Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][NH:28][C:29]2=[O:34]>CC1C=CC=CC=1C.[Cl-].[Na+].O.C(OCC)(=O)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:9]([CH3:19])([CH3:20])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][NH:28][C:29]3=[O:34])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Nc1cccc2c(=O)[nH]ccc12
Reactant: COc1c(C(C)(C)CC(O)(C=O)C(F)(F)F)ccc(C)c1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1c(C(C)(C)CC(O)(C=Nc2cccc3c(=O)[nH]ccc23)C(F)(F)F)ccc(C)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.4 %

Procedure:
225 mg (0.664 mmol) of (rac.) 4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal, 106.3 mg (0.664 mmol) of 5-amino-isoquinolin-1(2H)-one, and 0.39 ml (1.328 mmol) of titanium tetraisopropylate are stirred in 3.6 ml of o-xylene for two and one-half hours at 120° C. After cooling, the batch is poured onto 15 ml of saturated brine and diluted with ethyl acetate. After 20 minutes of vigorous stirring at room temperature, it is filtered via a column, filled with Extrelute. The residue is on silica gel (mobile solvent ethyl acetate/hexane). 224.7 mg (70.3%) of the desired compound is isolated.
Reaction SMILES: N([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)N.Cl>>[C:6]1([S:9]([OH:12])(=[O:11])=[O:10])[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: O=S(=O)(O)c1ccccc1

Procedure:
Claisen reaction of the commercially available p-methyl-acetophenone and trifluoroacetic acid ethyl ester gave 4,4,4-trifluoro-1-(4-methylphenyl)-butane-1,3-dione in good yield. The latter was further reacted with the commercially available p-hydrazino-benzenesulfonic acid in an inert solvent in the presence of hydrochloric acid to give the new 4-(5-p-methyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonic acid of formula (III) (yield over 80%),
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][N:2]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)N(C)CC(F)(F)F)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(F)(F)F)C(=O)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To methyl 6-(methyl(2,2,2-trifluoroethyl)carbamoyl)nicotinate (425 mg, 1.54 mmol) in tetrahydrofuran (17 mL) and water (8.5 mL) was lithium hydroxide monohydrate (193 mg, 4.60 mmol) added and the reaction mixture was stirred at ambient temperature over night. The organic solvent was evaporated, 1M hydrochloric acid added until an acidic pH was reached followed by extraction with ethyl acetate (3×25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield 366 mg (91%) of the title compound as a solid; MS (APPI/APCI) m/z 263[M+H+].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[C:23]([CH3:28])[CH:24]=[C:25]([OH:27])[CH:26]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38]O)=[CH:33][CH:32]=1)#[N:30].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][O:20][C:21]2[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([CH3:28])[CH:22]=2)=[CH:33][CH:32]=1)#[N:30]
Reactant: Cc1cc(O)cc(O)c1
Reactant: N#Cc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(O)cc(OCCc2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Triphenylphoshine (7.86 g; 30 mmol), 3,5-dihydroxytoluene (2.5 g; 20 mmol) and 2-(4-cyanophenyl)ethanol (4.41 g; 30 mmol) were dissolved in THF (50 mL). Diethylazodicarboxylate (5.22 g; 30 mmol; dissolved in THF (10 mL)), was added and the solution was stirred at room temperature overnight. The solvent was removed in vacuo and the white solid residue extracted with Et2O. Purification by flash chromatography (SiO2; toluene:EtOAc (10:1)) afforded 1.85 g (37%) of the sub-title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C(=O)CCC1=O.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1.[C:44]([NH2:48])([CH3:47])([CH3:46])[CH3:45]>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:6]
Reactant: CC(C)(C)N
Reactant: Nc1ccc(F)cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cc(F)ccc1N
Yield: 73.2 %

