Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[N:18][OH:19])[NH2:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:20](Cl)(=O)[CH3:21]>N1C=CC=CC=1>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:14])([CH3:15])[C:9]=2[CH:8]=[C:7]([C:16]2[N:17]=[C:20]([CH3:21])[O:19][N:18]=2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C(N)=NO)cc2c1OCC2(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: Cc1nc(-c2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)no1
Temperature: 95 °C
Yield: 52.4 %

Procedure:
To a solution of 7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzo-[b]furancarboxamide oxime (1.05 g, 4.0 mmol) in 20 mL of pyridine is added acetyl chloride (0.43 mL, 6.0 mmol). The reaction mixture is heated at 95° C. for 22 h and cooled to room temperature. Pyridine is removed in vacuo at 50° C.; the residue is partitioned between water and ethyl acetate. The organic layer is washed with water and with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 1.33 g of the crude product. Purification by flash column chromatography on silica gel (10% ethyl acetate-hexane) produces about 0.60 g (52%) of the title compound as a colorless solid: mp 81-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[N:14]([CH3:36])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([NH:28][C:29]2[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:16]=3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[C:37](O)(=O)[CH3:38]>>[CH3:1][O:2][C:3]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[N:14]([CH3:36])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[N:35]=[C:37]2[CH3:38])[N:16]=3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4]
Reactant: COC(C)(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Nc4ccccc4N)nc3n2C)CC1
Reactant: CC(=O)O
Product: COC(C)(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1
Yield: 21.1 %

Procedure:
A mixture of N1-(8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-6-morpholino-9H-purin-2-yl)benzene-1,2-diamine (177 mg, 0.368 mmol) in acetic acid (1.5 mL) was stirred at reflux for 5 hours. The reaction mixture was then concentrated and then purified first by flash chromatography (10% MeOH in DCM containing 1% 2 M ammonia in MeOH), followed by RP-HPLC to give 179 (0.0373 g, 21.1%). LCMS: M+H+=519.1.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22]>C(OCC)C.CCCCCC>[C:13]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[O:19][C:25](=[O:26])[NH:24][S:21]([Cl:20])(=[O:23])=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(NS(=O)(=O)Cl)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2,6-diphenyl phenol (25.0 g, 101 mmol) in 250 mL ethyl ether was added dropwise to a solution of chlorosulfonyl isocyanate (9.7 mL, 112 μmol) in 100 mL hexane at -15° C. under an atmosphere of nitrogen. The resulting white suspension was allowed to warm to room temperature over 2 hours. Concentrated in vacuo and triturated with ice cold hexane. Vacuum filtration afforded the title compound as a white solid, mp 159°-162° C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](C1C=CC=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>[Cu].O>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:2]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:30][CH:29]=1
Reactant: Cc1ccc(O)cc1
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Cc1ccc(Oc2ccc(C)cc2C(=O)O)cc1

Procedure:
393 G. of 2-iodo-5-methyl-benzoic acid in 150 ml. of nitrobenzene are heated to 145° C. 138 G. of potassium carbonate are added thereto in small portions with stirring. Subsequently, 156 ml. of 4-methyl-phenol and 276 g. of potassium carbonate are added. To the resulting mixture, 3 g. of copper powder are carefully added, and the mixture is subsequently stirred at 165° C. for 20 minutes. After cooling, 1.25 liters of water are added to the mixture which is then extracted twice with ether. The aqueous phase is acidified with hydrochloric acid and extracted twice with ether. The ethereal solutions are washed with water, dried over sodium sulfate and concentrated in vacuo. The residue (brown crystals) is recrystallized from 1100 ml. of methanol and 700 ml. of water, and there is obtained 2-(4-methylphenoxy)-5-methyl-benzoic acid, which after repeated recrystallization from methanol/water, melts at 113°-115° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C@@H:11]2[CH2:17][C@H:16]3[C@H:14]([CH2:15]3)[CH2:13][N:12]2C(OCC2C=CC=CC=2)=O)=[N:7][CH:8]=1>CO.CCOC(C)=O.[Pd]>[C@H:14]12[CH2:15][C@H:16]1[CH2:17][C@@H:11]([CH2:10][NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:29])([F:1])[F:28])=[CH:8][N:7]=1)[NH:12][CH2:13]2
Reactant: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2C[C@H]1CNc1ccc(C(F)(F)F)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(NC[C@@H]2C[C@@H]3C[C@@H]3CN2)nc1
Reaction time: 0.42 h

