesulfonic acid {4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-phenyl}-amide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing 7% of the corresponding Z isomer as a colourless solid, MS (ESI+): m/z=500.3 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([CH3:14])[CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:15])([CH3:3])[CH3:2].[CH3:16][O:17]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:13]=[C:12]([CH:16]=[O:17])[C:11]2[C:6]([C:5]=1[OH:15])=[C:7]([CH3:14])[CH:8]=[CH:9][CH:10]=2)([CH3:3])[CH3:2]
Reactant: Cc1cccc2ccc(C(C)C)c(O)c12
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cccc2c(C=O)cc(C(C)C)c(O)c12
Temperature: 0 °C

Procedure:
0.65 g of 2-isopropyl-8-methyl-1-naphthol was dissolved in 50 ml of dichloromethane and cooled down to 0° C. 1.3 ml of titanium tetrachloride was gradually dropped in the solution for reaction at 0° C. for 5 minutes, after which 0.9 ml of dichloromethyl methyl ether was gradually dropped and reacted at 0° C. for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were collected by filtration to obtain 0.7 g of the captioned compound as black crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][NH:37][CH3:38]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33]([N:37]([CH3:38])[CH3:36])[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1cc(N2CCN(C(=O)Cn3nc(-c4ccc(F)cc4)nc3-c3ccc(F)cc3)CC2)ncn1

Procedure:
40 mg 2-(3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-1-(4-(6-chloro-pyrimidin-4-yl)-piperazin-1-yl)-ethanone and 2 mL 2 M dimethylamine solution in THF were stirred 30 min at 170° C. under microwave condition. The mixture was purified by HPLC to give 19.1 mg of the desired product. Rt: 1.88 min (method I), (M+H)+: 505
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=[CH:3]1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:19]O)=[NH:18])=[N:15][CH:16]=1.O>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:19]=[C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[O:8][N:18]=2)=[N:15][CH:16]=1
Reactant: Cn1cncc1C(=O)Cl
Reactant: N=C(NO)c1ccc(Cl)cn1
Solvent: O
Solvent: c1ccncc1
Product: Cn1cncc1-c1nc(-c2ccc(Cl)cn2)no1
Temperature: 25 °C
Yield: 4.6 %

Procedure:
A mixture of 3-methyl-3H-imidazole-4-carbonyl chloride (91 mg, 0.5 mmol), 5-chloro-N-hydroxy-pyridine-2-carboxamidine (85.8 mg, 0.5 mmol) in pyridine (5 ml) was refluxed for 4 h and then cooled to room temperature. To the solution was added water (20 ml) and the product precipitated from the solution. The solid was collected by filtration and washed with water, dried to give 6 mg (5%) of the title compound. 1H NMR (CDCl3): 8.78 (d, J=2.4 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.87 (dd, J=2.7 Hz, J=8.7 Hz, 1H), 7.70 (s, 1H), 4.14 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[C:9]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][O:11][CH2:10]1.C(=O)([O-])O.[Na+]>C1COCC1>[C:5]([CH:4]([C:3]#[N:7])[C:9]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][O:11][CH2:10]1)#[N:6]
Reactant: COC(=O)C1(Br)CCOC1
Reactant: N#CCC#N
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(C#N)C#N)CCOC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
440 mg (11.00 mmol) of sodium hydride (60% in mineral oil) were initially charged in 30 ml of THF, and 726 mg (11.00 mmol) of malononitrile were added in portions. Thereafter, 2.3 g (11.00 mmol) of the compound obtained in example 11A in THF (50 ml) were added. The mixture was stirred at RT for 6 h and then heated to 50° C. overnight. After cooling, the mixture was admixed with saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated. The residue (2.66 g) was dried under high vacuum for 1 h and then converted without further purification.
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)C.ClC1C=CC(C2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:34][CH:33]=4)[N:26]=3)=[CH:23][NH:22][N:21]=2)=CC=1>>[CH2:44]([N:41]([CH2:42][CH3:43])[CH2:40][CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:27]2[N:26]=[C:25]([C:24]3[C:4]([C:5]4[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=4)=[N:21][NH:22][CH:23]=3)[CH:30]=[CH:29][N:28]=2)=[CH:33][CH:34]=1)[CH3:45]
Reactant: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3)n2)cc1
Reactant: CCOC(=O)c1cccc(C)c1
Product: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3cccc(C)c3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using ethyl-3-methylbenzoate (Aldrich 25,305-7) and 4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=12.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.[H-].[Na+]>CN(C)C=O>[O:17]1[CH2:16][CH:15]1[CH2:13][N:5]1[C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]2=[N:1][C:6]1=[O:7]
Reactant: BrCC1CO1
Reactant: O=c1nc2n(c(=O)[nH]1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1nc2n(c(=O)n1CC1CO1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
After dissolving 6,7,8,9-tetrahydropyrido[1,2-a][1,3,5]triazine-2,4-dione (CAS 133365-43-2) (195 mg) and epibromohydrin (321 mg) in N,N-dimethylformamide (1 ml), sodium hydride (60% in oil) (52 mg) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography. The title compound (189 mg) was thus obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:8]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(OCC)C>[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:8]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCCCN1c1ccccc1CCN1CCC(C2CCCCN2)C1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCCC1C1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of 1-(2-{2-[3-(piperidin-2-yl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one a12-1 (25 mg, 0.070 mmol, 1 eq) in diethylether (2 ml) at 0° C. are added triethylamine and acetic anhydride (7 μl, 0.077 mmol, 1.1 eq). The mixture is stirred for 1 hour at room temperature. The solvent is removed under vacuum. The residue obtained is purified by basic reverse phase chromatography (gradient: acetonitrile/H2O/ammonium formate from 5% to 95% of acetonitrile in 8 minutes) to afford 14.5 mg of 1-(2-{2-[3-(1-acetylpiperidin-2-yl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one 72 as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]#[N:14])[C:6](=O)[NH:7]2.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:6]1[C:5]([C:13]#[N:14])=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc2c(F)cccc2[nH]c1=O
Product: N#Cc1cc2c(F)cccc2nc1Cl