Procedure:
Stir and cool to 0° C. a solution of 2-amino-5-fluorobenzoic acid (7.75 g, 50 mmol), N-hydroxysuccinimide (6.9 g, 60 mmol) and dimethylaminopyridine (1.0 g) in dichloromethane (200 mL). Add, dropwise, a 1M solution of dicyclohexylcarbodiimide in dichloromethane (60 mL, 60 mmol), and stir at 0° C. for 1H. Add tert-butyl amine (20 mL, 190.3 mmol) by syringe and stir at 0° C. for 3 h and then at ambient temperature overnight. Pour onto a pad of silica gel and elute with 5% ethyl acetate/dichloromethane. Combine like fractions and concentrate to obtain a crude solid. Triturate the solid with heptane and filter to obtain 7.7 g (73%) of the title compound: MS 211(M+H), m.p. 77–78° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[C:18]3[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2].[CH:30]([C:32]1([C:38]([O:40][CH3:41])=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=O.C(C1(C(OC)=O)CCC1)=O>>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:7][CH2:8][C@H:9]([O:12][C:13]2[C:18]3[C:19]([O:22][CH2:23][CH:24]4[CH2:25][CH2:26][N:27]([CH2:30][C:32]5([C:38]([O:40][CH3:41])=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH2:28][CH2:29]4)=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(C=O)CCOCC1
Reactant: CC(=O)OC[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(O[C@H]5CC[C@@H](COC(C)=O)CC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using (cis-4-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexyl)methyl acetate (EXAMPLE 46, Step 3) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2].N1C=CN=C1.Cl[Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc2cc(O)ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 0.80 g (3.86 mMol) 6-hydroxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester [preparation see: J. Am. Chem. Soc. 97 (1974), 7305] in 8 ml DMF, 1.16 g (17 mMol) imidazol and 2.15 ml chlortriisopropylsilane (95%; 9.7 mMol) are added. After 50 min, the mixture is poured into ice-water and extracted twice with EtOAc. The organic phases are washed with 10% citric acid solution, 2× water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/EtOAc 29:1) gives the title compound: MS: [M+1]+=364; TLC(hexane/EtOAc 9:1): Rf=0.5.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])=[CH:15][CH3:16])[C:8]=1[NH2:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])=[CH:15][CH3:16])[C:8]=1[NH:9][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: CC=C(C)c1cccc(C)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=C(C)c1cccc(C)c1NC(=O)CCl
Reaction time: 8 h
Yield: 102.2 %

Procedure:
0.007 mole of chloroacetyl chloride was added dropwise to a mixture of 0.007 moles of 2-methyl-6-(1-methylprop-1-enyl)-aniline and 0.008 moles (1.15 ml) of triethylamine in methylene chloride at about but below 20° C. The mixture was then refluxed and then allowed to stand overnight at room temperature. The mixture was then again refluxed and allowed to stand for two days (over the weekend) at room temperature. Thin layer chromatographic (plate) analysis showed the presence of a small amount of starting material. An additional 0.55 ml of triethylamine and 0.3 ml of chloroacetyl chloride was added and the mixture again refluxed and allowed to stand overnight at room temperature. The mixture was then washed with aqueous sodium bicarbonate, dried and evaporated affording 1.7 g of the title compound as a slightly crystallized oil (m.p. 71°-74° C.).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:7][C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH:1]=[CH:2][CH3:3])([CH3:8])[CH3:6]
Reactant: C=CCBr
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC=COc1ccccc1C(C)(C)C
Temperature: 35 °C

Procedure:
Allyl bromide (69.2 ml), 2-t-butylphenol (122.9 ml) and potassium carbonate (121.6 g) were stirred in 265 ml of acetone at reflux temperature for 50 hours and then cooled to 35° C. Water (600 ml) was added and the resulting layers were separated. The aqueous layer was extracted with 600 ml of diethyl ether. The organic layer was combined with the aqueous layer's ether extract and the resulting solution was dried over sodium sulfate overnight. After sodium sulfate removal, the solvent was evaporated to provide, after further workup, 147 g of the subtitled intermediate.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH2:24]([O:26][C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[CH:30]=[CH:31][C:32]([CH2:33][O:2][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:3])=[CH:35][CH:36]=1)=[O:28])[CH3:25]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCOC(=O)c1ccc(CBr)cc1
Product: CCOC(=O)c1ccc(COC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 71.5 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (32.3 mg) and 4-ethoxycarbonylbenzyl bromide (28.1 mg) were used to obtain (2S,4S)-1-[[N-[4-(4-ethoxycarbonylbenzyl)oxycarbonyl bicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (34.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]([OH:25])=O)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]([NH2:26])=[O:25])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1cccc2c(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cccc12
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cccc12
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
N,N′-carbonyldiimidazole are added to 1.13 g 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid in 15 ml of tetrahydrofuran and the reaction mixture is stirred for 45 minutes at 60° C. Then ammonia gas is piped in at ambient temperature over a period of 25 minutes. The dark reaction solution is evaporated down using the rotary evaporator and the solid residue is stirred with water. Then it is acidified with 1 N hydrochloric acid and the precipitate formed is suction filtered, washed with water and dried in vacuo in the desiccator.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1)[CH3:16].S(=O)(O)[O-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CN(C)C(=O)C>[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:25][CH:26]=1)[CH3:16]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CCOC(=O)CCc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1
Temperature: 155 °C
Yield: 96.9 %

