Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[Na].[O:6]([CH2:11][CH:12]1[CH2:14][O:13]1)[CH2:7][CH:8]1[CH2:10][O:9]1>O>[CH2:1]([O:4][CH2:14][CH:12]1[O:13][CH:8]([CH2:10][OH:9])[CH2:7][O:6][CH2:11]1)[CH:2]=[CH2:3]
Reactant: C(OCC1CO1)C1CO1
Reactant: C=CCO
Agent: [Na]
Solvent: O
Product: C=CCOCC1COCC(CO)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17 %

Procedure:
136 ml of allyl alcohol (2.0 mole, Aldrich) is stirred under nitrogen at room temperature and 0.25 g of sodium is added to the mixture and stirring continued for 2.5 hours. Then 13.1 g of 2,2'-(oxybismethylene)bisoxirane (0.1 mole) is added and the mixture then heated at reflux for 18 hours. The mixture is then cooled to room temperature and with stirring is poured into 350 ml of water. The aqueous mixture is extracted with 2×200 ml portions of chloroform, the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the resulting yellow oil then vacuum distilled through a 10 cm vigreux column. The fraction distilling at 120°-123° @ 0.4 mm is collected yielding 3.2 g (18%) of the above compound.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40]C)=[O:39])[C:15]([C:16]5[CH:27]([C:28]([O:30]C)=[O:29])C(=O)[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].[CH3:46][O-:47].[Na+].[Na].[OH2:50]>O1CCCC1.CO>[CH3:1][CH2:2][C:3]1[C:21]2[N:22]=[C:5]([CH:6]=[C:7]3[C:8]([CH:43]=[CH2:44])=[C:9]([CH3:42])[C:10](=[CH:12][C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:15](=[C:16]([CH2:27][C:28]([OH:30])=[O:29])[C:17]5[NH:18][C:19]([CH:20]=2)=[C:23]([CH3:32])[C:24]=5[C:46]([OH:50])=[O:47])[N:14]=4)[NH:11]3)[C:4]=1[CH3:45]
Reactant: O
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1c(C)c2cc3nc(c(CC(=O)O)c4[nH]c(cc5nc(cc1[nH]2)C(C)=C5CC)c(C)c4C(=O)O)[C@@H](CCC(=O)O)[C@@H]3C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
The procedure of Smith and Bushell (M.J. Bushell, Ph.D. Thesis, Univ. of Liverpool, U.K., 1978) was used. The starting material, 1 gm of methyl pheophorbide-a, was dissolved in dry tetrahydrofuran (THF). To this was added sodium methoxide prepared by dissolving 200 mg sodium in 40 ml methanol, and the reaction was allowed to stir at room temperature for 1 hr. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in chloroform and treated with dichloromethane and ether, and the solid obtained was chromatographed on Alumina (Grade III) and eluted with toluene/dichloromethane 1/1. The major band, chlorin-e6 tetramethyl ester was recrystallized from dichloromethane/methanol to obtain 700 mg or 67% yield of the compound of formula ##STR6## By re-utilizing the remaining starting material, an overall yield of 88.7% was obtained, and the structure was confirmed by NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:11][O:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2ocnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2ocnc12
Yield: 90.6 %

Procedure:
To a suspension of 4-hydroxybenzoxazole (2.00 g, 14.8 mmol) (Musser et al., J. Med. Chem., 30, pp. 62-67 (1987)) in acetone (80.0 ml) was added dried K2CO3 (2.25 g, 16.3 mmol) followed by iodomethane (1.38 ml, 22.2 mmol). The reaction was heated under reflux under N2 for 4.5 h, then filtered and reduced in vacuo to afford the crude product. The resulting residue was purified by flash chromatography (25:75 ethyl acetate/hexane) to give 2.0 g (91%) of the title compound as a white crystalline solid: m.p. 72°-74° C.; IR (KBr) 3089, 1619, 1610, 1503, 1496, 1322, 1275, 1090, 1071, 780, 741; 1H NMR (CDCl3) δ 8.02 (1H, s), 7.32 (1H, t, J=8.0), 7.18 (1H, d, J=8.0), 6.81 (1H, d, J=8.0), 4.04 (3H, s). Anal. Calcd. for C8H7NO2 : C, 64.42; H, 4.73; N, 9.39. Found: C, 64.40; H, 4.84; N, 9.31; m/z (EI) 149 (M++1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:34])[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][C@H:16]([NH:18][C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26]C)=[O:25])=[O:20])[CH3:17])[CH2:10][C:9]2([CH3:33])[CH3:32])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:34])[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][C@H:16]([NH:18][C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([OH:26])=[O:25])=[O:20])[CH3:17])[CH2:10][C:9]2([CH3:33])[CH3:32])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)N[C@H](C)CC(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: C[C@H](CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)c1cccc(C(=O)O)c1

