Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([O:28][CH:29]2[CH2:32][NH:31][CH2:30]2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16]>C(Cl)Cl>[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([O:28][CH:29]2[CH2:30][N:31]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:32]2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: COC(=O)c1cc(OC2CNC2)c2c(c1)OC(C)(C)C2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(OC2CN(S(C)(=O)=O)C2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
Et3N (400 mg, 2.87 mmol) and methane sulfonyl chloride (75 uL, 0.97 mmol) were added to a solution of 4-(azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193c) (303 mg, 0.97 mmol) in CH2Cl2 (15 mL). The mixture was stirred at room temperature for 2 hr, quenched with 1N aqueous HCl (60 mL) and extracted with CH2Cl2 (60 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatograph to give a white solid (197 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ 7.10 (s, 1 H) 6.75 (s, 1 H) 5.02 (d, J=6.06 Hz, 1 H) 4.34 (dd, J=8.46, 6.69 Hz, 2 H) 4.08 (dd, J=8.72, 4.93 Hz, 2 H) 3.89 (s, 3 H) 3.00 (s, 2 H) 2.93 (s, 3 H) 1.50 (s, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([F:13])[C:3]=1[CH2:4][OH:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](Cl)=[O:28])[C@H:23]([CH2:30][CH3:31])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([F:13])[C:3]=1[CH2:4][O:5][C:27]([N:24]1[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:20])[CH2:22][C@H:23]1[CH2:30][CH3:31])=[O:28]
Reactant: CCOc1cc(F)c(CO)c(Cl)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(Cl)c1
Yield: 94 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-ethoxy-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (418 mg; 94%); MS (ISP): 462.4 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:32]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:32])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2cc(C(F)(F)F)ccc2NC1=O
Product: CC(C)(CC(=O)NC1CCc2cc(C(F)(F)F)ccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step H by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.34 (s,6H), 1.42 (s,9H), 1.98 (m,1H), 2.50 (d,14Hz,1H), 2.63 (d,14Hz,1H), 2.7-3.0 (m,3H), 4.50 (m,1H), 6.75 (d,7Hz,1H), 7.10 (d,8Hz,1H), 7.51 (br s,2H), 7.94 (br s,1H). FAB-MS: calculated for C21H28F3N3O4 443; found 444 (M+H,74%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[CH:27]=[O:28].[CH3:32][N:33]([CH3:36])[CH:34]=[S:35]>C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:27]([OH:28])[C:34](=[S:35])[N:33]([CH3:36])[CH3:32])[CH:29]=1
Reactant: CN(C)C=S
Reactant: COc1ccc(F)cc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(O)C(=S)N(C)C
Temperature: -78 °C
Yield: 28000.7 %

Procedure:
To a solution of lithium diisopropylamide, 2M in THF/n-heptane (210 mL, 583 mmol) was added THF (100 mL) and the solution cooled to −78° C. under nitrogen. This was then added dropwise over 1 h to a solution of the 5-fluoro-2-methoxybenzaldehyde (50 g, 0.32 mmol) and N,N-dimethylthioformamide (34.7 g, 389 mmol) in dry THF (200 mL). This was warmed to −5° C. and quenched with water (400 mL). The solution was filtered and washed with diethyl ether, the aqueous layer was extracted with ether (1 L). The combined organic layers were washed with water (500 mL), dried (MgSO4) and the solvent removed in vacuo to give a crystalline suspension in oil. This was triturated in ether and filtered to give a crystalline solid (21.8 g, 28%); δH (300 MHz, CDCl3) 7.16-6.81 (3H, m, ArH), 5.81-5.75 (1H, m, CHOH), 5.31-5.22 (1H, m, OH), 4.89 (3H, s, OCH3), 3.50 (3H, s, N(CH3)2) and 3.08 (3H, s, N(CH3)2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]2)=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]1[CH:12]([CH3:14])[S:13][C:9]1=[C:8]([C:15]([O:17]CC)=[O:16])[C:7]2=[O:20].[OH-].[K+].C(O)(C)(C)C.Cl>O>[Cl:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:28])[CH3:29])[CH2:23]2)=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]1[CH:12]([CH3:14])[S:13][C:9]1=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:20]
Reactant: CCOC(=O)c1c2n(c3c(Cl)c(N4CC[C@H](N(C)C)C4)c(F)cc3c1=O)C(C)S2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N(C)C)C4)c(Cl)c3n21
Temperature: 60 °C
Yield: 60.7 %

