Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][C:11]1[C:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:13]([O:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2.Cl[C:38](=[O:44])[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:10][C:11]1[C:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:13]([O:23][C:24]2[CH:30]=[CH:29][C:27]([NH:28][C:38](=[O:44])[CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:26][CH:25]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2
Reactant: COC(=O)CC(=O)Cl
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC(=O)Nc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
N-ethyldiisopropylamine (147 μL, 0.84 mmol, 3 equiv) was added to a solution of 38 (100 mg, 0.28 mmol, 1 equiv) in CH2Cl2 (5 mL) at 0° C. After 10 min, methyl 3-chloro-3-oxopropionate (60 μL, 0.56 mmol, 2 equiv) was added and the reaction was stirred at 0° C. for 3 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (100 mL). The organic layer was dried over MgSO4, filtered, concentrated and the residue purified by silica gel flash column chromatography (30% EtOAc:hexanes) to provide 41 (87 mg, 68%) as a yellow oil. 1HNMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 7.68 (s, 1H), 7.56 (m, 1H), 7.33-7.17 (m, 8H), 7.06-7.03 (m, 1H), 6.53 (m, 2H), 3.86 (s, 3H), 3.61 (s, 3H), 3.37 (s, 2H), 2.17 (s, 3H). MS m/z 455.87 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].B(F)(F)F.CCOCC.[Br:32]Br>ClCCl>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Br:32])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 134.3 %

Procedure:
5-Acetyl-8-benzyloxy-1H-quinolin-2-one (Preparation 6) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0° C. Boron trifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45° C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 min. The mixture was kept at 45° C. for an additional 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4×100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2×50 mL) and methanol (2×50 mL). The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[F:13][C:14]1[CH:15]=[CH:16][C:17]2[C:22]3[C:23]4[C:52](=[O:53])[NH:51][C:50](=[O:54])[C:24]=4[C:25]4[C:26]5[C:31]([N:32]([C@@H:34]6[O:42][C@H:41]([CH2:43]OS(C)(=O)=O)[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]6[OH:36])[C:33]=4[C:21]=3[NH:20][C:18]=2[CH:19]=1)=[CH:30][C:29]([F:49])=[CH:28][CH:27]=5>CN(C)C=O>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[C:22]3[C:23]4[C:52](=[O:53])[NH:51][C:50](=[O:54])[C:24]=4[C:25]4[C:26]5[C:31]([N:32]([C@@H:34]6[O:42][C@H:41]([CH2:43][N:5]7[C:1](=[O:11])[C:2]8=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]8[C:4]7=[O:6])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]6[OH:36])[C:33]=4[C:21]=3[NH:20][C:18]=2[CH:19]=1)=[CH:30][C:29]([F:49])=[CH:28][CH:27]=5.[C@@H:34]1([N:32]2[C:33]3[C:21]4[NH:20][C:18]5[CH:19]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=5[C:22]=4[C:23]4[C:52](=[O:53])[NH:51][C:50](=[O:54])[C:24]=4[C:25]=3[C:26]3[C:31]2=[CH:30][C:29]([F:49])=[CH:28][CH:27]=3)[O:42][C@@H:41]2[CH2:43][O:38][C@@H:37]([C@@H:39]2[OH:40])[C@H:35]1[OH:36]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OC[C@H]1O[C@@H](n2c3cc(F)ccc3c3c4c(c5c6ccc(F)cc6[nH]c5c32)C(=O)NC4=O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c1c1c3ccc(F)cc3[nH]c1c1c2c2ccc(F)cc2n1[C@@H]1O[C@@H]2CO[C@H]([C@H]1O)[C@@H]2O
Product: O=C1NC(=O)c2c1c1c3ccc(F)cc3[nH]c1c1c2c2ccc(F)cc2n1[C@@H]1O[C@H](CN2C(=O)c3ccccc3C2=O)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 130 °C
Yield: 21 %
Yield: 13 %

