Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)C.O[CH:7]([CH2:18][C:19]([CH2:22][Si](C)(C)C)=[C:20]=[CH2:21])[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:21]=[C:20]1[C:19](=[CH2:22])[CH2:18][CH:7]2[O:11][C:10]1([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH2:8]2
Reactant: C=C=C(CC(O)CCC(=O)c1ccccc1)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: C=C1CC2CCC(c3ccccc3)(O2)C1=C
Temperature: -78 °C
Yield: 96.8 %

Procedure:
1.50 mL of diethyl ether was added to 4-hydroxy-1-phenyl-6-trimethylsilanylmethyl-octa-6.7-diene-1-one (110 mg, 0.36 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (64.7 μL, 0.36 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/5) to obtain 74 mg of the product (96%).
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[O-]CC.[Na+:14].Br[CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17]>C(O)C>[O-:5][CH2:4][CH3:3].[Na+:14].[CH3:17][CH:16]([CH:3]([C:2]([O:9][CH3:10])=[O:8])[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)CC(=O)OC
Reactant: CCCC(C)Br
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCC(C)C(C(=O)OC)C(=O)OC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Sodium ethoxide was prepared from sodium metal (7.61 g) and absolute ethanol (200 ml). Dimethyl malonate (50.3 ml) was added dropwise to the ethanol containing sodium ethoxide. After heating to 80° C., 2-bromopentane (50 g) was added and the mixture was reflued for 24 h. Dimethyl (2-pentyl)malonate (62.7 g) was obtained after the usual work-up. Dimethyl (2-pentyl)malonate was added to a 50% potassium hydroxide solution and the mixture was heated for 3 h while water/ethanol being distilled off. After cooling, the solution was acidified with concentrated hydrochloric acid. Then, the solution was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the resulting product was heated to 180° C. until bubbling ceased. After distillation, colorless 3R,S-methy-caproic acid was obtained. Yield: 27.7 g (35%), b.p. 200° C./760 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
0.25 g (0.0011 mol) of 1-(4-chloro-benzyl)-piperidin-4-ol and 0.39 ml (0.0028 mol) of triethylamine were dissolved in 11 ml of toluene, treated with 0.184ml (0.0014mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.135 9 (39%) of 1-(4-chloro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as white crystals.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][N:49]1[CH:53]=[C:52]([CH2:54][NH2:55])[CH:51]=[N:50]1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:52]4[CH:51]=[N:50][N:49]([CH3:48])[CH:53]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cn1cc(CN)cn1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 76 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1-methyl-1H-pyrazol-4-yl)methanamine, the title compound was obtained as a colorless solid in 76% yield: 1H NMR (300 MHz, CDCl3) δ 7.45 (s, 1H), 7.39 (s, 1H), 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.08 (s, 1H), 5.84 (t, J=4.0 Hz, 1H), 4.44-4.39 (m, 4H), 3.88 (s, 3H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:22])[CH2:17][CH2:18][N:19]([CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:20][CH2:21]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC1(c2cccc(OCc3ccccc3)c2)CCNCC1
Reactant: BrCCCc1ccccc1
Agent: Cl
Product: FC1(c2cccc(OCc3ccccc3)c2)CCN(CCCc2ccccc2)CC1

Procedure:
This material was prepared by the alkylation of 4-(3-benzyloxyphenyl)-4-fluoropiperidine hydrochloride with 1-bromo-3-phenylpropane and subsequent salt formation with methanolic hydrogen chloride as described in Step 3 of Example 1 in 43% overall yield.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:18][CH:19]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])N(C)C)[C:14]([CH3:17])([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[CH3:15][C:14]([CH3:17])([CH3:16])[CH2:13][O:18][CH:19]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)COC(OCC(C)(C)C)N1CCN(c2ccccc2)CC1

