Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>CN(C=O)C.C(=O)(O)[O-].[Na+]>[CH3:18][N:19]([CH3:24])[S:20]([N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([C:3](=[O:4])[C:2]([F:1])([F:14])[F:15])=[CH:6]1)(=[O:22])=[O:21]
Reactant: O=C(c1c[nH]c2ncccc12)C(F)(F)F
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cc(C(=O)C(F)(F)F)c2cccnc21
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a solution of 107 mg (0.5 mmol) of 2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone in 2 mL of DMF was added 60% sodium hydride in mineral oil followed by 80 mg (0.56 mmol) of N,N-dimethylsulfamoyl chloride. The mixture stirred for 30 minutes and was then diluted with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with three 7 mL portions of brine, three 7 mL portions of saturated aqueous ammonium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was adsorbed onto silica gel and chromatographed on silica gel eluting with ethyl acetate-hexanes (10-100% gradient) to afford 88 mg (54%) of 3-(2,2,2-trifluoroacetyl)pyrrolo[2,3-b]pyridine-1-sulfonic acid dimethylamide as a white solid.
Reaction SMILES: [CH2:1]([CH:9]1[C:17]2[C:13](=[N:14][C:15]3[C:16]=2[CH2:18][CH:19]=[CH:20][C:21]=3[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:1]([CH:9]1[C:17]2[C:13](=[N:14][C:15]3[C:16]=2[CH:18]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]=[CH:20][C:21]=3[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1CCCC2=NC3=C(OCc4ccccc4)C=CCC3=C21
Reactant: CCCCCCCCBr
Product: CCCCCCCCC1C=CC(OCc2ccccc2)=C2N=C3CCCC(CCCCCCCC)C3=C21
Yield: 61.6 %

Procedure:
Using the procedure of Example 9, 2.9 g of 1,2,3,4-tetrahydro-1-octyl-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole from Example 62 was alkylated with 1.68 g of 1-bromooctane to produce 2.3 g (61.7%) of rac-1,2,3,4-tetrahydro-1,9-dioctyl-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole as a yellow oil after chromatographic purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([N+:10]([O-])=O)[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[H][H]>C(O)(C)C.C(O)(=O)C.[Pd]>[NH2:10][CH:3]([CH:2]([CH3:13])[CH3:1])[CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8]
Reactant: CC(C)C(C(O)C(F)(F)F)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)C(N)C(O)C(F)(F)F
Temperature: 5 °C

Procedure:
A solution of 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (17.1 g) in isopropanol (115 ml) and acetic acid (0.43 ml) was hydrogenated over 10% palladium on carbon (2.4 g) at 3.5 bar pressure until uptake of hydrogen was complete. The catalyst was removed by filtration through diatomaceous earth and the filter cake washed with isopropanol. The filtrate was evaporated under vacuum until no further isopropanol distilled and the residue dissolved in acetonitrile (40 ml). A solution of oxalic acid (3.94 g) in acetonitrile (80 ml) was added with stirring and the mixture cooled to 5° C. The product which crystallised was collected by filtration, washed with cold acetonitrile and dried at 50° C. to give 3-amino-4-methyl-1,1,1-trifluoro-2-pentanol as its oxalate salt (9.08 g).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12.C(N(C(C)C)C(C)C)C.[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][C:34](ON1C(=O)CCC1=O)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][C:34]([NH:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Reactant: Nc1cnn2c1NCC2
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn2c1NCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
To a solution of 7-amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole sulfuric acid salt (2.22 g) and N-ethyldiisopropylamine (2.84 g) in methylene chloride (70 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (3.15 g). The mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel eluting with 5% methanol/chloroform to give 7-[3-(tert-butoxycarbonylamino)propionyl]amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (2.2 g) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:32][S:33]([C:36]1[CH:37]=[N:38][CH:39]=[C:40](Br)[CH:41]=1)(=[O:35])=[O:34])([CH2:30][OH:31])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:32][S:33]([C:36]1[CH:37]=[N:38][CH:39]=[C:40]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:41]=1)(=[O:35])=[O:34])([CH2:30][OH:31])[CH3:29]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (200 mg, 0.56 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.4) (165 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (120 mg, 35%). MS (ISP) 600.2 [(M+H)+]; mp 228-231° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Product: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1

