Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:42]=[CH:41][C:12]2[N:13]([CH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH2:28][C:29]([F:32])([F:31])[F:30])[C:18]3=[O:33])=[N:15][C:11]=2[CH:10]=1)(C)(C)C.Cl>>[NH2:7][CH2:8][C:9]1[CH:42]=[CH:41][C:12]2[N:13]([CH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH2:28][C:29]([F:31])([F:30])[F:32])[C:18]3=[O:33])=[N:15][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCS(C)(=O)=O
Agent: Cl
Product: CS(=O)(=O)CCCn1c(Cn2c(=O)n(CC(F)(F)F)c(=O)c3ccccc32)nc2cc(CN)ccc21
Reaction time: 12 h
Yield: 49.5 %

Procedure:
To a solution of [2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-1-(3-methanesulfonyl-propyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (40 mg, 0.064 mmol) was added HCl (5 ml, 4.0 M in dioxane) and the mixture stirred for 12 h. The solvent was removed to give a white solid. The solid was purified by preparative HPLC to give 16.6 mg (40%) of 1-[5-aminomethyl-1-(3-methanesulfonyl-propyl)-1H-benzoimidazol-2-ylmethyl]-3-(2,2,2-trifluoro-ethyl)-1H-quinazoline-2,4-dione as a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13]C1C(C#N)=CN=CC=1.C(O)(=O)C(C)(C)C.OS(O)(=O)=O>[N+]([O-])([O-])=O.[Ag+]>[C:1]([C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([C:9]#[N:10])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccncc1C#N
Reactant: CC(C)(C)c1ccc(C#N)cn1
Agent: [Ag+]
Agent: CC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1cc(C(C)(C)C)ncc1C#N

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 6-tert-butylnicotinonitrile starting from 4-methylnicotinonitrile (0.5 g, 4.23 mmol), pivalic acid (2.2 g, 21.1 mmol), AgNO3 (0.09 g, 0.55 mmol), (NH4)2S2O8 (1.25 g, 5.5 mmol) and 7.5 ml 10% H2SO4. Purified by normal phase chromatography using 95/5 to 90/10 heptane/ethyl acetate. (Yield: 578 mg, 78%). 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (s, 9 H), 2.53 (s, 3 H), 7.28 (s, 1 H), 8.72 (s, 1 H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7](C(Cl)(Cl)Cl)[O:6][N:5]=1)[CH3:3].[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1>CO>[CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]2)[O:6][N:5]=1)[CH3:3]
Reactant: OCC1CCNCC1
Reactant: CC(C)c1noc(C(Cl)(Cl)Cl)n1
Solvent: CO
Product: CC(C)c1noc(N2CCC(CO)CC2)n1
Temperature: 50 °C
Yield: 34.1 %

Procedure:
A solution of 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (prepared as in Example 158, Alternative synthesis, Step 3, 179 g, 0.78 mol) in MeOH (300 mL) was treated with 4-piperidinemethanol (108 g, 0.94 mol) and stirred and heated at 50° C. overnight. The solvent was removed and the residue was purified by flash chromatography on a silica gel column to give {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (60 g, 34%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]1[CH:23]=[CH:24][CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][NH:13][CH2:12][C:11]1[CH:23]=[CH:24][CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1CN(C(=O)OC(C)(C)C)Cc1ccccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncn2c1CNCc1ccccc1-2
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 4H,6H-2,5,10b-Triaza-benzo[e]azulene-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (300 mg, 1.14 mmol) in DCM (30 mL), was added trifluoroacetic acid (3.42 mL, 3 ml/mmol) and the reaction mixture was stirred for 2 h. After the completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were removed in vacuo to afford 5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester trifluoroacetate (295 mg, 93%) as a gummy solid which was used without any further purification for the next step.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][N:4](C(OCC2C=CC3C(=CC=CC=3)C=2)=O)[CH2:3]1>CCO.C(OCC)(=O)C.[Pd]>[CH3:32][O:31][CH2:30][CH2:29][O:28][C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([O:8][C@@H:7]5[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]5[OH:1])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[CH:20][N:21]=[C:22]2[CH:27]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CCN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5O)c4n3)cnc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CCNC[C@H]5O)c4n3)cnc2c1
Reaction time: 19 h

