Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([O:18]C(C)(C)C)=[N:9][C:10]([O:13]C(C)(C)C)=[N:11][CH:12]=1.[CH3:23][C:24]1[CH:40]=[CH:39][C:27]2[C:28](=O)[C:29]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=3[CH2:31][CH2:32][C:26]=2[CH:25]=1>O1CCCC1>[CH3:37][C:34]1[CH:35]=[CH:36][C:29]2[CH:28]([C:7]3[C:8](=[O:18])[NH:9][C:10](=[O:13])[NH:11][CH:12]=3)[C:27]3[CH:39]=[CH:40][C:24]([CH3:23])=[CH:25][C:26]=3[CH:32]=[CH:31][C:30]=2[CH:33]=1
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Reactant: Cc1ccc2c(c1)CCc1cc(C)ccc1C2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (5.6 ml of a 2.5M solution in hexanes) was added dropwise to a solution of 5-bromo-2,4-bis(1,1,-dimethylethoxy)pyrimidine (example 1 step (i)) (3.85 g) in tetrahydrofuran (30 ml) at -78° C. The solution was stirred for 30 minutes and a solution of 10,11-dihydro-2,8-dimethyl-5H-dibenzo[a,d]cyclohepten-5-one (European Patent, 1993, 0 589 322 A1) (3.0 g) in tetrahydrofuran (20 ml) was added. The mixture was stirred at -78° C. for 45 minutes and room temperature for 15 minutes and then partitioned between brine and ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in glacial acetic acid (100 ml) and heated at 120° C. for 30 minutes. The solvent was evaporated and the residue azeotroped with toluene and triturated with diethyl ether to give a solid. Yield 4.03 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)[CH3:2].F[C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=1[CH:20]=[O:21].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:14]([N:13]([CH2:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:7][CH2:8]1)[C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=1[CH:20]=[O:21])[CH3:15]
Reactant: CCNC[C@H]1CC[C@H](CC(=O)OCC)CC1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2C=O)CC1

Procedure:
A stirred mixture of ethyl{trans-4-[(ethylamino)methyl]cyclohexyl}acetate (Intermediate 7; 130 mg; 0.57 mmol), 2-fluoro-5-(trifluoromethyl)benzaldehyde (100 mg; 0.52 mmol) and potassium carbonate (215 mg; 1.56 mmol) in toluene (4 mL) was heated at reflux for 14 h. The reaction was washed with H2O and sat. KHSO4 (10 mL each) and the aqueous layers were re-extracted with toluene (10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to afford ethyl [trans-4-({ethyl[2-formyl-4-(trifluoromethyl)phenyl]amino}methyl)cyclohexyl]acetate as a yellow oil. LCMS=400.2 (M+1)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]1O)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCC1Cc2c(-c3ccccc3)cccc2C1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1=Cc2c(cccc2-c2ccccc2)C1
Temperature: 0 °C
Yield: 72.2 %

Procedure:
To a 1-liter four-necked round flask (equipped with a stirrer, a dropping funnel and a thermometer) were fed 29.3 g (123.9 mmol) of 2-ethyl-1-hydroxy-4-phenylindane, 51.6 g (371.4 mmol) of triethylamine, 0.75 g (6.3 mmol) of 4-dimethylaminopyridine and 294 ml of methylene chloride. Then, a solution obtained by dissolving 19.2 ml (247.5 mmol) of methanesulfonyl chloride in 19.5 ml of methylene chloride was dropwise added slowly to the system while cooling with ice in a nitrogen atmosphere. After the addition was completed, the resulting mixture was reacted for another 3.5 hours at the same temperature. The reaction mixture was poured in 500 ml of ice water, then the organic phase was separated, and the aqueous phase was further extracted twice with 150 ml of methylene chloride. The whole organic phase was successively washed with a saturated NaHCO3 solution and a saturated salt solution, and dried with anhydrous Na2SO4. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography (developed with hexane), to obtain 19.7 g of the aimed product (mixture of two kinds of isomers) as a light yellow liquid (yield: 73%)
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CCl
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CNCc1ccc(Cl)cc1