Procedure:
A mixture of 0.44 g of ethyl 8-chloro-7-((S)-3-dimethylamino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate, 0.33 g of 85% potassium hydroxide, 2.0 ml of tert-butanol and 6.0 ml of water was heated at 60° C. for 1 hour with stirring. After cooling, the reaction mixture was neutralized with 10% hydrochloric acid, and evaporated. To the residue, water was added and the residue was extracted with chloroform. The extract was dried and acidified with ethanolic hydrochloride. The solution was evaporated and to the residue was added small amount of methanol. The precipitate was collected by filtration and dissolved with water. The solution was neutralized with 10% aqueous sodium hydroxide and extracted with chloroform. The extract was dried, evaporated and recrystallized from a mixture of chloroform and iso-propanol to give 0.25 g of the desired compound as pale yellow crystals, m.p. 161°-162° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[C:8](=[CH:12][CH:13]=1)[C:9]([OH:11])=[O:10])([OH:3])=[O:2].[C:17]1([C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N+]=[N-])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:17]1([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:15][C:14]([C:7]2[CH:6]=[C:5]([CH2:4][C:1]([OH:3])=[O:2])[CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:10])=[O:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccc(C(=O)O)c(C(=O)O)c1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Product: O=C(O)Cc1ccc(C(=O)OC(c2ccccc2)c2ccccc2)c(C(=O)OC(c2ccccc2)c2ccccc2)c1

Procedure:
0.52 g of 4-carboxymethylphthalic acid was dissolved in 10 ml of acetone, and a solution of 0.89 g of diphenyldiazomethane in acetone (20 ml) was dropwise added over a period of 15 minutes at room temperature with stirring. After completion of the dropwise addition, the mixture was stirred at room temperature overnight. Then, the solvent was distilled off, and then, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1→ethyl acetate) to obtain 0.67 g of the above identified compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=383.1, tR (minutes, Method F)=3.02
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccn1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(Cc1ccccn1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
180 mg (0.329 mmol) of (2R*,4S*)-2-benzyl-1-(2-pyridylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 50 mg (1.32 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR44## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.28, FD-MS: M+ =450.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[N+:24]([O-])=O)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[NH2:24])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a stirred suspension of the compound obtained in Step A (8.0 g) in ethanol (66 ml) and water (80 ml) at 60° C. was added sodium dithionite (11 g). The resulting mixture was stirred at 60° C. for 1 hour then ethanol was removed in vacuo. The suspension was extracted three times with ethyl acetate, the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was filtered on silica gel (eluent ethyl acetate) to afford 1-[(E)-3-(4-chloro-phenyl)-allyl]-4-(5-fluoro-2-amino-phenyl)-piperazine (4.1 g). 1H NMR (400 MHz, CDCl3) 2.6 (m, 4H), 2.9 (m, 4H), 3.2 (d, J=9 Hz, 2H), 3.7 (m, 2H), 6.2 (dt, J=18, 9 Hz, 1H), 6.5 (d, J=18 Hz, 1H), 6.6 (m, 2H), 6.7 (d, J=10 Hz, 1H), 7.2-7.3 (m, 4H); MS (ES+) 151/153, 346/348 (M+H+).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.O1CCOCC1.[OH-].[Na+]>O>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][C:1]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CC=CC2
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C1=CCc2c(cccc2OCC2CO2)C1

Procedure:
To a cooled solution of 15 g. (0.1 m.) of 5,8-dihydro-1-naphthol and 13.2 g. (0.14 m.) of epichlorohydrin in 38 ml. of p-dioxane, a cold solution of 4.9 g. of sodium hydroxide in 10 ml. of water is added dropwise. The mixture is refluxed three hours, cooled, and extracted with benzene. The benzene extract is washed with water, dried (MgSO4) and evaporated in vacuo to give 1-(2,3-epoxypropoxy)-5,8-dihydronaphthalene. Distillation of the crude oil at 1.2 mm., b.p. 139°-140°, gives a colorless liquid; λliq.max. film 1250, 910, 840 cm-1 (characteristic epoxy bands), CDCl3 4.13 (-C/H=C/H-), 2.5 - 3.5 (aromatic protons).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:12][C:13]1[S:14][C:15]2[CH:22]=[C:21](S(O)(=O)=O)[CH:20]=[CH:19][C:16]=2[N+:17]=1[CH3:18].Cl[C:28](=[O:36])[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>N1C=CC=CC=1>[CH3:35][O:34][C:32]([CH2:31][CH2:30][CH2:29][C:28](=[O:36])[CH:12]=[C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[S:14]1)=[O:33]
Reactant: Cc1sc2cc(S(=O)(=O)O)ccc2[n+]1C
Reactant: COC(=O)CCCC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: COC(=O)CCCC(=O)C=C1Sc2ccccc2N1C
Temperature: 55 °C

