Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:8]([C:21]([O:23]CC)=[O:22])=[CH:7]2>O.C(O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:8]([C:21]([OH:23])=[O:22])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
An aqueous solution of sodium hydroxide, prepared from 1.15 g (28.92 mmol) of sodium hydroxide pellets in 50 ml of water, is added to a solution of 7.6 g (24.10 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (obtained in step 2.1) in 240 ml of ethanol. The mixture is heated for two hours and then concentrated under reduced pressure. The resulting solid is taken up in 200 ml of water. The solution is washed with twice 100 ml of ethyl ether, acidified by successive additions of small amounts of concentrated hydrochloric acid and then extracted with 200 ml of ethyl acetate. The organic phase is finally washed twice with 100 ml of water and once with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. After drying at 50° C. under reduced pressure, 6.4 g of the expected product are obtained in the form of a solid that will be used as it is in the subsequent step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.CN([CH2:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)C>CCO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:16][CH2:15][N:14]([CH2:20][C:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:13][CH:12]=1
Reactant: C1=C(c2ccc3ccccc3c2)CCNC1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: CCO
Product: C1=C(c2ccc3ccccc3c2)CCN(Cc2c[nH]c3ncccc23)C1
Yield: 62.9 %

Procedure:
4-Naphthalen-2-yl-1,2,3,6-tetrahydropyridine (597 mg, 2.9 mmol) was reacted with 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.9 mmol) as exemplified in Example 4 to give the title compound (619 mg, 63%) as tan crystals, m.p. 223°-225° C. (EtOH); (Found: C, 81.05; H, 6.24; N, 12.19. C23H21N3 requires C, 81.38; H, 6.24; N, 12.38%); δH (DMSO-d6) 2.60 (2H, m, tetrahydropyridinyl CH2), 2.72 (2H, t, J 5.7 Hz, tetrahydropyridinyl CH2), 3.16 (2H, d, J 2.7 Hz, tetrahydropyridinyl CH2), 3.78 (2H, s, ArCh2N), 6.34 (1H, m, CH=CR), 7.04 (1H, dd, J 7.5, 1.5 Hz, 5-H), 7.40 (1H, d, J 2.3 Hz, ArH), 7.44 (2H, m, ArH), 7.66 (1H, dd, J 1.6, 7.8 Hz, ArH), 7.86 (4H, m, ArH), 8.06 (1H, d, J 7.5 Hz, 4-H), 8.20 (1H, d, J 1.5 Hz, 6-H, and 11.48 (1H, br s, NH); m/z (CI+, NH3) 340 (M+1)+.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[O:35]1[CH2:40][CH2:39][CH:38]([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([CH2:48][NH2:49])[CH2:44][CH2:43]2)[CH2:37][CH2:36]1.[OH-].[Na+]>O1CCCC1>[C:16]([O:15][C:13](=[O:14])[NH:1][C@@H:2]([C:10](=[O:12])[NH:49][CH2:48][CH:45]1[CH2:44][CH2:43][N:42]([CH2:41][CH:38]2[CH2:37][CH2:36][O:35][CH2:40][CH2:39]2)[CH2:47][CH2:46]1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: NCC1CCN(CC2CCOCC2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution consisting of 10 g of Boc-D-Phe-OH, 40 ml of tetrahydrofuran and 4.6 ml of N-methylmorpholine is slowly dripped into a solution of 5.4 ml of isobutyl chloroformate in 60 ml of tetrahydrofuran cooled to 0° C., at a rate such that the inner temperature does not exceed 5° C. The resulting mixture is maintained under stirring at 0° C. for 0.5 hours. A solution consisting of 8.0 g of (11) in 20 ml of tetrahydrofuran is then dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 5 hours. 100 ml of 1M NaOH is added to the mixture, and the tetrahydrofuran is evaporated at low pressure. The residue is taken up with dichloromethane and water; the organic phase is washed with water (2×), and after a solvent change with ethyl acetate at low pressure, compound (12) is crystallised from ethyl acetate to obtain 15 g of white solid. Yield 87%.
Reaction SMILES: [CH:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH:8]3[CH2:7][CH2:6][CH:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CCC(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)C1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 85.5 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-sec-Butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol) and 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 152 mg of the desired product as a white solid (50%). ESI-MS: 339 (M-16)+. 1H NMR (400 MHz, DMSO-d6) δ=8.30 (s, 1 H), 7.88 (s, 1 H), 7.75 (d, J=8.8 Hz, 1 H), 7.71-7.56 (m, 1 H), 7.24 (d, J=2.0 Hz, 1 H), 7.12 (dd, J=2.3, 8.8 Hz, 1 H), 4.70 (d, J=5.8 Hz, 1 H), 4.40-4.28 (m, 1 H), 3.55-3.41 (m, 2 H), 2.26-1.07 (m, 12 H), 0.94-0.79 (m, 3 H)
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:11])[CH3:8].Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>ClCCl>[CH:28]([O:27][C:25]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([CH3:23])[N:16]=2)[C:21](=[O:22])[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[CH:13]1)=[O:26])([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(=O)OC(C)C)c2nc(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Add pyridine (2.43 ml, 30.0 mmol) to a suspension of 7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (2.32 g, 10.0 mmol) in dichloromethane (100 ml), and then add isopropyl chloroformate (1.0 N in toluene, 30.0 ml). Stir the reaction mixture at room temperature overnight. Wash with brine (3×100 ml). Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify using silica gel column chromatography (gradient eluent, 0-60% ethyl acetate in hexane) to provide 7-methyl-4-oxo-4H-[1,8]naphthyridine-1,3-dicarboxylic acid 3-ethyl ester 1-isopropyl ester (1.31 g, 41%). MS (ES+): 319 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[F:12])=[O:4].[Cl:13][C:14]1[N:19]=[N:18][C:17](/[N:20]=[C:21](/N(C)C)\[CH3:22])=[CH:16][CH:15]=1.O>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([C:2]2[N:18]3[N:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]3=[N:20][C:21]=2[CH3:22])=[O:4])=[C:6]([F:12])[CH:7]=1
Reactant: C/C(=N\c1ccc(Cl)nn1)N(C)C
Reactant: O=C(CCl)c1ccc(Cl)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F