Procedure:
(trans)-Naphthalen-2-ylmethyl 3-hydroxy-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate (0.045 g, 0.072 mmol) was dissolved in 95% EtOH/ethyl acetate (1:1, 2 mL) and treated with 10% Pd/C (Degeussa type, 20 mg). The reaction was purged with argon then subjected to hydrogen atmosphere at balloon pressure. After 19 hours, the reaction was purged with N2 and treated with fresh catalyst (ca. 5 mg) and re-subjected to hydrogen atmosphere for 5 hours. The reaction was filtered through a nylon membrane (0.45 uM) and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient from 1-20% (6% NH4OH in MeOH)/ethyl acetate. A solid was recovered after concentration in vacuo. The solid was dissolved in MeOH (2 mL) and treated with 4 M HCl in dioxane (0.5 mL). After stirring for 10 minutes the solution was concentrated in vacuo, then re-dissolved in MeOH and re-concentrated three times. The material was dissolved in MeOH (1 mL) then added dropwise to Et2O (40 mL). A precipitate formed, and after stirring for 20 minutes, this precipitate was collected by filtration, washed with Et2O and dried under a blanket of nitrogen (15 mg). 1H NMR (400 MHz, CD3OD) δ 10.72 (d, 1H), 8.75 (s, 1H), 8.45 (d, 1H), 8.11 (D, 1H), 7.65-7.59 (m, 2H), 7.49-7.43 (m, 1H), 7.43-7.38 (m, 2H), 4.94-4.87 (m, 1H), 4.48-4.43 (m, 2H), 4.37-4.32 (m, 1H), 3.89-3.84 (m, 2H), 3.64-3.57 (m, 1H), 3.49-3.40 (m, 1H), 3.46 (s, 3H), 3.37-3.31 (m, 1H), 2.58-2.48 (m, 1H), 2.27-2.18 (m, 1H). MS APCI (+) m/z 435.1 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1ccc(C)c(C(=O)Cl)c1
Solvent: ClCCl
Product: Cc1ccc(C)c(C(=O)Nc2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1
Yield: 64.2 %

Procedure:
As described for Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.303 g (1.8 mmol) of 2,5-dimethylbenzoyl chloride in 10 ml of dichloromethane. The product is recrystallized from dichloromethane-hexane to give 0.43 g of crystals, m.p. 213°-216° C. Anal. Calc'd for C30H26N2O2 : C,80.7; H,5.9; N,6.3. Found: C,80.0; H,5.9; N,6.1.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:30]Br)[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:32]#[N:33].[Na+].C(OCC)(=O)C>CS(C)=O>[C:1]([O:9][CH2:10][CH:11]([CH2:30][C:32]#[N:33])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CCCCCCCCCCCCCCCCOCC(CBr)COC(=O)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCOCC(CC#N)COC(=O)c1ccccc1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
A mixture of 13.845 g (27.9 mM) of 2-bromomethyl-3-n-hexadecyloxypropyl benzoate n3 and 1.439 g (27.9 mM) of sodium cyanide (95% purity) in 150 ml of dimethylsulfoxide is heated at 90° C. for 1 hour. The product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with water (four times) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated to obtain 12.42 g of the crude product of the titled compound n3'.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[C:9]([O:11]C)=[O:10])[CH3:2].[OH-].[Na+]>CO.O>[C:9]([C:5]1[N:6]=[CH:7][S:8][C:4]=1[S:3][CH2:1][CH3:2])([OH:11])=[O:10]
Reactant: CCSc1scnc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCSc1scnc1C(=O)O
Yield: 84.1 %

Procedure:
6 g of methyl 5-ethylthio-1,3-thiazole-4-carboxylate were dissolved in 100 ml of methanol and heated with 1.2 g of NaOH in 10 ml of water under reflux for about 1 h. After the solvent had been removed in a rotary evaporator, the solids were removed by filtration, and the filtrate was acidified with 2N HCl solution. After drying, 4.7 g of the title compound, of melting point 158°-9° C., were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH2:6][CH2:5]2.C([O-])(=O)C.[K+].Br[C:28]1[C:32]2[C:33]([NH2:37])=[N:34][CH:35]=[CH:36][C:31]=2[S:30][CH:29]=1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(OCC)(=O)C.O.O1CCOCC1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[CH2:12][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:28]3[C:32]4[C:33]([NH2:37])=[N:34][CH:35]=[CH:36][C:31]=4[S:30][CH:29]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:21]
Reactant: Nc1nccc2scc(Br)c12
Reactant: O=C(Cc1cc(F)ccc1F)N1CCc2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 100 °C
Reaction time: 48 h
Yield: 62.8 %