Procedure:
A mixture of 2.76 g of (2R)-3-chloro-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester, 3.54 g of p-chlorobenzylamine, 3.25 g of N-ethyl-N,N-diisopropylamine and 20 ml of ethanol is heated under reflux for 48 hours. Removal of the solvent and chromatography yield (2S)-3-(p-chlorobenzylamino)-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester; 1H-NMR spectrum (in CDCl3): δ=7.4-7.17 (9H,m); 4.14-3.83 (3H,m); 3.71 (2H, ABq); 3.20 (2H,d): 2.6-2.5 (2H,m); 1.96-1.62 (2H,m); 1.25 (3H,t); 31P-NMR spectrum (in CDCl3): δ=53.9; 52.7.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(O[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Yield: 75 %

Procedure:
A mixture of potassium phthalimide (1.16 g, 6.29 mmoles) and 40 ml of dried N,N-dimethylformamide was heated up to 110° C. To this mixture was added dropwise a solution of methyl 22-tosyloxydocosanoate (2.20 g, 4.19 mmoles) in 70 ml of N,N-dimethylformamide, and the reaction mixture was reacted for 2 hours at 110° C. After the completion of reaction, the reaction mixture was subjected to the same after-treatment steps as in Reference Example 2, to give methyl 22-phthalimidodocosanoate (1.57 g, 95%) having the following properties.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:7]1[N:8]([CH3:21])[C:9]2[C:14]([C:15]=1[C:16](O)=[O:17])=[CH:13][CH:12]=[C:11]([O:19][CH3:20])[CH:10]=2)[CH3:6].[CH3:22][NH2:23]>>[CH3:22][NH:23][C:16]([C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[CH:12][CH:13]=2)[N:8]([CH3:21])[C:7]=1[CH2:5][CH3:6])=[O:17]
Reactant: CN
Reactant: CCc1c(C(=O)O)c2ccc(OC)cc2n1C
Solvent: O=S(Cl)Cl
Product: CCc1c(C(=O)NC)c2ccc(OC)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Thionyl chloride (0.383 ml, 4.45 mmole) was added to a solution of 2-ethyl-6-methoxy-1-methyl-1H-indole-3-carboxylic acid 73e (0.347 g, 1.48 mmole). The reaction mixture was heated to reflux for 30 min and concentrated. The residue was dissolved in 5 ml CH2Cl2 and added methylamine (2.0 M in THF, 2.22 ml, 4.44 mmole). The reaction mixture was stirred at room temperature for 1 hr, then concentrated. The residue was purified by flash column chromatography (2–5% CH3OH in CH2Cl2) to give yellow color solid (0.267 g, 73%). 1H NMR (CDCl3) δ 7.47 (1H, d, J=8.7 Hz), 6.80 (1H, s), 6.69 (1H, d, J=8.7 Hz), 3.47 (3H, s), 3.58 (3H, s), 3.00 (2H, q, J=7.4 Hz), 2.83 (3H, s), 1.14 (3H, t, J=7.4 Hz). ESIMS (MH+): 247.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:20][C:21]([CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)=O>>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:20]=[C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)[N:11]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1

Procedure:
Following the procedure in Example 7, step E using 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea and tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate provided tert-butyl 4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8](NCCCC)[N:7]=2)[CH2:3]1.C(OC(=O)NC1CN(C2C=CN=C([NH:34][CH2:35][CH2:36][CH2:37][CH3:38])N=2)C1)(C)(C)C.Cl.CO>C(O)=O>[NH2:1][CH:2]1[CH2:3][N:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:38][CH2:37][CH2:36][CH2:35][NH2:34])[N:7]=2)[CH2:5]1
Reactant: CCCCNc1nccc(N2CC(N)C2)n1
Reactant: CCCCNc1nccc(N2CC(NC(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: NCCCCc1nccc(N2CC(N)C2)n1
Temperature: 25 °C
Reaction time: 0.38 h
Yield: 98 %