Procedure:
5-Fluoro-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (0.80 g, 4.3 mmol) was heated in POCl3 (10 mL) for 3 hrs. The mixture was concentrated and partitioned in ethyl acetate and water. The organic layer was separated, washed with NaHCO3, dried and concentrated. The residue was crystallized from a mixture of hexane and ethyl acetate to give 2-chloro-5-fluoro-quinoline-3-carbonitrile 32-1 as a white solid (0.83 g). 1HNMR (CDCl3), δ, 8.82 (1H, s), 7.83-7.92 (2H, m), 7.33-7.41 (1H, m).
Reaction SMILES: O=C1N(C)C(=O)N(C)[CH:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:13][C:12]=2[OH:27])N1C.[OH-:29].[Na+]>O>[C:21]1([S:18]([NH:17][C:14]2[CH:13]=[C:12]([OH:27])[C:11](=[CH:16][CH:15]=2)[CH:4]=[O:29])(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1C(=O)N(C)C(c2ccc(NS(=O)(=O)c3ccccc3)cc2O)N(C)C1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1O
Yield: 98.8 %

Procedure:
432 g (1 mol) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-6-[2-hydroxy-4-benzenesulphonamido-phenyl]-s-triazine (93.5% pure product) are introduced into a solution of 280 g (7 mols) of sodium hydroxide in 600 ml of water. The mixture is boiled under reflux and under nitrogen for 6 hours. A pale brown solution is formed, from which small single crystals separate out. The contents of the flask are then poured onto a mixture of 700 ml of concentrated hydrochloric acid and 2 kg of ice and the yellow product which has separated out is filtered off. After washing with water and drying at 80° C, 274 g of 4-benzene-sulphonamido-salicylaldehyde of melting point 150° to 157° C are obtained. According to the oxime titration, the aldehyde is 94.8% pure and the yield is thus 93.6%. After recrystllisation from xylene (1 : 10), the aldehyde is obtained as colourless crystals of melting point 160° to 163° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Se](=O)=[O:19].[OH2:21]>O1CCOCC1>[OH2:8].[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:16]=[O:19])=[O:17])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:16]=[O:21])=[O:17])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)c1ccc(OCC2CCCCC2)cc1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)c1ccc(OCC2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 18.5 h

