Azzindani/Open_Reaction_Data huggingface dataset:
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[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[F:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:28][O:27][C:25]([C:21]1[CH2:22][CH2:23][N:24]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[F:30])[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[CH:29][C:19]=2[CH:20]=1)=[O:26]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 100 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 2-fluorobenzaldehyde (471 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (402 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl-7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (382 mg) as yellow oil.
Reaction SMILES: N1C=CN=C1.[C:6]([O:9][CH:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([OH:22])[CH3:21])[CH2:11]1)(=[O:8])[CH3:7].[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C)C=O>[C:6]([O:9][CH:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([O:22][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH3:21])[CH2:11]1)(=[O:8])[CH3:7]
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O)[C@@]4(C)CC[C@@H]32)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
Imidazole (203.7 gm, 2.28 mol) was added to a stirred suspension of 3-acetoxy-pregn-5-ene-20-ol (361 gm, 1 mol) in dimethylformamide (3.7 L). t-Butyldimethylsilyl chloride (228.9 mg, 1.52 mol) was added over a 10-15 min period. The mixture was stirred at room temperature for 3 days. The dimethylformamide was removed by decantation and methanol (50 mL) was added to it. Water (4 L) was added and the solution extracted with ethyl acetate (2×4 L). The precipitant remaining behind after decantation was dissolved in ethyl acetate and added to the above ethyl acetate extracts. The combined solvent extracts were washed with water, saturated salt solution, and dried over anhydrous magnesium sulfate. The solvent was removed by rotoevaporation and the product purified by column chromatography on silica gel eluted with 2:1 hexane-methylene chloride followed by 1:1 hexane-methylene chloride. The title compound was isolated as a mixture of 20α- and _β-isomers (363.3 gm, 76% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:6][C:21](=[O:22])[C:13]3[N:9]2[C:10]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[N:11][C:12]=3[CH3:14])=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cn(-c2cc(Cl)ccc2N)c(C2CCCCC2)n1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(C2CCCCC2)n2c1c(=O)[nH]c1ccc(Cl)cc12

Procedure:
1.45 g 4-Chloro-2-(2-cyclohexyl-4-methyl-imidazol-1-yl)-aniline were stirred in 25 ml toluene. 1.0 g Carbonyldiimidazole was added and the mixture was refluxed for 6 hours. After cooling 25 ml water was added, the product was filtered off, washed with 20 ml water and 25 ml toluene and dried.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH2:6]([SH:10])[CH2:7][CH2:8][SH:9].B(F)(F)F.CCOCC>ClCCl>[CH:2]([CH:1]1[S:10][CH2:6][CH2:7][CH2:8][S:9]1)([CH3:4])[CH3:3]
Reactant: SCCCS
Reactant: CC(C)C=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C1SCCCS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a mixture of isobutyraldehyde (9.1 mL, 100 mmol) and 1,3-propanedithiol (10 mL, 100 mmol) in dichloromethane at 0° C. was added boron trifluoride diethyl etherate (6.4 mL, 50 mmol). The resulting mixture was stirred at 0° C. for 30 min and at room temperature for 30 min. The reaction mixture was washed with brine, 5% NaHCO3, and brine again. The organic phase was separated and dried over Na2SO4, then concentrated to give 16 g (100%) of the title compound as a yellow liquid. This was carried to the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.057 (d, J=7.2 Hz, 3H), 1.059 (d, J=7.2 Hz, 3H), 1.80 (m, 1H), 1.97-2.08 (m, 2H), 2.82 (m, 4H), 4.00 (d, J=5.2 Hz, 1H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([CH3:34])[CH:28]=4)[CH:24]=[C:23]([CH3:35])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([CH3:35])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)=[CH:28][C:29]=1[CH3:34]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.5 %