Procedure:
Combine 2-chloro-1-(4-chloro-2-fluorophenyl)ethanone (1.5 kg, 5.44 mol), and (E)-N′-(6-chloropyridazin-3-yl)-N,N-dimethylacetimidamide (1.19 kg, 5.72 mol) in DMF (10.14 L) and heat at 120° C. for 5 h. After cooling, add water (30 L) and stir to crystallize the product. Collect the product by filtration and rinse the cake with water (2×12 L) and heptanes (2×10 L) then dry under vacuum to obtain title compound. (1.490 kg, 84.44%; mp=160° C., M+=324).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:50]([O:57][C:58](=[O:72])[NH:59][C@H:60]([C:65](=[O:71])[NH:66][CH2:67][CH2:68][CH:69]=O)[CH2:61][CH:62]([CH3:64])[CH3:63])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C>[Si:18]([O:17][C@H:16]1[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13][CH:12]1[C@H:10]([OH:11])[C@@H:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:1][CH2:69][CH2:68][CH2:67][NH:66][C:65](=[O:71])[C@H:60]([CH2:61][CH:62]([CH3:64])[CH3:63])[NH:59][C:58](=[O:72])[O:57][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reaction time: 3.5 h
Yield: 97.1 %

Procedure:
A solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxy-propanoate (200 mg, 0.277 mmol, obtained from Reference Example 6) and [(1S)-3-methyl-1-(3-oxo-propylcarbamoyl)-butyl]-carbamic acid benzyl ester (111 mg, 0.35 mmol, obtained from Reference Example 16) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (4 drops) and sodium triacetoxyborohydride (117 mg, 0.55 mmol) were added, and the resulting solution was stirred under nitrogen for an additional 3.5 hours. The reaction mixture was basified to pH 9 with sodium carbonate aqueous solution, and the aqueous layer was extracted with ethyl acetate (3×80 ml). The combined extracts were washed with saturated sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 2.5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (276 mg, 97%), as a white amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:18])=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:18][C:3]1[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2cc(C(F)(F)F)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc2cc(C(F)(F)F)cnc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
A mixture of 1.09 g of 3-methyl-6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one, one drop of dimethylformamide and 10 g of phosphorus oxychloride was stirred at 100° C. for 3 hours. The cooled reaction mixture was poured to a saturated aqueous sodium bicarbonate solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.61 g of 2-chloro-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([CH3:29])[CH:23]=[CH:22]2>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH3:29])[CH:23]=[CH:22]4)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3nc(C)ccc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg, 0.6 mmol; Example 2B) and 6-bromo-2-methylquinoline (200 mg, 0.9 mmol; Oakwood) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.19 (m, 4H) 2.41 (s, 3H) 2.77 (s, 3H) 2.91-2.98 (m, 1H) 3.08-3.29 (m, 4H) 4.32 (s, 2H) 6.89-6.94 (m, 1H) 6.96-7.01 (m, 1H) 7.21 (s, 1H) 7.52 (d, J=8 Hz, 1H) 7.66 (dd, J=9, 2 Hz, 1H) 7.87 (d, J=2 Hz, 1H) 8.12 (d, J=9 Hz, 1H) 8.32 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 368 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:24]([O:23][C:21]([NH:20][C:18]12[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:13][CH2:12][NH:11][CH2:19]2)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC12CCCCC1CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCCC1CCNC2

Procedure:
A 10% palladium-carbon catalyst (83.0 mg, 20 wt %) was added to a solution of 8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (optical isomer B) (415 mg, 1.11 mmol) in methanol (11.1 mL) in a nitrogen atmosphere. After the atmosphere was replaced with hydrogen, the mixture was stirred in a hydrogen atmosphere at room temperature for one hour. After the atmosphere was replaced with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure to give the title compound quantitatively.
Reaction SMILES: [Cl-].CON(C)[C:5](=[O:16])[CH2:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[F:15].Cl.[CH3:19]C(OC)(C)C>C1COCC1>[F:15][C:8]1[C:9]([F:14])=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[CH2:6][C:5](=[O:16])[CH3:19]
Reactant: COC(C)(C)C
Reactant: CON(C)C(=O)Cc1c(F)ccc(F)c1F
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)Cc1c(F)ccc(F)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of CeCl3 (438 g, 1779 mmol) and THF (12 L) was heated at 40° C. for about 2 h then cooled to 5° C. Methylmagensium chloride in THF (3 M, 3.4 L) was charged at 5-9° C. and then it was warmed up to 16° C. and held for 1 h. The suspension was re-cooled to −10 to −15° C. A solution of 17 (1.19 kg) in THF (2.4 L) was charged into the suspension over 15 min. After confirmation of completion of the reaction, the reaction mixture was transferred to a cold solution of hydrochloric acid (2 N, 8.4 L) and MTBE (5 L) in 5-10° C. The aqueous phase was separated and the organic layer was washed with aqueous 5% K2CO3 (6 L) and then 10% aqueous NaCl (5 L). The organic layer was dried over Na2SO4, concentrated to give crude 18 (917 g, >99 wt %) in 95% yield. The crude 18 was used in the next step without further purification. Analytically pure 18 was obtained by silica gel column.
Reaction SMILES: [CH:1]([Cl:4])([Cl:3])[Cl:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[O:16])[CH:10]=[C:11]([CH:13]=[O:14])[CH:12]=1.[OH-].[K+]>CN(C=O)C.CO>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]([OH:16])[C:1]([Cl:4])([Cl:3])[Cl:2])[CH:10]=[C:11]([CH:13]([OH:14])[C:1]([Cl:4])([Cl:3])[Cl:2])[CH:12]=1
Reactant: COc1cc(C=O)cc(C=O)c1
Reactant: ClC(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(C(O)C(Cl)(Cl)Cl)cc(C(O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 0.60 g (5 mmol) of chloroform in 2 mL DMF was added 0.1 64 g (1.0 mmol) of 5-methoxy-1,3-diformylbenzene (Provent, C; Chautemps, P.; Gellon, G.; Pierre, J.-L. Tetrahedron Lett. 1996, 347 1393-96). The reaction mixture was chilled to 0° C. and a solution of 39.5 mg (0.7 mmol) of potassium hydroxide in 0.2 mL of methanol was added. The reaction mixture was stirred for 20 min at 0° C., then was quenched by addition of 1 mL of 1 N hydrochloric acid. The reaction mixture was adjusted to pH=7, then extracted with EtOAc. The organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH2:26][C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1ccncc1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(Cc1ccncc1)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 93 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with pyridine-4-carbaldehyde using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylpyridin-4-ylmethylamine as a solid (93% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 426 as a solid (80% yield). NMR (CDCl3, 400 MHz), 2.35 (3H, s), 3.66 (2H, s), 3.88 (2H, s), 3.91 (4H, t, J=5.2), 4.07 (4H, t, J=5.2), 5.27 (2H, s), 7.32 (1H, s), 7.36 (2H, d, J=6), 8.61-8.62 (2H, m), 9.30 (2H, s). MS: (ESI+): MH+=449
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH2:21]([CH:28]1[CH2:33][CH2:32][N:31]([C:11]([C:7]2[NH:8][C:9]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([OH:1])[CH:10]=3)=[O:13])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc2ccc(O)cc2[nH]1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.6 %