Procedure:
To a round-bottomed flask were added 2-amino-4,6-dimethoxy-benzamide (0.161 g, 0.82 mmol), 3-(4-formyl-phenyl)-propionic acid ethyl ester (0.170 g, 0.82 mmol), sodium bisulfite (0.160 g, 0.902 mmol), p-toluenesulfonic acid (0.016 g, 0.082 mmol) and N,N-dimethylacetamide (10 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off and washed with water and methanol to obtain 3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionic acid ethyl ester (0.304 g, 97%). The compound 3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionic acid ethyl ester (0.304 g, 0.795 mmol) was taken up in a 1:1 mixture of THF and methanol (6 mL). A solution of potassium hydroxide (0.089 g, 1.59 mmol) in water (6 mL) was added to the reaction mixture and stirred at room temperature for 16 h. The solvent was removed and the reaction mixture was acidified with 1 N hydrochloric acid. The precipitated solid was filtered off and washed with water and methanol. The solid was further washed with methanol to obtain 3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic acid (0.143 g, 51%). Selected data: MS (ES) m/z: 355.0; MP 250.6-251.1° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2s1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: c1ccc2sc(N3CCNCC3)nc2c1
Temperature: 0 °C

Procedure:
A solution of 2-chlorobenzothiazole (5 g) in 20 mL of toluene is added dropwise to a refluxing solution of piperazine (20 g) in 150 mL of toluene. The solution is heated for an additional 24 hours, and after cooling at 0° C. for about 30 minutes, filtered. The filtrate is extracted with 10% acetic acid and the aqueous extracts are washed with ether, basified and extracted with dichloromethane. The dichloromethane layer is washed with water, dried and concentrated. The concentrated material is placed under vacuum overnight (6.8 g, m.p. 63-64° C.). 1H NMR (CDCl3) 7.62 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.29 (td, J=7.6, 1.2 Hz, 1H), 7.07 (t, J=8.0 Hz, 1H), 3.61 (t, J=5.2 Hz, 4H), 3.00 (t, J=5.2 Hz, 4H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:28](=[O:31])[CH2:29]Br)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:28](=[O:31])[CH2:29][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ncc(C(=O)CBr)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1ncc(C(=O)CN2CCOCC2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
Triphenylphosphine (110 mg, 0.42 mmol) in dichloromethane (1 mL) was added slowly to an ice cooled solution of 5-(2-butoxy-5-glycoloyl-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Example 33) (150 mg, 0.35 mmol) and carbon tetrabromide (140 mg, 0.42 mmol) in dichloromethane (3 mL). The solution was allowed to warm to room temperature. After 2 h further carbon tetrabromide (25 mg, 0.075 mmol) and triphenylphosphine were added and stirring continued for 2 h. Concentration and purification of the product by flash column chromatography (gradient elution with ethyl acetate/pentane (10:90-70:30) gave 5-[2-butoxy-5-(2-bromoacetyl)-3-pyridinyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one which was used without any further purification (slight contamination with triphenylphosphine oxide). 5-[2-Butoxy-5-(2-bromoacetyl)-3-pyridinyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (205 mg, 0.42 mmol) was dissolved in dichloromethane and the solution cooled to 0° C. Morpholine (54 mg, 0.62 mmol) and triethylamine (84 mg, 0.83 mmol) were added and the mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was evaporated and the residue dissolved in ethyl acetate, washed with water (twice), saturated sodium bicarbonate (twice) and brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (gradient elution 20% ethyl acetate/pentane:100% ethyl acetate:3% methanol/methyl acetate) gave 70 mg product.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[C:21]([O:27][CH3:28])=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[C:20]1[C:21]([O:27][CH3:28])=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=1)[C:29](=[O:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1CNCc1ccccc1
Reactant: CC(=O)Cl
Product: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1ccccc1)C(C)=O