Procedure:
To 1.7 g of 2,3-dimethyl-6-sulfobenzothiazolium tosylate in 20 mL of pyridine at room temperature is added 1.03 mL of methyl 5-chloro-5-oxovalerate. The mixture is heated at 50-60° C. for 3 hours. The pyridine solvent is removed under reduced pressure, and the reaction is worked up with chloroform and brine, and purified by silica gel column to yield 0.92 g of 2-(5-methoxycarbonyl-2-oxopentylidene)-3-methyl-3H-benzothiazole. A mixture of 0.45 g of this benzothiazole and 0.45 g of phosphorous oxychloride in 5 mL of dichloroethane is heated at reflux for 2 hours to generate 2-(2-chloro-2-methoxycarbonylpropylvinyl)-3-methylbenzothiazolium chloride. The volatile components are evaporated and the crude chloride is used without further purification. The crude chloride and 0.45 g of 2,3,3,7-tetramethyl-3H-pyrrolo[2,3-b]pyridinium tosylate is stirred in 5 mL of dichloroethane in the presence of 0.45 mL of triethylamine for 2 hours. The volatile components are removed under reduced pressure, and the residue is dissolved in 5 mL of methanol and added dropwise to a solution of 4.5 g of sodium iodide in 30 mL water. The sticky solid is purified on a silica gel column to yield Compound 79.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:25]12[CH2:31][CH:29]([O:30]1)[CH2:28][NH:27][CH2:26]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:27]4[CH2:26][C@@H:25]5[CH2:31][C@@H:29]([O:30]5)[CH2:28]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1NCC2CC1O2
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2C[C@H]3C[C@@H](C2)O3)cn1
Yield: 22 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (36 mg, 0.11 mmol) was converted, using rac-6-oxa-3-aza-bicyclo[3.1.1]heptane instead of 2,2,2-trifluoroethylamine, to the title compound (10 mg, 22%) which was obtained as a colourless gum. MS: m/e=410.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:9]([OH:11])=[O:10])([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[NH2:3].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>[OH-].[Na+]>[CH2:16]([O:15][C:13]([NH:3][C@:2]([CH3:1])([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(N)(CCC(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@@](CCC(=O)O)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a stirred solution of α-methyl-D,L-glutamic acid (10 g, 62 mmol) in 2 N sodium hydroxide (62 mL) at 0–5° C. was added benzyl chloroformate (12.7 g, 74.4 mmol) over 30 min. After the addition was complete the reaction mixture was stirred at room temperature for 3 hours. During this time the pH was maintained at 11 by addition of 2 N sodium hydroxide (33 mL). The reaction mixture was then extracted with ether (60 mL). The aqueous layer was cooled in an ice bath and then acidified with 4N hydrochloric acid (34 mL) to pH=1. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (60 mL) and dried (MgSO4). The solvent was removed in vacuo to give 15.2 g (83%) of N-benzyloxycarbonyl-α-methylglutamic acid as an oil: 1H NMR (CDCl3) δ 8.73(m, 5H), 5.77(b, 1H), 5.09(s, 2H), 2.45–2.27(m, 4H), 2.0(s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2([CH3:18])[CH2:17][CH2:16]2)=[C:9]([CH:19]([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.CN(C=O)C>[CH:19]([C:9]1[CH:8]=[C:7]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:12]=[CH:11][C:10]=1[CH2:13][O:14][C:15]1([CH3:18])[CH2:17][CH2:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1COC1(C)CC1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C#C[Si](C)(C)C)ccc1COC1(C)CC1
Temperature: 95 °C
Yield: 107.7 %

Procedure:
Using General Procedure D; 3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenyl 1,1,1-trifluoromethanesulfonate (Intermediate 164, 120.0 mg, 0.34 mmol) in triethylamine (2 mL) and anhydrous DMF (5 mL) was sparged with argon for 5 minutes. Trimethylsilyl acetylene (700.0 mg, 0.71 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(I) (24.0 mg, 0.03 mmol). The resulting reaction mixture was heated to 95° C. for 60 hours. The title compound 110.0 mg, (99%) was isolated by chromatography (0-1% EtOAc-hexanes).
Reaction SMILES: C([OH:3])C.[OH-].[Na+].[CH3:6][C:7]1[C:8]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:9]=2[C:10]2[C:11](=[O:24])N(C3C=CC(C)=CC=3)[C:13](=[O:16])[C:14]=2[CH:15]=1.Cl>O.C(OCC)(=O)C>[CH3:6][C:7]1[CH:15]=[C:14]2[C:13](=[O:3])[O:16][C:11](=[O:24])[C:10]2=[C:9]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[O:27][C:8]=12
Reactant: CCO
Reactant: Cc1ccc(N2C(=O)c3cc(C)c4oc5ccccc5c4c3C2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2c(c3c1oc1ccccc13)C(=O)OC2=O
Temperature: 25 °C
Yield: 91 %