Procedure:
In a sealable tube, to 5-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole (0.700 g, 1.988 mmol), bispinacolatodiboron (0.606 g, 2.385 mmol) and potassium acetate (0.585 g, 5.96 mmol) was added 1,4-Dioxane (15 mL) and the mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2Adduct (0.081 g, 0.99 mmol) was added and the reaction mixture was sealed and stirred for 48 hours at 100° C. The mixture was cooled to room temperature and treated with 5 mL of water, 3-bromothieno[3,2-c]pyridin-4-amine (0.501 g, 2.186 mmol) and sodium bicarbonate (167 mg, 1.988 mmol). The mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (0.085 g, 0.104 mmol) was added and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto water and ethyl acetate, then filtered. The filtrate was poured into a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Purified by Analogix silica gel cartridge 25/40, eluting with a gradient of 0-100% EtOAc/hexane. The compound came out at 100% EtOAc in 10 minutes. The pure fractions with the compound were combined. The solvents were evaporated and dried to give an off-white solid (526 mg) of the title compound 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine. LC-MS (ES) m/z=422.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (d, J=8.3 Hz, 1H) 7.82 (d, J=5.6 Hz, 1H) 7.42 (s, 1H) 7.35 (s, 1H) 7.12-7.31 (m, 5H) 5.41 (br. s., 2H) 4.31 (t, J=8.3 Hz, 2H) 3.96 (s, 2H) 3.23-3.31 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[NH2:20][C:21]([CH2:28][CH3:29])([CH2:26][CH3:27])[C:22]([NH:24][CH3:25])=[O:23]>>[CH2:26]([C:21]([NH:20][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])([C:22](=[O:23])[NH:24][CH3:25])[CH2:28][CH3:29])[CH3:27]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(S(=O)(=O)CC(C)C)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351 b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials. MS (EI): m/e=410.21 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:8][CH2:9][CH2:10][C:11](=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].[CH3:24][OH:25]>O>[CH3:24][O:25][C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:7]([CH3:6])=[CH:8][CH2:9][CH2:10][C:11](=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CC(=O)CCC=C(C)CCCC(C)(C)OC
Temperature: 25 °C
Reaction time: 40 h

Procedure:
The product can be obtained in the form of a mixture of E and Z isomers by adding dropwise 3 ml of concentrated sulfuric acid to a solution of 7.6 g of the product of Example 3 in 45 ml of methanol and stirring the mixture at room temperature for 40 hours. The mixture was diluted with water and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate and evaporated to dryness and the residue was chromatographed over silica and was eluted with a 9-1 benzene-ethyl acetate mixture to obtain 1.3 g of methyl 11-methoxy-7,11-dimethyl-3-oxo-6-dodecenoate in the form of a colorless oil.
Reaction SMILES: COC([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([O:16][CH3:17])=[CH:8][C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]1=2)=O.[OH-].[Na+]>O>[CH3:17][O:16][C:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:5][C:6]2[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=2[CH:8]=1
Reactant: COC(=O)N1c2ccccc2C=C(OC)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC1=Cc2ccccc2Nc2ccccc21
Temperature: 100 °C
Yield: 975.4 %

Procedure:
A mixture of 10-methoxy-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (19 g, 67.5 mmol), poly (ethylene glycol) 200 (20 ml) and sodium hydroxide solution 50% (13 ml, 246 mmol) is heated to 100° C. for 4hours. Water (30 ml) is added and the suspension is cooled to 20° C. and filtered. The filter cake is washed with water and dried at 60° C./30 mbar to yield 147 g of pure title compound (98%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]2[CH2:33][O:34][CH2:35][CH:29]2[CH2:28]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]5[CH2:33][O:34][CH2:35][CH:29]5[CH2:28]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: ClCCCN1CCC2COCC2C1
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(O)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CCC5COCC5C4)cc23)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
A mixture of 4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-ol (250 mg, 0.68 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (280 mg, 0.82 mmol, 1.2 eq) and K2CO3 (188 mg, 1.36 mmol, 2 eq) in DMF (10 mL) was stirred at 80° C. overnight and cooled to room temperature. To this, CH2Cl2 (50 mL) was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2), then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (140 mg, 45.50%), HPLC: 98.47%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 459.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.73-1.75 (2H, m), 2.35-2.46 (3H, m), 2.54-2.68 (2H, m), 2.65-2.70 (3H, m), 2.72-2.76 (2H, m), 2.96-3.03 (3H, m), 3.05-3.10 (2H, m), 3.71-3.90 (2H, m), 4.03 (1H, s), 4.22-4.27 (2H, m), 7.06-7.12 (1H, m), 7.13 (1H, s), 7.76-7.82 (2H, m), 7.85 (1H, s), 8.06-8.11 (1H, m), 8.55 (1H, s) ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].CI.Cl[CH2:27]Cl>CN(C)C=O>[CH3:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2)[C:5]([N:7]([CH3:27])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: CN(C(=O)Nc1cccnc1)c1ccc2c(ccn2C)c1
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)N(C)c1ccc2c(ccn2C)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a suspension of 80% sodium hydride (0.06 g; 2 mM) in dimethylformamide (5 ml), was added the monomethyl urea (E9) (0.5 g; 1.79 mM). After stirring at room temperature for 0.5 h, methyl iodide (0.12 ml; 1.93 mM) was added dropwise. Stirring was continued at room temperature for 1 h, then heated at 50° C. for 1 h. The reaction mixture was cooled in ice, then quenched with water. The mixture was then extracted with dichloromethane, washed with water, dried over sodium sulphate and evaporated to give the crude product (0.59 g). Chromatography on silica using dichloromethane as eluant afforded the title compound (0.31 g; 60%) which was recrystallised from cyclohexane to give a white solid (160 mg) m.p. 91°-92.5° C.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[OH-:8].[Al+3:9].[OH-].[OH-]>C(O)(=O)C>[C:1]([O-:4])(=[O:3])[CH3:2].[C:1]([O-:4])(=[O:3])[CH3:2].[OH-:8].[Al+3:9]
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)[O-]
Temperature: 125 °C
Yield: 95.6 %