Procedure:
Benzyl-[2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-amine and acetyl chloride were reacted as described in Example 11, Step 2 to provide N-benzyl-N-[2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-acetamide.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11](C=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)([O-])O[C:24](CC)([CH2:33]C)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.CN(C)C=O.C[O-].[Na+]>O.C(O)(=O)C>[C:16]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:9]=[CH:10][C:11]([CH:33]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:14][CH:15]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccc(OC)cc1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C=Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A mixture of 54.6 g (0.2 mol) of 4-diphenylaminobenzaldehyde, 51.6 g (0.2 mol) of diethyl-4-methoxybenzyl phosphonate, and 250 ml of dimethylformamide was placed in a 500 ml four-neck flask. 57.9 g of 28% sodium methylate was added dropwise to the above mixture with stirring at room temperature over a period of 15 minutes. Thus, the reaction was carried out at 50°to 60° C. for five hours. The thus obtained reaction mixture was diluted with 500 ml of water, and then made acid with the addition of acetic acid. Then the mixture was filtrated to obtain a wet cake. The thus obtained wet cake was washed with 100 ml of methanol three times, and recrystallized from a mixed solvent of ethanol and dioxane, whereby 46.2 g of 4-diphenylamino-4'-methoxystilbene was obtained as yellow crystals in the form of needles in a yield of 61.3%. The melting point of the obtained compound was 170° to 171.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11]([O:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]3)=[N:10][CH:9]=[N:8][C:7]=2[S:6][C:5]=1[CH3:28].I[CH3:30]>CN(C)C=O>[CH3:3][C:4]1[C:12]2[C:11]([O:13][CH:14]3[CH2:15][CH2:16][CH:17]([N:20]([CH3:30])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:18][CH2:19]3)=[N:10][CH:9]=[N:8][C:7]=2[S:6][C:5]=1[CH3:28]
Reactant: Cc1sc2ncnc(OC3CCC(NC(=O)OC(C)(C)C)CC3)c2c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sc2ncnc(OC3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2c1C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
Sodium hydride (220 mg, 9.17 mmol, 3.46 equiv) was added to a solution of tert-butyl N-[4-([5,6-dimethylthieno[2,3-d]pyrimidin-4-yl]oxy)cyclohexyl]carbamate (1.0 g, 2.65 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL) in several batches at 0° C. and the reaction mixture was stirred for 30 min. To this reaction mixture was added iodomethane (450 mg, 3.17 mmol, 1.20 equiv) dropwise at room temperature. The reaction mixture was stirred for 1 h at 30° C. and then quenched by the addition of 5 mL of water. The resulting solution was diluted with 50 mL of water, extracted with 2×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.6 g (58%) of tert-butyl N-[4-([5,6-dimethylthieno[2,3-d]pyrimidin-4-yl]oxy)cyclohexyl]-N-methylcarbamate as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine. LCMS (MH+): m/z=416.9, tR (minutes, Method C)=1.29
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].[CH2:17]([CH2:19][NH2:20])[OH:18]>C(O)C>[OH:18][CH2:17][CH2:19][NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12]
Reactant: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: NCCO
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1NCCO

Procedure:
A solution of 2-chloro-N,N-dimethyl-3-nitrobenzenesulfonamide (170 mg, 0.642 mmol) and ethanolamine (196 mg, 3.21 mmol) in ethanol (6 mL) was heated at reflux for 4 h. The solvent was removed in vacuo, and the residue was purified by column chromatography using heptane/ethyl acetate, 1:1 as an eluent affording 2-[(2-hydroxyethyl)amino]-N,N-dimethyl-3-nitrobenzenesulfonamide, 161 mg (87%). MS (ESI) mm/z 288 [M−H]. 1H NMR (400 MHz, CDCl3) δ ppm 1.92 (t, J=5.6 Hz, 1H), 2.83 (s, 6 H), 3.10-3.06 (m, 2H), 3.84-3.80 (m, 2H), 6.83 (t, J=8.0 Hz, 1H), 6.87 (broad s, 1H), 7.91-7.87 (m, 2H).