Procedure:
A mixture of 12.0 g of 4'-(cyclohexylmethoxy)acetophenone, 5.8 g of selenium dioxide, 1.4 ml of water and 70 ml of p-dioxane was refluxed with stirring at 120° C. for 18.5 hours, cooled and filtered through diatomaceous earth, washing with p-dioxane. The combined filtrate and wash was poured into 200 ml of water cooled to 8° C. The yellow solid was collected and dried. An 8.1 g portion of sodium bisulfite was dissolved in 500 ml of water. To this was added a solution of the above solid in a mixture of 300 ml of ethanol and 100 ml of p-dioxane. The resulting mixture was filtered and the filtrate stored at 0° C. for 48 hours. The resulting solid was collected, washed twice with water, p-dioxane and absolute ethanol and then dried. This solid was added to 535 ml of 0.5N hydrochloric acid and heated with stirring at 75° C. for 8 minutes and then cooled to 10° C. The solid was collected, dissolved in hot p-dioxane, filtered and 20 ml of water added to the filtrate. The filtrate was cooled to 0° C., giving the desired product as a white solid, m.p. 118°-121° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:17][NH:18][CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:19])[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CNC
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCc1nnc2c(N(C)C)nc3ccccc3n12
Reaction time: 0.33 h
Yield: 42 %

Procedure:
4-Chloro-1-ethyl-[1,2,4]triazolo-[4,3-a]quinoxaline (1.2 g., 0.005 mole), the product of Example 4, and 676 mg. (0.015 mole) of anhydrous dimethylamine in N,N-dimethylformamide (50 ml.) were stirred at 0° C. for 30 minutes and at room temperature for 2 hours. The reaction mixture was poured over ice and stirred for 20 minutes. The precipitate which formed was separated by filtration, washed with water and air dried. Recrystallization from chloroform and then from chloroform/cyclohexane afforded 510 mg. (42% yield) of 4-dimethylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 155°-8° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH3:27][N:28]([CH2:30][C:31]#[CH:32])[CH3:29]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:32]#[C:31][CH2:30][N:28]([CH3:29])[CH3:27])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: C#CCN(C)C
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(C)CC#Cc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Examples 43 and 60, Sonagoshira coupling of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and N,N-dimethylpropargyl amine gave 125.
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:20])([CH3:19])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[C:15]([NH:17][NH2:18])[N:16]=[C:11]2[CH:10]=[CH:9]1.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[C:28](O)=[O:29].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[CH3:2][Si:3]([CH3:20])([CH3:19])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[C:15]([NH:17][NH:18][C:28]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]3[CH3:21])=[O:29])[N:16]=[C:11]2[CH:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NN)cnc21
Reactant: CC1CCCCC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCCC1C(=O)NNc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
A flask containing a mixture of [5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-hydrazine hydrochloride (336 mg, 1.06 mmol) and (+/−)-2-methyl-1-cyclohexane-carboxylic acid (0.18 mL, 1.22 mmol) in dry dichloromethane (11 mL) was cooled to 0° C. (ice bath) under nitrogen atmosphere. To this cooled mixture was added triethylamine (0.31 mL, 2.1 mmol) and EDCI (278 mg, 1.45 mmol). After 30 minutes the cooling bath was removed and the material was stirred for 3 hours. An aqueous solution of 5% sodium bicarbonate (40 mL) and methylene chloride (30 mL) were added and the mixture was shaken in a reparatory funnel. The organic phase was collected and washed with brine (40 mL). The aqueous phases were back extracted with methylene chloride (2×30 mL). The organic phases were combined, dried (MgSO4), filtered and stripped. The crude remainder was purified by preparative TLC, using 45% ethyl acetate in hexanes to elute. The product band was collected, affording 152 mg of (+/−)-2-methyl-cyclohexanecarboxylic acid-N′-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-hydrazide as a golden brown oil, which solidified on standing. MS (M+H)+=404.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.C([O-])(=O)C.[Na+].[Na+].[I-:31]>CC(C)=O>[I:31][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Reactant: [I-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 0 °C

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (159 mg, 0.5 mmol) and sodium acetate (82 mg, 1 mmol) in acetone (7 mL) was treated with NaI (90 mg, 0.6 mmol). The mixture was refluxed for 2 h, and then it was poured into ice-water. The precipitated solid was collected by filtration, washed with water, and dried. The crude product was crystallized from EtOAc-hexane to give the title compound as yellow rods (105 mg); mp 155-160° C.; 1H NMR (CDCl3) 7.36 (s, 1H), 7.29 (s, 1H), 7.23 (s, 1H), 7.22 (d, J=6.5, 1H), 6.98 (d, J=8.3, 1H), 6.15 (s, 2H), 6.07 (s, 2H), 4.71 (s, 2H). Anal. calcd. for C17H11N2O4.(¼)H2O: C, 46.50; H, 2.62; N, 6.38. Found: C, 46.43; H, 2.53; N, 6.28.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[C:7]([NH2:9])=[O:8].C=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O.N>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[C:7]([NH2:9])=[O:8])[CH3:28]
Reactant: CNCc1cc(C(N)=O)ccc1Oc1ccc(SC)c(C(F)(F)F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CSc1ccc(Oc2ccc(C(N)=O)cc2CN(C)C)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 79 %