Procedure:
In a 250 ml hydrogenation flask phenylmethyl (1S,4S,6S)-4-({[5-(trifluoromethyl)-2-pyridinyl]amino}methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D11 (0.275 g) was dissolved in MeOH (20 ml) and Pd/C (0.0722 g, 0.068 mmol) was added. The resulting suspension was hydrogenated at atmospheric pressure. After 25 min UPLC (Acid GEN_QC) showed a main side product with rt=0.99, peak observed: 284 (M+1). The Pd/C was filtered on a celite pad, the solvent was removed under reduced pressure to give an off-white semisolid. This solid was dissolved in anhydrous EtOAc (20 ml) and Pd/C (0.0722 g, 0.068 mmol) was added. The suspension was hydrogenated at atmospheric pressure for 50 minutes (total time). The Pd/C was filtered on a celite pad, the solvent was removed under reduced pressure to give a yellowish solid, which was purified via Biotage SP4 (NH 25+M column; Cy/EtOAc: 1/0 to 75/25 15 CV, 75/25 3 CV, to 0/1 20 CV) to give the title compound D12 (0.100 g). HPLC (walk-up): rt=3.19 min MS: (ES/+) m/z: 272 (M+1). C13H16F3N3 requires 271. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22-8.32 (m, 1 H), 7.57-7.64 (m, 1 H), 7.21-7.28 (m, 1 H), 6.60 (d, 1 H), 3.12-3.26 (m, 1 H), 2.89-3.10 (m, 3 H), 2.37-2.47 (m, 1 H), 1.83-1.94 (m, 1 H), 1.05-1.18 (m, 1 H), 0.69-0.98 (m, 2 H), 0.42-0.52 (m, 1 H), 0.28-0.39 (m, 1 H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH:46]6[CH2:48][CH2:47]6)[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH:46]6[CH2:48][CH2:47]6)[CH:42]=[CH:43][N:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CC4CC4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CC4CC4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-cyclopropylmethylimidazol-2-yl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (125 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (68 mg) in dichloromethane (10 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified with silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-cyclopropylmethylimidazol-2-yl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (65.9 mg) (Compound 348) as yellow amorphous.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:34])=[C:25]([CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:26]=2)=[CH:18][CH:17]=1>>[CH3:34][C:24]1[O:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=3)=[CH:17][CH:18]=2)=[N:26][C:25]=1[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: Cc1oc(-c2ccc(-c3cccc(OC(F)(F)F)c3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 3-Trifluoromethoxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 417.1 (M+1)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[N:22][C:14]=3[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncccc1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-methylnicotinic acid (250 mg, 1.83 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) were placed in DCM (5 mL) and stirred at room temperature for 90 minutes. 3M LiOH (5 mL) was added. The reaction was stirred for 20 minutes and then was poured onto water. The mixture was then filtered and washed with water and DCM. The filtered solid was dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylnicotinamide (254 mg, 84% yield).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]([Si:13]([CH3:33])([CH3:32])[O:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21]2)([CH3:12])[CH3:11]>CN(C=O)C>[Br:8][C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([O:17][CH2:16][CH2:15][O:14][Si:13]([C:10]([CH3:11])([CH3:9])[CH3:12])([CH3:33])[CH3:32])[CH:19]=2)[NH:23][C:22]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2cc(OCCO[Si](C)(C)C(C)(C)C)ccc2[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
NBS (0.137 g, 0.771 mmol) was added to ethyl 5-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1H-indole-2-carboxylate (0.255 g, 0.701 mmol) dissolved in DMF (2 mL) and the resulting mixture was stirred overnight at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, dried over MgSO4, filtered and the solvent evaporated. Purification was accomplished by silica gel column chromatography (0 to 50% EtOAc/hexanes) to afford the title compound (0.121 g, 39%) as an oily solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.90 (br. s., 1H), 7.27 (d, 1H), 7.02-7.07 (m, 1H), 7.01 (s, 1H), 4.43 (q, 2H), 4.11 (t, 2H), 4.00 (t, 2H), 1.43 (t, 3H), 0.91 (s, 9H), 0.11 (d, 6H). LC-MS (ES+) m/z 442.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(Cl)=[S:12]>Cl>[N:1]([C:2]1[C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[C:11]=[S:12]
Reactant: Nc1cccc2ccoc12
Reactant: S=C(Cl)Cl
Agent: Cl
Product: S=C=Nc1cccc2ccoc12

