Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1B1OC(C)(C)C(C)(C)O1)[C:5]([NH2:7])=[O:6].Br[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[N:23][CH:22]=1>O1CCOCC1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].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>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)=[CH:35][CH:36]=2)=[N:23][CH:22]=1)[C:5]([NH2:7])=[O:6]
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2F)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4F)n4ccnc34)cc2)CC1

Procedure:
In the same way as described for Compound 127, step 4, using 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) benzamide (82 mg, 0.31 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (60 mg, 0.155 mmol) and Pd(PPh3)4 (45 mg, 0.038 mmol) in dioxane (0.68 mL), DMF (1.52 mL) and 1.5M Na2CO3 (0.83 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The title compound is isolated as a solid. HPLC (254 nm): Rt 1.92 min (95.0%); m/z (APCI) 446 (M+H)+.
Reaction SMILES: C1([CH:7]=[CH:8][C:9](C2C=CC=CC=2)=[O:10])C=CC=CC=1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([C:34](=[O:53])/[CH:35]=[CH:36]/[C:37]2[CH:38]=[CH:39][C:40]([O:48][CH2:49][C:50]([OH:52])=[O:51])=[C:41]([CH:47]=2)[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:31]=[CH:32][CH:33]=1.FC(F)(F)C([O-])=O>C(Cl)Cl>[CH2:9]([O:10][C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][NH2:24])=[CH:29][C:30]=1[C:34](=[O:53])/[CH:35]=[CH:36]/[C:37]1[CH:38]=[CH:39][C:40]([O:48][CH2:49][C:50]([OH:52])=[O:51])=[C:41]([CH:47]=1)[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:8]=[CH2:7].[F:17][C:18]([F:23])([F:22])[C:19]([O-:21])=[O:20]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)c1cc(/C=C/C(=O)c2cccc(OCCN)c2)ccc1OCC(=O)O
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: C=CCOc1ccc(OCCN)cc1C(=O)/C=C/c1ccc(OCC(=O)O)c(C(=O)OCC)c1
Yield: 76 %

Procedure:
Chalcone 3e was deprotected using trifluoroacetic acid in CH2Cl2 as described for 2f to yield a yellow solid (76%). HR-MS: Calc'd. 470.1815, Found 470.1810.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:46][C:47]([CH3:61])([CH2:50][N:51]1[CH:60]=[C:54]2[N:55]=[CH:56][C:57]([Br:59])=[CH:58][C:53]2=[N:52]1)[C:48]#[N:49]>CN(C=O)C>[Br:59][C:57]1[CH:56]=[N:55][C:54]2=[CH:60][N:51]([CH2:50][C:47]([NH:46][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:10][C:2]=3[F:1])([C:48]#[N:49])[CH3:61])[N:52]=[C:53]2[CH:58]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
2-Fluoro-4-trifluoromethoxybenzoic acid (80 mg, 0.357 mmole), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC.HCl, 78 mg, 0.4 mmole), 1-hydroxybenzotriazole monohydrate (HOBt.H2O, 69 mg, 0.45 mmole) and N-methylmorpholine (71 μL) were stirred in DMF (2 mL) for 20 minutes at room temperature prior to adding 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (100 mg, 0.357 mmole, described in Example 182). The mixture was stirred overnight at room temperature, quenched with a saturated solution of ammonium chloride and extracted with EA. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (17 mg, 9%). MS (ES): M/Z [M+H]=486. 1H NMR: (400 MHz, CHLOROFORM-d): 1.91 (s, 3H), 4.90 (d, J=14.1 Hz, 1H), 5.08 (d, J=14.1 Hz, 1H), 7.07 (d, J=12.1 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 8.02 (d, J=12.1 Hz, 1H), 8.15-8.28 (m, 2H), 8.38 (s, 1H) and 8.62 (d, J=2.0 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −108.6 (td, J=11.9, 9.2 Hz, 1F) and −58.3 (s, 3F). 2-fluoro-4-trifluoromethoxybenzoic acid was prepared as follows:
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[CH:29](=O)[CH2:30][CH2:31]C.[H][H]>CO.[Pd]>[CH2:19]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:18][CH2:17]1)[CH2:29][CH2:30][CH3:31]
Reactant: NC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Reactant: CCCC=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCN1CCC(c2nc3cccc(C(N)=O)c3o2)CC1
Yield: 13.8 %