Procedure:
A reaction mixture of 50 g. of m-trifluoromethylacetophenone and 50 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours under anhydrous conditions and then evaporated in vacuo to a thick orange-red oil. Hexane is added, the mixture is chilled and the desired product is collected by filtration as yellow crystals, m.p. 60.5°-62° C.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@:19]12(O)[N:26](C)[C@@H:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]=[CH:20]2.[Na].O>C(#N)C>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][C@@:11]23[N:26]([CH3:19])[C@@H:23]([CH2:24][CH2:25]2)[CH2:22][CH:21]=[CH:20]3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: COC(=O)C(C)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(C)(c1ccccc1)c1ccccc1)CC2

Procedure:
4.80 g (0.02 mol) of methyl 2,2-diphenylpropionate 3b, 2.78 g (0.02 mol) of tropenol, and 0.046 g of sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water, shaking from time to time. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4, and evaporated to dryness. From the residue, 4c is precipitated as the hydrochloride and this is recrystallized from acetone. Yield: 5.13 g (67% of theory); TLC: Rf value: 0.28 (eluent: sec-butanol/formic acid/water 75:15:10); melting point: 134° C.-135° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH3:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([O:29][CH2:33][CH2:34][O:35][CH3:36])([CH3:27])[CH3:28])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOC(C)(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: 70 °C
Reaction time: 17 h
Yield: 10.5 %

Procedure:
In a 10 mL pear flask, 2-(6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-ol (0.100 g, 0.252 mmol, Example #37) and NaH (60% in mineral oil, 0.025 g, 0.631 mmol) in THF (5 mL) and DMF (1 mL) were added to give an off-white suspension. 1-Bromo-2-methoxyethane (0.140 g, 1.01 mmol) was then added and the suspension was stirred at about 70° C. for about 17 h. The mixture was concentrated under reduced pressure and was purified by flash chromatography on silica gel MeOH/DCM (gradient 1-5% over 14 min) and then further purified by RP-HPLC (Table 1, Method m) to afford the title compound (0.012 g, 11%) as a white fluffy solid: LC/MS (Table 1, Method g) Rt=2.02 min; MS m/z 455.2 (M+H)+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])O.[Na+]>ClCCl>[F:7][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CF
Reaction time: 6 h
Yield: 12.1 %

Procedure:
Diethylaminosulfur trifluoride (3.3 g, 20.5 mmols) was added to dichloromethane (30 mL) solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.2 g, 15.9 mmols) under cooling with ice, and stirred at the same temperature for 6 hours. The reaction liquid was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. Then the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. Concentrating the reaction liquid under reduced pressure, the residue was purified on silica gel column chromatography (C-300; ethyl acetate:hexane=1:20) to provide the title compound (390 mg, 12%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[OH:14]>>[Cl:1][S:2]([C:11]1[CH:12]=[C:7]([F:6])[C:8]([OH:14])=[C:9]([F:13])[CH:10]=1)(=[O:5])=[O:3]
Reactant: Oc1c(F)cccc1F
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cc(F)c(O)c(F)c1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
Chlorosulfonic acid (112.6 g) was added dropwise with ice cooling to 2,6-difluorophenol (25 g). The reaction mixture was stirred at room temperature for an hour and poured into ice-water (600 ml), and the separated oily substance was extracted with methylene chloride. The methylene chloride layer was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-chlorosulfonyl-2,6-difluorophenol (31.5 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:34]=[CH:33][C:26]([CH2:27][N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:34]=[CH:33][C:26]([CH2:27][N:28]3[N:29]=[CH:30][CH:31]=[N:32]3)=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Brc1ccc(Cn2nccn2)cc1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(Cn4nccn4)cc3)s2)c(F)c1