Procedure:
A mixture of 5.0 g (28.2 mmol) of 6-hydroxy-indole-2-carboxylic acid [J. Chem. Soc. 1605-1608. (1948)], 4.4 ml (31.6 mmol) of triethylamine, 5.0 g (28.5 mmol) of 4-benzylpiperidine, 12.0 g (31.6 mmol) of HBTU (Advanced Chem. Tech.) and 50 ml of dimethylformamide is stirred at room temperature for 6 h. The precipitated product is filtered off and recrystallized from ethanol to yield 6.75 g (71%) of the title compound. Mp: 214-215° C. (ethanol).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:32]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][C:34](CO)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][C:34]([CH2:1][Br:5])=[N:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCc1cc(-c2ccccc2)n(Cc2ccccc2)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: BrCc1cc(-c2ccccc2)n(Cc2ccccc2)n1
Yield: 40.2 %

Procedure:
Carbon tetrabromide (2.5 g, 7.6 mmol) and then triphenylphosphine (2.0 g, 7.6 mmol) was added to (1-benzyl-5-phenyl-1H-pyrazol-3-yl)methanol (1.0 g, 3.8 mmol) in dicholomethane (38 mL) at 0° C. Upon completion of the reaction as monitored by LCMS, the reaction was filtered through silica washing with methylene chloride and then purified on an ISCO using 0-30% ethyl acetate/hexanes to give 1-benzyl-3-(bromomethyl)-5-phenyl-1H-pyrazole (0.5 g, yield 43%). MS (ESI) m/z: Calculated for C17H15BrN2: 326.04. found: 327.0 (M+H)+.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@H](O)CN
Reactant: O=CCC1Cc2ccc(F)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](O)Cn1ccc2c1-c1cc(F)ccc1C2
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A solution of 1.92 g of (RS)-2-(2-oxoethyl)-6-fluoro-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.51 g (65%) of (S)-1-(7-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[C:12](/[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)\[C:13]#[N:14])=[CH:7][CH:6]=1)C.O.S(=O)(=O)(O)O>CO>[CH3:24][O:23][C:17]1[CH:16]=[C:15](/[C:12](=[CH:11]/[C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=2)/[C:13]#[N:14])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CCOC(OCC)c1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COc1ccc(/C(C#N)=C/c2ccc(C=O)cc2)cc1OC
Yield: 81.7 %

Procedure:
4-Diethoxymethyl-benzaldehyde (4.16 g) and 3,4-dimethoxybenzyl cyanide (3.54 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-3-(4-diethoxymethyl-phenyl)-2-(3,4-dimethoxy-phenyl)-acrylonitrile (6.54 g, yield: 89%). The thus-produced (Z)-3-(4-diethoxymethyl-phenyl)-2-(3,4-dimethoxy-phenyl)-acrylonitrile (1.84 g) was dissolved in methanol, and water and 2N sulfuric acid were added to the resultant solution, followed by stirring, to thereby produce the target product (1.20 g, yield: 82%).