Procedure:
A mixture of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate (400 mg, 1.06 mmol), Pd/C (10% wt, 40 mg), butyraldehyde (96 mg, 1.58 mmol) in anhydrous methanol (15 mL) was purged with hydrogen at room temperature for 12 hr. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by prep-HPLC to give 2-(1-butylpiperidin-4-yl)benzo[d]oxazol-7-carboxamide (44 mg, yield 13%). 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.94 (t, 3H), 1.30-1.48 (m, 2H), 1.48-1.55 (m, 2H), 2.03-2.11 (m, 6H), 2.36-2.41 (m, 2H), 3.00-3.06 (m, 3H), 6.20 (s, 1H); 6.99 (s, 1H), 7.42-7.46 (t, 1H), 7.85-7.87 (m, 1H), 8.07 (dd, 1H); LC-MS (ESI) m/z: 302 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:16]([CH:17]=1)[CH2:15][CH2:14][O:13][C:12]1[C:7]2=[CH:8][C:9]([C:19]#[C:20][C:21]([OH:27])([CH3:26])[C:22](OC)=[O:23])=[C:10]([F:18])[CH:11]=1)(=[O:3])[NH2:2].[CH3:28][NH2:29]>>[F:18][C:10]1[C:9]([C:19]#[C:20][C:21]([OH:27])([C:22](=[O:23])[NH:29][CH3:28])[CH3:26])=[CH:8][C:7]2[C:6]3[N:16]([CH2:15][CH2:14][O:13][C:12]=2[CH:11]=1)[CH:17]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Reactant: CN
Product: CNC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20-mL sealed tube, methyl 4-[4-carbamoyl-12-fluoro-9-oxa-3,6-diazatricyclo[8.4.0.0[2,6]]tetradeca-1(14),2,4,10,12-pentaen-13-yl]-2-hydroxy-2-methylbut-3-ynoate (120 mg, 0.32 mmol, 1.00 equiv) was added into a solution of methanamine (30% w/w in ethanol, 5 mL). The resulting solution was stirred for 8 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 35 mg (29%) of 8-Fluoro-9-(3-hydroxy-3-methylcarbamoyl-but-1-ynyl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a yellow solid. LC-MS: (ES, m/z): 373 [M+H]; 1H-NMR: (300 MHz, DMSO-d6, ppm): δ 8.548 (d, 1H), 8.000-7.800 (m, 1H), 7.773 (s, 1H), 7.564 (br s, 1H), 7.108 (br s, 1H), 7.012 (d, 1H), 6.551 (s, 1H), 4.551-4.481 (m, 4H), 2.624 (d, 3H), 1.603 (s, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[C:20]2C(=[CH:16][CH:17]=[CH:18][CH:19]=2)C=[N:13][CH:12]=1.[Cl:21][CH2:22][CH2:23]Cl>>[Cl:21][C:22]1[C:23]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([O:10][CH3:9])=[C:12]([Br:1])[N:13]=1
Reactant: COc1cncc2ccccc12
Reactant: ClCCCl
Reactant: O=C1CCC(=O)N1Br
Product: COc1c(Br)nc(Cl)c2ccccc12

Procedure:
The material (Example 222a) was subjected to NBS bromination, thus 4-methoxy isoquinoline (Example 222a, 2.1 gm, 13.2 mmol) in 1,2-dichloroethane (DCE, 150 mL) was treated with N-bromosuccinimide (NBS, 1.5 gm, 8.4 mmol, 0.6×) at 70° C. for an hr followed by addition of second portion of 1.5 gm NBS. The dark brownish mixture was stirred for another hr before the addition of third portion of 1.0 gm NBS. The bromination was monitored by LC-MS until there was no starting material left. The crude mixture was evaporated to dryness and the desired product was filtered over a short bed of silica-gel (Type-H, Merck, 3 cm diameter by 1.5 cm height) eluted with straight hexanes first followed by gradually increasing the amount of ether. The desired product, (Example 222b), was isolated as an oily material (1.7 gm, 54%). LC/MS Rt-min (MH+) [method C]: 2.65 (238). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.04 (s, 3 H) 7.64 (t, J=7.58 Hz, 1 H) 7.76 (t, J=7.09 Hz, 1 H) 7.99 (d, J=8.31 Hz, 1 H) 8.11 (d, J=8.31 Hz, 1 H) 8.85 (s, 1 H). [3-Bromo-4-methoxy isoquinoline was previously prepared by a different procedure: Finkentey, Christel; Langhals, Elke; Langhals, Heinz. Chemische Berichte (1983), 116(6), 2394-7. NMR of the product was identical to that reported].
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25]>>[Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[OH:25])=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5 d from 6-chloro-5-(4-chloro-phenyl)-nicotinic acid (Example 5b) and (1R,2R)-2-amino-1-cyclohexanol to yield 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide as a colorless solid, MS (ISP) 364.9, 366.9 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[S:21])[NH:3]1.[H-].[Na+].I[CH3:25]>O1CCCC1>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4]([S:21][CH3:25])=[N:3]1
Reactant: CI
Reactant: Cn1[nH]c(=S)n(-c2ccccc2Oc2ccccc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nn(C)c(=O)n1-c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A solution of 900 mg of crude 2-methyl-4-(2-phenoxyphenyl)-5-thioxo-1,2,4-triazolidin-3-one in 50 mL of tetrahydrofuran was treated with 150 mg of sodium hydride (60% oil dispersion). After 5 minutes, 0.5 mL of iodomethane was added, and the mixture was stirred at ambient temperature overnight. The solid was removed by filtration and the filtrate concentrated to an oil. The oil was partitioned between ether and 1N hydrochloric acid solution. The organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was triturated in hexane/n-butyl chloride to afford 530 mg (56%) of the title compound of Step C, m.p. 129-130° C.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][Si:15]([CH3:25])([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([O:13][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Si:15]([CH3:14])([CH3:25])[CH3:24])=[CH:17][CH:18]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)c1ccc(CBr)cc1
Reactant: Cc1c(O)cnn(C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCc2ccc([Si](C)(C)C)cc2)cnn(C(C)(C)C)c1=O
Yield: 69.7 %