Procedure:
Example 8 was prepared from methyl 3-((R)-4-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-4-oxobutan-2-ylcarbamoyl)benzoate using the conditions described in Example 6. MS (ESI+)=473.2 (M+H)+. 1H NMR (CD3OD, 500 MHz) (NMR shows several rotamers) δ ppm 8.54 (t, J=1.6 Hz, 0.6 H), 8.46 (t, J=1.6 Hz, 0.4 H), 8.22 (d, J=7.7 Hz, 0.6 H), 8.17 (d, J=7.7 Hz, 0.4 H), 8.08 (d, J=8.2 Hz, 0.6 H), 8.02 (d, J=7.7 Hz, 0.4 H), 7.61 (t, J=7.7 Hz, 0.6 H), 7.57 (t, J=7.7 Hz, 0.4 H), 7.47 (d, J=8.8 Hz, 0.8 H), 7.32-7.25 (m, 2 H), 7.23 (d, J=8.3 Hz, 1.2 H), 4.64-4.46 (m, 1.4 H), 4.10 (dt, J=13.2, 2.5 Hz, 0.6 H), 4.04 (dd, J=12.6, 2.2 Hz, 0.6 H), 3.67-3.53 (m, 1.4 H), 3.17-3.03 (m, 1.6 H), 2.97 (dd, J=14.9, 6.1 Hz, 0.4 H), 2.67-2.46 (m, 2 H), 1.57-1.47 (m, 1 H), 1.40 (d, J=6.6 Hz, 1.8 H), 1.34 (d, J=6.6 Hz, 1.2 H), 0.83 (s, 1.2 H), 0.82 (s, 1.2 H), 0.76 (s, 1.8 H), 0.66 (s, 1.8 H); HPLC Method: Inj. Vol.=5 uL, Start % B=10, 12 Min. 100%, 15 Min. 100%, Flow Rate=1 ml/min, Wavelength 1=220, Wavelength 2=254, Solvent A=0.05% TFA in H2O:MeCN (95:5), Solvent B=0.05% TFA in H2O:MeCN (5:95), Col-1: Sunfire C18 3.5 um, 4.6×150 mm; Retention Time=10.92 min., Col-2: Xbridge Phenyl 3.5 um, 4.6×150 mm; Retention Time=10.45 min.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7]([OH:9])=O.[C:24]1([C:30]2[S:34][C:33]([NH2:35])=[N:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C:30]2[S:34][C:33]([NH:35][C:7]([C:6]3[C:5]4[CH:10]=[CH:11][C:12]([O:14][C:15]5[CH:20]=[CH:19][N:18]=[C:17]6[CH:21]=[CH:22][S:23][C:16]=56)=[CH:13][C:4]=4[O:3][C:2]=3[CH3:1])=[O:9])=[N:32][N:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Nc1nnc(-c2ccccc2)s1