Procedure:
A solution of 4-phenylpiperazine (0.162 g, 0.001 mol) and dimethylformamide dineopentyl acetal (0.346 g, 0.0015 mol) in anhydrous chloroform (5 mL) was refluxed for 10 hours. The solvent and excess reagent were removed (100° C./1 mm) to give the product in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:36])[NH:32][C:33]([NH2:35])=[O:34])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([O-])([O-])=O.[K+].[K+].S(OCC)(O[CH2:47][CH3:48])(=O)=O.O>CS(C)=O>[CH2:47]([O:14][C:13](=[O:15])[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:36])[NH:32][C:33]([NH2:35])=[O:34])=[CH:25][CH:24]=2)=[CH:20][CH:21]=1)=[CH:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=1)[CH3:48]
Reactant: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc(CCC(=O)NC(N)=O)cc3)cc2)cc(OC)c1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CCC(=O)NC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6 (0.40 g, 0.81 mmol) in dry DMSO (3 mL) was added K2CO3 (0.14 g, 0.98 mmol). To this, diethyl sulfate (0.115 g, 0.91 mmol) was added and stirred at room temperature for 30 min. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by column chromatography over silica gel and eluted with hexanes-ethyl acetate (3:1). Yield: 0.39 g, 92.2%.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:22][CH3:23])([O:20][CH3:21])[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:26]I.[Cl-].[NH4+]>CS(C)=O>[CH3:1][S:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:22][CH3:23])([O:20][CH3:21])[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)([CH3:26])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)C(SC)c1ccc(C(OC)(OC)c2cccs2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC(=O)C(C)(SC)c1ccc(C(OC)(OC)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Methyl α-methylthio[p-[dimethoxy(2-thienyl)methyl]phenyl]acetate (457 mg) was dissolved in 3 ml of anhydrous dimethyl sulfoxide, and 60 mg (65% content) of sodium hydride was added. The mixture was stirred at room temperature for 30 minutes. Then, 0.15 ml of methyl iodide was added, and the mixture was stirred at room temperature for 20 minutes. After adding an aqueous solution of ammonium chloride (0.5 g/30 ml), the mixture was extracted three times with 20 ml of methylene chloride. The extract was washed twice with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a Florisil column using benzene as an eluent to give 443 mg of methyl α-methylthio-α-[p-[dimethoxy(2-thienyl)methyl]phenyl]propionate as a colorless oil in a yield of 93%.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].CC(C)([O-])C.[K+].C(O[CH2:16][C:17]1[O:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:21]=1)(=O)C>CN(C)C=O.CO>[CH3:28][N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][C:19]1[O:18][C:17]([CH2:16][S:5][CH2:4][CH2:3][NH2:2])=[CH:21][CH:20]=1
Reactant: CC(=O)OCc1ccc(CCCCN(C)C)o1
Reactant: NCCS
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CCCCc1ccc(CSCCN)o1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Cysteamine hydrochloride (4.5 g) was added to a cooled solution of potassium-t-butoxide (8.98 g) in dry dimethylformamide (125 ml). The mixture was stirred for 20 min and [5-[4-(dimethylamino)butyl]-2-furanyl]methyl ethanoate (9.6 g) was added. The reaction was heated at 90° for 4 hr, poured onto an ice-water mixture and extracted with chloroform. Distillation of the organic extract gave a yellow oil which after column chromatography on silica, using methanol/0.880 ammonia (9:1) as eluent, and a further distillation afforded a colourless oil b.p. 140°/0.05 mm Hg. Found: C, 60.81; H, 9.86; N, 10.44. Calc. for C13H24N2OS: C, 60.91; H, 9.44; N, 10.93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=2[CH:13]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[O:7][C:6]=2[CH:13]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: NCC1COc2ccc(Cl)cc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNCC3COc4ccc(Cl)cc4O3)cc2o1
Yield: 8.5 %

Procedure:
2,3-Dihydro-7-chloro-1,4-benzodioxin-2-methanamine (1.72 g, 8.62 mmole), 7-(3-chloropropoxy)coumarin (1.88 g, 7.88 mmole), diisopropylethylamine (7.5 ml, 43.1 mmole) and sodium iodide (1.37 g, 9.14 mmole) were combined in 200 ml of DMF and heated at 80°-100° C. for 3 days under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue was column chromatographed on silica gel using first 0.5% methanol/dichloromethane and then 1% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum, during which procedure the free base began to come out of solution. This material was collected by filtration and recrystallized from isopropanol with addition of 4N HCl/isopropanol to give 0.27 g of white solid, monohydrochloride, m.p. 235°-242° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.BrC(C)C.O>C(OCC)C>[CH:2]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)([CH3:3])[CH3:1]
Reactant: [Li]CCCC
Reactant: C1=Cc2ccccc2C1
Solvent: O
Solvent: CCOCC
Solvent: CC(C)Br
Product: CC(C)C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (37 ml in hexane) was added to a solution of 1H-indene (6.30 ml) in anhydrous diethyl ether (40 ml) under nitrogen atmosphere at 15° C. The solution was stirred at room temperature for 10 min, 2-bromopropane (18.8 g) in anhydrous ether (100 ml) was added, and stirring was continued for 72 hours. Water (30 ml) was added, the phases were separated, and the aqueous phase was extracted with ether. The combined ether solutions was washed with water, dried (MgSO4) and condensed. The residue was distilled (50°-55° C., 0.03 mmHg) to give 1-isopropyl-1H-indene (5.95 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH3:14][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidine (example E.53) (0.11 g, 0.3 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.087 g, 0.4 mmol) according to the general procedure VI. Obtained as a light brown solid (0.028 g, 22%). MS (ISP) 421.1 [(M+H)+]; mp 153° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([F:27])[CH:14]=3)[C:5]2=[N:4][CH:3]=1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([F:27])[CH:14]=3)[C:5]2=[N:4][CH:3]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3nc(Cl)cnc23)cc1F
Product: CN(C)c1cnc2c(Oc3ccc(NC(=O)OC(C)(C)C)c(F)c3)ccnc2n1