Procedure:
To a cooled and stirred solution of 3′-[4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.45 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 ml), diethylether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane. The crude product was further purified by flash chromatography on silica gel (ethylacetate/heptane) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.29 g, 65%). MS (ISP) 450.1 [(M+H)+]; mp 201° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][N:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: NCc1ccccc1
Reactant: CN(C)c1ccc(CCOCCCCCCBr)cc1
Product: CN(C)c1ccc(CCOCCCCCCNCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
A mixture of 1,6-dibromohexane (73.84 g) 4-(N,N-dimethylamino)benzeneethanol (10 g), 50% w/v sodium hydroxide solution (200 ml) and TAB (3.4 g) was virgorously stirred at room temperature for 72 h, diluted with water (500 ml) and extracted with ER (2×100 ml). The dried extracts were evaporated to give a yellow oil which was purified by FCC eluting with H then H-EA (9:1) to give 4-[2-[(6-bromohexyl)oxy]ethyl]-N,N-dimethylbenzeneamine as a yellow oil. The benzeneamine (15 g) was added to benzylamine (45 ml) with stirring at 140° under nitrogen and stirring continued for 2 h. The benzylamine was removed in vacuo at 90°, the solution was partitioned between sodium bicarbonate (150 ml) and EA (2×100 ml) and the combined organic layers dried and concentrated to give a product which was purified by FCC eluting with ER-H (1:1→ER) to give the title compound as a yellow oil (11.1 g) t.l.c. (T-ET-A 95:4:1) Rf 0.62.
Reaction SMILES: [Br:1][C:2]1[C:16]([C:17]([OH:19])=O)=[C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:5]2=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:16]1[C:2]([Br:1])=[CH:3][CH:4]=[C:5]3[O:9][C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:7][C:6]=13)=[O:19])[CH2:24]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1c(Br)ccc2oc(-c3ccccc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1c(Br)ccc3oc(-c4ccccc4)nc13)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.2 %

Procedure:
A mixture of 5-bromo-2-phenylbenzo[d]oxazole-4-carboxylic acid (180 mg, 0.56 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (152 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (215 mg, 1.12 mmol) and 1-hydroxybenzotriazole (151 mg, 1.12 mmol) in DMF (2.5 mL) was stirred for 5 min at room temperature, then triethylamine (0.31 mL, 2.24 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-5-bromo-2-phenylbenzoxazole-4-carboxamide (31 mg, 12%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.25-8.23 (m, 2H), 7.62 (d, J=8.5 Hz, 1H), 7.60-7.53 (m, 3H), 7.48 (d, J=8.5 Hz, 1H), 7.12 (br s, 1H), 4.69-4.63 (m, 1H), 3.13 (d, J=10.0 Hz, 2H), 2.67 (td, J=12.5, 7.0 Hz, 2H), 2.54 (s, 3H), 2.05-1.93 (m, 3H), 1.60-1.52 (m, 1H), 1.43 (t, J=11.0 Hz, 2H), 1.15-1.10 (m, 2H); MS (ESI+) m/z 454 (M+H); HPLC 98.4% (AUC), tR=11.89 min.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:11][O:10][C:9]1[C:2]([O:1][CH2:13][CH2:14][CH3:15])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: COc1cccc(C=O)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(C=O)cccc1OC
Temperature: 25 °C
Yield: 101.2 %

Procedure:
A suspension of 2-hydroxy-3-methoxy-benzaldehyde (10.0 g, 65.6 mmol), 1-bromopropane (60 mL, 657 mmol) and K2CO3 (11.3 g, 82.1 mmol) in MeCN (250 mL) was heated to reflux for 12 h. The mixture was cooled to ambient temperature and the solution filtered. The filtrate was concentrated to give the title compound (12.9 g, quantitative) as light yellow oil: MS (ESI) m/e 195 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[CH:4][C:3]=1[N+:23]([O-])=O.CO>C(OCC)(=O)C.[Pd]>[NH2:20][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH2:23])[CH:4]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: O=[N+]([O-])c1cc(CCCCCc2ccc(O)c([N+](=O)[O-])c2)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(CCCCCc2ccc(O)c(N)c2)ccc1O
Reaction time: 4 h
Yield: 93.5 %

Procedure:
A mixture of 1,5-bis(4-hydroxy-3-nitrophenyl)pentane of Example 10 (6.6 g), ethyl acetate (150 ml), methanol (50 ml) and 300 mg of palladium/carbon (5%) was hydrogenated on a Parr hydrogenator for 4 hours. Then it was diluted with 100 ml of ethyl acetate, filtered and concentrated to give 5.1 g of an off-white solid. NMR and TLC confirmed the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]#[N:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:44][N:45]([CH3:59])[CH2:46][CH2:47][CH2:48][O:49][C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][C:51]=1[O:57][CH3:58]>>[C:17]([C:10]1[CH:11]=[C:12]([C:14]([NH:54][C:53]2[CH:55]=[CH:56][C:50]([O:49][CH2:48][CH2:47][CH2:46][N:45]([CH3:59])[CH3:44])=[C:51]([O:57][CH3:58])[CH:52]=2)=[O:16])[S:13][C:9]=1[S:8][C:7]1[C:6]([Cl:19])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1])#[N:18]
Reactant: N#Cc1cc(C(=O)O)sc1Sc1c(Cl)cncc1Cl
Reactant: COc1cc(N)ccc1OCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(NC(=O)c2cc(C#N)c(Sc3c(Cl)cncc3Cl)s2)ccc1OCCCN(C)C