Procedure:
To a solution of 0.9 g (0.005 mol) of 2-t-butyl-5-hydroxy-4-methyl-3(2H)-pyridazinone and 1.2 g (0.005 mol) of p-trimethylsilyl benzylbromide dissolved in 20 ml of N,N-dimethylformamide was added 1.0 g (0.007 mol) of potassium carbonate at room temperature under stirring. After addition, the resulting mixture was stirred at 120° C. for three hours. After allowed to cool, the reaction mixture was poured into 200 ml of water and extracted with 100 ml of benzene. The resulting benzene layer was washed with 100 ml of water, dried over anhydrous sodium sulfate, and freed of solvent by distillation to give 1.8 g of crude product. The crude product was recrystallized from 20 ml of hexane to obtain 1.2 g of 2-t-butyl-4-methyl-5-(p-trimethylsilyl benzyloxy)-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=2)[N:3]=1.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1>>[ClH:1].[ClH:1].[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=3)[N:3]=2)[CH2:33][CH2:32]1
Reactant: CSc1ccc(C(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: CSc1ccc(C(=O)NCCNc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1
Product: Cl
Temperature: 140 °C

Procedure:
296 mg of the product obtained in Stage 1 above and 393 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to approximately 140° C. for 6 hours. After evaporating the solvent, chromatography on silica is carried out (eluent methylene chloride/methanol/ammonium hydroxide 85/15/1.5) followed by taking up in an ethanolic solution of hydrochloric acid, leaving to crystallize, separating, drying under reduced pressure and 51 mg of expected product is recovered.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12]O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]C(Br)(Br)Br>C(Cl)Cl>[Br:33][CH2:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]1
Reactant: CCCCC[C@H]1CC[C@H](CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CBr)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A solution of 3.69 g of (trans-4-pentylcyclohexyl)methanol and 5.51 g of triphenylphosphine in 70 ml of methylene chloride at -30° C. was placed under argon gasification and treated portionwise within 15 minutes with 7.30 g of solid tetrabromomethane in such a manner that the internal temperature did not exceed -20° C. After completion of the addition, the cooling bath was removed and the mixture was stirred for a further 18 hours with gradual warming to room temperature. The mixture was then concentrated on a rotary evaporator and the resulting, semi-crystalline residue was triturated with 200 ml of warm hexane, filtered and the concentrated filtrate was chromatographed with hexane on a column of silica gel. There were obtained 4.79 g (97%) of trans-1-(bromomethyl)-4-pentylcyclohexane as a colourless liquid which was purified further by distillation; b.p. 82° C./0.08 mmHg.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[OH:10].[Na+].OO>C(Cl)Cl.O>[CH2:1]1[O:10][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1ccc(C2CO2)cc1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
0.0178 g (0.02 mmol) of the complex salt as described in Preparative Example 1 was added to a mixture of 0.208 g (2 mmol) of styrene in 20 ml of CH2Cl2 and 1.68 g (20 mmol) of sodium hydrogen carbonate in 20 ml of water. After a reaction time at room temperature of 10 minutes, 20 ml of H2O2 (30% strength) was added slowly over a period of 2.5 hours, with the temperature rising to 28° C. After a further 22 hours, the reaction was complete. The layers were separated and the organic phase was evaporated under reduced pressure. The product obtained was purified by column chromatography giving styrene oxide in a yield of 54% based on styrene.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CS(N)(=O)=O
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.40 g (26.7 mmol) of 6-bromo-2-pyridinecarboxylic acid were initially charged in 150 ml of tetrahydrofuran, 6.51 g (40.0 mmol) of carbonyldiimidazole were added and the mixture was boiled at reflux for 1 h. After cooling to room temperature, 3.81 g (40.0 mmol) of methanesulphonamide were added, the mixture was stirred for 10 min, then 6.10 g (40 mmol) of diazabicycloundecene (DBU) were added and the mixture was stirred at room temperature for 16 h.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][NH:6][C:7]([C:9]1([C:12]([F:15])([F:14])[F:13])[CH2:11][CH2:10]1)=[O:8].C1N=CN([C:25](N2C=NC=C2)=[S:26])C=1>C(Cl)Cl>[F:19][C:18]1[CH:17]=[CH:16][C:4]([CH2:5][NH:6][C:7]([C:9]2([C:12]([F:13])([F:14])[F:15])[CH2:10][CH2:11]2)=[O:8])=[CH:3][C:2]=1[N:1]=[C:25]=[S:26]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1F
Solvent: ClCCl
Product: O=C(NCc1ccc(F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Temperature: 50 °C