Procedure:
Method D6 was used with tert-butyl 4-(3-chloropyrido[2,3-b]pyrazin-8-yloxy)-2-fluorophenylcarbamate (270 mg, 0.67 mmol) and dimethylamine to give the product as a yellow solid. Yield: 233 mg (91%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2([C:32]#[N:33])[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=O)[CH3:28])[O:22][C:21]4=[O:30])=[CH:16][C:15]=3[F:31])[CH2:10][CH2:9]2)[CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2([C:32]#[N:33])[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[S:43])[CH3:28])[O:22][C:21]4=[O:30])=[CH:16][C:15]=3[F:31])[CH2:10][CH2:9]2)[CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4cccnc4)CC3)c(F)c2)C(=O)O1
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4cccnc4)CC3)c(F)c2)C(=O)O1
Yield: 58 %

Procedure:
By using procedure as described in Example 82 and by reacting (S)-N-{3-[4-(4-(pyridin-3-ylamino)-4-cyanopiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide and Lawesson's reagent the compound was obtained in 58% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]#[N:13])=[CH:4][N:3]=1.[CH3:14][O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CC(O)CC>[CH3:14][O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]#[N:13])=[CH:4][N:3]=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: COCCNS(=O)(=O)c1ccc(N)cc1
Reactant: C#CCOc1nc(Cl)ncc1C#N
Solvent: CCC(C)O
Product: C#CCOc1nc(Nc2ccc(S(=O)(=O)NCCOC)cc2)ncc1C#N
Yield: 66.8 %

Procedure:
A solution of 2-chloro-4-(2-propyn-1-yloxy)-5-cyanopyrimidine (Method 17; 219 mg, 1.13 mmol) and 4[N-(2-methoxyethyl)sulphamoyl]aniline (Method 38; 130 mg, 0.56 mmol) in 2-butanol (8 ml) was stirred at 50° C. for 18 hours. Solvent was removed under reduced pressure and the product recrystallized from methanol to give the title compound (145 mg, 67%). NMR: 2.90 (q, 2H), 3.15 (s, 3H), 3.25 (m, 2H), 3.70 (s, 1H), 5.20 (s, 2H), 7.55 (t, 1H), 7.75 (d, 2H), 7.90 (d, 2H), 8.80 (s, 1H); m/z 387.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:16]([O:20][C:21]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][C:22]=1B(O)O)[CH2:17][CH2:18][CH3:19]>>[C:27]([C:26]1[C:21]([O:20][CH2:16][CH2:17][CH2:18][CH3:19])=[C:22]([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:3]=2)[CH:23]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCCCOc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Product: CCCCOc1c(-c2cc(C=CC(=O)O)ccc2O)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 7.2 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 6.2 g (22.8 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 14 g (45.7 mmol) of 2-butyloxy-3,5-di-tert-butylphenylboronic acid obtained above, 700 mg (7%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3(O)[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc3c(N)ncnn23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxyazepane-1-carboxylate (2.45 g, 7.05 mmol) and triethylamine (2.95 mL, 21.2 mmol) in CH2Cl2 (49 mL) was added trifluoroacetic anhydride (1.99 mL, 14.1 mmol), dropwise. The ice bath was removed and the mixture was stirred at rt for 3 h. The reaction was quenched with H2O (40 mL) and the layers were separated. The organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness. The crude residue was purified by ISCO® chromatography using 1:1 ethyl acetate/hexanes to afford 1.66 g (72%) of the desired product. ES-MS m/z 330.11 [M+H]+, HPLC RT (min) 2.47.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:20][C:19]3[CH:18]=[C:17]([N:21]4[C:29](=[O:30])[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22]4=[O:31])[CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N+:34]([O-])([O-:36])=[O:35].[K+]>OS(O)(=O)=O>[N+:34]([C:16]1[C:17]([N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])=[CH:18][C:19]2[CH2:20][CH:11]([N:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:32])[F:33])[CH2:6][CH2:7]3)[CH2:12][CH2:13][C:14]=2[CH:15]=1)([O-:36])=[O:35]
Reactant: O=C1c2ccccc2C(=O)N1c1ccc2c(c1)CC(N1CCN(C(=O)C(F)(F)F)CC1)CC2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1c1cc2c(cc1[N+](=O)[O-])CCC(N1CCN(C(=O)C(F)(F)F)CC1)C2