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic acid 100 and 5-phenyl-[1,3,4]thiadiazol-2-ylamine in a similar manner as that described for example 102. 1H NMR (CD3CN/CD3OD) δ8.45 (1H, d, J=5.6 Hz), 8.00-7.95 (4H, m), 7.52-7.50 (4H, m), 7.48 (1H, d, J=2.3 Hz), 7.25 (1H, dd, J=8.6, 2.3 Hz), 6.66 (1H, d, J=5.3 Hz), 2.76 (3H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)[CH:22]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[CH:22]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC[C@H](CCCOCc3ccccc3)C2)c1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COCCC[C@H]2CCN(c3cncc(OC[C@@H]4CCCN4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a 25 mL round-bottom flask containing a solution of 3-[3(S)-[3-(benzyloxy)propyl]-1-pyrrolidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (500 mg, 1.01 mmol) in CH2Cl2/H2O (7.5/0.15 mL) was added CF3COOH (1.5 mL) at 0° C. under N2. The reaction mixture was stirred for 3 h at room temperature. After evaporation under reduced pressure, the crude product (310 mg) was purified by preparative HPLC (column: SunFire Prep C18, 150×19 mm, 5 μm particle size; UV detection at 270 nm; flow 20 mL/min; mobile phase: A, water with 0.05% CF3COOH; B, methanol; 40-50% B in A in 6 min, 50-100% in 1 min, back to 40% in 1 min). The eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3OH. The residue was washed with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine and dried. After concentrated in vacuo, the free amine (280 mg, 70%) was obtained as light-yellow solid. 1H NMR (CDCl3, 300 MHz) δ 7.66 (s, 1H), 7.61 (s, 1H), 7.37-7.30 (m, 5H), 6.34 (s, 1H), 4.54 (s, 2H), 4.01-3.94 (m, 2H), 3.54-3.49 (m, 3H), 3.48-3.22 (m, 3H), 3.12-3.00 (m, 2H), 2.91 (t, 1H , J=9.6 Hz), 2.36-2.23 (m, 1H), 2.21-2.10 (m, 1H), 2.06-1.79 (m, 3H), 1.76-1.50 (m, 6H). LC-MS (ESI) m/z 396 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:51])[C:9]([N:11]2[C:15]3[N:16]=[C:17]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:18]=[C:19]([C:20]4[CH:21]=[N:22][C:23]([N:26](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=[N:24][CH:25]=4)[C:14]=3[CH2:13][CH2:12]2)=[O:10])[CH:5]=C[CH:7]=1.[CH3:52][NH:53][CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1.N1(CCO)CCNC[CH2:63]1.CN(CCN1CCOCC1)C1C=C(NC(N2C3N=C(N4CCOCC4)N=C(C4C=NC(N(CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=NC=4)C=3CC2)=O)C=CC=1>>[CH3:51][N:8]([C:4]1[CH:3]=[CH:2][CH:7]=[C:52]([N:53]([CH3:63])[CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[CH:5]=1)[C:9]([N:11]1[C:15]2[N:16]=[C:17]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[N:18]=[C:19]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[N:22][CH:21]=3)[C:14]=2[CH2:13][CH2:12]1)=[O:10]
Reactant: OCCN1CCNCC1
Reactant: CNCCN1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3cccc(Br)c3)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccc(N(C)CCN4CCOCC4)c3)cn2)cc1
Product: CN(CCN1CCOCC1)c1cccc(N(C)C(=O)N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)c1
Yield: 22 %

Procedure:
Using 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-bromo-phenyl)-methyl-amide (112 mg) and methyl-(2-morpholin-4-yl-ethyl)-amine (25.8 mg) obtained in Step A in Example 1-D-139 instead of 2-piperazin-1-yl-ethanol, in the same manner as Step C in Example 1-D-153, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {3-[methyl-(2-morpholin-4-yl-ethyl)-amino]-phenyl}-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-227) as a brown solid (18.6 mg, 22%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>CN(C)C=O>[CH:21]([S:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH2:9])=[O:8])=[CH:10][CH:11]=1)(=[O:24])=[O:23])=[CH2:20]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCc1ccc(C(N)=O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CS(=O)(=O)NCc1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 299.6 %