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-cyano-thiophene-2-carboxylic acid (100 mg, 0.3 mmol) from step C of example 203, 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (126 mg, 0.33 mmol) and 4-(3-dimethylaminopropoxy)-3-methoxy-aniline (96 mg, 0.36 mmol) from the above. The crude material was purified by reverse phase HPLC and the title compound was obtained as a yellow solid (15.0 mg, 9% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.33 (1H, s), 8.85 (2H, s), 8.24 (1H, s), 7.29 (1H, m), 7.18 (1H, m), 6.94 (1H, m), 3.94 (2H, m), 2.34 (2H, m), 2.14 (6H, s), 1.84 (3H, s), 1.81 (2H, m). MS m/z: 537.17, 539.15 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[C:25]([CH3:26])[C:18]=34)=[C:12]([F:27])[CH:11]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:27][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:3]=[CH:2][N:7]=[C:6]([NH2:8])[N:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[C:25]([CH3:26])[C:18]=12
Reactant: Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c[nH]c2nccc(Oc3ccc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
50 mg (0.13 mmol) of 6-chloro-N4-{3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine are dissolved in 10 ml of ethanol. 36 μl (0.26 mmol) of triethylamine and 28 mg (0.03 mmol) of 10% palladium-on-carbon are added, and the mixture is hydrogenated under atmospheric pressure in a hydrogen atmosphere overnight. The mixture is then filtered through Celite®, and the celite is washed with methanol. The solvent is removed under reduced pressure and the crude product is purified by preparative HPLC.
Reaction SMILES: [CH2:1]([C:3]([OH:18])([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([N:28]([CH2:32][CH2:33][CH2:34]Cl)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:1]([C:3]([OH:18])([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:27][CH2:26][CH2:25][N:28]([CH2:32][CH2:33][CH3:34])[CH2:29][CH2:30][CH3:31])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCC(O)(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CCCN(CCC)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Product: CCCN(CCC)CCCOc1ccc(C(O)(CC)c2ccc(Cl)cc2)cc1

Procedure:
13.1 g. of α-ethyl-α-(4-chlorophenyl)-4-hydroxy-benzylalcohol, 14 g. of anhydrous potassium carbonate, 9.8 g. of dipropylaminopropyl chloride and 0.85 g. of tetrabutyl ammonium hydrogensulfate in 135 ml. of ethyl acetate are slightly boiled for 20 hours, under stirring. After cooling the mixture, the solvent is evaporated in vacuo. To the residue water and benzene are added. The phases are separated, the benzene solution is washed with water, dried over anhydrous potassium carbonate, filtered and evaporated. The residue is purified by vacuum fractionation. 13.8 g. of the desired end product are obtained, boiling at 198° to 200° C./1.33 Pa.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[C:10]=2[CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[C:41]1([CH:47]([CH3:51])[CH2:48][CH:49]=O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOC(C)=O>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[C:10]=2[CH:15]=[CH:49][CH2:48][CH:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:51])=[CH:7][CH:8]=1
Reactant: CC(CC=O)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C=CCC(C)c1ccccc1
Reaction time: 0.25 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-triphenyl-phosphonium bromide (0.2678 g, 0.451 mmol) was dissolved in THF (2.7 mL) at 0° C. Potassium tert-butoxide (1 M in THF, 0.5 mL, 0.50 mmol) was added and after stirring 15 minutes 3-phenyl-butyraldehyde (0.074 mL, 0.50 mmol) was added and the ice bath was removed. After 15 minutes, analytical LCMS indicated complete reaction. Standard aqueous workup followed by silica gel chromatography (0-20% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[N:18]=[N:19][C:20]4[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[NH:23][C:21]=4[N:22]=3)=[N:15][N:14]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:11]2=[N:12][CH:13]=1.[CH3:38][Si:39]([CH3:46])([CH3:45])[CH2:40][CH2:41][O:42][CH2:43]Cl>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[N:18]=[N:19][C:20]4[C:25]([CH3:26])([CH3:27])[C:24](=[O:28])[N:23]([CH2:43][O:42][CH2:41][CH2:40][Si:39]([CH3:46])([CH3:45])[CH3:38])[C:21]=4[N:22]=3)=[N:15][N:14]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:11]2=[N:12][CH:13]=1
Reactant: COc1ccc(Cn2nc(-c3nnc4c(n3)NC(=O)C4(C)C)c3cc(F)cnc32)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3nnc4c(n3)N(COCC[Si](C)(C)C)C(=O)C4(C)C)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.067 g (6.345 mmol) of cesium carbonate in DMF (30 ml) were added to 2.45 g (5.768 mmol) of the compound from Example 34A. 1.221 ml (6.922 mmol) of 2-(trimethylsilyl)ethoxymethyl chloride were then added, and the mixture was stirred at room temperature for 1 h. The solids were then filtered off and washed with DMF, the filtrate was concentrated and the residue was dried under high vacuum. This gave 4.45 g of crude material which were used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[CH3:27][C:28]1([CH:31]=O)[CH2:30][CH2:29]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([C:16](=[CH:27][C:28]3([CH3:31])[CH2:30][CH2:29]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CC1(C=O)CC1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(=CC2(C)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: -20 °C
Reaction time: 3 h