Procedure:
[1-(2-Chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester To a flask containing 2,4-dichloropyrimidine (1.6 g, 10.7 mmol) and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) in i-PrOH (40 mL) was added azetidin-3-yl-carbamic acid tert-butyl ester monohydrochloride (2.1 g. 12.2 mmol). The reaction mixture was heated to 70° C. for 72 h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by flash chromatography on SiO2 (100% hexane increasing gradient to 60% EtOAc-Hexane) to yield two isomeric products. The minor upper Rf product was obtained as a white solid (326 mg, 11%), and the desired major lower Rf product was also obtained as a white solid (2.1 g, 69%). [1-(2-Butylamino-pyrimidin-4-yl)azetidin-3-yl]-carbamic acid tert-butyl ester. To a solution of [1-(2-chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester (250 mg, 0.778 mmol) in i-PrOH (3.0 mL) was added butylamine (600 μL, 6.0 mmol). The reaction mixture was heated to 95° C. in a sealed tube for 36-48 h followed by cooling to room temperature. The reaction mixture was then concentrated and the crude residue purified by flash chromatography on SiO2 using (100% EtOAc increasing the gradient gradually to 5% 2M NH3-MeOH) to yield the desired product (260 mg, 92%). [4-(3-Amino-azetidin-1-yl)-pyrimidin-2-yl]-butyl-amine. To a solution of [1-(2-butylamino-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester (250 mg, 0.778 mmol) in formic acid (4 mL) was added 6N HCl (300 μL). The reaction mixture was stirred at room temperature for 15-30 minutes. Then, MeOH (10 mL) was added and stirred for 10 minutes. The contents were then concentrated and the crude residue purified by flash chromatography on SiO2 using an increasing gradient of (0 to 10% NH3/MeOH in CH2Cl2) to yield the desired product (225 mg, 98%) as the free base. MS (ESI): mass calcd. for C11H19N5, 221.3 m/z found, 222.2 [M+H]+. 1H NMR (CD3OD): 7.61 (d, J=7.3, 1H), 5.99 (d, J=7.1, 1H), 4.6-4.7 (m, 2H), 4.28-4.48 (m, 3H), 3.40 (bs, 1H), 1.54-1.62 (m, 2H), 1.31-1.41 (m, 2H), 0.90 (t, J=7.4, 3H). The compounds in Example 85 through Example 94 were prepared using methods analogous to those described for Example 84.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15](O)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1>>[C:26]1([CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C:15]([CH:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[CH2:6][C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[O:16])[CH2:20]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)C1c2ccccc2Cc2ccccc21
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1c2ccccc2Cc2ccccc21

Procedure:
9,10-Dihydroanthracene-9-carboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-9,10-dihydroanthracene-9-carboxamide.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].C[O:13][C:14]([CH3:16])=[CH2:15]>P(=O)(O)(O)O>[C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])=[C:5]1[CH2:11][CH2:15][C:14](=[O:13])[CH3:16])([CH3:3])=[CH2:2]
Reactant: C=C(C)OC
Reactant: C=C(C)C1CCC(C)(O)C1=C
Agent: O=P(O)(O)O
Product: C=C(C)C1CCC(C)=C1CCC(C)=O
Yield: 60.4 %