Procedure:
To a solution of 2-{7-[4-(Trifluoroacetyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1H-isoindole-1,3(2H)-dione (35 mg, 0.77 mmol) in conc. H2SO4 (2 mL) was added potassium nitrate (15 mg, 0.15 mmol) at 0° C. LC showed formation of the desired product within 10 minutes. The reaction was poured into ice, and extracted with DCM twice. The product was purified by mass-directed HPLC. LC-MS (IE, m/z): 503 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1)(=[O:39])=[O:38]>C1COCC1>[CH:13]1([C:11]2[S:12][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:46][CH:43]4[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]4)[N:7]=3)=[C:9]([C:17]3[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=4[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:10]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(C4CCC4)nc3-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)n2)CC1
Yield: 59 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.33 g, 1.9 mmol) in THF (2 mL) the title compound was obtained (0.075 g, 0.11 mmol, 59% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.08-7.97 (m, 1H), 7.59-7.18 (m, 7H), 6.17-5.73 (m, 1H), 3.84 (quin, J=8.4 Hz, 1H), 3.60-3.39 (m, 2H), 2.93-2.62 (m, 7H), 2.43-2.12 (m, 4H), 2.10-1.68 (m, 3H), 1.64-1.29 (m, 2H), m/z (ESI): 679 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].[CH3:11][N:12]([CH2:16][CH2:17]Cl)[CH2:13][CH2:14]Cl.Cl.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]1[CH2:17][CH2:16][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: CN(CCCl)CCCl
Reactant: COc1cccc(C)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: COc1cccc(C)c1N1CCN(C)CC1

Procedure:
A mixture of 2-methoxy-6-methylphenylamine (D28) (3.62 g, 26.4 mmol), mechlorethamine hydrochloride (12.7 g, 66 mmol) and potassium carbonate (15 g) in chlorobenzene (90 ml) was refluxed under argon for 20 h. The mixture was cooled and filtered, and the filtrate evaporated under reduced pressure to leave the title compound (D29) as a red oil which slowly crystallised on standing (5.4 g, 93%) MH+=221.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH2:5].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.FC1C=C(OC)C=C(F)C=1CN1[C:42]2[N:43]=[CH:44][CH:45]=[CH:46][C:41]=2[S:40](=[O:48])(=[O:47])[N:39]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[C:51]([O:57][CH3:58])[CH:50]=2)[C:38]1=[O:59]>CN(C=O)C>[Cl:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([CH2:4][N:5]2[C:42]3[N:43]=[CH:44][CH:45]=[CH:46][C:41]=3[S:40](=[O:48])(=[O:47])[N:39]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[C:51]([O:57][CH3:58])[CH:50]=3)[C:38]2=[O:59])=[C:6]([F:11])[CH:7]=1
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Reactant: NCc1c(F)cc(Cl)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2C(=O)N(Cc3c(F)cc(Cl)cc3F)c3ncccc3S2(=O)=O)cc1OC

Procedure:
The title compound (38 mg, 0.08 mmol) was prepared in two steps from (IntC1) (208 mg, 0.63 mmol), 2,6-difluoro-4-chlorobenzylamine (135 mg, 0.76 mmol) and N,N-diisopropylethylamine (113 uL, 0.63 mmol); followed by 1,1′-carbonyldiimidazole (166 mg, 1.0 mmol) in DMF (8.5 mL) using the methods of (95).