Procedure:
2,10-Difluoro-12,13-dihydro-12-[β-D-glucopyranosyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (1.0 g, 1.91 mmol) was dissolved in dry pyridine under nitrogen at room temperature and treated with flame-dried, powdered 4A molecular sieves (0.60 g). The mixture. was cooled to −20° C. for 15 min before methanesulfonyl chloride (0.26 mL, 3.34 mmol, 1.75 eq.) was added neat. The flask was sealed and stored at 0° C. for 6 h prior to concentration in vacuo. Purification of the residue by flash chromatography on silica gel (elution with tetrahydrofuran/dichloromethane/methanol, 68:30:2) gave an enriched fraction (280 mg, 24%) containing the title compound as well as a small amount of other closely-spaced by-products which was carried on directly. Potassium phthalimide (0.45 g, 2.43 mmol) was added in one portion to a stirred solution of 2,10-difluoro-12,13-dihydro-12-[6—O-(methylsulfonyl)-β-D-glucopyranosyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (200 mg, 0.33 mmol) in anhydrous dimethylformamide (10 mL) before the mixture was heated to 130° C. for 3 h, cooled to ambient temperature, and concentrated down in vacuo overnight. The residue was then taken up in ethyl acetate (some tetrahydrofuran was added) and washed with 0.1N hydrochloric acid and brine. Following drying and solvent concentration, the residue was purified by flash chromatography on silica gel (elution with 7% methanol in chloroform) to yield 2,10-difluoro-12,13-dihydro-12-[6-deoxy-6-(phthalimido)-β-D-glucopyranosyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (46 mg, 21%) as a yellow solid as well as the title compound (22 mg, 13%, 2 steps) also as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][S:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[C:12]([CH2:13][S:14][CH2:15][CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[C:11]([CH3:23])[O:10][N:9]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]
Reactant: Cc1onc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4noc(C)c4CSCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 3-(4-bromo-phenyl)-5-methyl-4-phenethylsulfanylmethyl-isoxazole and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:11]3=[C:27]([CH3:31])[N:28]=[C:29]([CH3:30])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[CH3:31][C:27]1[N:28]=[C:29]([CH3:30])[N:10]2[C:11]=1[C:12]([NH:14][C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)=[N:13][C:8]([C:4]1[CH:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:7]=[CH:6][CH:5]=1)=[N:9]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Nc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2nc(-c3cccc(NS(C)(=O)=O)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
A solution of 80 mg (0.19 mmol) of 3-[5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)-imidazo[5,1-f][1,2,4]triazin-2-yl]aniline from example 7, 20 mg (0.19 mmol) of methanesulfonyl chloride and 40 mg (0.38 mmol) of triethylamine in dichloromethane is stirred overnight at 20° C. The mixture is washed with aqueous sodium hydrogencarbonate solution, and the organic phase is dried and purified by HPLC.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:19]=[CH:18][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2].C(O)(=O)C.[BH4-].[Na+]>CS(C)=O>[N+:1]([CH2:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a solution of 2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (21.0 g, 81.9 mmol) described in Manufacturing Example 2-1-3, acetic acid (21 mL) in dimethyl sulfoxide (200 mL) was added sodium borohydride (4.96 g, 131 mmol) at room temperature while cooling appropriately. After addition of sodium borohydride, the cooling bath was removed, followed by stirring for 15 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate. The ethyl acetate layer was washed with water twice and with saturated aqueous sodium chloride once, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (16.3 g, 77.1%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH3:8].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:1]1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(-c2ccc(C(C)Br)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(C)n3ccnc3)nc2)cc1
Temperature: 50 °C
Yield: 71.6 %

Procedure:
To a stirred solution of 1H-imidazole (0.069 g, 1.0 mmol) in DMF (7 mL) was added 2-(1-bromoethyl)-5-(4-methoxyphenyl)pyridine (0.150 g, 0.50 mmol) and K2CO3 (354 mg, 2.5 mmol). The reaction was heated at 50° C. for about 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 100-200μ) using 2% methanol in DCM eluent to afford 2-(1-(1H-imidazol-1-yl)ethyl)-5-(4-methoxyphenyl)pyridine as an off-white solid (0.1 g, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, 1H), 7.99 (dd, 1H), 7.80 (s, 1H), 7.63 (d, 2H), 7.26 (s, 1H), 7.03 (d, 1H), 7.21 (d, 2H), 6.89 (s, 1H), 5.64-5.59 (m, 1H), 3.78 (s, 3H), 1.81 (d, 3H), LC-MS m/z calcd for [M+H]+ 280.14. found 280.2.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH2:15][OH:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[Si:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O.O>ClCCl>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH2:15][OH:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[O:21][Si:28]([CH3:31])([CH3:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1(CO)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Solvent: O
Solvent: ClCCl
Product: CC1(CO)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of 0.59 g of 4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 48 and 1.17 ml of 2,6-luthidine in 5 ml of dichloromethane was cooled to 0° C. under nitrogen, combined with 1.25 ml of trimethylsilyl trifluoromethanesulfonate and stirred. After 30 minutes, the reaction solution was poured into water and extracted with ether, and the combined organic layers were concentrated. The residue was dissolved in 10 ml of THF, 5% hydrochloric acid was added and the solution was stirred for 1 hour, after which the reaction solution was concentrated and extracted with water and ether. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane containing 9% ethyl acetate to give 0.62 g of 4,6-di-t-butyl-2-hydroxymethyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran as a colorless oil (yield 84%).
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([OH:14])(=[O:13])/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>O1CCCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[S:1][CH:9]([CH2:10][CH2:11][CH3:12])[CH2:8][C:7]([OH:14])=[O:13]
Reactant: CCC/C=C/C(=O)O
Reactant: Sc1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(CC(=O)O)Sc1cccs1