Procedure:
A solution of 4-aminomethylbenzamide (0.58 g) and triethylamine (1.1 ml) in dimethylformamide (DMF; 6 ml) was added to a solution of 2-chloroethanesulphonyl chloride (0.63 g) in DMF (4 ml) at -60° under nitrogen over 30 mins. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was evaporated to give a semi-solid (2.78 g) which was purified by column chromatography (D) to give the title compound as a solid (0.54 g) m.p. 142°-4°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.[OH:36][C:37]([CH3:42])([CH3:41])[C:38](O)=[O:39].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:38](=[O:39])[C:37]([OH:36])([CH3:42])[CH3:41])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)C(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
To 1-(2-chloro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1 of Example 312, were added 2-hydroxyisobutyric acid (7.0 mg, 0.07 mmol), dichloromethane (1.0 mL), HOBT (15.0 mg, 0.11 mmol), EDAC (21.0 mg, 0.11 mmol), and triethylamine (23.0 uL, 0.17 mmol). The reaction mixture was stirred at room temperature for 12 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 10.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Clc1cc(-c2ccccc2)ncn1
Yield: 37 %

Procedure:
Into a 100-mL round-bottom flask equipped with a reflux pipe were put 5.1 g of 4,6-dichloropyrimidine, 8.2 g of phenylboronic acid, 7.16 g of sodium carbonate, 20 mL of acetonitrile, and 20 mL of water, and the air in the flask was replaced with nitrogen. To this mixture, 0.347 g of bis(triphenylphosphine)palladium(II) dichloride was added and the mixture was irradiated with microwaves (2.45 GHz, 100 W) for 1 hour. Further, 2.07 g of phenylboronic acid and 1.79 g of sodium carbonate were added and the mixture was irradiated with microwaves (2.45 GHz, 100 W) for 1 hour. An organic layer was extracted from the obtained mixture with the use of dichloromethane. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The mixture was subjected to gravity filtration. A residue obtained by distilling off the solvent in the filtrate was purified by silica column chromatography with the use of dichloromethane as a developing solvent to give an objective substance as a white powder in a yield of 37%. Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). Synthesis Scheme (D-1) of Step 1 is shown below.
Reaction SMILES: [CH3:1][CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2[C:9]([CH2:11][CH2:12][CH2:13][C:4]=2[C:3]1([CH3:15])[CH3:14])=O.[C:16](O)(=O)C.[CH:20]([NH2:22])=[NH:21]>C(O)CCC>[CH3:14][C:3]1([CH3:15])[C:4]2[CH2:13][CH2:12][C:11]3[CH:16]=[N:21][CH:20]=[N:22][C:9]=3[C:5]=2[C:6]([CH3:8])([CH3:7])[CH:2]1[CH3:1]
Reactant: CC(=O)O
Reactant: N=CN
Reactant: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Solvent: CCCCO
Product: CC1C(C)(C)C2=C(c3ncncc3CC2)C1(C)C
Temperature: 118 °C

Procedure:
A 5 L reaction vessel was charged with Cashmeran™ (412 g, 2.0 mol, commercially available at IFF), formamidine acetate (1030 g, 10.0 mol), and butanol (1.2 L). The reaction mixture was heated to 118° C. for 4 hours and then cooled to 25° C. The reaction mixture was washed twice with brine (1 L) and purified by vacuum distillation to afford 6,7,8,9-tetrahydro-7,7,8,9,9-pentamethyl-5H-cyclopenta[H]quinazoline (260 g) having a boiling point of 140° C. at a pressure of 1.6 mmHg. Further recrystallization from ethanol afforded a solid with a melting point of 80.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.C(NC1C=CC([O:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([O:36][Si](C(C)(C)C)(C)C)[CH2:32][CH2:31]2)=O)=NC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.F>C(#N)C.CCCCCCC>[F:10][C:8]([F:9])([F:11])[C:5]1[CH:6]=[CH:7][C:2]([O:1][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)=[O:27])=[N:3][CH:4]=1
Reactant: Oc1ccc(C(F)(F)F)cn1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)Oc2ccc(NC(=O)c3ccccc3)cn2)CC1
Agent: F
Solvent: CC#N
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(C(F)(F)F)cn1)N1CCC(O)CC1
Reaction time: 18 h
Yield: 46.5 %