Procedure:
5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[4-(2H-1,2,3-triazole-2-ylmethyl)phenyl]amino}thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.320 mmol) and 2-(4-bromobenzyl)-2H-1,2,3-triazole (76 mg, 0.320 mmol) as the starting materials.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].C[N:18](C)C=O>>[NH2:18][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccnc(N)n1

Procedure:
The amine of formula (V) is thus obtained, and this is reacted with 2-chloropyrimidine-4-carboxamide of formula (VI) in an aprotic solvent, for example dimethylformamide, in the presence of a base, for example potassium carbonate, at a temperature of 20° to 80° C., especially 20° C. to 40° C., to give a 2-aminopyrimidine-4-carboxamide derivative of formula (I). The compound of formula (I) is, if desired, converted into an acid addition salt.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11](B1OB(C=C)OB(C=C)O1)=[CH2:12].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]([C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)=[CH2:12]
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: c1ccncc1
Product: C=Cc1ccc(C(C)=O)cn1
Temperature: 115 °C

Procedure:
The reaction mixture of 1-(6-bromopyridin-3-yl)ethanone (0.68 g, 3.41 mmol), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane:pyridine (1:1) (0.57 g, 2.39 mmol), potassium carbonate (0.85 g, 6.14 mmol), and Pd(Ph3P)4 (0.16 g, 0.14 mmol) in acetonitrile (10 mL) was degassed with argon for 5 minutes. Then it was heated in the microwave for 30 min at 115° C. The organic phase was removed using a pipette, dried (MgSO4), filtered and concentrated and purified by flash chromatography (SiO2; heptane/EtOAc, gradient 20-80%). Yield: 0.36 g (72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH3:12][C:13](O)([C:15]#[N:16])[CH3:14].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13]([C:15]#[N:16])([CH3:14])[CH3:12])=[CH:6][CH:5]=1
Reactant: CC(C)(O)C#N
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(NC(C)(C)C#N)cc1
Yield: 92 %

Procedure:
A mixture of 4-aminobenzoic acid methyl ester (0.32 g, 2.12 mmol), acetonecyanohydrin (3 ml) and sodium sulfate (1 g) was refluxed for 15 hours. After filtration to remove the sodium sulfate, the filtrate was washed with brine and extracted with ethyl acetate. The organic layer was concentrated and chromatographed (dichloromethane:acetone, 60:40) to yield 4-[(cyanodimethylmethyl)-amino]-benzoic acid methyl ester (49b) (0.398 g, 1.95 mmol, 92%) as a white solid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6]
Reactant: CC=CCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC=CCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hexen-l-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[C:7]([C:12](=[O:13])[C:23]2[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1ccc(C(=O)c2cc(C(C)(C)C)ccc2C(=O)O)cc1
Temperature: 0 °C
Yield: 54 %

Procedure:
Into a 500 ml three-necked flask, 36 g (176 mmole) of 4-t-butyl-phthalic anhydride, 27 g (200 mmole) of t-butylbenzene and 100 ml of dichloroethane were placed under a stream of argon and cooled to 0° C. To the obtained mixture, 56 g (420 mmole) of aluminum chloride was slowly added. After the addition was completed, the resultant mixture was stirred at the room temperature for one night. After the reaction was completed, ice was added slowly, and then concentrated hydrochloric acid was added. The formed precipitates were separated by filtration and washed well with water, and 32 g of the benzoic acid compound of the object compound was-obtained (the yield: 54%; a white powder).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.CN(C=O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30](F)[CH:29]=1>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[C:32]([NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([CH:19]4[CH2:20][CH2:21]4)=[O:18])[CH2:13][CH2:12]3)=[O:10])[CH2:5][CH2:4]2)[CH:33]=1
Reactant: NC[C@H]1CC[C@H](C(=O)N2CCN(C(=O)C3CC3)CC2)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: CN(C)C=O
Product: O=C(C1CC1)N1CCN(C(=O)[C@H]2CC[C@H](CNc3cc(Cl)ccc3[N+](=O)[O-])CC2)CC1
Temperature: 90 °C