Procedure:
A solution of 2-mercaptothiophene (51.1 g, 0.44 mol), trans-2-hexenoic acid (1) (49.1 g, 0.43 mol), triethylamine (29.3 g, 0.29 mol) in tetrahydrofuran (490 ml) was stirred and refluxed under nitrogen for 21 hours. The mixture was concentrated in vacuo and the residue was distributed between ethyl acetate (500 ml) and 3N hydrochloric acid (200 ml), the aqueous layer was separated and extracted with ethyl acetate (200 ml), the combined ethyl acetate extracts were washed with 3N hydrochloric acid, twice with water and dried over sodium sulfate. The solvent was evaporated in vacuo to yield pale yellow oily product weighing 99 g (100%), which was >96% pure by HPLC.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[CH:7][C:8]([Cl:13])=[C:9]([O:11][CH3:12])[CH:10]=1.[C:14]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1C[O:31]CC1>>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][C:24]([C:5]2[CH:6]=[CH:7][C:8]([Cl:13])=[C:9]([O:11][CH3:12])[CH:10]=2)([OH:31])[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cc(Br)ccc1Cl
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: II
Agent: [Mg]
Product: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Magnesium turnings (2.60 g) in a flask were stirred vigorously under vacuum at room temperature for 12 h and then the flask was filled with nitrogen gas. THF (20 mL) was added followed by the addition of one crystal of I2. The mixture was cooled to 0° C. and a solution of 5-bromo-2-chloroanisole (6.64 g) in THF (100 mL) was added in a period 20 of 10 min. The mixture was warmed up to room temperature and stirred at room temperature for 15 min before it was heated to 45° C. for 2 h to provide a solution of the Grignard solution. To 24 mL of the Grignard solution obtained from above (at −40° C.) was added N-Boc-piperidone (1.0 g) in one portion. The resultant mixture was warmed up to room temperature, stirred for 1 h and quenched by the addition of sat. aqueous NH4Cl solution (20 mL). The organic layer was separated and the aqueous layer was extracted by EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by flash chromatography to provide 4-(4-Chloro-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (502 mg).
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]=[C:22]1[N:27]2[CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH:26]2[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:24]2[CH2:23][C:22](=[O:21])[N:27]3[CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH:26]3[CH2:25]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CNCC2c3ccccc3CCCN12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC2c3ccccc3CCCN12
Reaction time: 1.5 h
Yield: 100.4 %

Procedure:
Triphenylmethyl chloride (0.47 g) was added to a mixture of 4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.31 g) and triethylamine (0.25 ml) in chloroform (25 ml, ethanol-free) at 0°. The mixture was maintained at 0° for 30 min then at room temperature for 90 min. The solution was washed with saturated sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, Et2O) to give the title compound (0.66 g, 100%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]([OH:16])=[O:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.C(=O)(O)[O-].[Na+].O.C(#N)C>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:29]1[CH:28]=[C:27]([C:2]2[CH:18]=[CH:17][C:5]3[C:6]4[N:7]=[C:8]([C:14]([OH:16])=[O:15])[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Temperature: 150 °C
Yield: 104.2 %