Procedure:
7-Amino-benzo[b]furan is reacted with thiophosgene in 3 N hydrochloric acid at room temperature over 1 hour to give 7-isothiocyanatobenzo[b]furan. (M. Pt. 45°-46° from petroleum ether.) Reaction of this isothiocyanate with ethanolamine in ether gives N-benzo[b]furan-7-yl-N'-2-hydroxyethylthiourea (m.pt. 138°-139° from methanol) which is used further in the crude state.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15]Br)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Na+].[I-].[CH3:29][C:30]([SH:33])([CH3:32])[CH3:31]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][S:33][C:30]([CH3:32])([CH3:31])[CH3:29])=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2CBr)cc1
Reactant: CC(C)(C)S
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)SCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 60.2 %

Procedure:
A 0° C. solution of the 2-(4-fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 194F (92.5 mg, 0.212 mmol) in acetone (2.5 mL) was treated with NaI (35 mg, 0.233 mmol), and after 5 minutes, the cooling bath was removed and the reaction warmed to 23° C. After 30 minutes, conversion to the 2-(4-fluorophenyl)-4-iodomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone was complete (thin layer chromatography, ethyl acetate/hexanes 4:1). The NaBr and residual NaI were filtered off through a pad of Celite®. Additional acetone (2 mL) was added along with 2-methyl-2-propanethiol (20.5 mg, 0.227 mmol), and the solution cooled to 0° C. before addition of Ag2CO3 (63 mg, 0.227 mmol). After 5 minutes, the cooling bath was removed and the solution warmed to 23° C. for 5 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes gradient 1:1 to 3:2) to provide the product (yield: 57 mg, 60%). mp 50-70° C. 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 3.14 (s, 3H), 3.65 (s, 2H), 7.13-7.21 (m, 2H), 7.63-7.70 (m, 2H), 7.79 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 8.13 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 447 (M+H)+. Anal. calc. for C22H23FN2O3S2: C, 59.17; H, 5.19; N, 6.27. Found: C, 59.48; H, 5.36; N, 5.90.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)Cl.CN(C)C.Cl[C:24]([O:26][CH2:27][C:28]#[CH:29])=[O:25]>C(Cl)Cl.O>[CH2:27]([O:26][C:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:24]([O:26][CH2:27][C:28]#[CH:29])=[O:25])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)=[O:25])[C:28]#[CH:29]
Reactant: C#CCOC(=O)Cl
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Agent: CN(C)C
Solvent: O
Solvent: ClCCl
Product: C#CCOC(=O)Oc1ccc(Cc2ccc(OC(=O)OCC#C)cc2)cc1
Yield: 93.6 %

Procedure:
A flask equipped with a stirrer, thermometer, nitrogen gas tube and reflux condenser was charged with 20.0 g of bis(4-hydroxyphenyl)methane, 50.0 g of methylene chloride and 23.0 g of trimethylamine. To the flask was added 26.0 g of propargyl chloroformate dropwise over one hour and the mixture was allowed to react for 6 hours at 30° C. After the reaction, the reaction mixture was treated with methylene chloride-water mixture and the organic phase was separated followed by drying over magnesium sulfate overnight. After filtering, the filtrate was evaporated in a rotary evaporator. The resulting crystals were recrystallized to give the title compound melting at 60° C. at a yield of 93.6% of theory.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]12[CH2:19][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=31)[C:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[Cl:22][CH2:2][CH2:3][CH2:4][C:5]12[CH2:19][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=31)[C:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCC12CC(c3ccccc31)c1ccccc12
Solvent: c1ccccc1
Product: ClCCCC12CC(c3ccccc31)c1ccccc12

Procedure:
The starting 9-γ-chloropropyl-9,10-dihydro-9,10-methanoanthracene was prepared by reacting 9-γ-hydroxypropyl-9,10-dihydro-9,10-methanoanthracene with thionyl chloride in benzene.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.[F:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]([CH3:36])[C:21]2[N:26]=[C:25]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[CH:24]=[N:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH:9]1([CH2:12][NH:13][C:33]([C:29]2[S:28][C:27]([C:25]3[CH:24]=[N:23][CH:22]=[C:21]([N:20]([CH2:19][C:18]4[CH:37]=[CH:38][C:15]([F:14])=[CH:16][CH:17]=4)[CH3:36])[N:26]=3)=[N:31][C:30]=2[CH3:32])=[O:34])[CH2:11][CH2:10]1
Reactant: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)O
Reactant: NCC1CC1
Solvent: NCc1ccccc1
Product: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)NCC1CC1
Yield: 75 %