Procedure:
The amide from example 177 (105 mg, 0.28 mmol) was suspended in DCM (3 mL) and treated with formaldehyde (37% aqueous, 35 μL, 0.425 mmol). The mixture was stirred for 30 minutes (dissolution had occurred by this stage) and then treated with sodium tri(acetoxy)borohydride (120 mg, 0.567 mmol). The reaction was stirred overnight and then diluted with water (5 mL), basified with 880 ammonia (1 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4) and evaporated to a white solid. Purification by flash chromatography [SiO2; DCM, MeOH, 880 NH3 (95:5:0.5)] afforded the title amide as a white powder (85 mg, 78%); Free base: δH (CDCI3, 400 MHz) 2.24 (6 H, s), 2.46 (3 H, s), 3.50 (2 H, s), 5.47-6.15 (2 H, brm), 6.85 (1 H, d), 7.03 (1 H, d), 7.23 (1 H, s), 7.35 (1 H, d), 7.71 (1 H, d), 7.90 (1 H, s); MS m/z (TS+) 385 (MH+)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]([OH:22])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[C:4](=[O:23])[CH2:3]1.[O:24]=[C:25]1[NH:30][C:29]2[CH:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>CN(C=O)C>[OH:22][C@H:9]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:35][C:32]2[CH:33]=[CH:34][C:28]3[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=3[CH:31]=2)[CH2:3][C:4]1=[O:23]
Reactant: COc1ccc2nccc([C@@H](O)CN3CCC(N)CC3=O)c2c1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2nccc([C@@H](O)CN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3=O)c2c1

Procedure:
A mixture of 4-amino-1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-2-one (4e) (1 equiv.), 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (in) (1.1 equiv.), and Na2SO4 in DMF is stirred until the imine has formed, then is filtered through a sintered glass funnel. The filtrate is concentrated to dryness in vacuo, and the residue is dissolved in MeOH. NaBH4 (1 equiv.) is added, and the reaction is stirred until the imine is consumed. The solvent is removed in vacuo and the residue is taken up in dilute HCl. The mixture is neutralized with dilute NaOH and extracted with CH2Cl2. Drying (Na2SO4), concentration, and flash chromatography on silica gel gives the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=1>O>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: O
Product: COC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 234.5 %

Procedure:
A mixture of morpholine (996 mg, 1 mL, 11.4 mmol) and 4-fluoro benzoic acid methyl ester (500 mg, 0.32 mmol) was stirred with heating at 120° C. for 48 hrs. Cold water then added, filtered the solid precipitated to afford 166 mg (23.15% yield) of 4-morpholin-4-yl-benzoic acid methyl ester. 1H NMR (CDCl3): δ 8.0 (d, 2H), 6.9 (d, 2H), 3.9 (m, 7H), 3.3 (t, 4H).
Reaction SMILES: [S:1]1[C:5]2[S:6][CH2:7][CH2:8][C:9](=O)[C:4]=2[CH:3]=[CH:2]1.Cl.[NH2:12][OH:13].O.C(O)C.C([O-])(=O)C.[Na+]>C(O)C>[N:12](=[C:9]1[CH2:8][CH2:7][S:6][C:5]2[S:1][CH:2]=[CH:3][C:4]1=2)[OH:13]
Reactant: NO
Reactant: O=C1CCSc2sccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCSc2sccc21

Procedure:
To a solution of 5,6-dihydrothieno[2,3-b]thiopyran-4-one (5.0 g, 29.4 mmol) in ethanol (98 ml) was added a solution of hydroxylamine hydrochloride (4.9 g, 70.6 mmol) in 2:1 water-ethanol (27 ml). Sodium acetate.3H2O (9.6 g, 70.6 mmol) in 2:1 water-ethanol (27 ml) was added and the solution was heated at reflux for 2 hours. The reaction mixture was concentrated to dryness, water was added and the solid product (5.3 g, 98%) was collected and dried. An analytical sample was prepared by recrystallization from acetonitrile; m.p. 123°-124° C.