Procedure:
5 ml of ethanol and 1.2 ml of a 5 N aqueous sodium hydroxide solution were added to 200 mg of 5-methyl-2-(4-methylphenyl)-1H-benzofuro[3,2-e]isoindole-1,3(2H)-dione. The mixture was refluxed for 30 minutes. Thereto was added 1.2 ml of concentrated hydrochloric acid. The resulting mixture was refluxed for 1 hour and then cooled to room temperature. Then, thereto were added 20 ml of ethyl acetate and 10 ml of water. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with 2.0 ml of acetic anhydride. The mixture was refluxed for 30 minutes, and then concentrated to dryness under reduced pressure. The residue was washed with diethyl ether and dried to obtain 140 mg (yield: 91%) of 4-methyldibenzofuran-1,2-dicarboxylic anhydride as light yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2]
Reactant: CCOc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(OCC)c1
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A 500 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with 3-ethoxyphenol (20.4 g, 148 mmol), K2CO3 (28.5 g, 222 mmol), and DMF (250 mL). To the resultant solution was added ethyl bromoacetate (27.1 g, 18.0 mL, 162 mmol) and the mixture stirred overnight. The solids were filtered off and rinsed with EtOAc (500 mL). The filtrate was washed with saturated aqueous NH4Cl (2×250 mL), H2O (2×250 mL), and brine (200 mL), filtered through phase separation paper, and concentrated in vacuo to give 33.6 g of ethyl 3-ethoxyphenoxyacetate as a colorless oil (100%). 1H NMR (60 MHz, CDCl3): δ 7.2-6.9 (m, 1H), 6.6-6.3 (m, 3H), 4.6 (s, 2H), 4.2 (qt, 2H), 4.0 (qt, 2H), 1.4 (t, 3H), 1.3 (t, 3H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 98% with a retention time of 5.3 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][C:18](=O)[NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC>O1CCCC1>[CH2:1]([N:8]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)CC(=O)NCCNCCN1
Solvent: C1CCOC1
Solvent: CSC
Product: c1ccc(CN2CCNCCNCCNCC2)cc1
Reaction time: 2 h

Procedure:
To a suspension of 890 mg (3.07 mmol) of 1-benzyl-3,11-dioxo-1,4,7,10-tetraazacyclododecane in tetrahydrofuran under nitrogen was added 2.64 ml of 8M borane-methyl sulfide complex (21.1 mol, 7 equivalents). The mixture was heated to reflux allowing the methyl sulfide to distill out of the reaction flask. After 2 hours, the reaction was quenched by the addition of 12 ml 1.8M hydrochloric acid in methanol and refluxed for an additional 3 hours. Volatiles were removed by evaporation, and the solid resuspended in methanol and reevaporated. The product was crystallized from methanol/ethyl acetate; yield 455 mg, 37%. Mass spectrum (CI): m/e 263 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>C(O)(=O)C.C(OCC)C>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:1]1[CH:24]=[CH:28][CH:27]=[CH:26]1)([O-:14])=[O:13]
Reactant: COC1CCC(OC)O1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc2c1=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3)cc2c1=O

Procedure:
A solution of N-(6-amino-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (90 mg, 0.285 mmol) and 2,5-dimethoxytetrahydrofuran (0.038 ml, 0.291 mmol) in acetic acid (0.5 ml) is refluxed for 80 minutes. The resulting suspension is filtered and the residue washed with ethyl acetate. The filtrate is concentrated in vacuo to give a brown solid which is suspended in diethyl ether and filtered to give a brown-orange solid as the desired pure product, m.p. 243-250° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:14][C:13]2[C:12]([NH:15][CH2:16][CH2:17][C:18]3[S:22][C:21]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[N:20][CH:19]=3)=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1)=[O:5])C.O[Li].O.Cl>C1COCC1.O>[F:36][C:33]([F:34])([F:35])[C:29]1[CH:28]=[C:27]([NH:26][C:24](=[O:25])[NH:23][C:21]2[S:22][C:18]([CH2:17][CH2:16][NH:15][C:12]3[C:13]4[S:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:19][N:20]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1cc2ncnc(NCCc3cnc(NC(=O)Nc4cccc(C(F)(F)F)c4)s3)c2s1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ncc(CCNc2ncnc3cc(C(=O)O)sc23)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of compound 66.1 (2 mmol) and LiOH.H2O (4 mmol) in THF (20 mL) and H2O (5 mL) was stirred at room temperature for 2 hours and then neutralized with 1.0 N HCl (4 mL). The reaction was concentrated to dryness to give 4-(2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-ethylamino)-thieno[3,2-d]pyrimidine-6-carboxylic acid (compound 66.2) which is used without further purification in the next step.