Procedure:
A mixture of N-(3-amino-4-fluorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (3.17 g; 11.5 mmol) and TCDI (3.07 g; 17.2 mmol) in DCM (50 mL) was heated overnight at 50° C. The mixture was concentrated and the residue was purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.[ClH:25]>O1CCOCC1.CCOCC>[ClH:25].[ClH:25].[CH3:10][NH:9][C:8](=[O:11])[C:6]1[CH:5]=[CH:4][C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:2]([CH3:1])[CH:7]=1
Reactant: CNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To tert-butyl 4-(2-methyl-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylate (1.90 g, 5.70 mmol) was added Hydrochloric acid solution (17.10 mL, 68.4 mmol) in dioxane at 23° C. The reaction was stirred at 23° C. for 30 min. The resulting suspension was diluted with Et2O (20 mL), filtered, rinsed with Et2O (3×10 mL), and the resulting solid was dried in vacuo to provide N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (1.70 g, 5.55 mmol, 97% yield) as an off-white, hygroscopic solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3 H) 2.72-2.79 (m, 3 H) 3.05-3.14 (m, 4 H) 3.17-3.28 (m, 4 H) 7.06 (d, J=8.34 Hz, 1 H) 7.64-7.68 (m, 1 H) 7.68-7.70 (m, 1 H) 8.29-8.39 (m, 1 H) 9.36 (br. s., 2 H). ESI-MS: m/z 234.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.C(=O)([O-])[O-].[K+].[K+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:39]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 19 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-tri methyl-1,2-dihydroquinoline (Reference Compound No. 5-3, 20.1 mg, 0.046 mmol), potassium carbonate (16.7 mg, 0.12 mmol) and benzyl bromide (6.6 μL, 0.055 mmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), and the mixture was stirred at 60° C. for 40 minutes. Ethyl acetate (50 mL) was added to the reaction mixture, and the whole was washed with water (50 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (5.1 mg) as a colorless oil. (Yield 19%)
Reaction SMILES: C([NH:14][CH2:15][CH2:16][C:17]1[C:18]([O:36][CH3:37])=[N:19][C:20]([C:32]([F:35])([F:34])[F:33])=[CH:21][C:22]=1[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])(C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[Si:25]([O:24][CH2:23][C:22]1[CH:21]=[C:20]([C:32]([F:35])([F:34])[F:33])[N:19]=[C:18]([O:36][CH3:37])[C:17]=1[CH2:16][CH2:15][NH2:14])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CCNC(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CCN

Procedure:
To a solution of the compound from Step I above (1.25 g, 2.36 mmol) in absolute ethanol (100 mL) was added 10% palladium on carbon (480 mg). The reaction mixture was placed in a Parr apparatus and shaken under 50 psi of hydrogen for 4 hours. The solution was filtered through a pad of Celite and concentrated in vacuo to yield the title compound. LC/MS: 365 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]([C:25]1([CH3:39])[CH2:30][CH2:29][C:28]2[C:31]([CH3:38])=[C:32]([OH:37])[C:33]([CH3:36])=[C:34]([CH3:35])[C:27]=2[O:26]1)#[CH:24].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[C:23][C:25]3([CH3:39])[CH2:30][CH2:29][C:28]4[C:31]([CH3:38])=[C:32]([OH:37])[C:33]([CH3:36])=[C:34]([CH3:35])[C:27]=4[O:26]3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cc3c(s1)-n1c(C)nnc1CN=C3c1ccccc1Cl)O2

Procedure:
The title compound was obtained by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][4,1]diazepine with rac-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol under the conditions described in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of rac-2-{[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][4,1]diazepin-2-yl]ethynyl}-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with m.p. 155°-160° with foaming. These crystals contained 1.5 molar amounts of water on the basis of the analytical and spectral data.