Procedure:
To a solution of (trans-4-aminomethyl-cyclohexyl)-(4-cyclopropanecarbonyl-piperazin-1-yl)-methanone (600 mg, 2.1 mmol) in DMF (5 mL) K2CO3 (565 mg, 4.1 mmol) and 4-chloro-2-fluoronitrobenzene (360 mg, 2.1 mmol) were added and the mixture was heated at 90° C. for 4 hours. Then the solvent was removed under reduced pressure and the residue was washed with 7 mL of H2O and the precipitate was filtered affording 788 mg of the titled compound (78% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[NH:4][C@@H:5]([CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C@H:17]([NH:37]C(OC(C)(C)C)=O)[CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C@H:17]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[C@H:5]([CH:45]([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[NH:4][C:3]([O:2][CH3:1])=[O:58]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(c1ccccc1)c1ccccc1
Yield: 95.4 %

Procedure:
Compound methyl[(2S)-1-({2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(diphenyl)silyl]oxy}butyl]phenyl}amino)-1-oxo-3,3-diphenylpropan-2-yl]carbamate (7, 305.4 mg, 0.382 mmol) was dissolved in a cold mixture of DCM (3 ml) and TFA (1 mL, 12.98 mmol) and the final solution stirred at 0° C. for 1.5 h, quenched at 0° C. by slow addition of saturated NaHCO3, then diluted with DCM, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated to afford 255 mg (95% yield) of the title compound as white foam submitted to the next step without further purification. MS: m/z=700.3 (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:23]I>>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)[CH3:23])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1nc(Nc2ccc(OC(C)C)cc2)c2ccccc2n1
Reactant: CI
Product: Cc1nc(N(C)c2ccc(OC(C)C)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (4-isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (164.3 mg, 0.56 mmol) and methyl iodide (0.25 ml, 3.92 mmol) by a procedure similar to Example 36. 1H NMR (CDCl3): 7.73 (d, J=7.8 Hz, 1H), 7.54-7.49 (m, 1H), 7.10-6.86 (m, 6H), 4.57-4.52 (m, 1H), 3.58 (s, 3H), 2.72 (s, 3H), 1.36 (d, J=6 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:10]([OH:13])(=O)[CH3:11]>>[CH:9]1[C:4]([NH2:1])=[CH:5][CH:6]=[C:7]([O:13][C:10]2[CH:11]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:8]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccccc1
Product: Nc1ccc(Oc2ccc(N)cc2)cc1

Procedure:
Into a 100 ml four-necked flask provided with a stirrer, an inlet tube for the supply of an inert gas and an outlet pipe for the discharge of said inert gas 0.654 g of pyromellitic anhydride, 0.60 g of 4,4'-diaminodiphenyloxide, 0.45 ml of acetic acid and 10.0 ml of nitrobenzene. The reaction mixture is heated to 120° C with stirring and passing an inert gas and maintained at this temperature for 1 hour. On completion of the reaction and cooling the reaction mixture, the precipitated polymer is filtered off, repeatedly washed with acetone and ethanol and dried in vacuum at 120° C ηinh in sulfuric acid is 0.67 dl/g. (0.05 g of the polymer in 10 ml of the solvent).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:24]([O:23][C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)=[CH:29][CH:28]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 81.1 %

Procedure:
A solution of compound D (31.5 g; 0.1278 mol), tert-butyl 4-aminobenzoate (48 g; 0.248 mol), N,N-diisopropylethylamine (50.3 g; 0.39 mol) in 400 mL of dioxane was refluxed for 72 h under magnetic stirring. The reaction mixture was filtered, concentrated and taken up with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulphate and concentrated. The crude mixture was purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate=9/1) to yield compound E (41.8 g; 81%).