Procedure:
A solution of 2-hydroxy-5-trifluoromethylpyridine (0.32 g, 2.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (0.90 g, 2.00 mmol) and triethylamine (0.20 g, 2.00 mmol) in acetonitrile (10 mL) was stirred at room temperature for three days. Hydrofluoric acid (min. 40% in water, 0.50 mL) was added and stirring was continued for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 75:25), followed by crystallisation from ethyl acetate:heptane, yielding the title compound (0.27 g, 47% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[C:9](Br)=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1.C([Li])CCC.C([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=O.O.[O:31]1CCC[CH2:32]1>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[C:9]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[CH2:32][OH:31]
Reactant: C1CCOC1
Reactant: O=Cc1ccncc1
Reactant: COc1cc(Br)c(C(OC)OC)cc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(-c2ccncc2)c(C(OC)OC)c(CO)c1OC

Procedure:
A solution of 6-bromo-3,4-dimethoxybenzaldehyde dimethyl acetal (20 ml) in tetrahydrofuran (100 ml) is cooled to −60° C., and thereto is added dropwise a 1.6 M solution of n-butyl lithium in hexane (45.1 ml) over a period of 20 minutes under nitrogen atmosphere. The mixture is reacted at the same temperature for 30 minutes, and thereto is added dropwise a solution of 4-formylpyridine (7.36 g) in tetrahydrofuran (50 ml) over a period of 20 minutes. The reaction mixture is reacted for one hour, and thereto are added water and ethyl acetate (200 ml). The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure to remove the ethyl acetate to give 3,4-dimethoxy-6-(4-pyridyl)hydroxymethylbenzaldehyde dimethyl acetal (15.4 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)CCC>>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[N:7]=[C:6]3[CH2:8][N:9]([C:11]([C:13]4[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=4[O:23][C@@H:24]([CH3:29])[C:25]([F:26])([F:27])[F:28])=[O:12])[CH2:10][C:5]3=[CH:4][CH:3]=2)=[CH:36][CH:37]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)nc2C1)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(-c3ccc(F)cc3)nc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C4) and tributyl(4-fluorophenyl)stannane. White solid. MS (m/e): 509.1 [M+H]+, 100%).
Reaction SMILES: C([O-])=O.[NH4+].[CH2:5]([O:9][C:10]([C:12]1[N:17]=[C:16](Br)[C:15]2[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[S:21][C:14]=2[C:13]=1[OH:29])=[O:11])[CH2:6][CH2:7][CH3:8].[CH2:30]([O:34][C:35]([C:37]1[C:38]([OH:54])=[C:39]2[CH:46]=[C:45]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[S:44][C:40]2=[C:41](Br)[N:42]=1)=[O:36])[CH2:31][CH2:32][CH3:33]>[Pd].C(OCC)(=O)C>[CH2:5]([O:9][C:10]([C:12]1[N:17]=[CH:16][C:15]2[CH:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[S:21][C:14]=2[C:13]=1[OH:29])=[O:11])[CH2:6][CH2:7][CH3:8].[CH2:30]([O:34][C:35]([C:37]1[C:38]([OH:54])=[C:39]2[CH:46]=[C:45]([C:47]3[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=3)[S:44][C:40]2=[CH:41][N:42]=1)=[O:36])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(-c3ccc(F)cc3)sc2c1O
Reactant: CCCCOC(=O)c1nc(Br)c2sc(-c3ccc(F)cc3)cc2c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1ncc2cc(-c3ccc(F)cc3)sc2c1O
Product: CCCCOC(=O)c1ncc2sc(-c3ccc(F)cc3)cc2c1O

Procedure:
A mixture of palladium on carbon (10%, 20 mg), ammonium formate (74.4 mg, 1.18 mmol), 4-bromo-2-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester and 7-bromo-2-(4-fluoro-phenyl)-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (50 mg, 0.118 mmol), example 34-c, in ethyl acetate (1.5 mL) was refluxed for 2.5 h. The catalyst was filtered off and the resulting solution was concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-60% ethyl acetate in hexanes to produce 11.0 mg of 2-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester and 10.0 mg of 2-(4-fluoro-phenyl)-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester. MS for 2-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester: (+) m/z 346.0 (M+1). MS for 2-(4-fluoro-phenyl)-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester: (+) m/z 346.0 (M+1).