Procedure:
15 drops of 85% phosphoric acid were added to a mixture, cooled in a laboratory autoclave, of 76 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol and 120 g of isopropenyl methyl ether. After gassing with nitrogen, the autoclave was brought, in an oil bath of 180° C, to an internal temperature of 150° C and held at this temperture until a distinct drop in pressure occurred (about 50-75 minutes). The reaction mixture was quenched by intensive cooling, treated with solid potassium hydroxide and concentrated under reduced pressure on a rotary evaporator. By fractional distillation over solid potassium hydroxide there were obtained 58 g (60%) of 3-isopropenyl-1-methyl-2-(3-oxobutyl)-cyclopent-1-ene; boiling point 0.01 = 69°-72° C; nD20 = 1.4836. The compound has a woody, camphoraceous, ionone-like fragrance.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19][CH2:18][CH2:17][C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:15][C:14]=3[CH:38]=2)=[CH:6][CH:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:47])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:47])[CH2:18][CH2:17][C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:15][C:14]=3[CH:38]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3=O)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
In methylene chloride (6 ml) was dissolved 7-(4-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzothiepine-4-carboxamide (199 mg). To the mixture was added at −30° C. m-chloroperbenzoic acid (93 mg), and the mixture was stirred at −30° C. for 30 minutes and added to an aqueous solution of saturated sodium thiosulfate. To the mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol=3/1→2/1, 1% triethylamine) to give 7-(4-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-oxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 83) (28 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(OC(C)(C)C)=O)=[C:18]([F:30])[CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.O1CCOCC1.[ClH:37]>CCOCC>[ClH:37].[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:30])[CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)c(F)c1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
A suspension of ethyl 4-amino-5-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (400 mg, 0.963 mmol) in 4N HCl in dioxane (9.63 mL, 38.5 mmol) was heated to 60° C. for 5 min, then cooled to rt and diluted with 40 mL ether. Filtration through a teflon membrane filter gave the title compound as a yellow solid (310 mg, 91.5% yield). 1H-NMR (DMSO-d6) 8.33 (s, 1H), 8.14 (s, 1H), 7.16 (d, J=12 Hz, 1H), 6.96 to 7.03 (m, 2H), 4.13 (q, J=8 Hz, 2H), 1.15 (t, J=8 Hz, 3H); MS [M+H]+=316.1; LCMS RT=2.39.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CCO.O>[C:11]1([CH:9]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:8])[OH:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(c1ccccc1)C(O)c1ccccc1
Temperature: 2.5 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 97.0 g of benzil in 1 liter of 95% EtOH was added 20 g of sodium borohydride. After stirring 10 minutes, the mixture was diluted with 1 liter of water and the mixture was treated with activated carbon. The mixture was then filtered trough supercel and the filtrate heated and diluted with an additional 2 liters of water until it became slightly cloudy. The mixture was then cooled to 0 to 5° C. and the resulting crytals were collected and washed with cold water. The crystals were then dried in vacuo.
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][OH:9].[CH3:10][C:11]1[C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)=[N:14][O:13][N:12]=1>C(OCC)(=O)C>[CH3:10][C:11]1[C:15](/[C:16](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8]/[OH:9])=[N:14][O:13][N:12]=1
Reactant: NO
Reactant: Cc1nonc1C(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1nonc1/C(=N/O)c1ccccc1
Temperature: 70 °C
Yield: 21.6 %

Procedure:
A pyridine (55 ml) solution of hydroxylamine hydrochloride (5.19 g, 73.0 mmol) was added to (3-methyl-1, 2, 5-oxadiazol-4-yl) phenylmethanone (3.43 g, 18.0 mmol) and heated to 70° C. for 21 hours with stirring. After the reacted solution was condensed, the residue was dissolved in ethyl acetate. After washing with diluted hydrochloride and subsequent washing with water, the residue was dried with magnesium carbonate. After removing the solvent and purifying the residue by column chromatography, (Z)-(3-methyl-1, 2, 5-oxadiazol-4-yl) phenylmethanone oxime (2.13 g) and (E)-(3-methyl-1, 2, 5-oxadiazol-4-yl)phenylmethanone oxime (0.79 g) were obtained.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH:19]([N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26])=[CH2:20].[H-].[Na+]>C1(C)C=CC=CC=1>[F:16][C:14]([F:17])([F:15])[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:7]=1)[C:3]([CH:23]1[CH2:24][CH2:25][N:21]([CH:19]=[CH2:20])[C:22]1=[O:26])=[O:18]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CN1CCC(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Reaction time: 12 h