Procedure:
At −78° C., 1.87 ml (1.87 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) were added dropwise to a solution of 500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 10 ml of THF, and the mixture was stirred for another 10 min 488 mg (5.80 mmol) of 1-methylcyclopropanecarbaldehyde were then added, and after a further 10 min the mixture was warmed to −20° C. After 3 h at −20° C., the reaction was terminated by addition of 30 ml of saturated aqueous ammonium chloride solution and the reaction mixture was extracted three times with 20 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was taken up in a little dichloromethane and purified by flash chromatography (24 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 257 mg (44% of theory)
Reaction SMILES: [CH3:1][S:2](Cl)=[O:3].[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][S:2]([CH3:1])=[O:3])=[CH:8][CH:7]=1
Reactant: CS(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methanesulfinyl chloride (2.06 g) in dichloromethane (20 mL) is added drop wise to an ice-cooled mixture of 4-bromoaniline (3.00 g) and N,N-diisopropylethylamine (10.63 mL) in dichloromethane (20 mL). The reaction mixture is allowed to warm to room temperature and stirred for 5 h. Water is added to the mixture and the organic phase is separated, washed with water, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:500:100) to give the title compound. LC (method 1): tR=0.82 min; Mass spectrum (ESI+): m/z=234, 236 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=1[F:28])[C:22](Cl)=[O:23]>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=1[F:28])[C:22]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1)=[O:23]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Solvent: c1ccncc1
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4cc(F)c(F)c(F)c4)cc3)cn2c1
Yield: 72.2 %

Procedure:
Prepared as described in the Amide Coupling section using 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.50 g, 2.24 mmol) and 3,4,5-trifluorobenzoyl chloride (0.436 g, 2.24 mmol) in dry pyridine (20 ml) to give the title compound (0.617 g, 72%) as a colourless solid, after work-up and recrystallisation from AcOH.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#N)=[C:7]([Cl:13])[CH:6]=1.C(O)=[O:16]>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:16])=[C:7]([Cl:13])[CH:6]=1
Reactant: COC(=O)Cc1ccc(C#N)c(Cl)c1
Reactant: O=CO
Product: COC(=O)Cc1ccc(C=O)c(Cl)c1
Temperature: 110 °C

Procedure:
A solution of (3-chloro-4-cyano-phenyl)acetic acid methyl ester 13 (7.4 g, 35.3 mmol) in 88% formic acid (100 mL) is combined with Raney-alloy (9.0 g) and heated to reflux for 10 hours at 110° C. After cooling to room temperature, the alloy is removed by filtration over Celite. The filtrate is concentrated to ˜10% of the original volume and diluted with EtOAc (250 mL) and washed three times with water (80 mL). The organic layer is dried (MgSO4), filtered and concentrated to afford crude product, which is purified by silica gel chromatography using an EtOAc/hexane gradient to give (3-Chloro-4-formyl-phenyl)-acetic acid methyl ester 14 as a wax-like solid. Another amount of product 14 is collected by reesterification of saponified byproduct (3-Chloro-4-formyl-phenyl)-acetic acid: 1H-NMR (400 MHz, CDCl3) δ=10.31 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 3.86 (s, 3H), 3.64 (s, 2H). MS calculated for C10H10ClO3 (M+H+) 213.0, found 213.3.