Procedure:
Following the procedure described in Example 1 (Part A), making variations as required to replace benzylamine with cyclopropane-methyl-amine to react with 2-{6-[(4-fluoro-benzyl)-methyl-amino]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid, the title compound was obtained in 75% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.58 (s, 1H), 8.05 (s, 1H), 7.25-7.31 (m, 2H), 6.98-7.05 (m, 2H), 5.95 (bs, 1H), 4.82 (s, 2H), 3.21-3.26 (m, 2H), 3.15 (s, 3H), 2.70 (s, 3H), 1.00-1.10 (m, 1H), 0.50-0.57 (m, 2H), 0.22-0.28 (m, 2H); MS (ES+) m/z 412.3 (M+1), Rt=1.52 min.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:26])=[CH:20][CH:19]=1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Yield: 83.8 %

Procedure:
The product of Example 11B (41 mg) and 2-(4-chlorophenyl)acetyl chloride (0.030 mL, 0.20 mmol) were treated using a method similar to that described in Example 1C to give the title compound (57 mg, 0.15 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.42 (dd, 1H), 8.19-7.97 (m, 3H), 7.41 (dd, J=3.3 Hz, 4H), 3.74 (s, 2H); MS (DCI) M/Z 399.2 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccs1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4cccs4)c23)c1

Procedure:
Analogously to Example 32,261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 168 mg (1.5 mmol) of thiophene-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(thien-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 0.15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and crystallization from ethyl acetate yield 4-(3-chloro-phenylamino)-3-[(thien-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p. 228-229° C., HPLC: tRet(grad20-100)=8-9; MS: (M)+=356.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:7]([NH2:10])([CH3:9])[CH3:8]>>[CH:7]([NH:10][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])([CH3:9])[CH3:8]
Reactant: C=CCCCBr
Reactant: CC(C)N
Product: C=CCCCNC(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
5-Bromo-1-pentene (42.3 mmol) was added to isopropylamine (423 mmol), and the mixture was stirred at 60° C. for 48 h in the dark in a sealed tube. Then the volatiles were evaporated at reduced pressure and the crude residue was dissolved in 50 mL of diethyl ether and washed twice with water. The organic phase was dried over Na2SO4. Evaporation of the solvent gave N-isopropylpent-4-en-1-amine as brownish oil (40%) which was used without any further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:9]2.[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:19][CH:20]=1)[CH2:9]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1CCN(Cc1ccc([C@H](C)N)cc1)C2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cccc2c1CCN(Cc1ccc([C@H](C)NC(C)=O)cc1)C2
Temperature: 25 °C

Procedure:
To 80 mg (0.24 mmol) (S)-1-[4-(5-methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-ethylamine hydrochloride (example XXXIII.2) in 2.0 mL DCM are added 67 μL (0.48 mmol) TEA and 34 μL (0.26 mmol) acetic anhydride and the resulting mixture is stirred at r.t. over night. 200 μL MeOH are added and the reaction mixture is purified by HPLC.
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][C:6]1[C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[O:9][C:10]=1[C:11]([OH:13])=[O:12]>CO>[CH3:1][O:12][C:11]([C:10]1[O:9][C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[C:6]=1[CH3:5])=[O:13]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1oc2ccccc2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetylchloride (6.7 mL, 91 mmol) was added dropwise to 750 mL dry methanol cooled on an ice-bath under N2 atmosphere. After completion of the addition, the solution was stirred at RT for 30 min. Subsequently, 16.0 g (90 mmol) 3-methyl benzo[b]furan-2-carboxylic acid was added and the solution was refluxed for 17 h under N2 atmosphere. The solution was cooled on an ice-bath to 0° C. and 500 mL ice-cold water was added. The resulting white precipitate was collected by filtration and washed with cold methanol. Yield: 16.1 g (94%) of a white solid. 1H-NMR (200 MHz, CDCl3): δ 7.72 (d, J=8 Hz, 1H), 7.60 (t, J=8 Hz, 1H), 7.53 (t, J=8 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 4.08 (s, 3H), 2.73 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]12(O)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.ClCCl.S(=O)(=O)(O)O>CCCCCCC>[C:13]12([C:6]3[C:7]([OH:12])=[CH:8][C:9]4[C:4]([CH:5]=3)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=4)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: ClCCl
Product: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
56 g (0.25 mol) of 6-bromo-2-naphthol, 38.2 g (0.25 mol) of 1-adamantanol and 500 ml of a mixture of dichloromethane and heptane (40/60) were introduced into a round-bottomed flask. 15 ml of concentrated sulfuric acid were added and the reaction mixture was stirred at room temperature for 48 hours. The solid was filtered off, washed with heptane (3×100 ml) and dissolved in ethyl ether and the organic phase was washed with water, separated by settling, dried over magnesium sulfate and evaporated. 60.1 g (67%) of the expected compound were collected, which compound had a melting point of 215°-6° C.