Procedure:
245.0 g of acetic anhydride and 48.0 g of acetic acid (100%) are added to 62.4 g (0.8 mol) of aluminium hydroxide, hydrargillite, Merck, in a 750 ml sulfonation flask, provided with a thermometer, a reflux condenser and a stirrer, and the mixture is heated to 125° C., with stirring. After a reaction time of 12 hours, the reaction product is cooled, filtered off, washed with 4 times 250 ml of water and dried for 12 hours at 130° C./15 mm Hg; 124 g (95.6%) of acicular aluminium monohydroxide diacetate are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:15]=1)[C:7](N(OC)C)=[O:8])[CH3:2].[CH2:22]([Mg]Br)[CH3:23]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7](=[O:8])[CH2:22][CH3:23])[CH:13]=[C:14]([S:16]([F:18])([F:21])([F:17])([F:19])[F:20])[CH:15]=1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: CCOc1cc(C(=O)N(C)OC)cc(S(F)(F)(F)(F)F)c1
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)CC)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Ethoxy-N-methoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (170 mg, example 24b) was dissolved in absolute THF (5 ml), and ethylmagnesium bromide (0.65 ml; 2 M in diethyl ether) was added dropwise at 0° C. while stirring. After addition, the ice bath was removed and the mixture was stirred at RT for 2 h. Then further ethylmagnesium bromide (0.1 ml) was added and the mixture was stirred once again for 2 h. Subsequently, 1N hydrochloric acid was added dropwise while cooling, followed by water and ethyl acetate. The organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 150 mg of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:19]=1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.Cl>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:19]=1[S:26]([NH:14][CH:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[C:2]([F:1])([F:15])[F:16])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1c(F)cc(F)cc1F
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
A mixture of 100 mg (0.44 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 101 mg (0.44 mmol) of 2,4,6-trifluorobenzenesulfonyl chloride in 8 mL of pyridine was stirred at room temperature for 2 hours, and warmed at 70° C. for 18 hours. The mixture was then cooled to room temperature and diluted with 1 N aqueous HCl until acidic and extracted with ethyl acetate. The combined organic layers was washed with 1 N aqueous HCl, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was crystallized from ether-hexanes to afford 40 mg (21%) of the title compound as a colorless powder. MS: m/z 423 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([F:20])=[N:11][C:12]2[C:17]([C:18]=1F)=[CH:16][N:15]=[CH:14][CH:13]=2.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)C>[CH:21]([NH:25][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[N:11]=[C:10]([F:20])[C:9]=1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([CH2:23][CH3:24])[CH3:22]
Reactant: Fc1cccc(Cl)c1-c1c(F)nc2ccncc2c1F
Reactant: CCC(C)N
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(C)Nc1c(-c2c(F)cccc2Cl)c(F)nc2ccncc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Step 1 (0.10 g) was dissolved in DMF (2 ml). Sec-butylamine (0.1 ml) and DMAP (0.001 g) were added and the mixture was stirred in a sealed tube at ambient temperature for 18 hours. The brown reaction mixture was diluted with diethyl ether, washed with brine and dried over sodium sulphate. After evaporation of the solvent the resulting yellow gum was purified by flash column chromatography on silica gel (40-60) in ethyl acetate:hexane 1:3 to give N-sec-butyl-3-(2-chloro-6-fluorophenyl)-2-fluoro-1,6-naphthyridin-4-amine as a dark yellow solid (0.06 g).