Procedure:
Trimethylsilyldiazomethane (11.5 mL) was added drop-wise to a solution of 3,5-bis-(trifluoromethyl)benzoic acid (2 g) in dry toluene (20 mL) and methanol (0.5 mL) previously cooled to 0° C. under a nitrogen atmosphere. The solution was stirred at r.t. for 1 hr, then concentrated in vacuo to give 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g) as a colourless oil. A solution of 3,5-bis-(trifluoromethyl)benzoic acid methyl ester (2 g) and 1-vinyl-2-pyrrolidinone (863 μL) was added to a mixture of sodium hydride (60% suspension in mineral oil—0.41 g) in dry toluene (30 mL) previously heated to reflux. The mixture was stirred for 12 hrs, then it was partitioned between saturated ammonium chloride solution and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH/AcOEt 8:2) to give the title compound (1.6 g) as a beige oil.
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.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[Br:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: NCc1ccccc1Br
Product: Nc1cc2ncnc(NCc3ccccc3Br)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmol) (described in a previous experimental) and 2-bromobenzylamine (0.84 g, 4.52 mmol) is stirred under N2 at 140° C. for 1 h, and the resulting product chromatographed on silica gel (1-5% EtOH/EtOAc) to give 7-amino-4-(2-bromobenzylamino)pyrido[4,3-d]pyrimidine (175 mg, 45%) as a light brown solid. 1H NMR (DMSO) δ 9.16 (1H, s), 8.85 (1H, t, J=5.7 Hz), 8.24 (1H, s), 7.64 (1H, d, J=7.8 Hz), 7.34 (1H, dd, J=7.7, 7.1 Hz), 7.31 (1H, dd, J=7.7, 2.4 Hz), 7.21 (1H, ddd, J=7.8, 6.9, 2.4 Hz), 6.50 (2H, brs), 6.39 (1H, s), 4.74 (2H, d, J=5.7 Hz).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[O:29])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[O:32]1[CH:33]=[CH:34][C:30]([C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[C:26]([C:2]3[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:25]=2)=[O:29])=[CH:31]1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)nc2)c1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-)phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 3.17 min, MH+ 442. NMR: δH [2H6]-DMSO 9.99,(1H, s), 9.29,(1H, t), 9.15,(1H, d), 8.38,(1H, s), 8.34,(1H, dd), 7.81,(2H, m), 7.75,(1H, d), 7.67,(1H, d), 7.31–7.25,(2H, m), 7.00 (1H, s), 6.94,(2H, m), 6.84,(1H, d), 4.51,(2H, d), 3.75,(3H, s), 2.32,(3H, s).
Reaction SMILES: [C:1]([CH:8]([NH2:14])[CH2:9][O:10][CH2:11][CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].C(O)(C)(C)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:13][CH2:12][CH2:11][O:10][CH2:9][CH:8]([NH2:14])[C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)C(N)COCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOC(=O)COCCOCC(N)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 2-(2-Boc-aminoethoxy)-ethanol (4.5 g, 24.39 mmol) in toluene (100 mL) was added 1.0 M potassium t-butoxide in t-butanol (36.6 L, 36.6 mmol) between −10 to −20° C. for 1.5 hrs and followed by addition of ethyl bromoacetate (8.15 g, 48.78 mmol). The resulting mixture was stirred for 3 hrs at a temperature between −10 to −20° C., followed by the addition of 0.25 N HCl (50 mL). The organic layer was separated and dried over anhydrous MgSO4. The solvent was removed and the residue purified using silica gel column chromatography (30 to 50% ethylacetate in hexane) to give [2-(2-Boc-aminoethoxy)-ethoxy]-acetic acid ethyl ester (4.0 g, 15.36 mmol, 63%). 1H NMR (300 MHz, CDCl3) δ 5.20 (s, 1H), 4.22 (q, 2H, J=7.29 Hz), 4.14 (s, 2H), 3.66–3.75 (m, 4H), 3.55 (m, 2H), 3.31 (m, 2H), 1.44 (s, 9H), 1.29 (t, 3H, J=7.29 Hz); 13C NMR (67.8 MHz, CDCl3 δ170.02, 155.72, 78.68, 70.52, 69.94, 68.29, 60.44, 40.04, 28.06, 13.85.