Procedure:
To a degassed solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (1.40 g, 4.29 mmol), 4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (1.0 g, 5.0 mmol), 2 M Sodium bicarbonate in water (6.0 mL, 10.0 mmol) and acetonitrile (8.0 mL, 200 mmol) in a microwave vial was added Tetrakis(triphenylphosphine)palladium(0) (0.499 g, 0.432 mmol). The vial was heated on the Emrys microwave at 150° C. for 20 minutes. Cooled to room temperature and diluted with ethyl acetate, the precipitate was filtered off, washed with ethyl acetate and water and dried under vacuum to give 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (1.4 g, 103% yield).
Reaction SMILES: C(OC([N:11]1[C:15](=[O:16])[CH2:14][C@@H:13]([C@H:17]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C:18]([OH:20])=[O:19])[O:12]1)=O)C1C=CC=CC=1.C(OCC)(=O)C>[Pd].C(O)C>[O:16]=[C:15]1[CH2:14][CH:13]([CH:17]([N:21]2[C:22](=[O:31])[C:23]3=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]3[C:25]2=[O:26])[C:18]([OH:20])=[O:19])[O:12][NH:11]1
Reactant: O=C(O)[C@H]([C@@H]1CC(=O)N(C(=O)OCc2ccccc2)O1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CC(C(C(=O)O)N2C(=O)c3ccccc3C2=O)ON1
Reaction time: 2.75 h

Procedure:
A 7.48 g. (17.6 mM) quantity of (αS,5S) 2-[(benzyloxy)carbonyl]-3-oxo-α-phthalimido-5-isoxazolidine acetic acid is dissolved in 150 ml. of ethyl acetate and 75 ml. of 95% ethanol. The solution is treated with 1.5 g. of palladium black and hydrogenated at 25° C. and 1 atmosphere of pressure. The reaction is stopped after 165 minutes, filtered, and the filtrate is evaporated in vacuo to yield 3-oxo-α-phthalimido-5-isoxazolidine acetic acid as a residue.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:2]=1.[CH2:16]([O:23][C:24]1[C:25]([F:33])=[C:26]([C:29]([F:32])=[CH:30][CH:31]=1)[CH:27]=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+].Cl>CO.O>[CH2:16]([O:23][C:24]1[C:25]([F:33])=[C:26]([CH:27]([C:15]2[C:9]3[C:10](=[N:11][CH:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[NH:13][CH:14]=2)[OH:28])[C:29]([F:32])=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1c(F)ccc(OCc2ccccc2)c1F
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1c(F)ccc(OCc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 750.0 mg, 0.003842 mol, prepared as in Example 17) in methanol (20.0 mL) were added 3-Benzyloxy-2,6-difluoro-benzaldehyde (526, 1.12 g, 4.5 mmol) and potassium hydroxide (1.50 g, 0.0267 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight and then poured into water, acidified with 1N HCl to pH around 2 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound (527, 700 mg, 35%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.N#N.[CH:25]1([C:28]#[CH:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>C1COCC1.CCOC(C)=O.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:25]1([C:28]#[C:29][C:2]2[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[CH2:27][CH2:26]1
Reactant: Cc1nnnn1C(=NOCc1csc(Br)n1)c1ccccc1
Reactant: C#CC1CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nnnn1C(=NOCc1csc(C#CC2CC2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.2 %

Procedure:
To a stirred solution of N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(5-methyl-1H-tetrazol-1-yl)-1-phenylmethanimine (0.2 g, 0.527 mmol, 1 eq.) in 3 ml dry THF “degassed” with N2, was added cyclopropylacetylene (0.069 g, 1.05 mmol, 2 eq.) followed by triethylamine (0.213 g, 2.1 mmol, 4 eq.), Copper Iodide (0.015 g, 0.079 mmol, 0.15 eq.) and Tetrakis(triphenylphosphine)palladium (0.030 g, 0.026 mmol, 0.05 eq.). The reaction was stirred for 20 hrs at room temperature for complete conversion. The reaction was diluted with EtOAc (50 ml), filtered through “Chem Elut” cartridge, washed with fresh EtOAc (2×20 ml) and the filtrate was concentrated. The residue was chromatographed on silica gel to give N-{[2-(cyclopropylethynyl)-1,3-thiazol-4-yl]methoxy}-1-(5-methyl-1H-tetrazol-1-yl)-1-phenylmethanimine (0.108 g, 56% yield) as a brown gum.